Pharmacology

УДК 615(075)
ББК 52.8ІЯ73
Ф 24
Рекомендовано Міністерством охорони здоров’я України
як підручник для студентів вищих медичних навчальних закладів
IV рівня акредитації, які опановують дисципліну англійською мовою
(лист № 08.01-47/1159 від 02.07.2009).
Рецензент и:
К ресю н В. Й. - завідувач кафедри загальної та клінічної ф армакології
Одеського державного медичного університету, член-кореспондент АМН
України, заслужений діяч науки і техніки України, д.мед.н., професор;
З в я г ін ц е в а Т . В . - завідувач кафедри фармакології та медичної рецептури
Харківського державного медичного університету, д.мед.н., професор.
А вт ори:
Б о б и р ь о в В. М. - завідувач каф едри експ ери м ен тальн ої та клін ічної
ф арм акології В Д Н ЗУ «У країнська медична стом атологічн а академ ія»,
заслужений діяч науки і техніки України, д.мед.н., професор;
Д ев’ягкіна Т. О. - професор кафедри експериментальної та клінічної фармакології
ВДНЗУ «Українська медична стоматологічна академія», д.мед.н., професор;
В аж нича О. М. - доцент кафедри експериментальної та клінічної фармакології
ВДНЗУ «Українська медична стоматологічна академія», д.мед.н., доцент;
Х ристю к В. М. - викладач кафедри експериментальної та клінічної фармакології
ВДНЗУ «Українська медична стоматологічна академія».
Фармакологія : підручник/Бобирьов В. М., Дев’яткіна Т. О.,

ф 24 Важнича О. М., Христюк В.М ..-Вінниця: Нова Книга, 2 0 1 0 -520 с.: іл.
ІБВН 978-966-382-292-1
П ідручник для студентів вищ их м едичних навчальних закладів IV рівня

акредитації складено згідно з програмою з фармакології та адресовано студентам
з ан глом овн ою ф орм ою навчання. В п ідручнику викладено основні розділи
фармакології, наведено характеристику лікарських засобів з урахуванням сучасних
поглядів па їхні механізми дії та застосування.
УДК 615(075)
Б БК 52.81я73
© В. М. Бобирьов., Т. О. Дев’яткіна,
О. М. Важнича, В. М.Христюк, 2010
ІSBN 978-966-382-292-1 © НОВА КНИГА, 2010
Recommended by the Ministry o f Public Health Care o f Ukraine
as a textbook for students of higher medical educational establishments o f the 4th
level o f accreditation with English as the language o f instruction
(the letter № 08.01-47/1159 o f 02.07.2009)
Reviewers:
K resy u n V a len tin J. - H ead o f the D epartm ent o f Com m on and C linical
Pharmacology o f Odessa State Medical University, Corresponding member o f the
Academy o f Medical Sciences of Ukraine, M.D., Ph.D., Professor
Zvyagintseva T etyana V. - Head o f the Department o f Pharmacology and General
Prescription of Kharkiv State Medical University, M.D., Ph.D., Professor
A uthors:
V ik tor M. B ob yrov - Head o f the Department o f Experimental and Clinical
Pharmacology o f HSEEU “Ukrainian Medical Stomatological Academy”, M.D.,
Ph.D., Professor
T etyana O. Devyatkina - M.D., Ph.D:, Professor ofthe Department ofExperimental
Mild Clinical Pharmacology o f HSEEU “Ukrainian Medical Sromatologica! Academy”
O len a M. V azh n ich a - M .D., Ph.D., A ssistant Professor o f the Department
o f Experim ental and C linical Pharm acology o f HSEEU “ Ukrainian Medical
Stomatological Academy”
Vadim M. K h r is ty u k - a Teacher o f the Department ofExperim ental and Clinical
Pharmacology o f HSEEU “Ukrainian Medical Stomatological Academy”
P h arm acology : a textbook / Viktor M. Bobyrov, Tetyana O. Devy

atkina, Olena M. Vazhnicha, Vadim M. K hristy u k-V innytsya:
NOVA KNYIIA Publishers, 2 0 1 0 .- 5 2 0 p.: il.
ISBN 078 966 182-292-1
I In і, мішці. Ini -.iiiili'iils id Inflict medical e d u c a tio n a l e s ta b lis h m e n ts o f t h e 4“' level

..I ,i. 1 1> ilil.il ii >ii Iill’, l i n n w n llv n n c t n u l i n g t o th e I’h u rm a c o lo g y s y lla b u s a n d a d d r e s s e d to
I » i'll .Ii ,|i> икіііг .Іт Іг и Г . I lie (смішок c o n ta in s (be m a in p a rts o f P h a r m a c o lo g y , g iv e s
lln > liiiia< i n i . I n o l n ic tlii null tliu g h b a s e d o n m o d e rn d a ta c o n c e r n in g th e ir m e c h a n is m s
н і in ним ш иї ii'ttipc
© V. M. Bobyrov, T. O. Devyatkina,
О. M. Vazhnicha, V. M. Khristyuk, 2010
ISBN 078-966-382-292-1 © N O V A KNYHA Publishers, 2010
4 PH AR M ACO LO G Y. V. M. Bobyrov, T. 0. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
CONTENTS
Abbreviations...................................................................................................................... 6
Preface...................................................................................................................................8
Chapter 1. G E N E R A L PH A R M A C O L O G Y . P H A R M A C O K IN E T IC S ........9
Chapter 2. G E N E R A L PH A R M A C O L O G Y . PH A R M A C O D Y N A M IC S... 18
Chapter 3. DRUGS IN H IB IT IN G A FFE R E N T IN N ER V A TIO N ...................26
Chapter 4. DRUGS STIM U LA TIN G A FFE R E N T IN N E R V A T IO N ............ 33
Chapter 5. C H O L IN E R G IC A G O N IST S...............................................................42
Chapter 6. C H O L IN E R G IC A N T A G O N IST S..................................................... 52
Chapter 7. A D R E N E R G IC A G O N IST S................................................................. 66
Chapter 8 A D R E N E R G IC ANTAGONISTS.
H ISTA M IN E- AND SE R O T O N IN -E R G IC D R U G S..................... 77
Chapter 9. DRUGS F O R G E N E R A L A N E ST H E SIA .........................................90
Chapter 10. ETH A N O L. H Y PN O TIC S.
A N T IE P IL E P T IC AND A N TIPA RK IN SO N IA N D R U G S ........100
Chapter 11. N E U R O L E PT IC S. A N X IO LY TICS. SEDATIVES.
L IT H IU M S A L T S .................................................................................. 115
Chapter 12. O P IO ID (N A R C O T IC ) A N A L G E SIC S........................................... 130
Chapter 13. N O N -O PIO ID A N A L G E S IC S............................................................143
Chapter 14. A N A LEPTIC S. PSY C H O M O T O R S T IM U L A N T S .................... 160
Chapter 15. A N TI-D EPRESSA N TS. ADAPTOGENS.
N O O TR O PS. A N O R E X IG E N S ........................................................ 172
Chapter 16. IN O T R O P IC D R U G S........................................................................... 186
Chapter 17. A N TIA N G IN A L D R U G S.....................................................................197
Chapter 18. A N T I-A R R H Y T H M 1C S..................................................................... 212
Chapter 19. ANTIHYPERTENSIVE DRUGS. HYPERTENSIVE AGENTS .226
Chapter 20. A N T I-A T H E R O S C L E R O T IC D R U G S ..........................................240
Chapter 21. DRUGS A C TIN G ON H E M O PO IE SIS (H E M A T IN 1C S).........252
Chapter 22. DRUGS A C TIN G ON B LO O D CO A G U LA TIO N
AND F IB R IN O L Y S IS ..........................................................................266
Chapter 23. DRUGS A C TIN G ON R ESPIR A TO R Y S Y S T E M ......................281
Chapter 24. G A ST R O IN T E SIN A L D R U G S......................................................... 295
Chapter 25. D IU RETICS. A N TI-G O A T DRUGS.
DRUGS A C TIN G ON T H E M Y O M E T R IU M ............................. 317
Chapter 26. H O R M O N A L P R E P A R A T IO N S......................................................334
Chapter 27. V ITA M IN S P R E P A R A T IO N S .......................................................... 358
CONTENTS 5
Chapter 28. ACIDS, A LK A LIS, SALTS. EN ZY M ES AND

ENZY M ES IN H IB ITO RS. G LU CO SE.
PR EPA R A TIO N S FO R TRA N SFU SIO N T H E R A P Y ............... 381
Chapter 29. A N T ISE PT IC S AND D ISIN FE C T A N T S........................................390
Chapter 30. G EN ER A L PR IN C IP L E S O F C H E M O T H ER A PY .
SU LFO N A M ID ES. C H E M O T H E R A P E U T IC S O F
D IFFE R E N T C H E M IC A L STRU CTU RE.
A N TIFU N G A L D R U G S...................................................................... 405
Chapter 31. A N T IB IO T IC S .......................................................................................421
Chapter 32. A N T ISPIR O C H E T A L DRUGS.
A N TIM Y CO BA CTERIA L DRUGS. A N TIV IRAL A GENTS....449
Chapter 33. A N T IPR O T O Z O A L D R U G S ............................................................ 465
Chapter 34. A N T IH E L M IN T IC S.............................................................................480
Chapter 35. PH A R M A C O TH ER A PY O F ACU TE P O IS O N IN G S ............... 488
Chapter 36. G EN ER A L P R E S C R IP T IO N .............................................................501
Selected references.........................................................................................................517
ABBREVIATIONS
ACE - angiotensin-converting enzyme
Ach - acetylcholine
ACTH - adrenocorticotropin
ADH —antidiuretic hormone
AIDS -aquired immune deficiency syndrome
AP - action potential
ATP - adenosin triphosphate
AV - atrio-ventricular
AZT - azidothymidine
BAL - British antilewisite
BP - blood pressure
cAMP - cyclic adenosyl monophosphate
CDCA - chenodeoxycholic acid
CHF - congestive heart failure
Chy - chylomicrones
cGMP - cyclic guanylyl monophosphate
CNS - central nervous system
COMT - catechol-orto-methyltransferase
COX - cyclooxygenase
CTZ - chemoreceptor trigger zone
DHFR - dehydrofolate reductase
DHPS - dehydropteroate synthase
DNA - desoxyribonucleic acid
ECG - electrocardiogram
EDRF - endogenous endothelial-derived relaxation factor
EDTA - edentate (ethylendiamine tetraacetic acid)
FAD - flavine adenine dinucleotide
FMN - flavine adenine mononucleotide
FSH - follicle-stimulating hormone
GABA - y-aminobutyric acid
GI tract - gastrointestinal tract
HDL - high-density lipoproteins
hCG - human chorionic gonadotropin
hMG - human menopaustic gonadotropin
HMG CoA -3-hydroxy-3-methyl-glutaryl-coenzyme A
HIV - human immunodeficiency virus
5H T -receptor- serotonin receptor
ABBREVIATIONS 7
IDDM - insulin-dependent diabetes mellitus

IM - intramuscular (-ly)
INH - isoniazid
IV - intravenous (-ly)
LDL - low-density lipoproteins
LH - luteinizing hormone
MAO - monoaminooxydase
mRNA - matrix RNA
MRSA - meticillin-resistant staphylococci
NAD - nicotinamide adenine dinucleotide
NADP - nicotinamide adenine dinucleotide phosphate
N1DDM - non-insulin-dependent diabetes mellitus
NREM-sleep - non-rapid eye movement sleep
NRTI - nucleoside reverse transcriptase inhibitor
NSAID - non-steroidal anti-inflammatory drug
PABA - para-aminobenzoic acid
PANS - parasympathetic autonomic nervous system
PBP - penicillin binding proteins
PDE - phosphodiesterase
PFOR - pyruvate ferredoxine oxyreductase
Pg - prostaglandin
P P A R - nuclear receptors connected with unsaturated fatty acids
REM-sleep - rapid eye movement sleep
RNA -ribonucleic acid
SA ~ sino-atrial
SANS - sympathetic autonomic nervous system
SC’ subcutaneous (-ly)
SSRI - selective serotonin re-uptake inhibitor
SI II somatotropic hormone
I , triiodthyronine
I , thyroxine
IIC11 thyrotropin-releasing hormone
IUN A transport RNA
111)('A ursodeoxycholic acid
V I.1)1, very low density lipoproteins
WPW-syndrome - Wolf-Parkinson-White syndrome
8 PH AR M ACO LO G Y. V. M. Bobyrov,T. 0. Devyatkina, 0. M.Vazhnicha,V. M. Khristyuk
PREFACE
Pharmacology is a branch o f medical science being a base for all clinical sciences.
The knowledge about drugs, their mechanisms of action and usage is necessary for
every doctor regardless the speciality.
The purpose o f the textbook is to help the students o f higher medical institu
tions o f the 4th level o f accreditation to study general concepts o f Pharmacology and
properties o f drugs acting on different systems o f the human body. This textbook has
been prepared in order to improve the students’ self-training for the lessons under
the conditions o f implementation o f the educational system o f Bolonga. It has been
written according to Pharmacology syllabus for higher educatonal medical institu
tions approved by the Ministry o f Health o f Ukraine.
The textbook consists o f 36 chapters. Chapters 1, 2 are devoted to general
pharmacology. All others, except chapter 36, include definitions o f the respective
groups, classification, data on pharmacokinetics, mechanism o f action, pharmaco
dynamics, indications, side-effects, and contraindications o f existing drugs. At the
end o f each chapter there are tests for self-control. Chapter 36 contains infonnation
about prescription o f different medicinal forms that is practical skill on Pharmacology.
To prepare represented textbook we have used international names o f prepara
tions, but sometimes Latin names also have been indicated (they are from the capital
letter and with typical endings -u m , -as, -a).
The textbook contains many illustrations which are necessary to understand
better the drugs mechanisms and effects.To illustrate this book we have used figures
created by ourselves, as well as illustrations from Color Atlas on Pharmacology
(Lullman H, Albrecht Z., Klaus M, DetlefB. Color Atlas o f Pharmacology -T hiem e:
Stuttgart-N ew -Y ork, 2 0 0 0 .-3 8 6 p.). Some figures are from the well known book
“Lippincott’s Illustrated Reviews: Pharmacology, 4,h Edition” edited by R.Finkel,
M.A.Clark, L.X.Cubeddu (Lippincott Williams and Wilkins, 2008. - 560 p.), Internet
search systems, and other sources.
The textbook contains a bibliography for further study.
All remarks and comments concerning the contents o f present textbook will be
taken into consideration by the authors for a future edition.
GENERAL PHARMACOLOGY.
PHARMACOKINETICS
DEFINITION OF PHARMACOLOGY
Pharmacology is the science about drugs. It studies their properties and use.
The main task o f pharmacology is to create new more effective medicinal drugs for
treatment and prophylaxis o f diseases.
Pharmacology is integrated into the system o f medical and biological sci
ences. It receives necessary information from Chemistry, Biochemistry, Genetics,
Microbiology, Immunology etc. At the same time, Pharmacology is the ground of
the pharmacotherapy in all branches o f the clinical medicine.
MAIN CONCEPTS OF PHARMACOLOGY

M edicinal drug is a medicinal remedy in the shape o f medicinal form.
M edicinal remedy is a medicinal substance approved for use in a clinic by the
special committee o f the country.
M edicinal substance is a chemical substance or biological active substance
which can prevent or lessen pathological processes and do a medical action.
M edicinalform is a distinctive size, shape and external appearance o f medicinal
substance convenient for use.
10 PH ARM ACO LO G Y. V. M. Bobyrov.T. 0. Devyatkina, 0. M.Vazhnicha, V. M. Khristyuk
DRUG DEVELOPMENT
D rug development includes many stages. It is very difficult and expensive.
The process starts with the synthesis o f novel chem ical compounds or obtain
ing o f m edicinal substances from various sources (plants, animal tissues, microbial
cultures, human cells).
The next stage o f drug development is preclinical testing with biochemical-
pharmacological investigations, toxicological investigations, study of pharmacokinet
ics and pharmaceutical technology (methods of drug formulation).
Clinical testing starts with Phase I. During this phase the future drug is studied
on healthy subjects and seeks to determine whether effects observed in animal experi
ments also occur in humans. In Phase //p o ten tial drug is tested on selected patients
for therapeutic effecacy in those diseases for which it is intended. In Phase I II the
drug is tested on large groups o f patients and compared with standard treatments.
During clinical trials many drugs are revealed to be unusable. It is known that only
one new drug remains from approximately 10000 newly synthesized substances.
The decision to approve a new drug is made by a National Regulatory Body.
Following approval, the new drug may be marketed under a trade name. Long-term
postlicensing studies are the purpose of Phase I V o f clinical trials.
GENERAL PHARMACOLOGY
G EN ERA L PH A R M A CO LO G Y is a division of Pharmacology which studies
general concepts o f this science. These concepts are connected with pharmacokinetics
and pharmacodynamics (fig. 1.1).
------------
PHARMACOLOGY = PHARMACOKINETICS + PHARMACODYNAMICS
V ----------------------------------------------------- J
Fig. 1.1. Two sections of Pharmacology.
PHARMACOKINETICS
Pharm acokinetics is the section o f Pharmacology that studies how the body
acts on the drug. It studies:
Routes o f administration
Absorption
Distribution
Biotransformation
Elimination
Excretion.
Chapter 1. G E N E R A L P H A R M A C O L O G Y . P H A R M A C O K IN E T IC S 11
ROUTS OF DRUGS ADMINISTRATION

Routs o f drugs administration are divided into enteral routs (through the gut),
parenteral routs (not through the gut), and topical application for local action (table 1.1).
Tablet. 1. Routs o f drugs adm inistration
Enteral routs Parenteral routs Topical application
1. Sublingual (under the tongue) 1. Injections 1. On the surface of skin

2. Oral (by mouth, per os) 2. Inhalations (through the 2. On the surface of mucous
3. Rectal (in rectum) respiratory pathways) membrane
3. Intranasal
4. Transcutaneous
After IV administration the drug has rapid onset and short duration o f action.
After oral administration it has slow onset o f action, lower concentration, and more
durative effect (fig. 1.2).
Fig. 1.2. The comparison of drug concentration in blood in different

routs of administration (by H. Lullmann, 2000).
After administration drug is absorbed and enter the blood. Then ii is transported
with blood and distributed in the body. After that drug is biotransformated and
excreted. These processes results in drugs’ inactivation and elimination (tig. 1.3).
12 PH AR M ACO LO G Y. V. M. Bobyrov.T. 0. Devyatkina, 0. M. Vazhnicha.V. M. Khristyuk
ADMINISTRATION
(IN T O TH E BODY)
V__________________________
'ii
Fig.1.3. Schematic representation of drug absorption, distribution, and elimination.
Fig. 1,4. Schematic representation of a drug crossing through the cell membrane.
DRUGS ABSORPTION
Absorption is the enter of n drug into the blood from the site o f administration.
First-pass metabolism can occur with orally administered drugs. Drugs admin
istered orally are list exposed to the liver and may be extensively metabolized before
i caching the lest »11lie body Drugs administered IV enter directly into the systemic
i in iilnlioit and has tilled access to the rest o f the body.
I lining lIn-al ran pi ion drug crosses cell membranes. There are such kinds of this
. i.ivnuc a s pavave tilllusion, filtration, active transport, and endocytosis (fig. 1.4).
I ' a v . n c i I i I I i i s i o i i and nitration through pores are realized on concentration gra-
1 11ii 11 and do not iet|uire energy of ATP (fig. 1.5). Active transport and endocytosis
ate at Itie veil against concentration gradient and require energy o f ATP.
A t
O P
: 00-0
°g °
°
o °0
°
o © o4l
A o
« o o 0 rS w
A*° °oo _ ° o
Fig. 1.5. Passive diffusion (A), active transport (B), and endocytosis (C).
Factors influencing absorption are:

Chemical structure
Water- or lipid-solubility
Ionization
A medicinal form
The route o f administration
The state o f tissues in the site o f administration.
Bioavailability is the fraction o f administered drug that reaches the systemic

circulation. Factors that influence bioavailability are solubility o f a drug, nature of
a drug, chemical instability, first-pass hepatic metabolism,
DRUGS TRANSPORT IN THE ORGANISM

Drugs transport in the body is realized:
by proteins ofthe plasma (e.g. aspirin, sulfa drugs, hormonal preparations, iron)
by lipoproteins o f the plasma (e.g. vitamin A, vitamin D)
by blood cells (e.g. antibiotics-macrolides)

by the water fraction o f the plasma (e.g. ions o f sodium and potassium,
glucose).
DRUGS DISTRIBUTION
Distribution is the process by which a drug leaves the blood stream and enters
the intersticium (extracellular fluid or the cells o f the tissues)
Distribution depends on:
The drug structure
The binding of drugs to plasma proteins
The blood flow
The capillary permeability (blood-tissue barriers, e.g. the blood-brain bar
rier, placental barrier).
BIOTRANSFORMATION OF DRUGS
Biotransform ation is metabolism o f drugs in the body. The main organ for
drugs metabolism is the liver. Biotransformation is realized in two stages (fig. 1.6).
Stage I Stage II
DRUG
(non-synthctic reactions) (synthetic reactions)
Active or, Inactive

most often, products ex
inactive creted from
products the body
Fig. 1.6. Stages of drugs biotransformation. a
Stage I reactions are non-synthetic and include oxidation, reduction, hydrolysis.

Microsomal oxidation/reduction with participation o f enzymes o f cytochrome P-450
system is an important way o f biotransformation o f many drugs. The result o f stage
I is the formation o f active or inactive products which enter the stage II reactions.
S ta g e II reactions are synthetic (conjugation with glucuronic and sulfuric acids,
méthylation, acethylation). They lead to the formation o f inactve metabolits excreted
from the body.
Drugs which increase the activity o f microsomal enzymes in the liver are named
the inductors o f m icrosom al oxidation (e.g. phénobarbital, chlorpromazine).
Drugs which decrease the activity of microsomal enzymes in the liver are named
the inhibitors o f microsom al oxidation (e.g. metronidazole).
MAIN PATHWAYS OF DRUGS EXCRETION

/'xcrcdon is the process by which drug leaves the body.
Dings are excreted:
* with urine (e.g. sulfa drugs, hypnotics and majority o f other drugs)
* with bile (e.g. antibiotic tetracycline)
* with mother’s milk (e.g. hypnotics, antibiotics, antihistamines)
* with saliva (e.g. bismuth preparations)
* with sweat ( e.g. bromides, chlorides)
with air (ether for narcosis).
The majority o f drugs are excreted by the kidneys. Hydrophilic drugs may be
excreted through the kidney in an unchanged form; lipophilic drugs are converted
into hydrophilic metabolites which are excreted with urine (fig. 1.7).
Hydrophilic drug ( ® ) Lipophilic drug
Renal Renal excretion

excretion of metabolite
Fig. 1.7. Renal excretion of hydrophilic (A) and lipophilic drugs (B) (by SI. Lullmann, 2000).
16 PH AR M ACO LO G Y. V. M. Bobyrov.T. 0. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
Drugs and their metabolites enter primary urine by glomerular filtration and
active secretion in proximal tubules (fig. 1.8). After that lipid soluble and un-ionized
drugs are reabsorbed in distal tubules. Ionized, lipid-insoluble substances stay in
urine and are excreted.
Fig. 1.8. Drugs elimination in the kidney.
PHARMACOKINETIC FACTORS
Pharm acokinetics is the mathematical description o f the rate and extent of
uptake, distribution o f drugs in the body.
Volume o f distribution is a calculation of the apperant volume in which a drug
is dissolved. It assumes that a drug is evenly distributed and that metabolism or
elimination has not taken place. Volume o f distribution does not correspond to any
real volume, but it reflects the presence o f the drug in various body fluid compart
ments and can be used to calculate the dose o f a drug needed to achieve a desired
plasma concentration.
H alf-life is the period o f time required for the concentration o f the drug to
decrease from C to Yz C.
Clearance is the volume o f plasma which is cleaned from the drug during 1
minute. Total body clearance is the sum ofthe clearances from the drug-metabolizing
and drug-eliminated organs.
Steady-state concentration is the plasma concentration o f a multiple dosed or
continously infused drug when the drug will accumulate until the amount adminis
tered per unit time is equal to the amount eliminated per unit time. The time needed
to reach steady-state concentration depends only on the half-life o f the drug.
TESTS FOR SELF-CONTROL

№1. Absorption is:
A. Drug’s penetration from the site of administration into the blood
B. Drug’s penetration from the blood into tissues
C. Chemical transformation of the drug
D. Drugs interaction
E. Binding to plasma proteins
№2. In the blood plasma drugs are transported:

A. In connection with albumens
B. In connection with lipoproteins
C. In connection with blood cells
D. In water fraction
E. All the listed.
№3. The energy-independent mechanisms of drugs crossing through the cell membrane are:
A. Active transport
B. Endocytosis
C. Passive diffusion
D. “Biological pumps”
E. Filtration through pores.
№4. Drugs administered by injections:

A. Have a slow onset of action
B. Must be sterile
C. Are suitable for emergence help
D. Need the special equipment
E. Are accompanied by trauma and pain.
№5. Phenobarbifal is the inducer of microsomal oxidation in the liver. Warfarin is

an anticoagulant also biotranformed in microsomes of the liver. What changes in warfarin
dosage may be necessary, if it is co-administered with phenobarbital?
A. The dose should be decreased due to the inhibition of metabolism of the drug
B. The dose should be increased due to the stimulation of metabolism of the drug
C. The dose should be without any changes
D. The dose should be abolished due to its accumulation
E. All is false.
Answers
№ 1 - A; № 2 - E ; № 3 - C, E; № 4 - B, C, D, E; № 5 - B.
GENERAL PHARMACOLOGY.
PHARMACODYNAMICS
PHARMACODYNAMICS
Pharm acodynam ics is the section o f Pharmacology which studies how the
drug acts on the body.
It describes:
Effects
The mechanism o f action
Drugs interactions
Doses
Dose-effect dependence «
Factors influencing a drug action.
TYPES OF DRUGS DOSES

The dose is the amount o f drug administered into the body.
The dose may be:
single (for single administration), daily (for the day o f treatment), total (for
the course o f treatment)
threshold (minimal dose which begins to act)
therapeutic (minimal, average, maximal) - the dose which has therapeutic action
Chapter 2. G EN ER A L P H A R M A C O LO G Y . PH A R M A C O D Y N A M IC S 19
toxic (minimal, average, maximal) - the dose which causes toxic action
mortal (the dose which causes the death o f animals in experiments)
striking dose (a large dose at the start o f treatment), supporting dose (an indi
vidual dose for supporting a therapeutic effect during long-term treatment).
TYPES OF DRUGS ACTION

Drugs action is displayed as changes in the function o f organs and systems.
There are such types o f drugs action:
• local (in the site o f administration), resorptive (after the absorption into
the blood)
direct (in the organ with target cells), indirect (in other organs, but due to
the action on the target organ), reflexive (by reflexes)
non-selective (on all cells), selective (on celected cells and tissues)
reversible (with restoration to the initial state after the elimination o f the
drug), irreversible (without the restoration to the initial state after the elimi
nation of the drug)
main effects (for which the drug is used), side-effects (unwanted effects of
a therapeutic dose of the drug).
The factors influencing drug action are the age, weight, gender, physiological
state, illness, genetic factors.
MECHANISMS OF ACTION
M echanism s o f action are events in cells caused by the drug.
Medicinal substances realize their action by:
changing ofthe enzymes activity (e.g. neostigmine as acethylcholinesterase
inhibitor) «
interaction with receptors (e.g. atropine as M-cholinoblocker)
• influence on ion channels (e.g. local anesthetics)
influence on the transport systems
• the antimetabolic mechanism (e.g. methotrexate as folate antagonist)
• the action at the genes level (e.g. anti-cancer drugs).
RECEPTOR THEORY
D rug receptor is a specialized target macromolecule. The drug binds to the
receptor with the formation o f a drug-receptor complex producing primary pharma
cological effect (fig. 2.1).
20 PH ARM ACO LO G Y. V. M. Bobyrov,T. 0. Devyatkina, 0. M.Vazhnicha,V. M. Khristyuk
DRUG
RECEPTOR
Fig. 2.1. Schematic representation of drug-receptor relationship.
Receptors are located:

- in membrane
- in cytoplasma
- in nuclei.
Nicotinic
acetylcholine
receptor
h i ?
Protein
cooh .... h \
U
Effect
t Subunit
consisting of
four trans
membrane
Na* K* domains
Fig. 2.2. Connection of receptors with G-proteins (A) and ion channels (B)
(by H. Lullmann, 2000).
Chapter 2. GEN ERAL P H A R M A C O LO G Y . PH A R M A C O D Y N A M IC S 21
Receptors fu n ctio n s are achieved by:

- ion channels (fig. 2.2)
- cyclic nucleotides (c AMP)
- G- proteins (fig. 2.2)
- C aân d protein-kinases.
Drugs interaction with receptors (fig. 2.3):

Agonist is the drug which stimulates the receptor, induces its conformation and
causes a specific cell answer (e.g. morphine is a strong agonist o f opioid receptors).
A ntagonist is the drug which inhibits the receptor - it interacts with the receptor
without its confonnation, prevents binding of ligand to the receptor resulting in the
absence of a specific cell answer (e.g. naloxone is an antgagonist of opioid receptors).
Agonist-antagonist is the drug which stimulates one subtype of the receptor, but
blocks another one (e.g. pentazocine is an agonist-antagonist o f opioid receptors).
Agonist Antagonist
induces active occupies receptor
confonnation of without con
receptor protein formational changes
Fig. 2.3. Interaction of an agonist and an antagonist with the pharmacological receptor
(adaptedfrom H. Lullmann, 2000)
22 PH AR M ACO LO G Y. V. M. Bobyrov.T. 0. Devyatkina, 0. M.Vazhnicha,V. M. Khristyuk
Table 2.1. Two types of drugs interaction
Pharmaceutical
Pharmacological
(before the administration,
(after the administration, inside the body)
outside the body)
1. Physical (changes in agregate 1. Pharmacokinetic (interaction during absorption, dis
state of drugs) tribution, biotransformation, and excretion)
2. Chemical (chemical reac 2. Pharmacodynamic (intraction in tissues during binding
tions between the drugs). to receptors).
COMBINED ACTION OF DRUGS

Com bined action o f drags is the action o f two or more co-administered drugs
on the organism (table 2.2).
Table 2.2. M ain kinds of drugs com bined action
Synergism Antagonism
(the strengthening of the effect) (the weakening of the effect)
1. Addition (C = A + B) 1. Chemical
2. Potentiation (C > A + B). 2. Physical
3. Physiological (competition in binding to re
ceptors, action on different receptors with the
opposite effect).
SIDE-EFFECTS
Side-effects are non-useful effects o f drugs in therapeutic doses:
direct toxic effects (e.g. ototoxicity, neurotoxicity, and nefrotoxifcity of
streptomycin)
allergic reactions as immune reactions o f hypersensitivity (e.g. anaphylaxis
caused by penicillin) (fig. 2.4)
idiosyncrasy as an abnormal reaction occurred after the fist drag administra
tion and caused by genetic factors (e.g. hemolysis o f erythrocytes afer the
use o f quinine in patients deficient on glucose-6-phosphate dehydrogenase)
embryotoxic, fetotoxic and teratotogenous effects as a negative influence on
the embrio and the fetus during pregnancy (e.g. hypoplasia o f tooth enamel
caused by tetracyclin) - table 2.3
Chapter 2. G EN ER A L P H A R M A C O LO G Y , PH A R M A C O D Y N A M IC S 23
a cancerogenous and mutagenous action as the ability to provoke the

development o f malignant tumors (e.g. secondary malignancy caused by
leukopoiesis inhibitors).
Mast coll
(tissue)
Receptor I basophilic
for IgE ® / granulocyte
(blooc)
Hist amino and other mediators
Urticaria, asthma, shock
Fig. 2.4. Allergic reaction (by H. Lttllmann, 2000).
Table 2.3. D rugs negative influence on the em bryo and the fetus
Age of the fetus

1-2 2,5-12 12-38
(weeks)
Development stage Nidation Embryo: organ The fetus: growth and
development maturation
Fetal death Malformation Functional disturbances
EFFECTS OF REPEATED DOSES OF DRUGS

Accum ulation (material and functional) is the accumulation o f the drug or its
effects (e.g, material accumulation o f digitoxin, functional accumulation o f antide
pressants).
Tolerance (habituation) is a decrease o f drug’s action after its repeated admin
istration (e.g, tolerance to hypnotics, alcohol, nitroglycerine, laxatives).
Tachyphylaxis is the rapid fonn o f tolerance developing during the first day of
treatment (e.g, tachyphylaxis to ephedrine).
24 PH ARM ACO LO G Y. V. M. B o b y ro v ,! 0. Devyatkina, 0. M. Vazhnicha,V. M. Khristyuk
D rug dependence is irresistible aspiration to take the drug for euphoria or

improvement o f condition.
There are two types of drug dependence:
• Physical dependence - if the patent wants to take the drug for altering
general state and mood. It is characterized by abstinence. Abstinence is a
phenomena o f deprivation. Ethyl alcohol and narcotic analgesics may cause
physical dependence.
• Psychological dependence - if the patient wants to take the drug for alter
ing the mood (for euphoria). Such kind o f drug dependence is caused by
psychomotor stimulants.

№1. All concerning doses o f drugs is correct, except:
A. Single dose is the dose for one administration
B. Therapeutic dose may be minimal, overage, and maximal
C. LD-50 causes the death o f 50% o f animals in experiments
D. Supporting dose is a high dose at the start of treatment
E. Toxic dose is the amount o f the drug causing poisoning.
№ 2. The notions connected with a combined action o f medications are:

A. Synergism and antagonism
B. Material accumulation
C. Drug dependence
D. Tolerance and tachyphylaxis
E. Elimination and excretion.
№ 3. Types o f drugs’ action are represented by:

A. A local and resorptive action
B. A reversible and irreversible action
C. A direct and indirect action
D. Pharmaceutical drugs interaction
E. A combined action o f drugs.
№ 4. The true information concerning the receptor mechanism o f action is:

A. The drug stimulating the receptor is its agonist
B. The drug inhibiting the receptor is its antagonist
C. The drug stimulating one subtype o f receptor and inhibiting another one is
an agonist-antagonist
Chapter 2. G E N E R A L P H A R M A C O LO G Y . P H A R M A C O D Y N A M IC S 25
D. The drug bound to the receptor with low affinity is a partial agonist
E. The drug without affinity to the receptor is its strong agonist.
№ 5. The patient with malaria was treated with quinine. Treatment was com
plicated by hemolysis of red blood cells. Such a side-effect caused by quinine in
patients with deficit of glucose-6- phosphate dehydrogenase is:
A. A direct toxic action
B. Idiosyncrasy
C. An allergic reaction
D. A cancerogenous action
E. A teratogenous action.
Answers
№ 1 - D; № 2 - A; № 3 - A, B, C; № 4 - A, B, C, D; № 5 - B.
DRUGS INHIBITING
AFFERENT INNERVATION
DRUGS INHIBITING AFFERENT INNERVATION

Drugs inhibiting afferent innervation are divided into local anesthetics, astrin
gents, adsorbents, and protectives (coverings).
DRUGS FOR LOCAL ANESTHESIA

Local anesthesia
Local anesthesia is reversibly inhibition o f the pain sensation in a limited area
o f the body without impairment o f consciousness. a
The kinds o f local anesthesia are:
• surface anesthesia
infiltration anesthesia
• conduction anesthesia
spinal anesthesia.
LOCAL ANESTHETICS
Local anesthetics are the drugs for local anesthesia. Their molecules have 3
common structural elements: lypophilic aromatic part, hydrophylic amine and ester
Chapter 3. D R U G S IN H IB IT IN G A F F E R E N T IN N E R V A T IO N 27
or amide linkage. All local anesthetics are weak bases and alkalic pH increases their
ability to penetrate lipophilic barriers and cell membranes (fig. 3.1).
Fig. 3.1. The influence of pH on properties of local anesthetics.
Classification
1. Esters o f para-aminobenzoic acid
- Procaine (Novocainum)
- Benzocaine (Anaesthesinum)
- Tetracaine (Dicainum)
2. Substituted amides o f acetalinidin
- Lidocaine
- Trimecaine
- Piromecaine
- Ultracaine (Articaine)
- Marcaine (Bupivacaine).
Distinctive features of local anesthetics of different groups

Existing groups o f local anesthetics differ from one another on duration o f ac
tion, biotransformation, stability in the site o f inflammation, and the interaction with
sulfonamides (table 3.1).
28 PH ARM ACO LO G Y, V. M. Bobyrov.T. 0. Devyatkina, 0. M.Vazhnicha, V. M. Khristyuk
Table 3,1. D istinguishes between the esters and the am ides
Esters Amides
Have short action Have long action
Are metabolized by esterases of blood Are metabolized in the liver
Are not active at acid pH (in the site of purulent Are active at acid pH (in the site of
inflammation) purulent inflammation)
Decrease the effect of sulfa drugs. Do not interact with sulfa drugs.
Mechanism o f action
Local anesthetics plug sodium-ion channels and in such a way block initiation
and propagation o f action potential (fig. 3.2).
Local anesthetic Propagated

impulse
f t
8Ü
Fig. 3.2. Mechanism of action of local anesthetics (by II. Lüllmann, 2000).
Purpose o f adrenaline addition to local anesthetics

Addition o f adrenaline to solutions o f local anesthetics causes constriction of
blood vessels. That results in a decrease o f the absorption o f a local anesthetic and
leads to the prolongation o f anesthesia.
Peculiarities o f preparations
Procaine (Novocainum) is an ester; dilates blood vessels; is used for infiltration,
conductive and spinal anesthesia; other indications are spasms o f blood vessels and
smooth muscles, pain syndromes, arrhythmia, toxicosis of pregnancy; may cause
allergic complications including anaphylaxis, collapse, hypotension, seizures (in

overdose).
Tetracaine (Dicainum) is an ester; dilates blood vessels; is more active and
more toxic than procaine; is used only for surface anesthesia.
Benzocaine (Anaesthes'miim) is an ester; is less active than procaine; is not
dissolved in water; is used only for surface anesthesia in burns, wounds, diseases of
skin and mucous membranes; is not toxic, but may cause methemoglobin formation
when is used on large areas o f skin lesions.
Lidocaine (Xycainum) is the amide; acts longer than procaine; is more active;
is suitable for all types o f anesthesia; is used for the treatment o f ventricular tachyar
rhythmia (IV).
Trimecaine is an amide; pharmacological properties are similar to lidocaine.
Bupivacaine (Marca'me) is an amide; is one of the most active local anesthetics;
is used for infiltration, conductive and spinal anesthesia; has toxic action on the heart.
Articaine is an amide; acts during 1-5 hrs; is used for infiltration and conductive
anesthesia; is widely used in dentistry.
ASTRINGENTS
Astringents are the agents that precipitate protein and form albuminates on the
surface of the damaged skin or the mucous membrane, thus protecting the receptors
from irritating factors and relieving pain.
CLASSIFICATION
1. Organic substances
- Tannin
- Tanalbinum
- herb o f Saint-John’s-wort (herba Hyperici)
- flowers o f chamomile (Jlos Chamommillae)
- leaves o f salvia (folium Salviae)
- bark o f oak (Cortex Quercus)
2. Non-organic substances
- Bismuth subnitrate.
Tannin is an organic astringent; is used in the form o f solution, ointment, powder
for external use; has astringent and anti-toxic action (is an antidote in poisonings
with alkaloids and salts o f metals); is used for gargling in diseases of oral mucose,
30 PH AR M ACO LO G Y. V. M. Bobyrov,T. 0. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
for processing o f burns, for lavage o f stomach in acute poisonings; may disturb
digestion if it is taken orally.
Tanalbinum is a compound o f tannin; is taken orally to treat dyspepsia, enteritis,
enterocolitis; does not bind to enzymes in the gut and does not disturb digestion.
Bark o f oak (Cortex Quercus) (fig. 3.3) is used in the form of decoction; is
applied for gargling in stomatitis, gingivitis, paradontitis; may be also used to treat
burns, wounds.
Leaves o f salvia (Folium Salviae), herb o f sa n t-john's-wort (Herba Hyperici),
flow ers o f cham om ile (Flos C ham om m illae) (fig. 3.3) are used in the form of
infusions; they have astringent, anti-inflammatory, antimicrobial effects, stimulate
regeneration o f tissues; indications are similar to indications for the use o f the oak
bark; are widely used in dentistry.
Bism uth subnitrate is non-organic astringent; is taken orally in ulcer o f the
stomach and duodenum, enterocolitis; is applied topically to treat wounds, ulcers,
and bums o f skin.
ADSORBENTS
Adsorbents are insoluble fine powders which have a large active surface capa
ble of fixing irritating and poisonous substances dissolved in water and gases, thus
preventing their absorption in the G1 tract and protecting receptors.
Peculiarities of preparations
Activated charcoal (Carbo activatus) is administered orally in the form of tablets
or non-dosed powder; is used in acute poisonings (as a universal antidote), as well
as in enterocolitis, enteritis, dyspepsia, meteorism.
PROTECTIVES
Protectives are the substances that form colloidal solutions covering the skin
and mucous membranes and prevent stimulation o f receptors. M ucus o f starch
(M ucilago Am yli) and decoction fr o m seeds o f f la x (Linum ) belong to this group.
They are applied topically to treat burns, wounds, ulcers in mucous membranes and
are taken orally in acute gastritis, enterocolitis or together with drugs which irritate
gastric mucosa.
Fig. 3.3. Medicinal plants containing astringent substances:

A - oak; B - sant john’s-wort; C - salvia; D-chamomile.
32 PH A RM ACO LO G Y. V. M. Bobyrov,T. 0. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk

№1. Local anesthetics from esters group are all, except:
A. Procaine (Novocainum)
B. Tetracaine (Dicainum)
C. Benzocaine (Anaesthesinum)
D. Cocaine
E. Lidocaine (Xycainum).
№ 2. Tannin realizes its anti-inflammatory action due to:

A. The formation o f albuminates on the surface o f the mucous membrane
B. The adsorbtion o f toxic substances
C. The formation o f colloidal covering on the mucous membrane
D. Local anesthesia
E. The irritation o f sensitive nerve endings.
№ 3. Local anesthetics have the following common properties:

A. They are bases
B. The anesthetic activity rises at alkaline pH
C. Ester local anesthetics are metabolized by esterases in blood
D. Amide local anesthetics are metabolized by hepatocytes
E. The duration o f action of esters is longer than that o f amides.
№4. The starch mucus realizes its action due to:

A. The formation o f albuminates on the surface o f the mucous membrane
B. The adsorbtion o f toxic substances
C. The formation o f colloidal covering on the mucous membrane
D. Local anesthesia
E. The protection o f sensitive nerve endings from irritation.
№ 5. Lidocaine was administered to the patient with ventricular tachyarrhythmia

and caused stabilization o f the heart rate. Tts mechanism o f action is:
A. The blockage o f sodium ion channels
B. The blockage o f calcium ion channels
C. The opening o f potassium channels
D. The blockage of adrenergic receptors
E. None o f the listed above.
Answers
№ 1 - E; № 2 - A; № 3 - A, B, C, D ;№ 4 - C , E ; № 5 - A .
f £L
*
A DRUGS STIMULATING
O ■ AFFERENT INNERVATION
DRUGS STIMULATING AFFERENT INNERVATION

They are represented by drugs increasing the frequency o f afferent impulses
running from sensitive nerve endings to CNS.
CLASSIFICATION
A. Irritants
- Menthol
- Mustard seeds
- Solution o f Ammonia
- Camphor
- Turpentine oil
B. Expectorants (reflexly acting)
- Herb of Thermopsis
- Root o î Althea
- Mucaltinum
C. Bitters
- Tincture o f Absinthium
D. Emetic drugs (reflexly acting)

- Root o f Ipecacuanna
- Copper sulfate
- Zinc sulfate
E. Laxatives and purgatives
1. Acting in the small intestine
- Castor oil
2. Acting in bowels
- Root o f Rheum
- Leaves o f Senna
- Bisacodyl
3. Acting in all the sections o f the intestine
- Magnesium sulfate
- Sodium sulfate.
IRRITANTS
Irritants are medications irritating sensetive nerve endings in the skin and
mucous membranes and producing local vascular reactions, reflexive actions, and
distractive effects.
Menthol
is crystals with pleasant aroma dissolved in lipids and alcohol
is contained in mint (fig. 4.1)
is applied topically, is administered sublingually (as Validolum) or by
inhalations
irritates cold-sensitive nerve endings in the skin and mucous membranes,
constricts blood vessels in the site o f application, that’s why locally de
creases the edema and exudation; initiates reflexes changing vascular tone
in the heart and brain tunics; decreases pain from internal orgarfs and deep
tissues (due to prevalence o f pain impulses from the covering tissues over
the impulsation from the internal tissues)
indications: myositis, myalgia, peripheral neuritis, neuralgia, arthritis, ar
thralgia, bronchitis, inflammation of respiratory airways, rhinitis, headache,
spasm o f coronary blood vessels (in the form of Validolum), in dentistry is
used as drops for a diminishing a toothache and for improvement o f taste
and odor o f dental pastes, dental powders
may cause disturbances o f breathing if it is used for inhalation in high
concentration.
Chapter 4 D R U G S S T IM U L A T IN G A F F E R E N T IN N E R V A T IO N 35
Mustard seeds
is a plant preparation (fig. 4.1) in the form o f a mustard plaster
• is applied topically
contains glycoside synegrin and enzyme myrosin; in warm water (38°C)
myrosin destroys synegrin with release o f mustard oil; this oil irritates sen-
setive nerve endings in the skin, dilates blood vessels and improves trophy
in the site o f application; has reflexive action and decreases pain in internal
tissues; reflexly lowers BP, decreases anginal pain, accelerates recovering
from pneumonia
indications: myositis, myalgia, peripheral neuritis, neuralgia, arthritis, ar
thralgia, pneumonia (is applied on the skin projections o f the lungs), angina
pectoris (on the area of the heart), hypertension (on the occipital area)
may cause severe irritation and burn o f the skin.
Fig. 4.1. Medicinal plants containing irritants: A - mint; B - mustard.
Solution of ammonia
has antimicrobial, weak detergent, irritating and reflexive actions
* is used for reflexive stimulation of respiration in syncope. For this purpose
it is applied on the beat of the cotton and used for inhalation through the
nose, irritates sensitive nerve endings in the nasal mucosa, initiates reflexes,
stimulates the centers in the medulla o f the brain and in such a way stimulates
respiration and increases BP
is used for processing o f surgeon’s hands
high concentration o f ammonia vapors may cause burn of the mucous
membrane and arrest o f breathing.
Cam phor
Camphor is a neurotropic drug (analeptic) with antimicrobial and irritative effects.
It is used topically to treat myositis, myalgia, peripheral neuritis, neuralgia, arthritis,
arthralgia, external otitis, for prevention of the skin necrosis in immobilized patients.
Expectorants
Expectorants are drugs which stimulate the secretion and expelling o f liquid
sputum from the bronchi.
Reflexly acting expectorants irritate receptors o f the stomach mucosa, initiate
reflexes, due to which increases the secretion o f bronchial glands, the contractility
o f the epithelium and muscles and help mucus expelling. Infusion from the grass of
Thermopsis (fig. 4.2) also excites the respiratory center. Decoction from the root o f
Althea and Mucaltinum (fig. 4.21 have a covering effect.
Fig. 4.2. Medicinal plants containing expectorants: A - Thermopsis; B - Althea.

! Iwipter 4. D R U G S S T IM U L A T IN G A F F E R E N T IN N E R V A T IO N 37
BITTERS
Bitters are drags stimulating appetite (appetizers) by irritation of receptors in
Ihe oral cavity. Tincture o f A bsinthium (fig. 4.3) is a representative of this phar
macological group.
Irritation o f taste-sensitive nerve endings initiates reflexes resulting in the
stimulation o f gastric juice production. The reflexive mechanism of the action o f
hitters was investigated by a Russian physiologist I.P.Pavlov.
Bitters are taken orally before meals in asthenia, a loss o f appetite after surgeries
and infections, in hypoacidic gastritis.
Bitters may cause inhibition o f gastric secretion if they are taken during or
after meals.
Fig. 4.3. Arthemisia absinthium containing bitter.
EMETIC DRUGS
Emetic drugs are medications provoking vomiting.
They are divided into:
I. Drugs of central action - apomorphine hydrochloride acting on the chemo-
i cecptors o f the trigger zone (CTZ) connecting to the emetic center. Apomorphine is
a dopaminergic preparation. It causes stimulation o f CTZ and provokes vomiting; is
used in acute poisonings; may cause the rupture o f stomach wall and esophagus, an
38 PH AR M ACO LO G Y. V. M. Bobyrov, T. 0. Devyatkina, 0, M. Vazhnicha, V. M. Khristyuk
increase in BP; is contraindicated in poisonings with acids and alkalis, ulcer o f the
stomach, acute abdomen, severe hypertension, pregnancy.
2. Drugs o f the peripheral action - p la n t drugs ofTherm opsis, Ipecacuanna,
sulfates o f zinc and copper. They are administered orally, irritate sensitive nerve
endings in the stomach and cause vomiting reflexly. Now these preparations are used
rarely.
LAXATIVES AND PURGATIVES (CATHARTICS)

Laxatives and purgatives (cathartics) stimulate afferent nerves to initiate a
reflex increase in gut motility (fig. 4.4).
Reflex
Irritation Vh m № ',' , ,..K v Peristalsis

of mucosa
Absorption J Secretion t
of fluid
Fig. 4.4 . Stimulation of peristalsis by mucosal irritation (by H. Liillmann, 2000).
Laxatives are classified according the site o f action, as well as by the origin.
P lant cathartics are divided into oils (Castor oil) and the drugs consisting of
anthraguinone derivatives.
Castor oil (Oleum Ricini) is bean oil which is hydrolyzed in the gut to the ri-
cinoleic acid and glycerol. The ricinoleic acid acts on the ileum and colon to induce
an increased fluid secretion and colonic contraction (fig. 4.5). It is used in acute
constipation.
A n th ra g u in o n e derivatives (drugs o f Senna, Rheum , Aloe, etc). They are
transformed to anthranol which irritates receptors o f colon and produces evacuation
in 8-10 hrs (fig. 4.6). The main drugs are senadexin, senade, cafiol etc.
Synthetic drugs - isaphenin, bisacodyl, sodium picosulfate (guttalax) also ir
ritate colon receptors and are used as antaguinone derivatives in chronic constipation.
Chapter 4. D R U G S S T IM U L A T IN G A F F E R E N T IN N E R V A T IO N 39
Fig. 4.5. Mechanism of action of Castor oil (by H. Liillmann, 2000).
oh o o • sugar
e.g., 1,8-Dihydroxy-
a nthraquinone gly co sid e
1,8-Dihydroxy-
anthrone ■A nthranol
Reduction
Sugar cleavage
Anthragulnone
g lyco sid e
Fig. 4.6. Mechanism of action of anthraqumone derivatives -

large-bowel irritant laxatives (by H. Liillmann, 2000).
40 PH ARM ACO LO G Y. V. M. Bobyrov, T. 0. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
Osmotic purgatives (m agnesium sulfate, sodium sulfate) increase lumen os-

molarity, drive additional fluid into the GI tract, and irritate intestine receptors. They
are used in intoxication, acute constipation, before some diagnostic procedures, or
in treatment with some antihelminthics.

№ 1. Mustard seeds realize their action by:
A. The formation o f albuminates
B. The absorption o f toxic substances
C. The formation o f colloidal covering
D. The stimulation o f nerve endings in the gut
E. The irritation o f sensitive nerve endings in the skin.
№ 2. Menthol is characterized by all, except:

A. The irritation o f sensitive nerve endings
B. A reflexive action on coronary blood vessels
C. The constriction o f blood vessels in the site o f application
D. Vasodilation in the site of application
E. The improvement o f taste and odor o f dental powders and pastes.
№ 3. The reflexly acting expectorants are:

A. Sodium bicarbonate
B. Trypsin
C. Mucaltinum
D. Infusion from the herb o f Thermopsis
E. Decoction from the root o f Althea.
8
№ 4. Bitters are:
A. Stimulants o f appetite
B. Suppressors o f appetite
C. Drugs for replacement therapy
D. Antimicrobial drugs for treatment o f peptic ulcer
E. Stimulants o f gastric secretion.
№ 5. A patient with chronic constipation was prescribed with a synthetic laxa

tive. This drug is in the form o f rectal suppositories. It is transformed into diphenol
and acts in the bowels. What drug was prescibed?
Chapter 4. D R U G S S T IM U L A T IN G A F F E R E N T IN N E R V A T IO N 41
A. Castor oil
B. Phenolphtalein
C. Magnesium sulphate
D. Root o f Rheum
E. Bisacodyl.
Answers
№ 1 - E; № 2 - D; № 3 -C , D, E ; № 4 - A , E ; № 5 - E .
15
O W CHOLINERGIC AGONISTS
AUTONOMIC NERVOUS SYSTEM

The autonom ic nervous system regulates the function o f internal organs. It is
divided into two sections: the sympathetic system (SANS) and the parasympathetic
system (PANS) which exert opposite actions (table 5.1).
Table 5.1. Som e distinguishing features in the structure

o f the parasym pathetic and sym pathetic nervous system s
Part of the system Parasympathetic system Sympathetic system

Centers (the 1Mneuron) Medulla of the brain, sacral Thoraco-lumbar region of the
region of the spinal cord spinal cord
Ganglia (the 2"d neuron) In the tissue of effector organs Near the spinal cord
or near it
CHOLINERGIC SYNAPSE
The nerve endings o f postganglionic parasympathetic nerves release a neuro
transmitter acetylcholine (fig. 5.1). Such synapses are named cholinergic synapses.
Chapters. C H O L IN E R G IC A G O N IS T S 43
Fig. 5.1. Structure of acetylcholine
Each synapse contains a presynaptic membrane, a synaptic gap (cleft), and a post-
synaptic membrane with cholinergic receptors (fig. 5.2). Acetylcholine is synthesized
in the presynaptic part o f the nerve ending. It is deposited in vesicles, releases into
Ihc synaptic gap, and interacts with cholinoreceptors on the postsynaptic membrane.
Acetylcholinesterase produces degradation of the neurotransmitter in the synaptic
gap. Choline is taken up by the neuron and used for the synthesis o f acetylcholine.
Fig. 5.2. Structure and function of cholinergic synapse (http://images.yandex.ru).

44 PH A R M ACO LO G Y. V. M. Bobyrov.T. 0. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
CHOLINORECEPTORS
There are two types o f cholinergic receptors:
—M -cholinoreceptors (muscarinic) with subtypes M p M2, M 3, M4, M5
- N-cholinoreceptors (muscarinic) with neuronal and muscular subtypes.
Cholinoreceptors are located in different organs and tissues, but some o f these
tissues are characterized by prevalence o f M- orN-cholinergic receptors (table 5.2).
Table 5.2. Location o f cholinergic receptors
M-cholinoreceptors N-cholinoreceptors
CNS CNS
Eye Adrenal medulla
Heart Carotid glomerulus
Blood vessels Sympathetic and parasympathetic ganglia
Bronchi (smooth muscles, glands) Skeletal muscles
Gut (smooth muscles, glands)
Urinary bladder
Uterus
Sweat glands
CHOLINERGIC DRUGS
Cholinergic drugs are preparations acting on cholinergic neurotransmission.
They are divided into cholinergic agonists (= cholinomimetics, cholino-positive
drugs) and cholinergic antagonists (= cholinoblockers, cholino-negative drugs)
(fig. 5.3). Cholinomimetics increase cholinergic neurotransmission. Cholinoblockers
decrease cholinergic neurotransmission.
Fig. 5.3. Cholinergic drugs.

Chapter 5. C H O L IN E R G IC A G O N IS T S 45
CHOLINOMIMETICS
Classification
A. M-,N-cholinomimetics
1. Direct-acting
- Acetylcholine
- Carbachol (Carbocholinum)
2. Indirect-acting (anticholinesterases)
- Neostigmine (Proserinunt)
- Physostigmine
- Pyridostigmine
- Galanthamine hydrobromide
- Isoflurophate
- Phosphacolum
- Arminum
IS. M-cholinomimetics
- Pilocarpine hydrochloride
- Aceclidinum
('. N-cholinomimetics
- Cytitonum
- Lobeline hydrochloride.
DRUGS WITH M-CHOLINOMIMETIC EFFECTS

Carbahol, pilocarpine, Aceclidinum, and anticholinesterases have clinically signifi
cant M-cholinomimetic activity and indications grounded on such activity (table 5.3).
Table 5.3. P harm acodynam ics and indications

for M -,N- and M -cholinom im etics
M-cholinomimetic effects Indications

Miosis (constriction of eye pupils) Glaucoma
Spasm of accommodation
(i emulation of eye lens for near vision)
A decrease in intra-eye pressure______
Stimulation of glands secretion Xerostomia
An increase in salivation
An increase in smooth muscles tone Atonia of the intestine and urinary bladder
after surgeries______________________
itindycardia Arrhythmia
IHood vessels dilation
Side-effects
1. Hypersalivation
2. Pain in the abdomen
3. Diarrhea
4. Spasm o f bronchi
5. Bradycardia
6. Frequent urination
7. Sweatiness.
Carbachol (Carbacholinum) has the chemical structure similar to acetylcholine,
but is not destroyed by cholinesterases; is direct acting M-, N-cholinomimetic with
the prevalence o f M-cholinergic activity; now is applied topically for the treatment
o f glaucoma (eye drops).
P ilocarpine is an alkaloid from Pilocarpus pinnatifolius (fig. 5.4), is a
M-cholinomimetic; has strong systemic M-cholinomimetic activity, but is toxic;
nowadays is used only for the treatment o f glaucoma (eye drops, eye ointment, or
eye membranes), seldom is used in xerostomia.
Aceclidinum is a synthetic preparation; is administered SC, 1M, or topically
(eye drops); is not toxic; does not penetrate CNS; is M-cholinomimetic; is used for
the treatment o f atonia o f the intestine and urinary bladder, as well as for glaucoma.
Fig. 5.4. Pilocarpus pinnatifolius containing pilocarpine

Chapter 5, C H O L IN E R G IC A G O N IS T S 47
ANTICHOLINESTERASES
Anticholinesterases are indirect-acting M-, N-cholinomirnetics with a reversible
or irreversible type o f action.
Anticholinesterases bind to acetylcholinesterase in the synaptic gap, inhibit it
and decrease acetylcholine destruction.
The result is the accumulation o f the acetylcholine amount in the synaptic gap
and an increase in acetylcholine interaction with M- andN-cholinoreceptors (fig. 5.5).
Pharmacodynamics
all M-cholinomimetic effects on internal organs (similar to those o f carba-
chol and pilocarpine)
an increase in neuromuscular transmission resulting from the accumulation
o f acetylcholine at the neuromuscular junction.
0 acetylcholine acetylcholinesterase \0 receptor
Fig. 5.5. Mechanism of action of anticholinesterases (http://www.picsearch.com).

Side-effects
They are the same as the side-effects o f direct M-,N- and M-cholinomimetics.
Physostigm ine is an alkaloid from Phyzostignia venenosum (fig. 5.6); is well
absorbed; penetrates CNS; has a reversible anticholinesterase action; is used for
the treatment o f glaucoma, intoxication by atropine, cholinoblockers, and tricyclic
antidepressants, early stages of Alzheimer’s disease; is toxic.
Galantamine is an alkaloid from Galanthus Woronowi(fig. 5.6); is administered
SC, 1M; penetrates into CNS; has a reversible anticholinesterase action; is used for
the treatment o f paralysis, neuritis, early stages o f Alzheimer’s disease and other
neurological diseases; is not used in glaucoma due to its irritative action.
N eostigm ine is a synthetic preparation; is administered orally, SC, IV, topi
cally (eye drops); does not penetrate CNS; has a reversible anticholinesterase action
(4-6 hrs); is used for paralysis, neuritis, myasthenia gravis, atonia o f the intestine
and urinary bladder, some kinds o f arrhythmia, glaucoma, poisoning with atropine,
overdose of tubocurarine; m ay be used for stimulation o f labor activity; in dentistry
is applied for xerostomia; is less toxic than physostigmine.
Fig. 5.6. Medicinal plants containing anticholinesterases:

A - Phyzostigma venenosum', B - Galanthus Woronowi.
Pyridostigmine acts longer, but is less potent than neostigmine; is used orally
for the treatment o f neurological diseases and myasthenia gravis.
Phosphacolum is an irreversibly acting anticholinesterase with long-lasting
action; is toxic and used only for glaucoma (eye drops).
Acute poisoning with organophosphates

(irreversible anticholinesterases)
Signs:
- hypersalivation
- nausea, vomiting
- spasm o f bronchi, edema o f the lungs
- convulsions
- unconcsiousness
Emergency help:
- Reactivators o f cholinesterase (dipyroxim, alloxim, izonitrozin), IM,
- Atropine, IM.
N-CHOLINOMIMET1CS
N-cholinom im etics are cholinergic agonists stimulating N-cholinoreceptors.
Pharm acodynam ics

They stimulate N-cholinoreceptors in zona carotis and initiate a reflexive in
crease in the activity o f the respiratory and vasomotor centers resulting in the short
stimulation o f breathing and elevation o f BP.
They also stimulate N-cholinoreceptors in the adrenal medulla, increase the
secretion o f epinephrine, which causes vasoconstriction and the elevation of BP
(tig. 5.7).
Cytitonum is the name o f a cytizine solution; is administered IV, acts 3-5 min;
stimulates N-cholinoreceptors; reflexly stimulates respiration and increases BP; is
used for emergency help in respiratory arrest and collapse; is an ingredient o f com
bined tablets against tobacco abuse.
Lobeline is an alkaloid; is administered IV and acts during 3-5 min; the mecha
nism o f action is similar to Cytitonum; is used for emergency help in the respiratory
arrest, asphyxia, asphyxia o f newborns; is used to treat tobacco abuse in the form
o f combined tablets “Lobesil”; is not used for collapse due to its ability to provoke
transitory a decrease in BP resulting from the stimulation o f n.vagus center.
50 PH ARM ACO LO G Y. V. M. Bobyrov,T. 0. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
Fig. 5.7. Mechanism of action of N-cholinomimetics
NICOTINE
It is a tobacco alkaloid with a dose-dependent action on N-cholinoreceptors.
Effects of nicotine are manifested in tobacco smoking. Nicotine causes dependence
that leads to abuse o f tobacco and results in the development o f cardiovascular and
lungs pathology.

№1. Cholinomimetics may cause all the following side-effects, except:
A. Bradycardia
B. Bronchospasm
C. Salivation
D. Constipation and urinary retention
E. Sweating.
№2. Only one preparation is N-cholinomimetic:

A. Carbochol
B. Lobeline
C. Neostigmine
D. Aceclidinum
E. Pilocarpine.
№3. Anticholinesterases are used for the treatment of:

A. Atropine (belladonna) poisoning
B. Postoperative paralytic ileus (atony o f intestines)
C. Overdose of depolarizing myorelaxants
D. Myasthenia gravis
E. Glaucoma.
№4. N-cholinomimetics:
A. Are stimulants o f respiration
B. Are drugs for emergency help
C. Have long duration o f action
D. Are used for the treatment of glaucoma and atony of the G1 tract
E. Are drugs for relief o f tobacco smoking.
№5. In the complex treatment of a child suffering from cerebral palsy, the
doctor decided to include anticholinesterase drug penetrating CNS and moderately
improving mental development. Choose this drug.
A. Phosphacol
B. Neostigmine (Proserinum)
C. Galanthamine
D. Pilocarpine
E. Cytitonum.
Answers
№ 1 - D; № 2 - B; № 3 - A, B, D, E; № 4 - A, B, E; № 5 - C.
t at
J n CHOLINERGIC
O V ANTAGONISTS
ANTICHOLINERGIC DRUGS
Cholinergic antagonists are also called cholinergic blockers. They bind to
cholinoreceptors, but do not trigger the usual receptor-mediated intracellular effects.
These drugs are divided into two groups: M-choiinoblockers (antimuscarinic agents)
and N-cholinoblockers (ganglionic blockers and neuromuscular blockers (fig. 6,1).
[ CHOLINERGIC ANTAGONISTS
Fig. 6.1. Groups of cholinergic antagonists.

Chapter 6. C H O L IN E R G IC A N T A G O N IS T S 53
M-CHOLINOBLOCKLERS
M -cholinoblockers are the drugs which block neurotransmission in the mus
carinic synapses o f the parasympathetic nerves and decrease the effects o f parasym
pathetic innervation. They also block M-cholinoreceptors in sympathetic neurons
innervating sweat glands.
Classification
A . Non-selective
1. Natural agents
- Atropine sulfate
- Hyoscine (Scopolamine hydrobromide)
- Platyphylline hydrotartrate
2. Synthetic and semisynthetic agents
- Methacinum
- Ipratropium bromide (Atrovent)
B. Selective
- Pirenzepine (Gastrocepine).
ATROPINE SULFATE
Atropine is an alkaloid, tropine derivative (fig. 6.2). It is water- and alcohol
soluble.
H3C - - (
N — CH
CH.
Fig. 6.2. Chemical structure of atropine.
Atropine is contained in such medicinal plants as Atropa Belladonna (deadly

nightshade), Hyoscianus niger, Datura stramonium (fig. 6.3).
Fig. 6.3. Atropa Belladonna containing atropine
Pharmacokinetics
is administered orally, 1M, SC; is applied topically (eye drops)
is rapidly, but poorly absorbed in the gut
binds to plasma proteins (18%)
penetrates CNS and placenta
is metabolized in the liver by atropinase
is excreted with urine
has T '/2 = 2 hrs; acts on internal organs during 4 hrs; influences eye tissues
during 7-10 days after instillation into the conjunctival sack.
M echanism of action
Atropine competes reversibly with acetylcholine at M-cholinoreceptor.
It binds to receptors and prevents binding o f acetylcholine to these sites
(fig. 6.4).
• Atropine has a non-selective action: it interacts with all the subtypes of
M-cholinoreceptors.
Atropine is both a centra! and peripheral muscarinic blocker.
Chapter 6 C H O L IN E R G IC A N T A G O N IS T S 55
Acetylcholine = black points Atropine = grey points

Fig. 6.4. Mechanism of action of atropine: A - normal condition of cholinergic synapse;
B - synapse condition in the presence of atropine (http://www.picsearch.com).
Pharm acodynam ics

weak local anesthesia in the site of application
in CNS: therapeutic doses - a sedation and antiparkinsonian effect; large
doses - excitation, hallucinations, and coma
in the eye: dilatation of pupil (midriasis), inability to focus for near vision (=
cycloplegia, paralysis o f accomodation), an increase of intraocular pressure
in the cardiovascular system: therapeutic doses - tachycardia, no effect on BP
• in the respiratory system: dilation of bronchi and a decrease in the secretion
o f bronchial glands
in the gut: reducing of the secretion o f saliva and gastric juice, a decrease
in the tone and motility; antispasmotic activity
in the urinary system: relaxation of the smooth muscles o f the urinary blad
der and urinary pathways
the inhibition o f sweat secretion
antidote properties in acute poisonings with M -cholinomimetics, anti
cholinesterases and toxic mushrooms containing muscarine; reducing ofthe
vagal action of morphine and some adverse effects o f general anesthetics.
Indications
Trauma of the eye, inflammation in the eye (cycloplegia and midriasis are
“pharmacological bandage” producing eye immobilization)
56 PH ARM ACO LO G Y. V. M. Bobyrov.T. 0. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
Diagnostics o f eye diseases, the measurement o f refraction for the correct

selection o f glasses
Bradycardia, AV block
Hypersalivation
Gastric ulcer
Acute pancreatitis
Cholecystitis
Billiary or renal colic
• Enuresis
Premedication
Acute poisoning with muscarine-containing mushrooms, M-cholinomimetics,
anticholinesterases, or morphine.
%
Side-effects Contraindications
I. Dilated pupils resulting in photo 1. Glaucoma
phobia 2. Tachycardia, taciarrhythmia
2. Blurred vision 3. Atonia o f the GI tract, achalasia,
An increase in intraocular pressure, ulcerative colitis
an attack o f glaucoma in someone 4. Prostate hyperplasia, adenoma of
with latent condition prostate
4. Tachycardia 5. Hepatic insufficiency
5. Dry mouth 6. Hyperthyroidism
6. Constipation 7. High body temperature
7. Retention of urine 8. Toxicosis o f pregnancy
8. Flushed skin 9. Cerebral pathology in children
9. A rise in body temperature. 10. Childhood or old age.
Acute poisoning with atropine

Signs:
- restlessness, disorientation, hallucinations, delirium, coma
- midriasis, absence o f pupils’ reaction to the light
- dryness of the skin and mucous membranes
- dysphagia
- retention o f urine
- hyperemia of the skin
- elevated body temperature.
Em ergency help:
- neostigmine or other anticholinesterases (as an antidote); they cause ac
cumulation o f acetylcholine in synapses that results in the liberation of
receptors from atropine
- chlorpromazine (to decrease psychotic disorders)
- barbiturates (to decrease seizures).
PECULIARITIES OF OTHER PREPARATIONS

Scopolam ine is another alkaloid contained in Atropa Belladonna and Scopolia.
It has pharmacokinetics and peripheral effects similar to atropine; the central action
is greater and longer than that o f atropine; inhibits activity o f VIII pair o f cranial
nerves and decreases motion sickness, produces sedation and short-memory block
ing, has antiparkinsonian effect; has a strong and short (5-6 hrs) action on the eye;
is used for the prevention and treatment o f motion sickness, for the complex therapy
o f psychic diseases, Parkinson’s disease, for premedication; has side-effects similar
to those o f atropine.
Pluiyphylline is an alkaloid from Senecioplatyphylus\ has the central action less
than that of atropine; has a short (5-6 hrs) action on the eye; causes inhibition o f the
vasomotor center and a direct myotropic action on blood vessels, that’s why dilates
blood vessels and lowers BP; may be used to treat spasms o f cerebral and coronary
blood vessels, as well as to treat hypertension.
M ethacinum is a synthetic preparation, non-selective M-cholinoblocker; is
more potent than atropine in dilation o f bronchi, the inhibition o f gasrtric secretion,
and a decrease o f the uterus tone; at the same time, it does not penetrate CNS, does
not act on the eye, has poor influence on the heart rate; is used in bronchial asthma,
ulcer o f the stomach, colic, premedication, and the danger o f miscarriage.
Ipratropium brom ide is a quaternary derivative of atropine, non-selective
M-cholinoblocker in the form o f aerosol; is not absorbed in the lungs and acts on
M-cholinoreceptors only in bronchi; dilates bronchi; is used for the prevention of a
bronchial asthma attack; has not significant side-effects (may cause unpleasant taste).
Pirenzepine is selective M -cholinoblocker inhibiting gastric secretion; is
administered orally, IM, IV; produces maximal concentration in blood plasma in
2-3 hrs after oral administration; has a half-life o f 10-12 hrs; does not penetrate
C'NS and placenta; is used for the treatment of ulcer of the stomach and duodenum,
/ollinger-E llison’s syndrome, the prevention o f peptic ulcers caused by stress; may
cause dry mouth, blurred vision, retention o f urine, but side-effects are minimal in
comparison with atropine.
N-CHOLINOBLOCKERS
N-cltolinoblockers are the drugs, which block neurotransmission in the nicotinic
synapses in ganglia or in skeletal muscles.
GANGLIONIC BLOCKERS
Ganglionic blockers are preparations which block N-cholinorecepors in ganglia.
Classification
1. Quaternary amines
- Hexaméthonium (Benzohexonium)
- Hygronium
- Pentaminum
2. Tertiary amines
- Pachycarpine hydroiodide
- Pirilenum.
HEXAMETHONIUM
It is a synthetic compound containing quaternary nitrogen.
Pharmacokinetics
is administered IM, IV, and orally
is poorly aborbed in the G 1 tract
does not penetrate CNS
acts during 3-4 hrs.
M echanism of action «
The drug blocks N-cholinoreceptors in sympathetic and parasympathetic
ganglia and disturbs the autonomic regulation of internal organs (pharma
cological denervation) (fig. 6.5).
It inhibits the propagation o f the nervous impulses running to effector organs
along both sympathetic and parasympathetic fibres.
The main result o f sympathetic ganglia blockade is a decrease o f BP.
The blockade o f parasympathetic ganglia is manifested by sympatholytic
and antisecretory effects.
Under these conditions sensitivity o f effector organs to humoral stimuli
stays normal or is increased.
Fig. 6.5. Mechanism'of action of ganglionic blockers.
Pharm acodynam ics

the dilation of blood vessels, redistribution of blood in the body, lowering
o f BP
the dilation o f bronchi
• a decrease in secretion and motility of the bowels, spasmolytic action
a decrease in the tone o f the urinary bladder and urinary pathways
an increase in the sensitivity o f myometrium to oxytocin resulting in the
stimulation o f uterus contractions in the labor
a decrease in'sweat secretion
changes in intraocular pressure which depends on the type of glaucoma.
Indications
Hypertensive emergence
Hypertension (rarely)
Controlled hypotension in surgeries
Edema o f the lungs
Edema o f the brain
Bronchial asthma attack
Colic
Ulcer of the stomach (rarely).
60 PH ARM ACO LO G Y. V. M. Bobyrov,T. 0. Devyatkina, 0. M.Vazhnicha, V. M. Khristyuk
1. Hypotension 1. Hypotension, collapse
2. Orthostatic collapse (postural 2. Severe atherosclerosis
hypotension) 3. Closed-angle glaucoma
3. Dry mouth 4. Atony o f the gut
4. Constipation 5. Adenome o f prostate
5. Retention of urination 6. Severe diseases of the heart,
6. An increase o f intraocular pressure in liver, and kidney.
patients with closed-angle glaucoma.
PECULIARITIES OF O THER PREPARATIONS

H ygronium is a short-acting potent ganglia blocker; is administered only by IV
infusion; is used for controlled hypotension in surgeries, edema o f the lungs, edema
o f the brain, severe hypertensive crisis, for the control o f BP in patients with aortha
anevrism emergence.
P entam inum is less potent than hexaméthonium, acts during 1,5 hrs, is admi
nistered IV, IM for emergency help in acute hypertension, a bronchial asthma attack,
colic, as well as for controlled hypotension in surgeries.
Pirilenum is a synthetic preparation with the structure of tertiary amine, that’s
why is taken by mouth, is well absorbed in the gut, penetrates CNS, acts during
6-8 hrs; is used to treat gangliolitis, spasms o f peripheral blood vessels, bronchial
asthma, gastric ulcer (rarely); has side-effects similar to that o f hexaméthonium.
Pachycarpine is an alkaloid from Sophorapachycarpa(fig. 6.6); is administered
orally, IM, SC; penetrates CNS, acts during 8-12 hrs; is a ganglia blocker, stimulates
uterus contractions, improves functions o f skeletal muscles; is used to treat gangl
iolitis, spasms o f blood vessels, nervous diseases, myopathy, may be used for the
stimulation of the labor activity; has high toxicity.
M YO RELAXAN TS
M yorelaxants (neorom uscular blockers) are cholinergic drugs which interfere
with the transmission o f nervous impulses in the synapses o f skeletal muscles caus
ing their relaxation.
Classification
1. Non-depolarizing agents
- d-Tubocurarine chloride
Fig. 6.6. Sophora pachycarpa containing pachycarpine.
- Pancuronium bromide
- Pipecuronium bromide
- Mellictinum
2. Depolarizing agents
Succinylcholine (Dithylinum).
TUBOCURARINE
Tuhocurarine is an alkaloid from a plant-derived arrow poison o f South
American natives. It contains two quaternary nitrogen atoms which are common to
all other muscle relaxants (fig. 6.7).
F ig . 6.7. C hem ical structure o f d-tubocurarine.

Pharm acokinetics
is administered IV
is not absorbed in the gut due to the presence o f quaternary nitrogen atoms
does not penetrate CNS
total myorelaxation develops in 20-30 min and lasts about 20-40 min which
needs artificial lungs ventilation, restoration of the muscle tone lasts 20-30 min.
It binds to endplate N-cholinoreceptors without exciting them and acts as
a competitive antagonist towards acetylcholine.
It blocks neuromuscular transmission by the prevention o f acetylcholine
binding to such nicotinic receptors (fig. 6.8).
Blockade of ACh receptors

No depolarization of
endplate
Fig. 6.8. M echanism o f action o f d-tubocurarine (by II. U illm aim , 2000).
Pharm acodynam ics

muscular paralysis which occurres firstly in the muscles o f fingers, neck,
face, extremities, trunk, then in intercostal muscles, and the diaphragm (with
the inability to breath).
Indications
myorelaxation under the conditions o f general anesthesia
seizures caused by seizure poisons and some infections.
Side-effects
1. Spasm o f bronchi and urticaria (due to histamine release from mast cells)
2. Lowering o f BP (due to weak ganglia blocking activity).
Contraindications
Myasthenia gravis, bronchial asthma, childhood.
Decurarization
The duration o f the action o f d-tubocurarine can be shortened by the adminis
tration o f neostigmine. Inhibition o f acetylcholine esterase causes the concentration
o f acetylcholine released at the endplate to rise. Competitive “displacement” by
acetylcholine o f tubocurarine from the receptors allows transmission to be restored.
PECULIARITIES OF OTHER
NON-DEPOLARIZING M YO RELAXAN TS
Pancuronium is a synthetic compound, is more potent than tubocuracine, has a
longer duration o f action, does not cause release o f histamine or ganglionic blockade,
may cause an increased heart rate and BP (due to blockade of M, cardiac receptors).
Pipecuronium is similar to pancuronium, does not cause tachycardia and an
increase of BP.
M ellictinum is an alkaloid; contains tertiary nitrogen atom, is absorbed after the
oral administration, is less potent than tubocurarine, but acts longer; is used to treat
neurological diseases with muscle spasticity; may cause weackness, hypotension; is
contraindicated in myasthenia.
SUCCINYLCHOLINE
is a double acetylcholine molecule
is administered IV; has a short duration o f action (total myorelaxation and
stop o f breathing lasts 3-5 min) and does not need artificial lungs ventila
tion; is destroyed by butiryl cholinesrerase in blood
like acetylcholine, acts on endplate N-cholinoreceptors, stimulates them, and
causes depolarization of postsynaptic membrane; degradates more slowly
than acetylcholine and therefore remains in the synaptic gap for several
minutes, causing the endplate depolarization of corresponding duration. This
depolarization triggers a propagated action potential (AP). A new AP can
be elicited at the endplate only if the membrane has been repolarized, that’s
why skeletal muscles stay without new nerve impulses and are relaxed (fig.
6.9). The order o f myorelaxation is the same as for tubocurarine
is used in short surgeries, intubation of thrachea, endoscopy, reposition of
bone fractures
may cause fibrillation o f skeletal muscles at the start o f action, hyper
kalemia, cardiac arrhythmia, an increase o f intraocular pressure, pain in
skeletal muscles after the surgery, long-lasting apnoea in patients deficient
on butiryl cholinesterase (in this case emergency help is hemotransfusion
and artificial lungs ventilation).
In clinic they also use centrally acting m uscle relaxants. These agents
lower muscle tone by augmenting the activity of intraspinal inhibitory neurons.
They are used in the treatment o f painful muscle spasms, e.g. in spinal disorders.
Benzodiazepines enhance the effectiveness o f the inhibitory transmitter GABA at
GABAa receptors. Baclofen stimulates GABABreceptors. Clonidine acts pesynapti-
cally on a,-adrenoceptors and inhibits release o f exitatory aminoacid transmitters.
Succinylcholine
F ig . 6.9. Mechanism of action of succinylcholine (by H. Lullmann, 2000).

TESTS FOR SELF-CO N TR O L

№1. Succinylcholine (Dithylinum):
A. Is depolarizing myorelaxant
B. Has short duration o f action
C. May cause lasting apnoea in some patients
D. Is suitable for short surgeries
E. All the listed.
№ 2. Ganglionic blockers:
A. Block N-cholinoreceptors in parasympathetic ganglia
B. Block N-cholinoreceptors in sympathetic ganglia
C. Block N-cholinoreceptors in skeletal muscles
D. Block N-cholinoreceptors in CNS
E. Block N-cholinoreceptors both in parasympathetic and sympathetic ganglia.
№ 3. Indications to the use o f atropine are:

A. Gastric ulcer
B. Colic
C. Atonia of the gut after the surgery
D. Bradycardia
E. Preanesthetic medication.
№4. The true statements concerning M-cholinoblockers are:

A. Atropine is used to treat glaucoma
B. Scopolamine is used in motion sickness
C. Plathyphylline dilates blood vessels and lowers BP
D. Pirenzepine is for the treatment of gastric ulcer
E. Pirenzepine is for the treatment and diagnostics o f eye diseases.
<
y>
№ 5. The administration of ipratropium in patients with bronchial asthma is
not accompanied by numerous side-effects which are characteristic for atropine and
other M-cholinoblckers due to:
A. The inability to penetrate through the blood brain barrier
B. The inhibition o f M-cholinoreceptors in the bronchi only
C. The inhibition o f all the types o f M-cholinoreceptors
D. The inhibition o f cholinesterase
E. Significant protein binding.
Answers
№ 1 - E; № 2 - E; № 3 - A, B, D, E; № 4 -B , C, D; № 5 - B.
ADRENERGIC
AGONISTS
SYMPATHETIC NERVOUS SYSTEM

The sympathetic nervous system is a section o f the autonomic nervous system.
Centers o f SANS are located in thoraco-lumbar segments o f the spinal cord (the
1st neuron). Ganglia o f SANS are located near the spinal cord and form Truncus
sympathycus (the 2nd nueron). The neurotransmitter released by sympathetic nerve
endings is norepinephrine (= noradrenaline) (fig. 7.1).
OH
Fig. 7.1. C hem ical structure o f norepinephrine.
ADRENERGIC SYN APSE

Synapses, in which norepinephrine is the neurotransmitter are named adrenergic
synapses (fig. 7.2).
( hapter 7. A D R E N E R G IC A G O N IS T S 67
Fig. 7.2. Adrenergic synapse and its function (by H. Lullmann, 2000).
Norepinephrine is synthesized in the presynaptic part of the neuron. It is depos-

IIічI in vesicles. Non-storaged neurotransmitter is destroyed by monoamine oxidase
(МЛО). When the nerve impulse arrives, norepinephrine is liberated into the synaptic
gup. It interacts with receptors on the presynaptic and postsynaptic membranes.
Minding to presynaptic receptors terminates the release o f the neurotransmitter. In
synaptic gap 20% o f norepinephrine is degradated by catechoI-O-methyltransferase
((< >MT). Another part of neurotransmitter (80%) is re-uptaken by the presynaptic
membrane.
A D R EN O C EPTO R S
I here are two types o f adrenoceptors and some subtypes in each family (fig.7.3).
I hey are located in CNS, as well as in many peripheral tissues (table 7.1).
68 PH AR M ACO LO G Y, V, M, Bobyrov,T. 0, Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
Fig. 7.3. T ypes and subtypes o f adrenoceptors.
Table 7.1. Localization and main effects o f adrenoceptors
R e c e p to r L o ca liz atio n E ffects

B lood vessels C onstriction, ft o f blood pressure
Spleen C onstriction
Eye M ydriasis
U rine bladder ft o f sphincter closure
a. B lood vessels C onstriction

Pancreas ■ft o f insulin release
All adrenergic synapses ft- o f norepinephrine release
H eart ft o f rate and contractility

P,
Fat tissue ft o f lipolysis
9
B lood vessels Vasodilation
B ronchi D ilation
U terus R elaxation
Pancreas ft o f g lucagon’s release
L iver ft o f glycogenolysis
Skeletal m uscles ft o f glycogenolysis
P3 Pancreas ft o f insulin secretion

Fat tissue ft o f lipolysis
M ast cells ft o f degranulation
ft o f release o f allergy m ediators
ttwipter 7. A D R E N E R G IC A G O N IS T S 69
ADRENERGIC DRUGS
Drugs acting on adrenergic synapses are named adrenergic drugs. They are
divided into two groups: adrenergic agonists and adrenergic antagonists (adreno-
Mockers and sympatholytics) - fig.7,4.
Adrenergic agonists are also named adrenopositive drugs or adrenomimetics.
Adrenergic antagonists are also named adrenonegative agents. Among them
Ihere are substances inhibiting adrenergic receptors (adrenoblockers) and substances
inlluencing the store and re-uptake o f norepinephrine (sympatholytics).
Fig. 7.4. D rugs influencing adrenergic synapses.
ADRENERGIC AGONISTS
Adrenergic agonists are drugs stimulating adrenergic neurotransmission.
Classification
■I. ß-adrenomimetics
1. Direct-acting
- Adrenaline hydrochloride (Epinephrine)
2. Indirect-acting
- Ephedrine hydrochloride
It. a-adrenomimetics
1. Non-selective
Noradrenaline hydrotartrate (a,, a 2 > ß)
2. Selective
Phenylephrine (Mesatonum) (a,)
Naphazoline (Naphthyzinum) (a2)
Halazolin (Xylometazoline) (a2)
< / / - adrenomimetics
70 PH AR M ACO LO G Y. V. M. Bobyrov.T. 0. Devyatkina, 0. M .Vazhnicha,V. M. Khristyuk
1. Non-selective
- Isoprenaline (Isadrinum) (p,, P2)
2. Selective
- Dobutamine (p,)
- Salbutamol (Albuterol) (P2)
- Fenoterol (P2)
ADRENALINE
It is a catecholamine, the hormone produced by the adrenal medulla.
Pharm acokinetics
is administered SC, IV (rarely), intracardially (in the heart arrest), or topically
is destroyed in the GI tract, that’s why is not administered orally
• does not penetrate CNS
is biotransformed by enzymes in blood
acts during 15 min on intern organs and during 30 min on metabolic proc
esses.
Adrenaline acts by the stimulation o f all the types o f adrenoceptors.
P harm acod ynam ics Indications

A n increase in autom aticity, conductivity, and H eart arrest
contractility o f the heart
C onstriction o f blood vessels Prolongation o f local anethesia A cute
inflam m ation o f the m ucous m em brane o f
the nose or the eye
E levation o f blood pressure Shock, collapse a
B ronchodiiation B ronchial asthm a attack
A n increase in glucose concentration in blood H ypoglycem ic com a
Inhibition o f allergy A naphylactic shock
M ydriasis Pupil dilatation.
A decrease in intra-eye pressure. O pen-angle glaucom a.
Side-effects
1. Excitement, tremor
2. Hypertension
3. Arrhythmia
4. Hyperglycemia.
Chapter?. A D R E N E R G IC A G O N IS T S 71
Contraindications
Hypertension, severe atherosclerosis, heart arrhythmia, diabetes mellitus,
hyperthyroidism
EPHEDRINE
The drug is not a catecholamine by its structure (fig. 7.5).
OH NH- С Н з
Fig. 7.5. C hem ical structure o f ephedrine.
It is an alkaloid from Ephedra equisetica (fig. 7.6).
Fig. 7,6. Ephedra equisetica containing ephedrine.
Pharmacokinetics
is administered orally, SC, 1M, IV, or topically
* is absorbed in the GI tract
• penetrates CNS
is metabolized in the liver
• is excreted by the kidney
* acts during 4-6 hrs.
72 PH ARM ACO LO G Y. V. M. B o b y ro v ,! 0. Devyatkina, 0. M. Vazhnicha,V. M, Khristyuk
Ephedrine stimulates the release of noradrenaline, inhibits the re-uptake of
noradrenaline (indirect action) (fig. 7.7).
It has a weak direct action on adrenoceptors.
Drug enhances release

of norepinephrine from
vesicles.
POSTSYNAPTIC
TARGET CELL
MEMBRANE
Fig. 7.7. Mechanism of ephedrine’s action

(adapted fr o m R. F in k el e t al., 200H).
Pharm acodynam ics

the stimulation o f CNS, an increase in the ability to mental and physical
work, euphoria
the stimulation o f the heart function
vasoconstriction
the elevation o f BP
the dilation o f bronchi
the inhibition o f the gut motility
the retention of urine
mydriasis.
Chapter 7. A D R E N E R G IC A G O N IS T S 73
Indications
• Shock, collapse
Anaphylactic shock
Bronchial asthma
Bronchospasm
AV block, bradycardia
• Acute rhinitis
Acute conjunctivitis
• For pupil dilatation
Pathological narcolepsia
Myasthenia
Enuresis.
Side-effects
1. Insomnia
2. Anxiety, restlessness, insomnia
3. Tachycardia
4. Palpitation
5. Hypertension
6. Rash on the skin
7. Tolerance and tachyphylaxis
8. Drug dependence.
The drug should not be used in sportsmen (as a doping)
a-ADRENERGIC AGONISTS
a-adrenom im etics are drugs stimulating a-adrenoceptors. Noradrenaline is
a natural neurotransmitter which binds to all types o f adrenoceptors, but only the
stimulation o f a-adrenoceptors is clinically significant.
These preparations are characterized by common pharmacological effects and
indications (table 7.2).
Table 7.2. Com m on pharm acological effects

and indications for a-adrenom im etics
a -a d re n o m im e tic effects In d ic a tio n s

V asoconstriction Shock, collapse
An increase in BP P rolongation o f local anesthesia
Mvili'iusis w ithout cycloplegia R hinitis, conjunctivitis
G laucom a, diagnostics o f eye diseases
N oradrenaline is a catecholamine; it has a non-selective action on adrenocep
tors with a preferable action on a-adrenoceptors; has a short-durative action, is ad
ministered only by IV infusion in collapse and acute hypotension; may cause strong
vasoconstriction and the necrosis o f soft tissues, if it is administered SC or IM; is
contraindicated in blood loss, cardiogenic shock, long-lasting shock.
Phenylephrine (M esatonum) is a non-catecholamine; has a selective action
on c^-adrenoceptors; may be taken orally, is administered SC, IM, IV, or topically;
has the duration o f action o f 4-6 hrs; is used in acute and chronic hypotension, for
prolongation o f local anesthesia, for producing o f midriasis, as well as for a decrease
in edema o f the mucous membrane in acute rhinitis or conjunctivitis.
N aphazoline and halazolin are non-catecholamines; have a selective action
on a 2-adrenoceptors, are used as nasal drops for acute rhinitis, nasal bleeding, and
rhinoscopia; cause tolerance and tachyphylaxis.
p-ADRENERGIC AGONISTS
P-adrenomimetics are agonists o f (5-adrenoceptors and increase the neurotrans
mission in such synapses. They have some common pharmacological properties and
indications (table 7.3).
Table 7.3. C om m on effects and indications for p-adrenom im etics
(5-adrenom inietic effects Indications

D ilation o f bronchi Bronchial asthm a, spasm o f bronchi
An increase in the heart rate H eart block, bradycardia
An increase in the heart w ork D anger o f pregnancy interruption.
A decrease in the m yom etrium tone.
Isoprenaline (Isadrinum ) is a synthetic catecholamine; has a non-selective ac
tion on p,- and p2-adrenoceptpors; is administered sublingually, by inhalation, or IV;
is used in a bronchial asthma attack, heart block, some types o f cardiogenous shock.
Salbuiam ol is a non-catecholamine; has a selective action on P2-adrenoceptors,
acts longer than isoprenaline; does not act on the heart; is used in bronchial asthma,
bronchospasm and before bronchoscopia.
Fenoterol (Partusisten) is a non-catecholamine; has a selective action on P2-
adrenoceptors, acts during 4-6 hrs; does not act on the heart; is used in bronchial
asthma and in danger o f pregnancy interruption.
Chapter 7. A D R E N E R G IC A G O N IS T S 75
D obutam ine has a selective action on ßâdrenoceptors; increases cardiac

output; is administered by IV infusion for the emergency treatment o f acute heart
insufficiency and cardiogenous shock.
COMPARISON OF
ADRENOMIMETICS-CATECHOLAMINS
Adrenomimetics with catecholamine structure are distinguished by their affinity
to adrenergic receptors (fig. 7.8).
OH p P OH OH n
a 9 °° 0 X * » e X 13
HC-CHj- nh2 a h c - c h 2- n h ß h c - c h 2- n h
U OHÖ 0 OH CH3 a OH HC-
HC-CH,
Norepinephrine f t Epinephrine Isoproterenol ■
I
a a
q U
^
n
u ' a a
a
“
a
" a
CH
a1"
Fig. 7.8. Chemical structure of catecholamines and their

affinity to a- and (3-adrenoceptors (by H. Lullmann, 2000).
This affinity depends on the structure o f substitute radicals. They may be methyl
in adrenalin or isopropyl in isoproterenol. Noradrenaline has not such substitutes in
its side chain.
The represented data result in peculiarities of pharmacological effects. It is a
typical evidence o f dependence o f drug’s effects on its chemical structure (table 7.4).
Table 7.4. D ependance o f catecholam ines’

effects on their chem ical structure
E ffect A d renaline N oradrenaline Isoprenaline

An increase in heart rate + + + + + +
An increase in blood pressure + + 4- + + -
1Jilation o f bronchi + + ± + + +
A decrease in gut function + + + + + +
An increase in glucose level

+ + + ± ±
{hyperglycem ia)
A decrease in tone o f uterus + + + ± + +

№ 1. Adrenaline is used to treat all the conditions, except:
A. Acute bronchial asthma
B. Capillary bleeding after tooth extraction
C. Anaphylactic shock
D. Angina pectoris
E. Hypoglycemia.
№ 2. The drug used to prevent premature labor is:

A. Dobutamine
B. Metoprolol
C. Isadrinum
D. Adrenaline
E. Partusisten (Fenoterol).
№ 3. Ephedrine:
A. Releases stored noradrenaline from nerve terminals
B. Produces bronchodilation
C. Stimulates CNS
D. Rises systolic blood pressure
E. Produces AV block.
№ 4. Isoprenaline (Isadrinum) is:

A. Contraindicated in tachyarrhythmia
B. Synthetic catecholamine
C. Bronchodilator
D. Stimulant o f the heart function
E. Cardioselective adrenomimetic.
№ 5. To perform fundoscopy, ophthalmologist instilled in the eye an agent

capable o f causing midriasis without cycloplegia. Point out this agent.
A. Phenylephrine (Mesatonum)
B. Noradrenaline
C. Atropine
D. Pilocarpine
E. Isoprenaline (Isadrinum).
Answers:
№ 1 - D ; № 2 - E; № 3 - A, B, C, D; № 4 - A, B, C, D; № 5 A.
B Q ADRENERGIC ANTAGONISTS.
2 O HISTAMINE-AND
6 V SEROTONIN-ERGIC DRUGS
ANTI-ADRENERGIC DRUGS
Anti-adrenergic drugs are preparations for a decrease in the neurotransmis
sion in adrenergic synapses due to blockade o f adrenoceptors or due to presynaptic
inhibition o f norepinephine release (fig. 8.1).
F ig . 8.1. G roups o f anti-adrenergic drugs.

78 PH ARM ACO LO G Y. V. M. Bobyrov.T. 0. Devyatkina, 0. M, Vazhnicha, V. M. Khristyuk
C lassification
A. a-adrenoblockers
1. Non-selective
- Phentolamine hydrohloride
- Tropaphenum
2. Selective
- Prazosin
- Doxazasin
B. ß-adrenoblockers
1. Non-selective
- Propranolol (Anaprilinum)
- Oxprenolol
2. Selective
- Metoprolol
- Talinolol
- Atenolol
C. a-, ß-adrenoblockers
- Labetal o I
- Carvedilol
D. Sympatholytics
- Guanethidine (Octadinum)
- Reserpine.
a-ADRENOBLOCKERS
a-adrenoblockers are preparations which bind to a-adrenoceptors and prevent
their stimulation by norepinephrine.
Q
They bind to a-adrenoceptors and make impossible the interaction between
norepinephrine and adrenoceptors.
Pharmacodynamics
the dilation o f peripheral blood vessels, reducing of peripheral resistance,
an increase in venous capacity
a decrease in BP
the improvement o f trophy o f peripheral tissues
the stimulation o f gut motility
Chapter 8. ADRENERGIC ANTAGONISTS. HISTAMINE- A N D SEROTONIN-ERGIC DRUGS 79
the stimulation of the salivary, lacrimal, pancreatic, and respioratory tract

secretions
a decrease o f urine retention in patients with prostate hyperplasia.
Indications
Hypertension
Spasms o f peripheral blood vessels (Raynaud’s disease)
Frostbites, trophic ulcers
• Pheochromacitoma (diagnostics and treatment)
• Prostate hyperplasia.
Side-effects
1. Headache, vertigo
2. Hypotension
3. Weakness
4. Insomnia ^
5. Orthostatic collapse
6. Tachycardia
7. Vomiting, nausea, diarrhea
8. Rhinitis.
Phentolam ine hydrochloride has a non-selective action (blocks a,- and a 2-
ndrenoceptors); is administered orally or IV; has a short duration o f action; has many
side-effects; causes tachycardia due to the blockade o f a 2-adrenoceptors and disorders
in back-cross regulation of norepinephrine liberation in synapses.
Prazosin has a selective action on a (-adrenoceptors; is taken orally; acts during
■1-6 hrs; is used for the treatment o f hypertension; has less side- effects.
Doxazosin has a selective action on c^-adrenoceptors; is taken orally; has a
more durative and strong action than prazosin; decreases urine retention in patients
with adenoma of prostate; is used for the treatment o f hypertension and adenoma
of prostate.
p-ADRENOBLOCKERS
/l-adrenoblockers are preparations which bind to (3-adrenoceptors and prevent
(heir stimulation by norepinephrine.
80 PH ARM ACO LO G Y. V. M. B obyrovJ. 0. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
PR O PR AN O LO L (ANAPRILINUM)
Pharmacokinetics
is administered orally, IV, topically (eye drops)
is absorbed in the G1 tract
• binds to proteins in blood serum
penetrates CNS
• is metabolized in the liver
Propranolol blocks P(-adrenoceptors in the heart and ß2-adrenoceptors in other
organs (blood vessels, bronchi, etc).
Pharm acodynam ics

a decrease in automaticity of myocardium
a decrease in excitability of myocardium
a decrease in conductivity of myocardium
• a decrease in the heart rate {anti-arrhythmic effect)
decreases the heart contractility, striking and minute volume
a decrease in the consumption of oxygen by myocardium {antianginal effect)
• a decrease in the renin’s secretion in the kidney
the lowering o f BP {antihypertensive effect)
the lowering of intraocular pressure
sedative action
an increase in the tone o f bronchi 9
the stimulation of gastric secretion
an increase in the peripheral resistance o f blood vessels (at the beginning
o f the therapy)
antagonism to adrenaline as to its lipolytic and hyperglycemic action,
indications
Hypertension
Ischemic heart disease (angina pectoris, myocardial infarction)
Supraventricular tachyarrhythmia
Hyperthyroidism
• Migraine
Glaucoma.
Side-effects C on traind ications

1. B radycardia 1. B radycardia
2. H ypotension 2. H ypotension
3. Increasing o f the heart incom petence 3. Severe heart failure
4. H eart block 4. H eart block
5. Spasm o f bronchi 5. B ronchial asthm a
6. H ypoglycem ia w hen insulin is given 6. U lcerative disease
together w ith propranolol 7. D iabetes m ellitus
7. F atique, drow siness, vertigo, depression 8. Disturbances o f peripheral blood circulation
8. Disturbances o f the sexual function in men. 9. Pregnancy.

Metoprolol has a cardioselective acticfp on [^-receptors (fig. 8.2); is taken orally
for the treatment o f hypertension, angina pectoris, and arrhythmia; does not cause
spasm o f bronchi and an increase of gastric secretion; may be used in patients with
bronchial asthma, ulcerative disease, and diabetes mellitus.
Talinolol has a cardioselective action on (^-receptors; has inner sympathomi
metic activity and a membrane stabilizing effect (does not inhibit the heart contractility
and conductivity); has less side-effects and less contraindications connected with the
influence on Ppadrenoceptors.
A tenolol has a cardioselective action on P re c e p to rs; is similar to metopolol.
f PROPRANOLOL ^ METOPROLOL, ATENOLOL ^
H E A R T (p.) ) H E A R T (P,) J
L- {
BRONCHI (P,)
BLOOD VESSELS ( P ,P )
GI TRACT (P,) j
F ig . 8.2. T argets o f action o f propranolol and cardioselective P-adrenoblockers.

a-, p-AD REN O BLO CKER S

a-, p-adrenoblockers are preparations which bind both to a- and p-adrenoceptors,
prevent their stimulation by norepinephrine, and disturb adrenergic neurotransmission.
LA B E T A LO L
- blocks both a- and P-adrenoceptors
- has the action on p-receptors, which is 3 times more potent than the action
on a-receptors
- is less active than propranolol
- is less active than phentolamine
- is taken orally or IV
- is indicated for the control o f hypertension
- is contraindicated in the heart block, spasm of a bronchi, pregnancy.
SYMPATHOLYTICS
Sym patholytics are adrenergic antagonists of presynaptic action.
RESERPINE
is an alkaloid from Rauwolfia serpentine
decreases the storage o f norepinephrine that leads to destruction o f neu
rotransmitter by MAO in axonal cytoplasma resulting in a decrease of
neurotransmission in adrenergic synapses (fig. 8.3)
penetrates CNS, has a central and peripheral action (table 8.1)
has an antihypertensive, sedative and antipsychotic action
is administered orally, IM or IV ,
acts during 8-12 hrs
is indicated in hypertension
may cause disturbances o f sleep, depression, bradycardia, spasm ofbronchi,
stimulation o f gastric secretion, diarrhea.
GUANETHIDINE (OCTADINUM)
is a synthetic compound of simple structure
produces active storage and uptake instead o f norepinephrine, decreases
neurotransmitter release
does not penetrate CNS, has only peripheral action (table 8.1)
Chapter 8 ADRENERGIC ANTAGONISTS. HISTAMINE- A N D SEROTONIN-ERGIC DRUGS 83
Normal Reserpine depletion
Fig. 8.3. Mechanism of reserpme’s action: A - normal condition of

adrenergic synapse; B - adremergic synapse in the presence of reserpine.
has antihypertensive action, decreases intraocular pressure

is taken orally or topically (in the form o f eye drops)
action is slow and long (it starts to act «a 2-4 days afterthe beginning o f treat
ment and continues to act during 10-14 days after the ending o f treatment)
is indicated for hypertension, glaucoma, some types of arrhythmia
may cause orthostatic hypotension and side-effects connected with preva
lence o f PANS (bradycardia, spasm of bronchi, stimulation o f gastric secre
tion, diarrhea, enlargement o f salivary glands).
Table 8.1. C om parison of sym patholytics
D rugs R E S E R P IN E G U A N E T H ID IN E
Chem ical structure A lkaloid S ynthetic com pound
M echanism o f action Inhibition o f biogenic A ctive uptake and storage,
am ines storage not a transm itter
C entral action + -
Peripheral action + +
M ain effect V aricosity, J. BP V aricosity, | BP
HISTAMINERGIC DRUGS
llistam'mergic agents include histamine and antihistamines.
HISTAMINE
H istam ine is biologically active amine which regulates the tone of smooth mus
cles, allergy, inflammation, and secretion o f exocrine glands. It realizes its action by
the binding with histamine receptors. In a clinic histamine is used rarely.
ANTIHISTAMINES
Antihistam ines are drugs which antagonize effects of histamine by the blockage
o f histamine receptors or by a decrease o f histamine liberation.
Classification
1. Drugs stabilizing mast cells membranes
- Cromolyn sodium (Sodium cromoglycate, Intal)
- Ketotifen (Zaditen)
2. Blockers o f H^histamine receptors
- Diphenhydramine (Dimedrolum)
- Tavegil
- Suprastinum
- Promethazine (Diprazinum)
- Diasolinum
- Quifenadine (Phencaroium)
- Loratadine
- Phexofenadine
3. Blockers o f H2-histamine receptors
- Ranitidine
- Famotidine.
M AST C E L L STABILIZERS
Crom olyn sodium

• is administered by inhalation
stabilizes basophiles membranes, prevents the release o f histamine and
other allergy mediators
is used for the prophylaxis o f the bronchial asthma attack, allergic rhinitis,
and conjunctivitis
may cause the irritation o f respiratory pathways, spasm o f bronchi, head
ache, cough.
Ketotifen
is administered orally
stabilizes basophiles membranes, prevents the release of histamine and other
allergy mediators; has a weak antihistamine and sedative action
is used for the prophylaxis o f bronchial asthma attack
may cause such side-effects as drowsiness, dry mouth, dizziness, throm
bocytopenia
is contraindicated for patients whose job needs quick motor reaction.
B LO C K E R S OF H-HISTAM INE R ECEPTO R S

DIPHENHYDRAMINE (DIMEDROLUM)
Diphenhydramine is a synthetic drug, dimethylaminoethano! derivative (fig. 8.4).
Fig. 8.4. C hem ical structure o f diphenhydram ine.
Pharmacokinetics
is administered'brally, 1M, IV, rectally, topically (ointment, eye drops)
is absorbed in the GI tract
is metabolized in the liver, is the inductor o f microsomal oxidation
is excreted by urine
has the duration o f action o f 6-8 hrs.
The drug blocks H^histamine receptors and inhibits effects of histamine,
especially allergic reactions
It blocks cholinergic receptors
It blocks adrenergic and serotonin receptors.
Pharm acodynam ics

the inhibition o f a histamine action
a decrease of allergic reactions
a decrease in edema o f tissues due to histamine
a decrease in permeability o f blood vessels wall
a decrease o f inflammation
a decrease in spasms o f smooth muscles
ganglia blocking effect
sedative and hypnotic effect
anti-emetic effect
potentiative action.
Indications
1. Allergic diseases (angioneurotic edema, hay fever, urticaria, vasomotor
rhinitis, serum sickness)
2. Allergic complications o f blood transfusion
3. Allergic complications o f pharmacotherapy
4. Hemorrhagic capillary toxicosis
5. Radiation sickness
6. Motion sickness
7. Insomnia
8. The potentiation o f general anesthesia.
Side-effects
1. Weakness, fatigue, psychomotor impairment, depression
2. Dry mouth
3. Blurred vision
4. Urinary retention a
5. Gastro-intestinal disturbances
6. Changes o f the effects o f other drugs.
The drug should not be used during driving or together with alcoholic drinks.
PECULIARITIES O F OTH ER PREPARATIONS

Tavegil is taken orally; acts during 12 hrs; has a strong antihistamine and weak
sedative effect.
Suprasfinum is taken orally, IM, IV; has an overage antihistamine and sedative
effect accompanied by a significant M-cholinoblocking action.
P ro m e th a z in e (D ip ra sin u m ) is a d m in iste re d o ra lly , 1M, IV; blocks

a-adrenoceptors; has denominated sedative, hypnotic and vestibuloprotective ac
tions; may be used for the treatment o f motion sickness and vestibule disturbances;
may cause hypotension.
Diazolinum is taken orally; acts during 48 hrs; has a minimal sedative action
(day-time antihistamine).
Loratadine is taken orally; acts during 48 hrs; has an overage antihistamine
action; does not penetrate CNS, has not a sedative action (day-time antihistamine).
Phencarolum is taken orally; blocks H,-receptors and increases the enzymic
inactivation o f histamine; has an overage antihistamine and antiserotonin action, but
a minimal sedative action.
B LO C K E R S OF H2-HISTAMINE R ECEPTO R S
These preparations block H2-histamine receptors and decrease gastric secretion.
They have common indications: ulcerative disease, symptomatic ulcer, gastroe-
sophagitis. Detailed description o f these drugs is represented in Chapter 24.
Ranitidine is administered orally (1-2 times a day), IV; side-effects: headache,
vertigo, weakness, skin rash, thrombocytopenia.
Famotidine is administered orally or IV (1 -2 times a day); inhibits basal gastric
secretion, as well as stimulated secretion; is more effective; has less side-effects.
SEROTONIN-ERGIC DRUGS
Serotonin-ergic drugs are agents which stimulate or block serotonin receptors
t. ^
(5-HT).
SEROTONIN ADIPINATE
is administered IV or 1M
is the agonist of serotonin receptors
decreases the permeability o f the blood vessels wall
is used as an anti-hemorrhagic agent in hemorrhagic vasculitis, hypo- and
aplastic anemia, thrombocytopenia, hemorrhagic syndrome accompanied
the anti-cancer chemotherapy
may cause pain in abdomen, pain in the heart, headache, elevation o f BP,
GI disturbances, decreases diuresis after a quick IV administration.
CYPROHEPTADIN (PERITOL)
is taken orally
is a strong antagonist o f serotonin receptors; also blocks H,-histamine recep
tors and cholinergic receptors
is an anti-allergic agent; blocks hypersecretion o f ACTH and STH
is used in allergy, migraine, anorexia
may cause somnolence, dry mouth, vertigo, ataxia, skin rash.
TES TS FOR SELF-CO N TR O L

№ 1. Only one drug belongs to a-adrenoblockers:
A. Carbochol
B. Adrenaline hydrochloride
C. Prazosin
D. Propranolol
E. Guanethidine.
№2. All the drugs are used for the treatment of hypertension, except:
A. Prazosin
B. Anaprilinum
C. Diphenhydramine
D. Labetalol
E. Reserpine.
№ 3. The following statements concerning guanethidine are correct

A. It is a potent antihypertensive agent
B. It causes vasodilatation
C. It blocks ß-adrenoceptors
D. It acts presynaptically
E. It blocks a-adrenoceptors.
№ 4. Dimedrolum is applied in a clinic for:

A. The treatment o f bronchial asthma
B. Allergic diseases
C. Allergic complications o f pharmacological therapy
D. Hemorrhagical diathesis
E. Hypertension.
№ 5. An adrenoblocking drug was prescribed for the treatment o f angina pec

toris, but bradycardia, bronchospasm, and gastric ulcer had beendeveloped.What
drug was used? What drug from the same pharmacologicalgroup may be used for
the replacement of the first remedy?
A. Labetalol, propranolol for its replacement
B. Propranolol, metoprolol for its replacement
C. Propranolol, prazosin for its replacement
D. Phentolamine, metoprolol for its replacement
E. Propranolol, diphenhydramine for its replacement.
Answers:
№ 1 - C; № 2 - C; № 3 - A, B, D; № 4 - B, C, D; № 5 - B.
9
0)
S’ % | DRUGS FOR GENERAL

O W ANESTHESIA
DRUGS INHIBITING CNS

Drugs inhibiting CNS are divided into eight groups (fig. 9.1). They include
general anesthetics, sedatives, hypnotics, neuroleptics, anxiolytics, analgesics, anti
convulsants, and antiparkinsonian drugs.
Drugs inhibiting CNS

D
Drugs for general anesthesia ^
c Sedatives
J
£ Hypnotics
D
£ Neuroleptics
D
£ Anxiolytics
D
Analgesics
£ Anticonvulsants
£ Antiparkinsonian drugs
Fig. 9.1. Main groups o f CNS inhibitors.

Chapter 9. D R U G S F O R G E N E R A L A N E S T H E S IA 91
G E N E R A L ANESTHESIA
General anesthesia (narcosis) is a reversible suppression o f CNS with the aboli
shing o f pain and all kinds o f sensitivity, with myorelaxation and unconsciousness
(fig. 9.2).
Fig. 9.2. Main goals of general anesthesia (by H. Lüllmann, 2000).
Disparities between general and local anesthesia

General anesthesia and local anesthesia both are used for abolishing o f pain in
surgery, but they have significant distinctinctive features (table 9.1).
Table 9.1. D isparities between general and local anesthesia
G eneral anesthesia L ocal anesthesia

- T otal abolihing o f pain - L ocal abolishing o f pain
- A loss o f consciousness - N orm al consciousness
R elaxation o f skeletal m uscles - N orm al m uscular tone
=■ A bolishing o f reflexes - N orm al reflexes
U sage for all kinds o f surgeries - U sage for uncavitary surgeries
Main concepts of general anesthesia

• Induction to anesthesia (inductive narcosis) is the start o f narcosis which
should be pleasant for the patient
Basis narcosis is the maintenance o f narcosis for ail the periods o f surgery
• Mixed narcosis is the combined usage o f general anesthetics from one
pharmacological group (Halothane + Nitrous oxide)
Combined narcosis (balanced anasthesia) is the combined usage of general
anesthetics and preparations from another pharmacological group (ganglia
blockers, myorelaxants, etc.) (fig. 9.3)
Safety margin is the difference between the dose that causes surgical an
esthesia and the dose that causes lethal suppression o f the respiratory center
• Premedication (preanesthetical madication) is the administration o f prepa
rations for the potentiation o f narcosis, as well as for the prophylaxis of
side-effects o f general anesthesia.
Fig. 9.3. B alanced anesthesia (by H .Lüllm arm , 2000).
DRUGS FOR G E N E TR A L ANESTHESIA

According to their routs o f administration general anesthetics are divided into
inhalation anesthetics and preparations f o r I V anesthesia. These two groups are
distinguished by some properties (table 9.2).
INHALATION ANESTHETICS
Inhalation anesthetics are preparations for general anesthesia which are ad
ministered by inhalation through a special mask or system.
Table 9.2. Distinguishes between inhalation and IV general anesthetics
In h a la tio n a n e sth e tic s D ru g s fo r IV a n e sth e sia

- Inhalation adm inistration - IV adm inistration
- L ong duration o f narcosis - Short duration o f narcosis
- Strong m yorelaxation - W eak m yorelaxation
- W ell m anaged anesthesia - U nm anaged anesthesia
- U sage for cavitary surgeries - U sage for short uncavitary surgeries
CLASSIFICATION
1. Volatile liquids
- Ether for narcosis (Aether pro narcosi)
- Halothane (Phthorothanum)
- Isoflurane
2. Gaseous anesthetics
- Nitrous oxide
- Cyclopropane
It is based on the lipid solubility o f inhalation general anesthetics and their
ability to dissolve in the cel! membrane lipids resulting in the inhibiting o f neuro
transmission (fig. 9,4).
f \ < \
Binding to Changes in
m embrane lipids m em branes viscosity
V K J
V
/ \ f \
A decreasç, Changes o f perm eability
in depolarization o f ion channels
V \ J
u
f \ / \
Inhibition of NARCOSIS
neurotransm ission
V y \ J
Fig. 9.4. M echanism o f action o f inhalation general anesthetics.
Stages o f narcosis
Deepening of narcosis lepds to the development of four stages o f general anesthesia:
I. Analgesia with the absence o f pain and the possibility to carry out short
surgeries;
94 PH ARM ACO LO G Y. V. M. Bobyrov,T. 0. Devyatkina, 0. M. Vazhnicha,V. M. Khristyuk
II. E xcitem ent with many disturbances in the organism (motor and speech
excitement, heart arrhythmia, heart arrest, changes in BP, irregulary respiration,
respiratory arrest, spasm o f bronchi, spasm o f larinx, vomiting, hypersalivation),
which make surgerical intervention impossible;
III. Surgical anesthesia (planes 1-4), which is characterized by a loss o f pain,
unconsciousness, myorelaxation, absence o f reflexes, stability of BP and respiration
that is suitable for the majority o f surgeries;
IV. A w akening with the restoration of CN S functions (if the concentration o f the
drug decreases), or m edulla paralysis (if the concentration o f the general anesthetic
increases).
Ether fo r narcosis is a volatile inflammable liquid with specific odor; 80% o f dose
is excreted unchanged with the air (fig. 9.5); has a wide safety margin o f the narcosis
action, but a long stage o f excitement; is used for basis mono- and combined narco
sis; irritates the upper respiratory' pathways; may cause pneumonia after the surgery.
H alothane (Phthorotanum ) is a volatile liquid; contains fluorine; is not inflam
mable; has a strong narcosis action , but weak analgesia; has long stage o f analgesia
without the excitement stage; dilates bronchi (may be used for the termination of
a severe bronchial asthma attack); dilates blood vessels; lowers BP; increases the
myocardium sensitivity to catecholamines (adrenaline and noradrenaline are con-
F Br
N20 Nitrous oxide
■ i
F -C -C -H
H5C2OC2H5 Ether i i
Halothane
F Cl
Fig. 9.5. Routes o f elimination o f inhalation anesthetics (by H. Lullmann, 2000).

traindicated during this narcosis); decreases the tone o f uterus; is metabolized in the
liver (fig. 9.5) and may cause liver lesion; is used for combined general anesthesia.
Isoflurane is similar to halothane; displays good myorelaxation and rapid
recovery; has a less negative influence on the heart and liver; is the best agent in
pediatric patients.
Nitrous oxide is a gaseous anesthetic; is biologically inert (fig. 9.5); has a weak
narcosis action (is not used as a sole anesthetic for surgeries); does not cause good
myorelaxation; has strong analgesia; a rapid onset o f action and recovery; is used
for analgesia in traumas, myocardial infarction, or labor, as well as for inductive and
combined narcosis; is not toxic; may cause hypoxia in concentration about 80%.
DRUGS FOR INTRAVENOUS ANESTHESIA

Intravenous anesthetics are drugs for general anesthesia which are adminis
tered IV.
CLASSIFICATION
According to the duration of action
1. Long-acting (more than 60 min)
- Sodium oxibutyrate
2. Intermediate-acting (20-30 min)
- Thiopental-sodium
3. Short-acting (10-20 min)
- Ketamine (Ketamini hydrochloridum, Kalipsol)
4. Ultra-short-acting (3-5 min)
- Propofol
- Propanididum
According to the mechanism of action

1. GABA-ergic
2, Barbiturate-ergic^
- Thiopental-sodium
1. Opioid-ergic
- Ketamine
•1 O f an unknown mechanism o f action
Propofol
Propanididum.
CHLORIDE CHANNEL
Some IV general anesthetics, hypnotics, tranquilizers, and other CNS inhibitors
realize their effects by interaction with receptors o f C l' channels (fig. 9.6).
cr
Fig. 9.6. Cloride channel (adaptedfrom R. Finkel etal., 2008).
SODIUM OXIBUTYRATE
By its chemical structure, the drug is the analogue o f GABA (natural inhibiting
neurotransmitter).
Pharmacokinetics
is administered IV, IM, orally
begins to act in 5-7 min after IV administration
acts during 2-4 hrs
is completely metabolized in the body. a
Sodium oxibutyrate stimulates GABA-receptors o f C lchannels (fig.9.7).
A result is the opening o f C l'channels and an increase in Cl" influx into
the cell.
Increased C f concentration leads to the hyperpolarization o f the cell mem
brane and more difficult depolarization.
These processes result in the reduction of neurons excitability, sleep, and
general anesthesia.
Pharm acodynam ics

General anesthesia
• A sedative action
• A hypnotic action
• An anti-seizure action
• An antihypoxic action
A nootropic action (after a long-term treatment).
^ Stim ulation o f G A B A -receptors ^

u
^ O pening o f C l channels ^
V
( ft C l entry into the cell y
H yperpolarization o f cell m em
brane. D ifficult depolarization
r R educed excitability j
c
1
N A R C O SIS
J
Fig. 9.7. M echanism o f action o f sodium oxibutyrate.
Side-effects
The drug is not toxic, but may cause hypokalemia.
t*

Thiopental sodium is administered IV; begins to act in 1-3 min; acts during
20-30 min; is destroyed in microsomes o f the liver; is accumulated in the fat tissue;
stimulates barbiturate receptors o f CL-ion channels; displays a rapid onset o f ac-
Iion; has potent anesthesia, poor analgesia, and little myorelaxation; has a hypnotic
action; is used for the induction to narcosis, general anesthesia in short-term surger
ies and diagnostic investigations; may cause the suppression of respiration, apnea,
hmnehospasm, laryngospasm, hypotension, arrhythmia, liver lesions, lowering of the
hotly temperature, thrombophlebitis; is contraindicated in the heart failure, bronchial
nxlhma, diseases o f the upper respiratory pathways, shock, acidosis.
Ketamine is administered IV, IM; begins to act in 30-60 sec after the admin
istration; acts during 15-30 min; may be administered repeatedly in a lower dose;
stimulates different types of opioid receptors, serotonin receptors, GABA receptors,
cholinoreceptors, and adrenoceptors; causes “dissociative narcosis”; causes general
anesthesia accompanied by strong analgesia during narcosis and after it (6-8 hrs);
stimulates blood circulation (increases the heart rate, a minute volume of the heart
and BP); does not inhibit respiration; does not cause myorelaxation; does not inhibit
reflexes; has an psychotomimetic action at the start and at the end o f narcosis; may
cause postoperative hallucinations; is indicated for short-term surgeries, inductive
narcosis; diagnostic investigations, endoscopy, cateterization o f the cavities o f the
heart; is suitable under the conditions o f shock; may be used in children; causes such
side-effects as muscles regidity, block o f upper respiratory pathways, psychomotor
excitement; is contraindicated for patients with hypertension and disturbances of
cerebral blood circulation.
Propanididum is administered IV; begins to act in 10-30 sec after the admin
istration; acts during 3-5 min; is metabolized by cholinesterase in blood; causes
general anesthesia; increases the rate of respiration and the heart rate at the beginning
o f narcosis; decreases BP at the beginning o f narcosis (insignificantly) without the
depressing of the myocardium; is used for short-term surgeries, diagnostic investiga
tions, and painful bandagings; may cause vomiting, nausea, headache, hypersalivation,
thrombophlebitis, anaphylaxis due to the liberation o f histamine.

№ 1. The III stage o f general anesthesia (a stage o f surgical anesthesia) is mani
fested by all, except:
A. 4 planes o f its development
B. Excitement
C. A progressive a decrease in the muscular tone
D. A progressive a decrease in reflexes
E. Stability o f BP (at planes 1-2).
№ 2. Only one IV general anesthetic has antihypoxic and nootropic properties:

A. Ketamine
B. Propofol
C. Sodium oxibutyrate
D. Kalipsol
E. Thiopental-sodium.
i It.ipU'r 9. D R U G S F O R G E N E R A L A N E S T H E S IA 99
№ 3. Nitrous oxide is characterized by the following properties:

A, Good analgesia
II. Good anesthesia
( ’. Poor muscle relaxation
I). High liver toxicity
!i. Usage in obstetrics.
№ 4. Ketamine is:
A, A long-acting general anesthetic
H. An increasing cardiac output
( ’. Producing profound analgesia
I). Not abolishing reflexes
E, Used for short operations.
№ 5. Lowering o f BP has been developed during the surgery under the combined
Hcm-iiii anesthesia including halothane. The anesthesiologist chooses Mesatonum
lot die correction of the patient’s condition because adrenaline or noradrnaline are
i tiuhnindicated in this case. What is the ground of such contraindications?
A. I Ialothane’s liver toxicity
IL llalothane’s neurotoxicity
C' A combined action o f general anesthetics
1> I lalothane’s ability to dilate blood vessels
I The sensibilization o f the myocardium to catecholamines.
Answers:
N" 1 B; № 2 - C; № 3 - A, C, E; № 4 - B, C, D, E; № 5 - E.
a. A ETHAN0L- HYPNOTICS,
c 1 1 1 ANTI-EPILEPTIC AND
O i l # ANTIPARKINSONIAN DRUGS
ETHAN O L
(Alcohol, Spiritus aethylicus)
Ethanol’s chemical structure is C2H5OH. It is a water and lipid-soluble liquid
with a specific odor.
Pharmacokinetics
is applied topically, IV, orally, or by inhalation
after the oral administration, it is absorbed in the oral cavity, in the stomach
(less than 20% o f a dose), in the small intestine (80% o f administered dose)
penetrates CNS and the placenta barrier
is metabolized in the liver (fig. 10.1)
is excreted with urine and with air.
Pharm acodynam ics

Ethanol has local and resorptive actions.
Local action o f ethanol

The inhibition o f oxidoreductases
( hupter 10. ETHANOL. HYPNOTICS. ANTI-EPILEPTIC A N D ANTIPARKINSONIAN DRUGS 101
• The dénaturation o f proteins

The irritation o f sensitive nerve endings, local hyperemia
• Alcohol vapor changes the surface tension of the surfactant in the lungs.
I'lTeCtS
an antiseptic action
* a disinfective action
» an irritating action
a tannic effect
4 an antifoam action (after inhalation).
Im lien tion s to to p ica l a p p lica tio n
The processing of the surgeon’s hands and the surgical area (70%)
The processing o f instruments (95%)
Compresses (40%)
The inhalation in the mixture with oxygen in pulmonary edema
Preparing alcohol solutions and tinctures.
Resorptive action o f ethanol

M tu'huiiisui o f action
l ilhanol acts as inhalation general anesthetic with a narrow safety margin.
* It is an energy substrate for the organism (fig. 10.1).
ft fieri»
an anxiolytic action
* an anti-shock effect
• Ihe stimulation of energy metabolism
an increase in BP
4 an increase in heat irradiation
4 changes in gastric secretion (till 20% -stimulation, about o f2 0 % - suppression)
a diuretic action resulting from the inhibition of vasopressin secretion
an antidote action.
Indications to IV and oral adm inistration

• Shock (20%, IV)
Abscess or gangrene o f lung (20%, IV)
Cachexia (20%, IV)
Producing sclerosis in the varicose vein (70%, inside the pathological vein)
Alcoholizing o f nerves (inside the nerve at the surgery)
Diagnostics o f the gastric function (10%, orally)
• Acute poisoning with methanol (20%, IV).
Acute poisoning with ethanol

M ain signs: E m ergency help:
a specific odor the lavage o f the stom ach w ith a
euphoria, excitem ent, then sleeping and com a solution o f potassium p erm anga
hyperem ia o f the face, th en paleness nate
a decrease in BP analeptics (B em egridum )
the suppression o f respiration glucose, insulin, and vitam ins
hyporeflexia preparations (IV)
hypoterm ia nootrops (pyracetam , IV).
unvoluntary urination.
A lcoh ol abuse (alcoholism)

It is tolerance and physical/psychological dependence (due to the participation
o f acetaldehyde in the synthesis o f opioid peptides).
M ain disorders in the organism:
- Alcohol encephalopathy
- Alcohol polyneuritis
- Alcohol myocardiopathy
- Alcohol cirrhosis
- Hypoacidic gastritis
- Impotency in men
- A negative influence on the fetus in pregnant women.
Abstinence is manifested as alcohol delirium.
Treatment o f alcoholism
The therapy o f alcohol abuse is carried out by the production o f a conditioned
reflex to the alcohol, combining its usage with such drugs as Emetine hydrochloride
or Teturam (Disulfiram) (fig. 10.2). Disulfiram blocks acetaldehyde dehydrogenase,
inhibits alcohol metabolism with the accumulation o f toxic acetaldehyde. Nausea,
vomiting and other disturbances caused by this process are the basis o f negative
reflex to alcohol.
I h.tpter 10. ETHANOL. HYPNOTICS. ANTI-EPILEPTIC A N D ANTIPARKINSONIAN DRUGS 103
D ISU L F IR A M
Ethanol
> A cetald eh yde A cetate
Inhibition o f acetaldehyd e d eh y
drogenase
A cetald eh yde accu m ulation ■=>
N ausea, vom itin g, -0- BP, heart
ache, sense o f aw e =>
N egative reflex on alcohol
Fig. 10.2. M echanism o f action o f disulfiram .
HYPNOTICS
Hypnotics are the drugs for the treatment of insomnia. They induce the onset
ol sleep and maintain it. Normal sleep is characterized by two stages: REM-sleep
(Kapii! Eye Movement Sleep) and NREM-sleep (Non-Rapid Eye Movement Sleep).
I lie slate o f sleep differs from the waking state by the activity o f neurotransmitters
In llic brain (fig. 10.3).
Nnurons with
li«n»mltters:
I llnlmnine —
Acutylcholine—■
u lulnm ate —
N m splnephrine
UAHA ...
Fig. 10.3. Neurotransmission in the brain in the waking state and NREM sleep
104 PH ARM ACO LO G Y, V. M. Bobyrov,T. 0. Devyatkina, 0, M .Vazhnicha,V. M. Khristyuk
CLASSIFICATION
1. Barbiturates
- Phénobarbital
- Barbital
- Ethaminal (Aethaminalum-natrium)
2, Benzodiazepines
- Nitrazepam
3. Aliphatic compounds
- Chloral hydrate
- Bromisovalum
4, Other preparations
- Zolpidem
- Zopiclone
PHENOBARBITAL
It is a derivative of the barbituric acid (fig. 10.4). The substance is not soluble
in water, but solubility is increased in alkalic pH.
9
Fig. 10.4. C hem ical structure o f phénobarbital.
Pharm acokinetics
is taken orally
is absorbed in the small intestine
is strongly bound to proteins in plasma
is metabolized in microsomes o f the liver
is the inductor o f microsomal oxidation
( h.ipter 10. ETHANOL. HYPNOTICS. ANTI-EPILEPTIC A N D ANTIPARKINSONIAN DRUGS 105
is accumulated (material accumulation)

• starts to act in 30-60 min after the administration and acts during 6-8 hrs,
stays in the body during 1-2 days.
• The drug binds to barbiturate receptors o f chloride channels.
That results in enhancement o f GABAA-receptors’ activation and opening
o f chloride channels.
• An increase in the CT influx leads to the membrane hyperpolarization, dif
ficult depolarization, and the inhibition o f neuron functions,
Pharmacodynamics
* a hypnotic action with the change in normal sleep structure (inhibition of
REM-sleep)
a sedative action
• an anti-epileptic action
* the potentiation o f the effect o f other drugs inhibiting CNS.
Indications
» Insomnia
* Epilepsy with grand mal
• Ictrerus in newborns
* As the ingredient o f combined sedative preparations
* As the ingredient o f combined analgesic preparations.
Side-effects
I, The after-action syndrome (weakness, drowsiness, apathy, slow motor
icm lion in the morning)
& The return-syndrome after rapid cancellation o f the drug
1 Tolerance due to the induction o f microsomal oxidation (fig. 10.4)
•1 Drug dependence
5 Changes in pharmacokinetics o f other drugs due to the induction o f micro-
timml oxidation (fig. 10.4)
(> The suppression of respiration
/ I lypotension
H I,iver lesions.
Contraindications
Liver and renal diseases, hypotension, intermitted purpura, age about 60 or till
10 years old, pregnancy.
The drug should not be used in patients whose job needs quick motor reaction,
as well as for long treatment.
B A R BITU R A TES
Tolerance
Induction
o f m icrosom al C hanges in pharm acokinetics o f
oxidation in co-adm inistered drugs
the liver
C ontraindication for the

patients w ith interm itted purpura
M ETABO LITES
Fig. 10.4. Inhibition o f m icrosom al oxidation by phcnobarbital and its result.
Acute poisoning with barbiturates

M ain signs: E m ergency help:
- sleep, com a - the lavage o f the stom ach
- hyporeflexia - activated charcoal
- a decrease o f the m uscles tone - laxatives (m agnesium sulfate)
- suppression o f respiration - hem odilution and forced diuresis
- hypotension - hem odialysis
- hypotherm ia - alaleptic Bem egridum (antagonist o f barbiturates).

Nitrazepam is a benzodiazepine derivative; is the agonist of benzodiazepine
receptors o f Cl' ion channels; has a hypnotic action with minimal changes in the
normal sleeping structure; has anxiolytic, sedative, centra! myorelaxative and po
tentiative effects; is used in insomnia, neurosis, epilepsy, abstinence in alcoholics;
has less side-effects than phenobarbital (less tolerance, drug dependence, and return
syndrome); does not produce the activation o f liver enzymes.
Chloral hydrate is administered orally or rectally; is converted to trichloretha-
nol; has an anti-seizure and sedative action; is applied in seizures, insomnia, and
( h.ipter 10. ETHANOL. HYPNOTICS. ANTI-EPILEPTIC A N D ANTIPARKINSONIAN DRUGS 107
severe cough in children; irritates mucous membranes (is used with the addition o f
March mucus).
Bromisovalum contains bromine; has a hypnotic and sedative action; is weaker
limit other hypnotics; is used rarely.
Zolpidem , zopiclone are modern preparations; are not benzodiazepines, but
modify benzodiazepine receptors; do not influence the normal structure of sleep; do not
produce an anticonvulsant action, myorelaxation, tolerance, and withdrawal effects.
ANTICONVULSANTS
EPILEPSY AND ITS PHARMACOTHERAPY

Epilepsy is the disease of the brain with attacks of seizures. There are some
types o f epilepsy (fig. 10.5).
I' ij>. 10.5. T ypes o f epilepsy as the basis for differential pharm acotherapy.
Principles of the treatment of epilepsy

The choice o f the drug according to the type o f epilepsy
A long-term treatment
The oral administration o f drugs
An equal dose o f a new drug, if the change o f preparation is needed
Slow cancellation o f the drug.
ANTI-EPILEPTIC DRUGS
Anti-epileptics are drugs o f a different chemical structure which prevent attacks
o f epilesy (fig. 10.6).
Carbamazepine Phenytoin Phénobarbital Ethosuximide
Fig. 10.6. Chemical structure of anti-epileptics.
CLASSIFICATION
1. Preparations for the treatment o f epilepsy with grand mal
- Phénobarbital
- Phenytoin (Dipheninum)
- Carbamazepine (finlepsin)
- Valproic acid
- Sodium valproate
2. Preparations for the treatment o f epilepsy with petit mal
- Valproic acid
- Clonazepam
- Ethosuximide.
Most excitory nerve cells utilize glutamate and most inhibitory nerve cells
utilize GABA. Glutamate receptors comprise three subtypes, o f which
<h.tpler 10. E T H A N O L HYPNOTICS. ANTI-EPILEPTIC A N D ANTIPARKINSONIAN DRUGS 109
the NMDA subtype has he greatest therapeutic importance. N-metyl-D-

aspartrate (NMDA) is a synthetic selective agonist. The stimulation o f these
receptors permits the entry of both N a+ and C aîn to the cell.
Phenytoin, phénobarbital, and a lamotrigine inhibit release o f glutamate
(fig. 10.7).
Excitatory neuron
Inhibition of
glutamate
release:
phenytoin,
lamotrigine
phen; Darh>?3! :
Na+-channel Enhanced
inactivation:
\
\ carbamazepinei
valproic acid ]
■ ahenytoin |
Gabamimetics: !
benzodiazepine
barbiturates
vigabatrin
tiagabine
gabapentin
Fig. 10.7. Sites of action of antiepileptic drugs (byH. Lüllmann, 2000).
• Benzodiazepins and phénobarbital increase the inhibition by the release of

physiological amounts o f GABA and its interaction with G ABAa receptors
o f chloride channels.
Valproic acid decreases GABA catabolism by the inhibition o f GABA
transaminase.
* Other preparations realize their actioin by antagonism to glutamate, a direct
GABA-mimetic action, regulation o f GABA re-uptake.
110 PH ARM ACO LO G Y. V. M. Bobyrov.T. 0. Devyatkina, 0. M.Vazhnicha,V. M. Khristyuk
PHENYTOIN
is taken orally, is quickly absorbed in the GI tract, is metabolized in the
liver, stays in the organism for a long time, is excreted by urine and bile,
accumulates
promotes carrying out N a+ from neurons; decreases the Ca++ contain and
energy processes in the epileptic focal area; increases GABA concentra
tion, as a result, suppresses the induction and irradiation o f excitement in
the motor areas in the brain
has an anti-epileptic action; an anti-arrhythmic action; a weak sedative action
is used in epilepsy with grand mal, tachyarrhythmia (especially in acute
poisoning with cardiac glycosides), M enier’s disease
may cause side-effects, such as vertigo, ataxia, tremor, nystagmus, diplopia,
respiratory disturbances, an increase o f the body temperature, skin rash,
hyperplastic gingivitis.

Carbamazepine is the agonist o f benzodiazepine receptors of CL'ion channels;
has anti-epileptic and anxiolytic effects, decrease pain syndromes and vestibular
disturbances; is indicated in epilepsy with grand mal, petit mal, mixed forms, hyper
kinesis, neuralgia o f n.trigeminus, M enier’s disease; may cause nausea, vomiting,
drowsiness, ataxia, accomodation disturbances.
E thosuxim ide suppresses polysynaptic reflexes o f the spinal cord, decreases
neurons lability, decreases the irradiation o f impulses from the epileptic area; is used
for the treatment o f epilepsy with petit mal; may cause such side-effects as weakness,
vertigo, dyspepsia, disturbances of hemopoiesis and kidneys.
Sodium valproate (or the valpoic acid) inhibits GABA transaminase and pro
duces accumulation o f GABA in the brain, is used for the treatment o f grand mal,
petit mal, mixed and local forms o f epilepsy; has such side effects as drowsiness,
ataxia, dyspepsia, decreasing o f blood coagulation.
PREPARATIONS FOR EM ER G EN CY
HELP IN A SEIZURES A TT A C K
Diazepam (IV or 1M )
Sodium oxibutyrate (IV or 1M)
Magnesium sulfate (IV or IM)
• Chloral hydrate (rectally)
Chapter 10. E T H A N O L HYPNOTICS. ANTI-EPILEPTIC A N D ANTIPARKINSONIAN DRUGS 111
Tubocurarine (IV,under the conditions o f artificial lungs ventilation)

General anesthesia by halothane.
PARKINSON’S DISEASE AND ITS PHAR M ACO TH ER APY

The main signs of P arkinson’s disease are tremor, muscular rigidity, hypoki
nesia, hypersalivation. The main disorders in CNS are lesions in striatum resulting in
(he diminished amount o f dopaminergic neurons in the substantia nigra. This leads
lo the onset o f dopamine/acetylcholine imbalance (fig. 10.8).
The ways o f the pharm acological m anagem ent o f P arkinson’s disease are:
1. The stimulation of dopaminergic processes with
- Levodopa
- Nacom
- Midantan
2, The inhibition of central cholinergic processes by
- Cyclodol
Tropacine.
Parkinson’s disease ° f acetylcholine
Fig. 10.8. Main disorders in CNS resulting in Parkinson’s disease

(by H. Liillmann, 2000).
Levodopa is the precursor of dopam ine (fig. 10.9). It is administered with the pur
pose to replenish the dopamine deficiency in specific regions o f the brain. Dopamine
Ihelfdocs not cross the blood-brain barrier but levodopa is actively transported into
Ihe CNS and is converted to dopamine in the brain. Large doses o f levodopa are
required, because much o f the drug is decarboxylated to dopamine in the periphery,

resulting in side effects. Levodopa avoids hypokinesia; has a little action on muscles
regidity and tremor and is used for the treatment of Parkinson’s disease. It may cause
dyspepsia, orthostatic hypotension, arrhythmia, psychic disturbances. It is significant
to know the following drugs interactions observed during the intaking o f levodopa:
vitamin B(>decreases the effect o f levodopa; MAO inhibitors administered together
with levodopa may cause hypertension.
Nacom is a combined preparation containing levodopa and carbidopa which
decreases the metabolism o f levodopa in peripheral tissues and enhances the effec
tiveness o f preparation (fig. 10.9).
M'ulantan blocks glutamate receptors in the cortex (fig. 10.9), decreases their
influence on the neostriatum, protects neurons in substantia nigra, increases the
sensitivity o f dopamine receptors to the mediator; avoids hypokinesia and muscles
regidity; has antiviral activity: is used for the treatment o f Parkinson’s disease and
symptomatic parkinsonism; may cause such side-effects as insomnia, hallucinations,
headache, orthostatic hypotension, dyspepsia.
L-Dopa Carbidopa
Inhibition of dopa-
decarboxylase
Dopamine precursor
Amantadine
NMDA
receptor:
Blockade
of ionophore:
attenuation
of cholinergic
neurons
Acetylcholine antagonist
Fig. 10.9. C hem ical structure and m echanism o f action o f levodopa,

carbidopa, m idantan, and benzatropine (by H .Liillmann, 2000).
Chapter 10, E T H A N O L HYPNOTICS. ANTI-EPILEPTIC A N D ANTIPARKINSONIAN DRUGS 113
Cyclodol blocks cholinoreceptors in basal ganglia o f the brain; avoids hypoki

nesia, regidity, and hypersalivation; is used for the treatment o f Parkinson’s disease
and symptomatic parkinsonism; may cause a peripheral M-cholinoblocking action.
Benzatropine has a similar mechanism of action (fig. 10.9).

№1. Hypnotic with benzodiazepine structure is only:
A. Phénobarbital
B. Zolpidem
C. Zopiclon
D. Thiopental sodium
E. Nitrazepam.
№ 2. The concentration o f ethanol for IV administration in cachexia is:

A. 40%
B. 96%
C . 70%
D. Absolute ethanol
E. 20%.
№ 3. Phenytoin exerts the following useful effects:

A. Anti-epileptic
B. Gum hypertrophy
C . Coarsening of facial features
D. H yperglycem ia"
E. Anti-arrhythmic.
№4. Ethanol is:

A. A long acting general anesthetic
B. A neuronal depressant with local antimicrobial action
C . Causing acute and chronic poisonings
D. Is used mainly as antiseptic
li. Used for short operations in a polyclinic.
№ 5. An antiparkinsonian drug influencing dopaminergic processes in basal

Bimgiia of the brain was prescribed to patient suffering from Parkinson’s disease.
114 PH ARM ACO LO G Y. V. M. Bobyrov,T. 0. Devyatkina, 0. M.Vazhnieha, V. M. Khristyuk
It is known, that this preparation also has antiviral activity and may be used for the
prophylaxis o f influenza. Which o f the listed drugs was prescribed?
A. Levodopa
B. Nacom
C. Cyclodol
D. Amantadine (midantan)
E. Carbidopa.
Answers:
№ 1 - E; № 2 - E ; № 3 - A, C, E; № 4 - B, C, D; №5 - D,
£ AI AI
g
NEUROLEPTICS.
ANXIOLYTICS.
o i l SEDATIVES. LITHIUM SALTS
PSYCHOTROPIC DRUGS
Neuroleptics, anxiolytics, and sedatives are drugs for the treatment o f psychic
disorders o f different severity. Neuroleptics (major tranquilizers) are the strongest
among these preparations and have an antipsychotic action (fig.l 1.1). Anxiolytics
F ig. 11.1. M ain groups o f psychotropic drugs and their potency.

116 PH ARM ACO LO G Y. V. M. B obyrovJ. 0. Devyatkina, 0. M.Vazhnicha, V. M. Khristyuk
(minor tranquilizers) are characterized by anxiolytic and sedative effects. Sedative

drugs are the least potent and have only a sedative effect. Lithium salts are specific
agents to treat mania.
ANTIPSYCHOTIC DRUGS
SCHIZOPHRENIA
Schizophrenia is the type o f psychosis characterized by delusions, hallucina
tions, thinking and speech disturbances. The illness often initially affects people
during adolescence and is a chronic and disabling disorder. It has genetic component
and reflects some biochemical abnormality in the brain, possibly the overactivity of
the mesolimbic dopaminergic neurons.
NEUROLEPTICS
Neuroleptics are drugs which are used to treat schizophrenia and some other
psychotic states, such as manic states and delirium.
CLASSIFICATION
A. Typical neuroleptics
1. Phenothiazines
- Chlorpromazine (Aminazinum)
- Trifluoperazine (Triftazinum)
- Flunazine (Phthorphenazinum)
2. Butyrophenones
- Flaloperidol
- Droperidol
3. Thioxanthenes
- Chlorprothixene
B, Atypical neuroleptics
1. Dibenxzodiazepines
- Clozapine
2. Benzamides
- Sulpiride.
Chapter 11. N E U R O L E P T IC S . A N X IO L Y T IC S . S E D A T IV E S . L IT H IU M S A L T S 117
DISTINGUISHES BETW EEN

TYPICAL AND ATYPICAL NEUROLEPTICS
Typical neuroleptics block D,-, D,-, I I - and D4-dopamine receptors; cause
extrapyramidal disturbances (drug parkinsonism)
A typical neuroleptics block 5-HT,- receptors, a 2-adrenoceptors, D4-dopamine
receptors, have a weak action on D.-dopamine receptors, do not cause extrapyramidal
disturbances.
CH3
/
c h 2- c h - c h - n ^
N ^ „ Cl CH3
^ s ^
Fig. 11.2. C hem ical structure o f chlorprom azine.
Pharmacokinetics
• is administered orally, IM, IV
is absorbed in the G1 tract, but absoption is poor
maximal concentration is determined in 2-4 hrs
• binds to albumins in the blood plasma (95-98%)
• is the inductor of microsomal oxidation
is excreted by urine, bile, and mother’s milk
acts during 6-8 hrs, T 'Æ= 30 hrs
• accumulates.
Mechanism of action
Chlorpromasine blocks dopamine receptors; exerts preference for D,-dopamine
ti'icplors, prevents the interaction of dopamine with a receptor, decreases an intracel-
lulat response (fig. 11.3).
118 PH ARM ACO LO G Y. V. M. B o b y ro v ,! 0. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
It also b lo ck s s e ro to n in re
c e p to rs , c h o lin e r g ic r e c e p to r s ,
a-adrenoceptors, H ^histamine recep
tors (fig. 11.4).
Chlorpromazine acts in the mes-
olimbic system, hypothalam us, ex-
trapyramidal system, trigger zone of
the emetic center, ascending reticular
system of the brain. It has a peripheral
action (antimuscarinic, anti-adrener-
gic, and antihistamine).
Pharm acodynam ics

an antipsychotic action (a m
decrease in hallucinations Neuroleptic r,
■I
and agitation) drugs
Dopamine
an anxiolytic action (a de
crease in anxiety and stress)
a sedative action (a decrease
in restlessness)
a decrease in psycho-motor
excitement
Dopamine
ahypnotic action receptor blocked
an anti-seizure action
cataleptic effect (absence
o f active movements under DECREASED
the conditions o f the normal INTRACELLULAR
RESPONSE
muscle tone)
an anti-emetic action (a de Fig. 11.3. Dopamine-blocking
crease in nausea and vomit mechanism of action of neuroleptics
ing caused by cancer chemo (byR. Finkel etal., 2008).
therapy or radiation)
an antihypertensive effect
hypothermia and poikilothermia (lowering in high body temperature, as
well as normal temperature)
a potentiative action
weak anti-inflammatory and anti-allergic actions
Chapter I t , N E U R O L E P T IC S . A N X IO L Y T IC S . S E D A T IV E S . LIT H IU M S A L T S 119
C H L O R P R O M A Z IN E
■0 £ $ £
d o p a m in e a -a d re n o - se ro to n in H ^ h ista m in e M -c h o lin o -
re ce p to c e p to r re c e p to r recep to r re c e p to r
Fig. 11.4. R eceptors w hich are blocked by chlorprom azine.
Indications
Psychosis, schizophrenia
Psycho-motor excitement
Seizures attack
• Premedication
Severe vomiting o f central origin
Hypertensive crisis
Hyperthermia
Hibernation (a decrease in normal body temperature during surgeries on
the brain or on the heart)
Combined therapy o f pain syndromes
Skin diseases accompanied by severe itch.
Side-effects C o n tra in d ic a tio n s

Irritation in the place o f injection 1. D iseases o f the liver and
Pain in the stom ach kidney
Irritation o f the skin an d jm ico u s m em branes 2. D iseases o f blood
C onfusion, blurred vision, dry m outh, hyposecrction 3. H ypothyroidism
in the stom ach, constipation, urinary retention (due to 4. T hrom boem bolism
M -cholinoblockage) 5. O rganic diseases o f the
H ypotension, orthostatic reactions, lightheadedness brain and spinal cord
(due to the blockage o f a-adrenoceptors) (traum a, cancer, insult)
L iver lesions, icterus 6. G astric ulcer
inhibiting in hem opoiesis (leukopenia, agranulocytosis) 7. Pregnancy and lactation.
D erm atitis, phototoxicity
Parkinsonian sym ptom s, such as akathisia and tardive
dyskinesia (due to the blockage o f dopam inoreceptors
in the nigrostriatal pathw ay)
It). Neuroleptic syndrome (apathy, depression, parkinsonism)
11. T he aggravation o f acute agitation accom panying

w ithdraw al from alcohol
12. T he aggravation o f epilepsy
13. A m enorrhea, galactorrhea, infertility, im potence (due
to the depression o f hypothalam us)
14. A llergy
15. Tolerance.
PECULIARITIES OF OTH ER PREPARATIONS

Typical neuroleptics
Trifluorperazine (Triftazinum ) contains fluorine; is more active in its anti
emetic action and in the influence on the extrapyramida! system; is less active in
potentiation, anti-seizure, and antihistamine actions; may cause sedative or stimulating
effect according to the form o f the disease.
Flunazine (Phthorphenazinum ) contains fluorine; has strong antipsychotic
and anti-emetic actions; manifests a stimulating action in lower doses and a sedative
action in bigger doses; is effective for the treatment o f long durative schizophrenia;
may be used in neurosis (lower doses).
Haloperidol is from butyrophenone derivatives; has strong antipsychotic, po
tentiative, anti-emetic and sedative actions, denominated catalepsy; is effective for
the treatment o f acute psychosis; may be used for neuroleptanalgesia; often causes
extrapyramidal disturbances.
Droperido! has a strong and short action; has no cholinoblocking activity; has
anti-shock, anti-arrhythmic, antihypertensive actions; strong catalepsy; is used for
neuroleptanalgesia, before, during and after operations, in shock and myocardial
infarction.
C hlorprothixene is a thioxanthene derivative; has a sedative action, decreases
depression; has weak anti-seizure effect; does not cause catalepsy; is used in psy
choses accompanied by depression, in neurosis (lower doses).
Atypical neuroleptics
Clozapine (Asaleptin) has an antipsychotic action with sedation; does not cause
catalepsy and extrapyramidal disturbances; does not cause apathy; is effective in the
resistance to other preparations.
Sulpiride has a strong anti-emetic action and a weak cataleptic action; has no
sedative, anti-seizure and potentiative effects; has an antidepressive action; is used
for the treatment o f psychic diseases accompanied by apathy, as well as o f psycho
somatic diseases.
CO N CEPT ABO UT N EUR O LEPTAN ALG ESIA

Neuroleptanalgesia is the kind o f general anesthesia when neuroleptic (droperi-
dol) and narcotic analgesic (fentanyl) are administered together (IV). In this case
neuroleptic produces psychic suppression and a narcotic analgesic causes abolishing
o f pain. Co-administered, they display a synergic action.
ANTI-ANXIETY DRUGS
ANXIETY
A nxiety is the state o f tension, apprehension or uneasiness. The symptoms
o f severe anxiety are mental disturbances accompanied by tachycardia, sweating,
trembling, palpitation. Episodes of mild anxiety are common life experiences and
do not warrant treatment. The symptoms o f severe or chronic anxiety may be treated
with anti-anxiety drugs.
ANXIOLYTICS
Anxiolytics are drugs to treat anxiety and stress. They are also named m inor
tranquilizers, ataractics.
CLASSIFICATION
1. Benzodiazepines
- Chlordiazepoxide (Chlosepidum)
- Diazepam (Sibaspnum)
- Phenazepam
- Medazepam (Mezapam, Rudotel)
- Gidazepam
2. Preparations o f another chemical structure
- Buspirone
- Benactyzime (Amizilum)
- Meprobamate (Meprotanum).
Antagonist of benzodiazepines is Flumazenil.
CLORDIAZEPOXIDE
The drug is a benzodiazepine derivative (fig. 11.5).
1 A
122 PH ARM ACO LO G Y. V. M. Bobyrov.T. 0. Devyatkina, 0. M.Vazhnicha,V. M. Khristyuk
NH-CH,
Cl
Fig. 11.5. C hem ical structure o f chlordiazepoxide.
Pharmacokinetics
is administered orally, IM, IV
• is absorbed in the G I tract
penetrates CNS
is excreted by urine
has a long-durative action, T!4= 24-48 hrs.
Benzodiazepine-receptor is the part o f the benzodiazepine-GAB A-chloride
ion channel complex.
The drug binds to benzodiazepine receptors o f Cl- ion channels and opens
them (fig. 11.6).
Cl" ions entry is increased that leads to hyperpolarization of cell membranes.
Depolarization gets worse and decreasing o f neurons excitement in the
limbic system and midbrain developes. It results in an anxiolytic action.
Pharm acodynam ics

An anxiolytic action (a decrease in anxiety, panic, and stress)
A sedative action
A hypnotic action
A central myorelaxative action (due to action on spinal polysynaptic reflexes)
An anti-seizure action
• A potentiative action (a drug addition, if analgesics, general anesthetics, or
other CNS inhibitors are administered together with this drug).
Chlordiazepoxide
Inhibition of / GABA=
Y-amino-
excitation
butryc acid
s— ' GABA-receptor
GABA-gated Cl -channel
Fig. 11.6. Mechanism of action of chlordiazepoxide (by H. Liillmann, 2000).
Indications
• Neuroses
Stress, emotional overstrain
Sleeping disorders induced by emotional overstrain
• Neurological diseases with muscle spasticity
Seizures
Abstinence in chronic alcoholics
• Psychosomatic diseases
Premedication. *•
S ide-effects C on traind ications

1. W eakness 1. Jobs that needs increased attention
2. D row siness 2. M yasthenia
3. A decrease in attention and rapidness o f 3. D iseases o f the liver and kidney
m otor reactions 4. Pregnancy.
4. A taxia
5. Skin itch
6. A m enorrhea
7. Im potence
H D rug addition
D rug dependence.

Diazepam (Sibazonum) is administered orally, 1M, IV; maximal concentration
after oral administration develops in 30-90 min; elimination is characterized by two
phases (the 1st short phase with distribution o f the drug in tissues during 3 hrs and
the 2nd long-lasting phase with T'A= 48 hrs); is more potent than clordiazepoxide,
especially in an anti-seizure effect; causes a decrease in night gastric secretion and
arrhythmia; is suitable to treat a seizure attack; may be used in combined therapy of
ulcerative disease and heart arrhythmia.
Phenazepam is administered orally; maximal concentration is in 1-2 hrs; has
T'A = 6-10 hrs; is stronger than clordiazepoxide or diazepam; has a strong hypnotic
action and muscle relaxation.
M eduzepam is taken orally; is less potent, but does not cause hypnotic effect
and myorelaxation (so named “day-time” tranquilizer); may be used in patients who
need increased attention for their jobs.
G id a zep a m is “day-time” tranquilizer; is taken by mouth; begins to act in 30-60
min and acts during 1-4 hrs; has T'A = 87 hrs; has an anxiolytic action, psychostimu-
lating and antidepressant effects; has not a hypnotic effect; is well tolerated; is used
to treat neuroses accompanied by asthenia and depression.
C O N C EP T A B O U T ATA R AC TA N ALG ESIA

The ataractanalgesia is the kind o f general anesthesia when the tranquilizer
and the narcotic analgesic are administered together (IV).
SEDATIVES
Sedatives are the drugs to treat restlessness and light forms o f anxiety.
Classification
1. Non-organic preparations
- Sodium bromide
- Potassium bromide
2. Vegetable preparations
- Tincture from valerian
- Tincture from Leonurum
3. Combined preparations
- Corvalolum
- Valocormidum.
SODIUM BROMIDE
Pharmacokinetics
is taken orally in the form o f solution or mixture
quickly penetrates CNS
is excreted by urine, saliva, and sweat
excretion depends on the concentration o f chloride-ions in blood plasma
accumulates in the body.
Mechanism of action
It increases inhibition in CNS.
Effective dose depends on the type o f higher nervous activity.
Pharm acodynam ics

a sedative action (a decrease in restlessness and anxiety)
a hypnotic action
an anti-epileptic action.
Indications
Light forms of neuroses, neurasthenia, hysteria
Restlessness
Insomnia
Epilepsy
* Light forms of hypertension.
Side-effects
The accumulation of bromides results in bromism.
M ain signs:
- drowsiness, weakness, apathy, memory disturbances
- skin rash
- rhinitis
- cough.
Treatment:
- to drink much liquid
- sodium chloride with meals
~ diuretics, especially ethacrynic acid.
V E G E T A B L E PREPARATIONS
Sedatives o f vegetable origin are galenic preparations from medicinal plants,
such as valerian, Leonurum and some other plants (fig. 11.7).
They have common pharmacological properties:
are taken orally
the mechanism o f action is not known
the main effects are sedative, hypnotic, spasmolytic
the indications to use are light fonns of neurosis, neurasthenia, insomnia,
cardioneurosis, somatic diseases with neurotic syndrome, spasms of stomach
and intestine.
Fig. 11.7. Medicinal plants containing sedatives

A - Valeriana, B - Leonurum
COMBINED SEDATIVE PREPARATIONS

Corvalolum is a mixture for oral administration (drops for taking inside),
contains ethylic ester o f the bromine-isovalerianic acid, 2% o f phénobarbital, 3% of
mint oil, sodium hydroxide, alcohol, and water; has a sedative, spasmolytic and light
hypnotic action; is used in neuroses, spasms o f coronary blood vessels, tachycardia,
spasms in the gut.
Chapter 11. N E U R O L E P T IC S . A N X IO L Y T IC S . S E D A T IV E S . LIT H IU M S A L T S 127
Valocormidum contains tincture from valerian, tincture from the lily o f the
valley, tincture from Belladonna, sodium bromide, menthol, and distil water; is used
in neuroses accompanied by bradycardia.
DRUGS USED TO TR E A T MANIA
MANIA AND BIPOLAR (MANIC-DEPRESSIVE) DISORDER

M ania is an affective disorder characterized by elevated, expansive, or irrita
ble mood, accompanied by increased activity, pressure of speech, flight o f ideas,
decreased need for sleep, distractibility, or involvement in activities that have high
potential for painful consequences. Patients that cycle between depression and mania
have the diagnosis of bipolar affective disorder.
CLASSIFICATION
I. Lithium salts
- Lithium carbonate
- Lithium oxibutyrate
Other preparations
- Carbamazepine
Clonazepam
- Valproic acid.
LITHIUM C A R B O N A TE
' Pharm acokinetics

* is taken orally
is absorbed in the gut completely, but absorption lasts during 8 hrs
* maximal concentration develops in2-4 hrs
* does not bind to plasma proteins
* 95% o f the dose is excreted with urine and 5% - with sweat
* T '/a - 19 hrs
* therapeutic effect developes in 1-3 weeks after the start o f the treatment.
Mechanism of action
Lithium disturbs sodium transport and in such aw ay inhibits Ca-dependent
liberation o f norepinephrine and dopamine in synapses o f the brain.
Lithium salt also inhibits the re-uptake o f norepinephrine and dopamine.

At the same time it does not influence serotonin.
Pharm acodynam ics

a decrease in manic behavior
the stabilization o f mood, reduce in frequency and magnitude o f mood
swings
the prevention o f phase o f mania in patients with bipolar disorder.
Indications
Bipolar affective disorder (manic-depressive disease)
Manias
Side-effects
1. Weakness, tremor, ataxia, pseudotumor o f the brain, hyperreflexia, extrapy-
ramidal disturbances, headache, vision disturbances
2. Nausea, vomiting, diarrhea, abdominal pain, an increase in size of salivary
glands, dry mouth
3. Renal dysfunction (glucosuria, proteinuria, creatinuria)
4. Thyroid enlargement, hypo- or hyperthyroidism
5. Skin rash
6. Teratogenous action (congenital cardiac anomalies).
A small therapeutic index o f the drug necessitates frequent monitoring o f the

lithium level in blood serum.
T E S TS FOR SELF-CO N TR O L a
№1. Only one preparation in the list belongs to “day-time” tranquilizers:
A. Chlorpromazepine
B. Chlorprothixene
C. Chlordiazepoxide
D. Gidazepam
E. Diazepam.
№ 2. All o f the following are observed in patients taking neuroleptics, excepi:

A. Increased BP
B. Orthostatic hypotension
C. Parkinsonian symptoms
D. Altered endocrine function
E. Phototoxicity.
№ 3. Anxiolytics:
A. Are the drugs to treat a manic-depressive disorder
B. Are the drugs to treat panic and phobia
C. Bind to dopamine receptors in the brain
D. Bind to benzodiazepine receptors o f chloride ion channels
E. Act in the limbic system, midbrain, and hypothalamus.
№ 4. Lithium salts are characterized by:

A. Complete and durative absorption in the gut
B. Competition with sodium in cells o f the brain
C. A small therapeutic index
D. Minimal side-effects and low toxicity
E. The ability to prevent neurosis.
№ 5. A 60 year-old woman addressed her doctor complaining of side-effects

Which appeared during the treatment with chlorpromazine (Aminazinum). She was
Iroubled with tremor and disturbances o f movements. What is the mechanism o f
these side-effects?
A. The activation of hyppocampus
B. The inhibition o f reticular formation (c^-adrenoceptors)
C. The inhibition of neostriatum (D2-receptors)
I). The inhibition of hypothalamus
It. The inhibition o f neogortex.
Answ ers
№ 1 - D; № 2 - A; № 3 - B, D, E; № 4 - A, B, C; № 5 - C.
IM IIOmm
O
/ OPIOID (NARCOTIC)
ANALGESICS
PAIN SENSATION AND LIMITATION OF PAIN
Nociception
Pain is a signal about the danger for the organism. At the same time, it causes
discomfort, decreases the quality o f life, may be unbearable, may cause a pain shock.
Nociception is pain sensation. It includes sensative nerve endings, afferent
nerves, afferent pathways in the spinal cord, thalamus, and the cortex of the brain
(fig. 12.1).
Thalamus is the main collector of pain impulses. Strong nociceptive stimuli
irradiates on the medulla o f the brain resulting in a pain shock.
Nociception is realized in the following way. Nociceptive terminals of primary
sensory neurons are stimulated by noxious stimuli. Action potentials are generated,
pass along the peripheral afferent sensory fiber and arrive at junctions between the
peripheral afferent fibers and the spinal cord neurons in the dorsal horn. The ar
rival of the action potentials causes the opening o f voltage-gated Ca^channels in
the pre-synaptic membrane. An increased influx o f C a^causes vesicles containing
neurotransmitter to release their contents into the synaptic gap. Neurotransmitters
(glutamate, substance P) bind to receptors on the postsynaptic membrane. Activation
Chapter 12. O P IO ID (N A R C O T IC ) A N A L G E S IC S 131
Cerebrum Somatic sensory

cortex
Hypothalamus
Periaqueductal gray
matter
Mldbraln
Mid-medulla Nuclei in rostral

ventral medulla
nuclei
Cervical
spinal cord Dorsal hom
neurons
Fig. 12.1. Anatomy structures connected with nociception

(http://www.picsearch. com).
132 PH ARM ACO LO G Y. V. M. B obyrovJ. 0. Devyatkina, 0. M.Vazhnicha, V. M. Khristyuk
o f such receptors enables the efflux o f K+and influx o f C a^ and N a+ into the post-
synaptic cell that leads to the transmission o f impulses along the axons o f the spinal
cord neurons to the brain. Information about pain is received and processed by higher
centers in the brain and the individual perceives pain.
Antinociception
Antinociception is the limitation o f pain in the body. It is realized by opioid
receptors and their ligands.
The main subtypes o f opioid receptors are mu (p )-, kappa ( k)-, sigma (o), delta
(S)-receptors (fig. 12.2).
Fig. 12.2. Subtypes of opioid receptors and processes mediated by them.
They are located in CNS (brainstem, medial thalamus, spinal cord, hypothala
mus, limbic system), sensory nerve fibers and their terminals. Opioid receptors are
also located in peripheral tissues (myocardium, GI tract, immune organs, bones).
Ligands o f opioid receptors are endorphins, enkephalins, dynorphins.
Opioid receptors take part in the limitation of pain, limitation o f stress, regula
tion o f sleeping, and emotional behavior. They mediate respiration, cough, nausea,
vomiting, maintenance o f BP, pupillary diameter, stomach secretion (fig. 12.2).
The stimulation of opioid receptors results in the inhibition of adenyl cyclase
and a decrease in the cAMP content. Coupling o f receptors to G-proteins of K+chan
nels leads to the opening o f channels and hyperpolarisation. Coupling to G-proteins
o f C a^ channels leads to the inhibition o f these channels and a decrease in the Ca+t
influx (fig. 12.3).
( Iwpler 12. OPIOID (NARCOTIC) ANALGESICS 133
To reduce the level o f perceived pain, endogenous opioids are released by in-
Iri neurons in the dorsal horn in response to severe or persistent pain. The opioids bind
In ( i proteins associated with p type opioid receptors, with the following results: the
Inhibition of the presynaptic release o f glutamate and an increased K" conductance
m toss the postsynaptic membrane. These events prevent the transmission o f pain to
the higher centers (fig. 12.3).
To combat the severe pain, the administration o f exogenous opioids (e.g. mor
phine) mimics the effects of endogenous opioids at the p opioid receptor (fig. 12.3).
FI« 12.». Mechanism of action of endogenous opioids, exogenous opioids (morphine)

and their antagonists (naloxone) (by H. Lullmann, 2000).
OPIOID (NARCOTIC) AN ALGESICS

iiiulf>i’sics are drugs reversibly and selectively inhibiting pain in the body
w iiln iu i significant changing o f consciousness.
There are two groups o f analgesics:

opioid (narcotic) analgesics
• non-opioid (non-narcotic) analgesics.
Opioid analgesics are the drugs to relieve intense pain which mimic the action
o f endogenous opiopeptides and may cause drug dependence.
The disparities between opioids regarding efficacy and potential for dependence
reflect differing affinity and intrinsic activity profiles for the individual receptor
subtypes. There are strong agonists o f opioid receptors, partial agonists, and agonist-
antagonists of these receptors.
Strong agonists have high affinity for p-receptors, varying affinities for 8- and
k- receptors and low affinity for o-receptors.
Partial antagonists have low intrinsic activity.
Agonists-antagonists act as agonists on one subtype and as partial agonists or
as pure antagonists on another.
The abuse potential o f narcotic analgesics is determined by kinetic properties,
because development o f drug dependence is connected with rapid build-up o f the
brain concentration.
CLASSIFICATION OF OPIOID AN ALGESICS

AND THEIR ANTAGONISTS
A. Strong agonists o f opioid receptors
1. Natural compounds
- Morphine hydrochloride
- Codeine phosphate
- Omnoponum
2. Synthetic compounds
- Tremeperidine (Promedolum) ,
- Fentanyl
II M ixed agonists-antagonists and partial agonists o f opioid receptors
- Pentazocine
- Buprenorphine
- Nalorphine hydrochloride
C Analgesic with opioid and non-opioid mechanism o f action
- Tramadol hydrochloride
D. Antagonists o f opioid receptors
- Naloxone hydrochloride
- Naltrexone.
<httpioi M. OPIOID (NARCOTIC) ANALGESICS 135
MORPHINE
M orphine is an alkaloid of opium. O pium is a dried juice from unripe semen
t tipMili'H o f poppy (Papaver somniferum) (fig. 12.4). It contains more than 20 al-
kttlnuk Among them there are phenanthrene derivatives (morphine, codeine) and
Ui)(|utnuline derivatives (papaverine).
Fig. 12.4. Papaver somniferum containing morphine.
Mtuphine is a phenanthrene derivative (jig. 12.5).
Fig. 12.5. C hem ical structure o f m orphine.

136 PH ARM ACO LO G Y. V. M, Bobyrov,T. 0. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
Pharmacokinetics
is administered orally, SC, 1M, JV, epidurally, intrathecally in the spina! cord
penetrates the biood-brain barrier
is metabolized in the liver by conjugation with the glucuronic acid
• is the inhibitor o f the liver enzymes
is excreted by gastric epithelium and absorbed once more
finally is excreted with urine
begins to act in 10-20 min after the injection or 20-30 min after the oral
administration
Morphine stimulates all the types o f opioid receptors.
It has high affinity for p-receptors and some action for other opioid recep
tors (fig. 12.3).
In such a way it suppresses neurotransmission in the nociceptive system
that results in the rising o f pain threshold in the spinal cord and altering of
the brain perception o f pain.
Pharm acodynam ics

analgesia (a decrease in all the kinds o f pain; changes in perception o f pain
- sensation o f pain is not unpleasant)
• euphoria (sense o f well being), then sleep
sedation
potentiation o f other drugs inhibiting CMS
the inhibit ion o f the respiratory center resulting in respiratory depression
the inhibition o f the tussive center resulting in a decrease o f cough a
the inhibition of the vomiting center
the inhibition of the thermoregulation center in hypothalamus
the stimulation o f the n. vagus center resulting in bradycardia
the stimulation o f the trigger zone o f the emetic reflex that leads to vomiting
in some patients after the Is' administration o f morphine
the stimulation of the n. ocuiomotorius center resulting in miosis
the stimulation of vasopressin production
the dilation o f peripheral veins
an increase in the tone o f sphincters in the GI tract, bile and urinary pathways
an increase in the tone o f bronchi.
tlm pln 12, OPIOID (NARCOTIC! ANALGESICS 137
Indications
Traumatic shock
• Myocardial infarction (together with atropine)
* Colic (together with atropine)
Pain associated with cancer
* Pain after surgeries
• Pre-anesthetic medication
Pulmonary edema
Cough dangerous for life (the danger o f pulmonary bleeding or pneumo
thorax).
Side-effects C on traind ications

1 1iq iie ssio n o f respiration 1. Insufficience o f respiration
) Sleeping 2. C ranial traum a
1 1 iiphoriu 3. A cute abdom en
4 V om iting 4. C achexia
4 llsp n le n sio n 5. C hildren till 3 (due to the higher
U 1 levnlion o f intracranial pressure sensitivity o f the respiratory
1 t uuslipation cen ter to m orphine in such p a
* 1nlem nec (to the respiratory depressant, anal tients)
gésie, euphoric and sedative effects) 6. E lderly patients after 65 years old
y III ii)'dependence. (due to an increased sensitivity o f
III t liunges in effects o f other drugs acting on the respiratory center to m or
IN S phine).
Acute poisoning with morphine

Stuns:
the state o f sleep,Unconsciousness
the presence of reflexes
normal muscular tone
miosis
bradycardia
Chain-Stocks’ breath
Ihe retention of urination
spasm o f the intestine and bowel.
I nwrpency help:
I he lavage o f stomach by 0,5% solution o f potassium permanganate
Naloxone, IV (an antagonist o f narcotic analgesics)
Atropine (for a decrease in the vagal action o f morphine).
O piate a b u se
O piate abuse is physical and psychical dependence on morphine (or other opioid
analgesic). In opiate abuse, “smark” is self administered by an injection to achieve a
faster peak concentration in the brain and an intense psychic effect.
A quick abolishing o f narcotic substance causes abstinence (insomnia, nausea,
vomiting, spastic pains in the abdomen, joint pains). Abstinence results from a back-
cross decrease in the synthesis o f endogenous ligands o f opioid receptors during a
long-term use o f exogenous opioids.
Compositions o f naltrexone with buprenorphine, as well as antibodies to mor
phine are used to treat opiate abuse.

OMNOPONUM
is the mixture of opium alkaloids
contains 50% o f morphine and 50% o f codeine, papaverine, thebaine and
other alkaloids
is administered orally, SC
is less active than morphine
does not cause spasms in the GI tract.
CODEINE
• an is opium alkaloid; is taken orally
is less potent analgesic than morphine; is an active inhibitor of the tussive
center at doses that do not cause analgesia; potentiates the action o f sedative
drugs and analgesics; produces less euphoria, less respiratory suppression,
and less disturbances o f the GI tract functions; has lower abuse potential
• is used as antitussive and as an ingredient of combined analgesic or seda
tive drugs
may cause suppression o f respiration, constipation, tolerance, drug depend
ence.
TRIMEPIRIDINE (PROMEDOLUM)
is a synthetic preparation with a structure unrelated to morphine
is administered orally, SC, IM, IV; begins to act in 10 min after IV admin
istration and acts during 3-4 hrs
( Iwpler 12. O P IO ID (N A R C O T IC ) A N A L G E S IC S 139
• yields morphine in 2-4 times on analgesic activity; causes less inhibition of

the respiratory center, less stimulation of the n. vagus and emetic centers; has
spasmolytic action on the GI tract; stimulates uterus contractions without
a negative influence on the fetus
• is indicated in acute severe pains, premedication, myocardial infarction,
colic, labor.
FENTANYL
• is a synthetic preparation with a structure unrelated to morphine
• is administered TV, IM; action begins 1-3 min after the administration and
lasts 15-30 min
• exceeds morphine in 100-400 times; when combined with droperidol it
produces dissociative anesthesia
• is used for neuroleptanalgesia, premedication, analgesia in myocardial
infarction, colic
• may cause such side-effects as suppression o f respiration, motor excitement,
rigidity o f muscles of the chest and extremities, hypotension, bradycardia,
an increase in blood pressure in the small cycle o f blood circulation
• is contraindicated to patients with lung diseases, as well as in obstetrics.
PENTAZOCINE
• is a synthetic preparation
isadministered orally, SC, IM, IV, or rectally; acts during 3-4 hrs
• is an agonist-antagonist o f opioid receptors. It acts as an agonist on
K-receptors and as a weak antagonist at p- and 8-receptors.It also binds to
o- receptors that results in dysphoria
• is less potent than morphine (analgesia is mainly due to the activation of
icceptors in the spinal cord)
• produces less inhibition o f respiration, less spasm o f smooth muscles in the
( il tract; less euphoria and drug dependence
is used to relieve moderate pain; may be used in children and for analgesia
in labor
in high dose causes such side-effects as nausea, vomiting, vertigo, sweating,
hyperemia of skin, suppression o f respiration, dysphoria, abstinence in opi
nio abusers, tachycardia, an increase in BP (IV), an increase in intracranial
pressure, a decrease in the activity o f the gut
• is contraindicated in diseases o f the liver and kidney, cranial trauma, prone
In seizures, pregnancy, opiate abuse
is not used with morphine and other agonists o f opioid receptors, because
may block their analgesic effects.
NALORPHINE
is a synthetic preparation with a structure related to morphine
is administered IV, IM, SC
is the agonist-antagonist o f opioid receptors; is a weak narcotic analgesic
and competitor o f morphine in binding to receptors
decreases the main and side-effects o f morphine
is used in acute poisoning with morphine and other narcotic analgesics
is not used as a narcotic analgesic, because may cause psychic excitement,
anxiety, hallucination
in higher dose may cause nausea, vomiting, headache, miosis, drowsiness,
psychic excitement
is not used in morphine abused patients due to its ability to provoke with
drawal syndrome.
BUPRENORPHINE
is a synthetic preparation
is administered orally and parenterally and has a long duration o f action
is a partial agonist o f p-receptors
is suitable to control o f chronic severe pains
is used in combined preparations to treat opiate abuse
may cause respiratory depression, a decrease in BP, nausea, dizziness
intoxication with buprenorphine cannot be reversed with antagonists,
because the drug dissociates very slowly from the opioid receptors and
competitive occupacy o f the receptors cannot be achieved as fast as the
clinical situation demands.
TRAM ADOL
is administered orally, IV, IM., rectally; acts during 3-6 hrs
has a mixed mechanism o f action (opioid + non-opioid). It is a weak agonist
o f p-receptors and is partially antagonized by naloxone. It inhibits the re
uptake o f norepinephrine and serotonin that leads to the reinforcement of
spinal inhibition o f pain impulses
( Implrr V). OPIOID (NARCOTIC) ANALGESICS 141
is less potent than morphine; does not influence respiration and GI functions,
rarely causes drug dependence
is indicated for the control o f intermediate and severe, acute and chronic
pains
causes such side-effects as headache, vertigo, dormancy, sweating, lowering
o f BP, tachycardia, dry mouth, allergy, seizures (in overdose).
N ALOXONE
is administered IV,IM; has a rapid start o f action and half-life of 1-1,5 hrs
is a non-selective antagonist o f opioid receptors (it is competitive antago
nist at p-, k- and 6-receptors, with 10-fold higher affinity for p-receptors
(fig. 12.3)
abolishs effects of opioid analgesics including effects of agonist-antagonists;
reverses the coma and respiratory depression in opioid overdose; does not
produces pharmacological effects in normal individual, but provokes a
withdrawal syndrome in morphine abusers
is used in acute poisoning with narcotic analgesics and acute alcohol poi
soning.
N ALTREXONE
is non-selective antagonist of opioid receptors similar to naloxone
is metabolically more stable than naloxone and is taken orally; has a long
duration o f action (to 48 hrs)
is used in opiate-dependence maintenance programs and in the treatment
o f chronic alcoholism.

Nil I. The incorrect statement about morphine is only:
A It is an antagonist o f opioid receptors
It ll is the most effective by parenteral administration
< |( causes euphoria and sedation
I ) II causes respiratory depression
I Its effects are antagonized by naloxone.
№ 2. The side-effects of opioid analgesics include all, except:

A. The inhibition o f respiration
B. Stimulation o f anti-diuretic hormone release
C. Drug dependence
D. Tolerance
E. The suppression o f hemopoiesis.
№ 3. Pentazocine is:
A. An agonist-antagonist o f opioid analgesics
B. A less potent analgesic than morphine
C. The most potent in its ability to cause drug dependence
D. Agent caused dysphoria
E. The antagonist o f opioid receptors used in acute poisoning with morphine.
№ 4. Naloxone is used in acute poisoning with opioid analgetisc due to:

A. Agonism to opioid receptors
B. Competitive antagonism with opioid agonists
C. A rapid onset o f action
D. A long duration of action
E. The ability to cause abstinence in morphine abusers.
№ 5. A man was taken to the emergency department with numerous traumas

o f the chest and head. The surgeon proposed to inject morphine to relieve patient’s
condition, but the anesthesiologist rejected the proposition o f his colleague. Why is
morphine contraindicated in this case?
A. It increases intracranial pressure
B. It stimulates the vagal center
C. It decreases intraocular pressure
D. It causes miosis
E. It depresses the center o f a cough reflex.
A n sw e rs
№ 1 - A; № 2 - E; № 3 - A, B, D; № 4 B, C; № 5 - A.
I
O 13 I
I W
y NON-OPIOID
ANALGESICS
PROSTAGLANDINS
Origin and sy nth esis

Prostaglandins (Pg) are the derivatives o f the arachidonic acid. Relative sub-
»iHnics are thromboxane, prostacyclin, and leukotrienes. The arachidonic acid is a
lur constituent o f cell membrane phospolipids; it is released by phospolipase A2
and forms the substrate oTcyclooxygenases (COX) and lipooxygenases (fig. 13.1).
COX is the enzyme responsible for the formation of prostaglandins. There are
two isozymes: COX-1 and COX-2. COX-1 is a constitutive; COX-2 is induced in
llu> process o f inflammation (fig. 13.2).
Biological effects
» Pg are the regulators o f inflammation
They increase pain sensation: pain receptors become more sensitive to
inflammatory mediators, such as bradykinin and serotonin (fig. 13.3)
Pg rise the set point o f hypothalamic thermoregulatory neurons and increase
the body temperature (fig. 13.3)
A ra c h id o n ic
P h o s p h o lip id
Acid
P hospholipase A
C yclooxygenase
P rostaglandin
E,
F ig. 13.1. S ynthesis o f prostaglandins (http://w w w .picsearch.com ).
Intestine M acrophages
Platelets L eukocytes
Stom ach F ibroblasts
K idney E ndothelial
Cells
Fig. 13.2. Peculiarities o f COX -1 and C O X -2 (http://www.picsearch.com).

Chapter 13. N O N -O P IO ID A N A L G E S IC S 145
PGE,, PGI, produce the dilation o f arterioles, PGF2a - venoconstriction

(fig. 13.3)
Pg promote the production of the gastric mucus and reduce the formation
o f the gastric acid
They stimulate labor contractions and regulate menstruation (fig. 13.3)
PGE2, PGL, produce the dilation o f bronchi, PGF2a causes the constriction
o f bronchi
• PG regulate the renal blood flow
Thromboxane A, and prostacyclin regulate platelet aggregation and vascular
diameter.
Prostaglandins
J L± [H+] T
Mucus
production Û
Kidney
function
—K — —>
b —iAnrJ „ /a v tV .
Impulse
frequency in
sensory fiber if
j J Nociceptor
I sensibility £
W W W y W w v lt - f
i Pain stimulus *•
Fig. 13.3. Biological effects of prostaglandins (by IS. Lüllmann, 2000).
NON-OPIOID AN ALG ESICS

Non-opioid analgesics are drugs for a decrease o f intermediate and weak pain,
mlly resulting from inflammation
1hey always have:
an analgesic action
146 PH ARM ACO LO G Y. V. M. ßobyrov, T. 0. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
an anti-inflammatory action
an antipyretic action
Drugs with the prevalence of anti-inflammatory activity are named non-steroidal
anti-inflam m atory preparations (N SA ID s) (fig. 13.4). Structurally they can be
grouped into salicylates, carbonic acids, or enolic acids. Their main effects are similar
and the choice between NSAIDs is dictated by their pharmacokinetics and side-effects.
Fig. 13.4. Expression of effects ofNSAlDs.
Drugs with the prevalence o f analgesic and anti-pyretic activity are named
an algesics-antipy reties (fig. 13.5).
Fig. 13.5. Expression of effects of analgesics-antipyretics.
CLASSIFICATION
According to the chem ical structure
1. Salicylates
- Acetylsalicylic acid (Aspirin)
2. Pyrazoles
- Metamizole (Analginum)
- Phenylbutazone (Butadionum)
Llm ptcr 13. N O N -O P IO ID A N A L G E S IC S 147
I I'enamates
Mefenamic acid
4 Indolacetic acid derivatives
lndomethacin
4 Phenylacetic acid derivatives
Diclofenac-sodium
ft Propionic acid derivatives
Ibuprofen
7 Para-aminophenol derivatives
Paracetamol (Acetominophen)
N Oxicams
Piroxicam
Meloxicam (Movalis)
¥ C'oxibs
Celecoxib
According to the mode of action
,4 N<in-selective inhibitors o f COX-1 a n d COX-2
I, Mainly with a peripheral action
- Acetylsalicylic acid
- Phenylbutazone
- Metamizole
- Mefenamic acid
- Indometacin
- Diclofenac-sodium
- Ibuprofen
- Piroxicam „
Mainly with a central action
Paracetamol
H Selective inhibitors o f COX-2
Meloxicam
Celecoxib.
Mechanism of anti-inflammatory action

Inhibition o f COX by non-opioid analgesics leads to a decrease in the synthesis
»I piuNluglandins (PgE,) (fig, 13.6). That results in a decrease o f the permeability
til blond vessels in the site o f inflammation, inhibition o f hyaluronidase activity,
Mithlll/iition of lysosomal membranes, and a decrease in lysosomal enzymes release.
148 PH ARM ACO LO G Y. V. M. Bobyrov,T. 0. Devyatkina, 0, M. Vazhnicha, V. M. Khristyuk
The inhibition o f energy processes in the area o f inflammation and the inhibition ol
leukocytes activity are also observed. All the listed events lead to a decrease in the
exudation stage o f inflammation. Some most active preparations (e.g. indometacin)
inhibit fibroblasts’ activity and decrease the proliferation stage of inflammation.
IN H IB IT IO N O F C O X A N D B PC SY N T H E SIS
J
-0- perm eab ility o f blood vessels J
-0- hyaluronidase activity j
B lysosom al enzym es release J
~ -O’ energy processes ^

■c
B leukocytes activity
c D
Fig. 13.6. Mechanism of anti-inflammatory action of non-opioid analgesigs
Mechanism of anti-pyretic action

The set point o f the body temperature is programmed in the hypothalamic
thermoregulatory center. A stable body temperature is due to the balance between
heat production and heat output. Pyrogens elevate the set point o f the hypothalamic
temperature controller. The body responds by restricting a heat loss and elevating
heat production that results in the fever.
Non-opioid analgesics inhibit COX and decrease the synthesis o fP g E 2 .in the
hypothalamus. In such a way they decrease the sensitivity of the hypothalamus to
pyrogens, increase heat output and lower high body temperature without the action
on the normal temperature (fig. 13.7).
M echanism of analgesic action

Inhibition o f COX by non-opioid analgesics leads to a decrease in the synthe
sis o f prostaglandins. That results in a decrease o f the sensitivity o f nociceptors to
inflammatory mediators and an increase o f the pain threshold. Such events cause a
decrease in the transmission o f pain impulses in CNS and relief o f pain.
Mechanism of anti-platelet action

Some non-narcotic analgesics (e.g. the acetylsalicylic acid) may cause the
inhibition of COX-1 in platelets and a decrease in thromboxane A 2 synthesis. That
Fig. 13.7. Mechanism of antipyretic action of non-opioid analgesics

(by H. Lallmann, 2000).
results in the inhibition of platelet aggregation and adhesion, normalization of blood
viscosity and prevention of thrombus formation.
In higher doses non-narcotic analgesics also inhibit prostacyclin synthesis.
Some other m echanism s of action

In high concentrations NSAIDs influence nitric oxide-dependent processes, in
hibit 5-lipoxigenase, and reduce the production o f leukotrienes. They activate PPAR
connected with colorectal carcinogenesis, act on apoptosis signalling.
ACETYLSALICYLIC ACID (ASPIRIN)

Acetylsalicylic acid is salicylate, a weak organic acid (fig. 13.8).
Pharmacokinetics
• is taken orally, sometimes IM, IV (Acelysin)
* is absorbed in the stomach and the small intestine by passive diffusion
(absorption is increased by acidic pH in the stomach)
150 PH ARM ACO LO G Y. V. M. B o b y ro v ,! 0. Devyatkina, 0. M.Vazhnicha, V. M. Khristyuk
COOH
Fig. 13.8. Chemical structure of acetylsalicylic acid.
binds to albumins in blood plasma

crosses the blood-brain barrier and placenta
displays maximal concentration in blood in 2 hrs after the administration
concentrates in the adrenal glands, liver, heart, lungs
• at normal low doses, is hydrolyzed to salicylate and the acetic acid by es
terases present in tissues and blood (fig. 13.10)
is metabolized in the liver where salicylate is converted to water-soluble
conjugates
is excreted with urine (alkalic pH increases the excretion o f aspirin and its
metabolites)
acts during 4-6 hrs; has a duration o f anti-platelet action o f 7 days
at normal low dose of600mg/day, has a half-life o f 3,5 hrs; at anti-inflamma
tory doses (>4g/day), has a half-life o f 15 hrs or more due to the saturation
o f hepatic metabolic pathway.
Aspirin is a non-selective inhibitor o f COX-1 and COX-2 in peripheral
tissues and in CNS.
It irreversibly acetylates and thus inactivates COX (fig. 13.9). All other
non-opioid analgesics are reversible COX inhibitors.
Pharm acodynam ics

an anti-inflammatory action (a decrease in exudation)
an anti-pyrexiae action (a decrease in high body temperature)
an analgesic action (a decrease in intermediate and weak pain)
an anti-platelet action (an irreversible decrease in platelet aggregation)
an anti-gout action (an increase in output o f urates)
hapter 13. N O N -O P IO ID A N A L G E S IC S 151
Fig. 13.9. Acétylation of COX by acetylsalicylic acid.
the stimulation o f respiration (at therapeutic doses, aspirin increases alveolar

ventilation; at high doses, it works directly on the respiratory center resulting
in hyperventilation and respiratory alkalosis)
the dilation o f blood vessels ( in higher doses)
• the stimulation of synthesis o f glucocorticoids (in higher doses)
• an increase in the secretion and excretion o f bile
changes in pH o f blood (in higher doses)
• hypoglycemia (inJhigher doses).
Indications
Rheumatism
• Fever
• Arthritis
Headache, toothache, myalgia, neuralgia
• Gout
• Dysmenorrhea
• Prophylaxis o f re-thrombosis, myocardial infarction, or insult
• Thombophlebitis
• Patent ductus artriosus
Prevention o f colorectal cancer.
f
1. Allergy (resulting from acetylation of albumins by 1. Allergy to salicylates
aspirin) 2, Ulcerative disease of the
2. Skin rash stomach and duodenum
3. Spasm of bronchi, “aspirin asthma” (resulting from 3, Ulcerative colitis
the inhibition of Pg synthesis and overproduction of 4. Bleeding
leukotrienes) (fig. 13.10) 5. Bronchial asthma
4. Gastric ulceration (resulting from a decrease in prosta 6. Inhibition of hemopoiesis
cyclin synthesis in the gastric wall, as well as from the 7. Hepatic and renal impair
irritation of the gastric mucosa) (fig. 13.10) ment
5. Vertigo 8. Pregnancy.
6. Thrombocytopenia
7. Hypocoagulation. bleeding
8. A decrease in renal blood flow, the retention of so
dium and water
9. Disturbances in normal development of pregnancy,
prolonged labor, bleeding tendency in the mother and
infant, a premature closure of ductus arteriosus
10. Reye’s syndrome in children (hepatitis and cerebral
edema).
Concomitant administration o f aspirin with many classes of drugs may produce

undesirable side-effects:
Aspirin + Antacids = B aspirin’s absorption
Aspirin + Sulfinpyrazone, probenecid = 0 urate excretion
Aspirin + Heparin, oral anticoagulants = hemorrhage
Aspirin + Barbiturates, thyroxine = f t effects and toxicity.

INDOMETHACIN
is an indolacetic acid derivative
is one o f the most active non-narcotic analgesics, belongs to N SAID s
anti-inflammation is the strongest effect: it inhibits exudation, as well as
proliferation
exceeds aspirin in anti-inflammation, analgesia, and anti-pyrexia
is administered orally, rectally, topically; displays maximal concentration in
2 hrs after the oral administration; has a half-life o f 2-3 hrs; is metabolized
in the liver; is excreted with urine (2/3) and with bile (1/3)
( hrtpter 13. NON-OPIOID ANALGESICS 153
Fig. 13.10. Group-specific side-effects of aspirin and other NSAIDs

is indicated in rheumatism, collagenosis, arthritis, gout, glomerulonephritis,

trauma o f joints and soft tissues, thrombophlebitis, tendovaginitis, myositis,
myalgia, neuralgia (typically in the form o f ointment); is also beneficial in
the control o f the pain associated with uveitis and postoperative ophthalmic
procedures, in fever caused by Hodgkin’s disease, in treating patients with
ductus arteriosus „
has such side-effects as headache, vertigo, dormancy, depression, pain in the
epigastric area, ulcer o f the stomach, nausea, a decrease in appetite, gastro
intestinal bleeding, skin rash, leukopenia, aplastic anemia, disturbances in
the renal function, acute pancreatitis, hepatitis and jaundice
• is contraindicated in ulcerative disease, bronchial asthma, infections, preg
nancy, lactation, epilepsy, Parkinson’s disease, psychic disorders, anemia.
DICLOFENAC-SODIUM
is a phenylacetyc acid dervative
• anti-inflammation is the strongest effect
• belongs to NSAID s, exceeds aspirin and indomethacin
is administerefd orally, IM, topically (gel, ointment)

displays maximal concentration in plasma in 1-2 hrs after the oral ad
ministration; binds to proteins in blood plasma (96% of preparation); has
concentration in synovial liquid which exceeds the same in blood in 5 times
and half-life in synovial liquid (8 hrs) which is more durative than the same
in blood (3 hrs); is excreted with urine and bile
has indications similar to indications o f indometacin; is approved for a
long-term use in the treatment o f rheumatoid arthritis, osteoarthritis, and
ankylosing spondilitis
is less toxic than indomethacin, but may cause a loss of appetite, pain in
epigastric area, meteorism, constipation, diarrhea, rarely ulceration in the
stomach, gastro-intestinal bleeding, headache, drowsiness, thrombocytope
nia, nasal bleeding, microhematuria, allergy, skin rash.
IBUPROFEN
is a propionic acid derivative
is an active anti-inflammatory and analgesic agent, belongs to NSAID s
has high effectiveness for the treatment o f joint diseases
is administered orally and applied topically (gel, ointment)
is used for arthritis, osteoarthrosis, a joint form o f rheumatism, bursitis,
tendovaginitis, trauma o f joints and soft tissues
is untoxic; has minimal influence on the gastric mucosa
may be used in pregnant women.
PIROXICAM
is a preparation from oxicams
has a strong durative anti-inflammatory action, belongs to NSAID s
is taken orally once a day; has a half-life o f 40-45 hrs, thus is administered
once a day; is metabolized in the liver and excreted with urine in the form
o f glucuronides
is used to treat rheumatism, rheumatoid arthritis, ankylosing spondilitis,
osteoarthritids, acute gout
may cause such side-effects as gastric ulceration, skin rash, the inhibition
o f blood formation, toxic action on CNS.
MEFENAMIC ACID
is fenamate
has structural similarity to salicylates; belongs to N SAID s
anti-inflammation and analgesia exceed those o f aspirin; apyrexia is equal

to that o f aspirin, is the inductor o f interferon
is used for the treatment o f arthritis, arthralgia, myalgia, neuralgia, headache,
toothache, fever
has less side-effects in comparison with salicylates; may cause nausea, pain
in the abdomen, diarrhea associated with the inflammation of the bowel.
METAMIZOLE (ANALGINUM)
is a pyrazole derivative (fig. 13.11)
belongs to analgesics-antipyretics; has strong analgesic and anti-pyretic
activity, but weak anti-inflammatory activity
Fig. 13.11. Chemical structure, routs of administration, and side-effects

и! nlinlgcsics-antipyretics: A - metamizole, В - paracetamol (by H. Lullmann, 2000).
is administered orally, IM, IV, rectally (fig. 13.11)

begins to act in 20 min after the IM injection; acts during 3-4 hrs
is potentiated by antihistamines
is indicated in intermediate and weak somatic pains (headache, toothache,
myalgia, neuralgia, arthralgia), visceral pans, control of intermediate post
operative pain, fever, dysmenorrhea
may cause allergy, the inhibition o f hem opoiesis (agranulocytosis)
(fig. 13. II).
P A R A C ET A M O L (ACETAMINOPHEN)
is a para-aminophenol derivative (fig. 13.11)
has intermediate analgesic and anti-pyretic activity, a weak anti-inflam
matory action, does not affect platelet aggregation (belongs to analgesics-
anlipyretics)
is mainly centrally acting preparation
is administered orally, rectally (fig. 13.11)
is metabolized in the liver to form inactive glucuronated and sulfated me
tabolites; is partially transformed into N-acetyl-benzoquinoneimine (a highly
reactive and dangerous metabolite), which is inactivated by SH-groups of
glutathione
is used in headache, pains in muscles and joints, the fever associated with
infection and inflammatory diseases; is an analgesic-antipyretic o f choice
for children with viral infections or chicken pox
is untoxic; rarely causes disturbances in the renal function (renal tubular
necrosis and hypoglycemic coma as complications o f prolonged large-
dose therapy); in acute overdose, may provoke hepatic necrosis due to the
interaction o f N-acetyl-benzoquinoneimine with hepatic proteins (should
be treated by acetylcysteine, a substitute o f glutathione)
may be used in children, as well as in adult patients
may be handed over to the patient without prescription; is one o f the most
popular preparations in the world.
MELOXICAM (MOVALIS)
• is a drug from oxicams
• is a selective inhibitor o f COX-2; N SA ID \ does not influence platelet ag
gregation and gastric mucosa
has a mainly peripheral action
( Itapter 13. N O N -O P IO ID A N A L G E S IC S 157
is administered orally, IM
• is absorbed in the GI tract; develops maximal concentration in 1 hr after the
IM injection; displays stable concentration in plasma in 3-5 days after the
start o f treatment; has concentration in synovial fluid which is more than
that in plasma; has half-elimination o f 20 hrs, is excreted with urine and bile
• is used to treat arthritis, arthrosis, spondylitis, rheumatoid arthritis
may cause such side-effects as dyspepsia, gastric ulceration, gastro-intestinal
bleeding, hepatic and hematological disturbances, skin rash, headache (in
0,1-1% o f patients)
• is contraindicated to patients with hypersensitivity to NSAIDs; should be
used under the physician’s supervision in the cases o f gastro-intestinal
diseases, heart failure, cirrhosis o f the liver, chronic renal diseases.
CELECOXIB
• belongs to the group of coxibs
• is selective inhibitor o f COX-2; N SA ID , acts in the site of inflammation
does not influence platelet aggregation, as well as the gastric mucosa
• is taken orally
is absorbed in the GI tract; develops maximal concentration in plasma in
2-3 hrs after the administration; is bound to plasma proteins, has half-life
o f 8-12 hrs; displays stable concentration in 5 days after the start o f the
treatment; penetrates the blood-brain barrier and placenta
• is used in rheumatoid arthritis, osteoarthrosis
• may cause pain in the epigastrium, dyspepsia; very rarely: gastritis, stoma
titis, ulcer o f the stomach, dysphagia, gastro-intestinal bleeding, headache,
vertigo, insomnia, depression, an increase in intracranial pressure, hyper
tension, tacftycar3ia, etc.
• is contraindicated to patients with acute gastric ulcer, hypersensitivity to
NSAIDs.
AMIZON
• is a modern preparation
• is a derivative o f the isonicotinic acid
• bus properties o f non-narcotic analgesic, direct antiviral and im m une
stim ulating activity
• is taken orally 2-4 times daily; develops maximal concentration in 2-2,5 hrs
after administration: has half-elimination from tissues o f 2-3 hrs and half
158 PH ARM ACO LO G Y. V. M. Bobyrov, T. O. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
elimination from blood o f 13-14 hrs; is metabolized in the liver and excreted
with urine
has anti-inflammatory, anti-pyretic, and analgesic actions resulting from
inhibition o f Pg synthesis; has antiviral activity resulting from direct influ
ence on viruses, as well as from interferon induction; is stimulant both of
cell and humoral immunity
is indicated in influenza, acute viral respiratory infections, herpes, the
treatment and non-specific prophylaxis of viral and bacterial infections,
osteochondrosis, arthritis, neuralgia, acute and chronic inflammation in
patients with surgical and gynecological pathology
produces such side-effects as unpleasant taste, edema o f nasal mucosa.
T ES TS FO R SELF-CO N TR O L
№ 1. The main mechanism o f non-opiod analgesics action is:
A. The inhibition o f prostaglandins synthesis
B. The inhibition o f cyclooxygenase
C. The inhibition o f monoaminooxidase
D. An increase in noradrenaline release
E. The inhibition o f dopamine reuptake.
№ 2. All the listed drugs are non-selective inhibitors o f COX, except:

A. indomethacin
B. Diclofenac sodium
C. Ibuprofen
D. Acetaminophen
E. Celecoxib.
№ 3. Non-opioid analgesics exert the following effects:

A. An antipyretic action
B. Immunity suppression
C. An anti-inflammatory action
D. An analgesic action
E. A hypnotic action.
№ 4. The following statements concerning paracetamol are true:

A. It is a weaker anti-inflammatory agent than aspirin
B. It reduces the fever o f viral infections in children
C. It is an aspirin substitute in patients with peptic ulcer

D. It disturbs hemopoiesis
E. It may cause spasm o f bronchi.
№ 5. A patient with toothache relieved his pain with the help o f metamizole
(Analginum). Point out another useful effect o f this drug that contributes to the
improvement o f the patient’s condition:
A. A sedative effect
B. An anti-inflammatory effect
C. An anti-platelet effect
D. An antioxidative effect
E. An antimicrobial effect.
Answers:
№ 1 - B; № 2 - E; № 3 - A, C, D, № 4 - A, B; № 5 - B.
14
a)
<4-1
a
ANALEPTICS.
TO PSYCHOMOTOR
sz
O STIMULANTS
DRUGS STIMULATING CNS

Drugs stimulating CNS are preparations which increase the activity o f some
structures o f the brain. They are divided into groups according to their site o f action
and main effect (fig. 14.1).
D R U G S ST IM U L A T IN G C N S
A n alep tics (stim ulants o f m edulla o f brain)
P sychom otor stim ulants (stim ulants o f brain cortex) j
A n tid ep ressants (drugs decreasing depression)
N ootrops (cognition enhan cers)
A d ap togen s (w orking capacity enhan cers)
A ctop rotectors (enhan ces o f ability to physical w ork) ^
A n orexigen s (cen trally actin g app etite inh ib itors) j
Fig. 14.1. Main groups of CNS stimulants.

Chapter 14. A N A L E P T IC S . P S Y C H O M O T O R S T IM U L A N T S 161
ANALEPTICS
Analeptics are the drugs which stimulate mainly the respiratory and vasomotor
centers in medullar part o f CNS.
They always have such effects as:
an increase in respiration resulting from the stimulation o f the respiratory
center
an increase in BP resulting from the stimulation o f vasomotor center
• a decrease in the action o f drugs inhibiting CNS (an awakening effect)
• seizures (in higher doses)
CLASSIFICATION
A ccording to the type of action
1. Direct-acting
- Bemegridum
- Aethimizolum
- Strychnine nitrate
- Caffeine (Caffeine-sodium benzdate)
2. Indirect-acting (M-cholinomimetics)
- Cytitonum
- Lobeline
V Mixed-acting
Camphor
Sulfocamphocaine
Nikethamide (Cordiaminum)
Carbogenum.
I Membrane-tropic
Camphor
Sulfocamphocaine
) Marbiluratergic
Bemegridum
1 Ben/.diazepinergic
Nikethamide
4 I’uimergic
<'a Heine
Aethimizolum
4 (tlu m e rg ic
strychnine.
CAMPHOR
Camphor is a bicyclic ketone (fig. 14.2), may be natural or synthetic.
CH,
Fig. 14.2. Chemical structure of camphor.
Natural and synthetic camphor are isomeric forms and both have pharmacologi
cal activity. Natural camphor is contained in a camphor tree (fig. 14.3).
Camphor is indissolved in water, but is well dissolved in oil and alcohol, has
a specific aroma.
Fig. 14.3. Camphor tree containing natural camphor.
Pharmacokinetics
is administered SC, orally, or topically
penetrates the blood-brain barrier
is metabolized in microsomes o f the liver
is excreted with urine, bronchial liquid, nursing mother’s milk.
MuMittM I A A N A L E P T IC S . P S Y C H O M O T O R S T IM U L A N T S 163
Mechanism of action
• <'nmphor is a mixed-acting analeptic. It has a direct and indirect action.
• Direct action includes disturbances in the permeability o f the neuronal
membrane to Na+. They results in an increase o f Na+concentration in the
cells that leads to the maintenance o f the excitement o f neurons in the me
dulla o f brain (fig. 14.4).
• Hie indirect component o f cam phor’s mechanism o f action is realized by
Itie stimulation o f chemoreceptors o f zona carotis and a reflexive excitation
ofeenters in the prolonged medulla (fig. 14.4).
Pharm acodynam ics

• it local action (antiseptic, irritating, trophic, whitening)
C h an ge in N a+ transp ort through

m em brane
An increase in N a+
concen tration in cells
I An Increi
reuse in excitation
! M M n f m o f prolonged m edulla
N 14 4. M echanism o f cam p h o r’s action: A - direct action; B - indirect action.

the stimulation o f the respiratory center in its moderate suppression resultin;’,

in the acceleration and deepening o f breath
the stimulation o f the vasomotor center in its suppression resulting in ail
increase o f BP
an awakening action and a decrease in the effects of CNS inhibitors
a positive inotropic action (an increase in strength of heart contractions under
the conditions of heart failure resulting from the enhance of the myocardium
sensitivity to catecholamines and the intensification o f metabolic processes)
the improvement o f microcirculation
the inhibition o f platelet aggregation
an expectorant action resulting from excretion by bronchial glands
the stimulation o f lactation.
Indications
A moderate suppression o f respiration caused by infections and intoxications
Collapse, shock
Acute and chronic heart failure
Pneumonia
Skin diseases, external otitis, myalgia, myositis, arthralgia, arthritis, for
the prophylaxis o f trophic disturbances o f the skin in long lying patients
(topically).
1. A llergy 1. H ypersensitivity to cam phor
2. Seizures 2. Epilepsy, prone to seizures
3. Infiltrate in the site o f injection 3. Should not be adm inistered
4. Fat em bolism if the drug is adm inistered IV or IM. IV or IM.

Sulfacam phocaine is a complex compound o f camphor and procaine; is water-
soluble; is administered SC, IM, IV; is not applied topically; is used for the suppres
sion o f respiration, collapse, shock, overdose of drugs inhibiting CNS, heart failure;
is contraindicated to patients with allergy to procaine.
Nikethamide (Cordiammum) is a commercial name of 25% solution of diethyla
mide o f the nicotinic acid; is administered IV, IM, SC, orally; has a short action; is a
mixed-acting analeptic (its direct action results from the inhibition o f benzodiazepine
receptors o f Cl'channels); has typical analeptic effects; improves metabolism in the
heart and liver; is indicated in the suppression o f respiration, collapse, shock, overdose
Ih«ph*i 14 A N A L E P T IC S . P S Y C H O M O T O R S T IM U L A N T S 165
h I ( NS inhibitors, chronic heart failure (orally); may cause seizures, hyperemia of

III» ikiii. pain in the site o f injection; is contraindicated to patients with epilepsy,
hii excitement, hypersensitivity to the nicotinic acid.
is a synthetic preparation, a derivative of piperidine; is adminis-
l#t*d IV, is not bound to plasma proteins and begins to act quickly; is widely dis-
lllhtileil in the body; is metabolized in the liver and excreted with urine; is a strong
dll»* t in ling analeptic inhibiting barbiturate receptors o f Cl' ion channels; an awak-
tniltu 111 1mu is the strongest effect in comparison with other effects o f Bemegridum
(fey llth in I ion Bemegridum is more potent than other analeptics); is indicated in
i (till» poisonings with barbiturates, alcohol, narcotic analgesics; overdose of general
* IfWMhoiii x, suppression o f respiration; may cause seizures, tremor, hyperventilation,
: iftltVthniiii, is contraindicated in epilepsy, psychomotor excitement, intoxication
i Wllll «M/IIIC poisonings.
\ itilttm lzo lu m is a synthetic preparation, an imidazole derivative; is admin-
| felsspd IV, IM, and orally; has short action; is a direct-acting analeptic inhibitinig
I l^fiiim hu- 1 oceptors; decreases phosphodiesterase activity, thus increases cAMP in
: pH « Ini', pharmacological effects, which by their strength form the line: the stimu-
ittiiHi ol llie respiratory center; the stimulation o f vasomotor center and awakening
I plhiM. piiiihiees the stimulation o f ACTH secretion resulting in anti-inflammatory
p H mill allergic effects, displays cognitive enhance, the improvement o f the tone
Ilf Htvm milium and skeletal muscles, dilates bronchi; increases surfactant synthesis
id (he lungs, is used in the suppression o f respiration, asphyxia o f newborns, the
JIRifiliyhixis of lungs athelectasis during inhalation genera! anesthesia, bronchial
Dtlliiiin. pneumonia, rheumatoid arthritis; may cause dyspepsia, vertigo, restlessness,
iHiiminiii, is contraindicated in epilepsy, psychic disorders, excitement.
Strychnine is an alkaloid o f vomiting nut (fig. 14.5); is administered SC and
(HnIIv. I*, dued-acting drug inhibiting glycine receptors; acts mainly on the spinal
|mhH, «liiuuhile.s reflexive activity of the spinal cord; stimulates the cortex parts of
pulv #»ix, especially a vision analyzer; is used in neurological diseases accompanied
to* livpm num. paralysis, paresis, asthenia, disturbances o f vision resulting from en-
M>|t!mlviix. nlonia of the GI tract and urinary bladder, impotence; is used very rarely
itite lo high loxicity: is a seizure poison (Seizures caused by strychnine are treated
fey mi on l.ix,mis).
I H th w n u M is a mixture o f 3-7% CO, and 93-97% O, is administered by
H»li»l«llon, Inis n mixed action; is a physiological stimulant o f the respiratory center;
It HMil Ini Ihe treatment o f asphyxia, respiratory arrest, prophylaxis of athelectasis
Mid pinuiiuunin after inhalation general anesthesia, suppression of respiration; may
(■in«», »uppicssiun of breathing if concentrations o f CO, will be high.
166 PHARMACOLOGY. V. M. Bobyrov.T. 0. Devyatkina, 0. M, Vazhnicha, V. M. Khristyuk
Fig. 14.5. Vomiting nut containing strychnine.
PSYCHO M OTO R STIMULANTS

Psychomotor stim ulants are the drugs stimulating mainly cortical part of CNS,
They always increase mental and physical performance.
CLASSIFICATION
A. Purinergic
1. Methylxantines
- Caffeine (Cofeinum natrii-benzoas)
- Theophylline
B. Adrenergic
1. Phenilalkilamines
- Amphetamine (Phenaminum)
2. Piperidine derivatives
- Meridile
3. Sydnonimine derivatives
- Mesocarb (Sydnocarb).
CAFFEINE
Caffeine is an alkaloid. It is methylxantine (fig. 14.6).
Caffeine is contained in coffee, tea, cola drinks, chocolate candy, and cocoa
(fig. 14.7). It is water-soluble, but salts o f caffeine (Coffeinum-natrii benzoas) are
better soluble than caffeine.
I
CH3
Fig. 14.6. Chemical structure of caffeine.
Pharmacokinetics
is administered orally, SC, 1M, IV
is well absorbed in the GI tract
is excreted with urine and mother’s milk
acts during 4 hrs; T'A = 3,9 -5,3 hrs, is completeliy eliminated for 24 hrs.
Fig. 14.7. Plants containing caffeine: A - Coffe arabica; B - Thea chinensis.

Caffeine blocks all the subtypes o f adenosine receptors and decreases their
inhibiting influence in the brain. In such a way it increases excitement in
the brain cortex and some other areas of CNS.
Caffeine stimulates the translocation o f extracellular calcium into cells.
It inhibits phosphodiesterase and increases cAMP concentration in cells.
The drug also increases the activity o f phosphorilase resulting in an increase
o f glycogen metabolism and forming of the energy.
Pharm acodynam ics

a psychostimulant action (an increase in the excitement in the cortex o f the
brain; a decrease in the time o f answer to different irritants; an increase in
mental and motor activity; a decrease in fatigue and somnolence)
an analeptic action (direct stimulation o f the respiratory and vasomotor
centers in the brain medulla)
the stimulation o f reflexive activity o f the spinal cord
changes of heart rate, which depend on the ratio between a direct action on
the heart and an indirect one resulting from the stimulation o f the center of
n.vagus (as a rule, an increase in heart rate)
action on blood vessels, which is the sum of the central action (vasoconstric
tion) and the peripheral action (vasodilation): blood vessels in the heart,
lungs, kidney, skeletal muscles are dilated; blood vessels in the brain cov
ers are dilated from the first, then - constricted (that results in a decrease
o f headache)
the elevation o f BP (in some individuals - lowering o f BP or without
changes)
the stimulation o f gastric secretion
a diuretic action. a
Indications
A decreased mental and physical ability to work
• Asthenia
Fatigue
Hypotension
Collapse
The suppression o f respiration
Diagnostic o f the gastric secretory function
Headache (as the an ingredient o f combined preparations for headache).
Side-effects C ontraindications
1. Agitation, anxiety 1. Psychomotor excitement
> Insomnia 2. Hypertension
1. Tachycardia, arrhythmia 3. Arrhythmia
•1, Hypertension 4. Atherosclerosis
5. Pain in stomach 5. Hyperthyroidism
6. Drug dependence 6. Gastritis, ulcer o f stomach
7. Withdrawal syndrome (lethargy, irritability,
headache in users who have consumed more
than 600mg per day).
PECULIARITIES OF OTHER M ETHYLATED XANTINES

Theophylline is taken orally; has a half-life about 8,5 hrs; has a cellular mecha
nism like caffeine; causes more CNS stimulation than caffeine; increases cardiac
work and diuresis, is an active bronchodilator; is used to treat bronchial asthma,
apnea and bradycardia in premature infants; is not used widely due to toxicity and
questionable efficacy.
AMPHETAMINE
is adrenergic psychomotor stimulant, phenylalkilamine
• is taken orally, is completely absorbed from the GI tract, metabolized in the
liver, and excreted with urine, penetrates CNS, acts during 4-6 hrs
increases the release of catecholamines into the synaptic gap, is a weak
MAO inhibitor; produces the alteration o f behavior which is due mainly to
a release of dopamine; causes peripheral effects mediated primarily through
the release of nofepinephrine (fig. 14.8)
causes strong psychostimulation, euphoria, anorexia, a peripheral adreno-
mimetic action
• is indicated for an increase of mental and physical capacity to work, narco
lepsy, attention deficit syndrome
• is used very rarely due to its side-effects
• may cause insomnia, irritability, weakness, tremor, confusion, delirium,
panic state, anorexia, hypertension, tachycardia, arrhythmia, tolerance,
addition
• causes psychic and physical dependence, “amphetamine psychosis”
• the treatment of overdose includes the acidification o f urine, administration
o f chlorpromazine, labetalol for cardio-vascular normalization.
170 PH ARM ACO LO G Y, V. M. Bobyrov.T, 0. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
Amphetamine
t Norepinephrine
|Serotonin
Dopamine
% INCREASED
RESPONSE RESPONSE
Fig. 14.8. Mechanism of amphetamine’s action (by R. Finkel etu i, 2008).
PECULIARITIES OF OTH ER ADRENERGIC

PSYCHO M OTO R STIMULANTS
Sydnocarb is an adrenergic psychomotor stimulant, a sydnoimine derivative; is
taken orally; has a slow onset o f psychomotor stimulation, does not produce euphoria,
motor agitation, an increase in BP or other peripheral adrenomimetic effects; is used
for the treatment of asthenia with dormancy and apathy, attention deficit in children,
for a decrease in asthenia and myorelaxation caused by neuroleptics and anxiolytics;
has such side effects as anxiety, anorexia, hypertension; is contraindicated to patients
with agitation, arrhythmia, atherosclerosis, hypertension.

№ 1. Caffeine exerts all the following CNS effects, except:
A. An increase in BP
B . Sedation
C. Psychic stimulation
D. An increase in gastric secretion
E. A decrease in fatigue.
№ 2. Bemegridum is:
A. The antagonist o f adenosine receptors
B. The antagonist o f barbiturate receptors
C. The agonist o f barbiturate receptors
D. A psychomotor stimulant
E. The stimulant o f ACTH secretion.
№ 3. The correct statements concerning nikethamide are:

A. It is analeptic
B. It has a mixed action
C. It suppresses respiration
D. It increases BP
E. It stimulates the respiratory center.
№ 4. Psychomotor stimulants are used for:

A. Relief o f pain
B. Asthenia
C. Attention deficit in children
D. Increase the capacity to mental and physical work
E. Insomnia.
№5. For the prophylaxis o f pneumonia after the inhalation general anesthesia
mixed acting analeptic was used. This analeptic is administered by inhalation and
includes two gaseous ingredients. What drug was most probably used?
A. Nitrous oxide
B. Cyclopropane
C. Carbogenum „
D. Nikethamide
E. Camphor.
Answers:
№ 1 - B; № 2 - B; № 3 - A, B, D, E; № 4 - B, C, D; № 5 - C.
H. A C ANTIDEPRESSANTS.
5 I 1 ADAPTOGENS. NOOTROPS.
O I W ANOREXIGENS
AN TIDEPRESSANT A G EN TS
DEPRESSION
Depression is a mood altering disease, an affective disorder. It is characterized
by hopelessness, despair, inability to experience pleasure in ordinary life, a loss of
interest to usual activity, suppression of appetite, sleep disturbance. a
There are three types o f depressions: 1) reactive (or secondary); 2) endogenous;
3) manic-depressive disease.
According to the biogenic m onoam ine theory, the development o f depression
results from the deficiency of monoamines (norepinephrine and serotonin) in certain
areas o f the brain. The pharmacological management o f depression includes the
regulation o f adrenergic and serotoninergic processes in CNS.
ANTIDEPRESSANTS
Antidepressants are the drugs for the treatment o f depression.
Chapter 15. A N T ID E P R E S S A N T S . A D A P T O G E N S . N O O T R O P S . A N O R E X IG E N S 173
CLASSIFICATION
A. Inhibitors o f monoamine re-uptake

1. Non-selective inhibitors o f the monoamines re-uptake
- Imipramine (Imizinum)
- Amitriptyline
2. Selective inhibitors o f the serotonin re-uptake
- Fluoxetine
3. Selective inhibitors o f the norepinephrine re-uptake
- Maprotiline
B. MAO inhibitors
1. Non-selective (MAO-A and MAO-B)
- Phenelzine
- Tranylcypromine
- Nialamidum
2. Selective (MAO-A)
- Pirlindole (Pirazidolum)
- Moclobemide
C. Atypical antidepsessants
- Trazodone
- Mianserin
According to the additional action
A. Thymoleptics (+ a sedative effect)
- Amitriptyline
H Thymoerectics (+ a psychostimulating effect)
- Nialamidum
(' Mixed acting
Imipramine
- Pirlindole.
IMIPRAMINE
It has atri-cyclic structure (fig. 15.1).
Pharmacokinetics
• is administrated orally or IM
• is well absorbed in the G1 tract
174 PH ARM ACO LO G Y. V. M. Bobyrov,!. 0. Devyatkina, 0. M.Vazhnicha, V. M. Khristyuk
penetrates CNS
is metabolized in the liver and excreted with urine and bile
has a half-life o f 4-17 hrs
has a latent period (a therapeutic effect develops slowly in 2-3 weeks after
the start o f the treatment).
CH 3
Fig. 15.1. Chemical structure of imipramine.
The mechanism o f action includes the inhibition o f the norepinephrine re
uptake resulting in an increase o f adrenergic processes in brain structures
(fig. 15.2).
It is also connected with the inhibition o f the serotonin re-uptake resulting
in an increase o f the serotonin amount in synapses that leads to an increase
in serotonin inhibiting influence in the limbic system (fig. 15.2).
Imipramine and other tri-cyclic antidepressants block central and peripheral
M-cholinoreceptors. A sedative and antimuscarinic action is due to such
blockade. «
It also blocks a-adrenergic receptors and histamine receptors.
Pharm acodynam ics

an anti-depressive action
a thymoieptic action in the emotional sphere (a sedative or weak psycho
stimulant action)
the absence o f CNS stimulation or mood elevation in normal individuals
a peripheral M-cholinoblocking action
an antihistamine action.
Antidepressant
drug blocks
re-uptake of
neuro
transmitter.
rsgfe'Modest postsyn aptic respon se
Fig. 15.2. Mechanism of action of monoamine re-uptake inhibitors: TCA - tri-cyclic anti
depressants; SSRI - selective serotonin re-uptake inhibitors (by R. Finkel eta l, 2008).
Indications
• Severe major depression
• Enuresis (in children older than 6 years).
1. Excitement 1. Psychic excitement
2. Insomnia 2. Schizophrenia
3. An increase in agitation and halluci 3. Glacouma
nation 4. Adenoma of prostate
4. Headache 5. Atony o f the urinary bladder
5. Tremor 6. Diseases o f blood
6. Lowering o f BP, orthostatic hypo 7. Diabetes mellitus
tension 8. Tuberculosis
7. Tachycardia, arrhythmia 9. Infections
8. Allergy 10 . Severe diseases o f the heart, liver,
9. Changes in the blood film and kidney
10. Dry mouth 11. Should not be taken in the evening
11. Disturbances o f accomodation 12. Should not be taken together or

12. An increase in intraocular pressure after the withdrawal o f MAO-
13. The retention o f urine inhibitors due to the danger of
14. Constipation elevation in the BP, rise in body
15. Drug dependence. temperature, convulsions, coma.
PECULIARITIES OF O TH ER RE-UPTAKE INHIBITORS

Am itriptyline has a tri-cyclic structure; is administered orally or IM, manifests an
antidepressant action in 10-14 days after the start o f the treatment; is a non-selective
inhibitor of the monoamines re-uptake; is a thymoleptic; does not provoke agitation
and hallucinations, does not cause insomnia; may be taken in the evening; is indi
cated to patients, in whom depression is accompanied by panic and anxiety; has a
M-cholinoblocking action and side-effects resulting from an antimuscarinic effect.
Fluoxetine contains fluorine; is taken orally; a half-life is 1-10 days; is charac
terized by a latent period of 1-4 weeks; is a selective serotonin re-uptake inhibitor
(SSR1); possesses a psychostim ulation effect; has not M -cholinoblocking and
adrenobloking effects; is widely used to treat depression, neurotic bulemia, neurotic
anorexia, panic disorders, some pain syndromes, premenstrual syndrome; has low
toxicity, but may cause headache, nervousness, insomnia, appetite disturbances, skin
rash, sexual disturbances; should not be combined with non-selective MAO-inhibitors
(may cause serotonin syndrome).
NIALAMIDUM
• is taken orally, has a latent period o f 12-14 days
is a non-selective MAO-inhibitor: inhibits both MAO-A and MAO-B. In
such a way prevents the inactivation o f monoamines within the neuron and
increases the release o f monoamines into the synaptic space. That is why
it increases the neurotransmission in certain areas of the brain (fig. 15.3)
• is thymoerectic
increases the effects o f adrenomimetics and sympathomimetics, is a reser-
pine antagonist
decreases pain syndromes
is used in depressions unresponsible to tri-cyclic antidepressants, depressions
accompanied by severe anxiety, phobic states, pain syndromes, neuralgia
o f n.trigeminus
has side-effects, such as insomnia, headache, hypotension, dry mouth,
constipation, a cheese syndrome (it occurs in patients treated with MAO-
inhibitors after the use o f cheese, beer, and other products containing
tyramine; manifests by hypertensive crisis and cerebro-vascular accidents;
needs IV injection o f ot-adrenoblocker as emergency help).
PECULIARITIES OF OTH ER MAO-INHIBITORS

Pirlimlole has a tetra-cyclic structure; is a selective inhibitor MAO-A with a
reversible action; has regulatory influence on emotions: causes psychostimulation
under the conditions o f fatigue and dormancy, as well as sedation under the condi
tions o f anxiety; has not M-cholinoblocking properties; is indicated in depressions,
manic-depressive disease, some types o f schizophrenia, has low toxicity; may be used
in patients with glaucoma, adenoma o f prostate, myocardial infarction.
MAO inhibitors prevent

inactivation of monoamines
within a neuron, causing
excess neurotransmitter
to diffuse into the synaptic
space.
Norepinephrine
Serotonin
Dopamine
SYNAPTIC
CLEFT
POST-
SYNAPTIC
NEURON
4
Postsynaptic response
4
F ig . 15.3. M e c h a n ism o f actio n o f M A O - in h ib it o r s (by R F inkel et al., 2008).
C O N C EP T A B O U T ATYPICAL ANTIDEPRESSANTS
Atypical antidepressants are modern preparations which differ from typical
antidepressants by their mechanism o f action. This mechanism of action is represented
by the blocage o f a 2-receptors and an increase in the norepinephrine release or by
the inhibition o f serotonin receptors.
NOOTROPIC DRUGS
Nootropic drugs (cognition enhancers) are the drugs for improving memory
and ability to acquisition of new knowledge.
CLASSIFICATION
1. Pyrolidon derivatives
- Piracetam (Nootropil)
2. GABA derivatives
- Phenibutum
- Pantogamum
- Picamilonum
3. Neuropeptides
- Sinacten-Depo
- Thyroliberin
- Melatonin
- Cerebrolysin
4. Cerebrovascular drugs
- Vinpocetin (Cavinton)
- Nicergoline (Sermion)
- Pentoxyphylline
- Cinnarisine
5. Pyridoxine derivatives
- Pyritinol (Pyriditolum, Encephabol)
6. Antioxidants
- Mexidol.
PIRACETAM
By its chemical structure piracetam is similar to a cyclic form o f GABA
(fig. 15.4).
Chapter 15. A N T ID E P R E S S A N T S . A D A P T O G E N S .N O O T R O P S .A N O R E X I G E N S 179
k conh 2
Fig. 15.4. Chemical structure of piracetam.
Pharmacokinetics
is well absorbed from the GI tract, has bioavailability of 90%
develops maximal concentration blood in 30 min after the administration;
maximal concentration in the brain - in 1-4 hrs after the administration
penetrates CNS and placenta »
does not metabolized in the organism
acts during 12 hrs.
Mechanism of action
Piracetam has a combined mechanism of action. It acts due to binding to
receptors, as well as due to the regulation o f cell metabolism.
The influence on cognition results from the stimulation o f aspartate and
glutamate receptors, GABA a and GABABreceptors.
It increases macromolecules synthesis, stimulates glucose metabolism and
the production of ATP, increases the turnover of neurotransmitters, inhibits
lipid peroxidation, normalizes the structure and functions of cell membranes,
decreases cortical discharge o f L-proline.
It also inhibits phosphodiesterase, increases the content o f cAMP in cells,
thus dilates blood vessels in the brain and has an anti-platelet action.
Pharm acodynam ics

a nootropic action: stimulation o f the higher cortical function in the delay
or disturbances of their development, improving the memory, enhancing
cognition, the stimulation o f educational process
the regulation of emotional state (a weak dose-dependent psychostimulating

or tranquilizing effect)
a stress-protective action with the development o f active forms of adaptation
an antihypoxic action (an increase in the brain stability to hypoxia)
a cytoprotective action (an increase in the brain stability to neurotropic
poisons)
an anti-seizure action in some forms o f epilepsy
an increase in the efficacy o f the treatment by neuroleptics and antidepres
sants, a decrease in their side-effects
• a decrease o f abstinence in alcohol abused persons
the improvement o f cerebral blood circulation
the reduction o f blood viscosity
a cardioprotective action (a decrease o f the myocardium lesion under the
conditions o f hypoxia).
Indications
A. Long-lasting treatm ent
Memory disturbances with vascular, traumatic, infective, intoxication and
somatogenic genesis
Cognition disturbances in elderly patients associated with senile dementia
and Alzheieimer’s disease
Cerebral circulation disturbances, cerebral atherosclerosis
Chronic alcoholism
• Mental deficiency in children
Cortical myoclonus epilepsy
Sickle-cell anemia (as an additional drug)
B. Urgent therapy s
Trauma o f the brain
Edema o f the brain
Stroke
Comatose states
• Acute intoxications with neurotropic poisons
Abstinence in alcohol abusers
Myocardial infarction (as an additional drug)
Hypoxia o f the fetus and newborn
C. Use in healthy personsfor improving education processes, memory, and adaptation.

Side-effects and contraindications

Piracetam is low toxic (an acute toxic dose is 1Og/kg of the body weight). Rarely
it can cause nervousness, anxiety, insomnia.
The drug has no significant contraindications.

Vinpocetin (cavinton) is an alkaloid; is administered orally and IV (by IV infu
sion); is the inhibitor of phosphodiesterase and increases the cAMP concentration in
cells; dilates cerebral blood vessels; improves cerebral circulation; has nootropic and
antihypoxic actions; decreases vertigo associated with circulation disturbances; increases
glucose metabolism in the brain; has an anti-platelet action; is indicated in acute and
chronic disturbances of cerebral blood circulation, cerebral atherosclerosis, memory
disturbances associated with cerebral ischemia, vertigo, the pathology of blood vessels
in the retina and internal ear; may cause hypotension, arrhythmia, hyperemia of the face.
Pentoxiphylline, by its chemical structure is similar to alkaloid theobromine;
is administered orally, IV; is a phosphodiesterase inhibitor; dilates both cerebral and
peripheral blood vessels of an arterial type; has an anti-platelet action; has nootropic
action, especially associated with the pathology of cerebral circulation; is indicated
in acute and chronic disturbances of cerebral and peripheral blood circulation, is
chemic stroke, diabetic angiopathia, angiopathia o f ocular blood vessels; has such
side-effects as hypotension, weakness, vertigo, hyperemia o f the skin, dyspepsia; is
contraindicated to patients with myocardial infarction, bleeding, hypotension, severe
atherosclerosis, pregnancy.
Nicergoline (sermion) is administered orally and IV (by IV infusion); has an
a-adrenoblocking action, dilates cerebral and peripheral blood vessels, improves
cerebral and peripheral circulation, thus displays a nootropic action in CNS; has
indications similar to that o f pentoxiphylline; may cause hypotension, a decrease in
cardiac output, vertigo, weakness, hyperemia o f the skin, pain in the epigastrium.
AD A PTO G EN S
Adaptogens are the drugs improving adaptation and non-specific resistance of
the organism. Majority o f adaptogens have a vegetable origin (fig. 15.5).
CLASSIFICATION
1. Preparations from medicinal plants
- Tincture o f Ginseng
- Tincture o f Schizandra
- Tincture o f Aralia
- Liquid extract o f E/euterococcus
2. Preparations from animal tissues
- Pantocrinum
Fig. 15.5. Medicinal plants containing adaptogens:

A - Panax Ginseng, B - Schizandra chinensis, C - Leuzea carthamoides.
All adaptogens have the common mechanism of action and similar pharmaco
logical properties. They are taken orally. Pantocrinum may be administered 1M, SC.
Mechanism of action
Mechanim o f action is connected with steroidal compounds and is based
on the activation of RNA synthesis, intensification o f protein synthesis,
stimulation o f glucose metabolism and ATP synthesis, inhibition of lipid
peroxidation.
Regulation o f the activity o f the hypophysial-adrenal system is a very im
portant component in the adaptogens’ mechanism o f action. They limit the
activity o f this system under the conditions o f acute stress or stimulate it
under the conditions o f chronic exhausting stress.
Pharm acodynam ics

an increase in resistance to unfavorable factors
the optimization of adaptation
a decrease in negative influence o f acute and chronic stress on the organism
an increase in physical and mental working capacity
the restoration o f normal daily rhythms

a decrease in atherogenesis
the stimulation o f cardiovascular system, an increase in low BP
the normalization o f decreased appetite
the stimulation of reproductive processes, especially in males
the stimulation o f non-specific immunity.
Indications
Asthenia
• Hypotension
Vegeto-vascular dystonia
Recovery period after infections
Atherosclerosis
Sexual asthenia, impotence
Stress and adaptation in healthy persons
Physical and mental overstrain
Non-specific prophylaxis of infections.
Side-effects
1. Restlessness, nervousness, insomnia
2. Hypertension
3. Hyperglycemia.
Contraindications
Insomnia, hypertension, bleeding, menstruation, severe atherosclerosis, organic
heart lesions. Should not be taken in the evening!
<**
A C TO P R O TEC TO R S
Actoprotectors are the drugs for the stimulation o f working capacity without
following asthenia, euphoria, or drug dépendance. There is a new pharmacological
group with one preparation.
BEMITHYLUM
stimulates glucose metabolism and increases the synthesis o f ATP and
creatinphosphate
stimulates physical working capacity, increases the resistance to oxygen
insufficiency; increases the outer temperature; improves immunity
is indicated in the stimulation o f working capacity, asthenia, the recovery

period after traumas and infections
has minimal side-effects, but may cause headache, face hyperemia, dyspep
sia, nausea, vomiting, allergy.
ANOREXIGENS
A norexigens are the drugs decreasing appetite due to their central activity.
CLASSIFICATION
1. Catecholaminergic (stimulating CNS)
- Amfepranone (Phepranonum)
- Chlorpheniramine (Desopimonum)
- Mazindol
2. Serotoninergic (suppressing CNS)
- Fenfluramine.
The 1st group preparations increase the release and decrease the re-uptake
o f norepinephrine and dopamine in CNS. That’s why they produce the
stimulation o f the saturation center resulting in a decrease o f appetite and
the limitation of the meal quantity.
The 2nd group preparations decrease the concentration of serotonin in CNS
and inhibit the limbic system influence on the hunger center. In such a way
they decrease appetite and limit the meals quantity.
Pharm acodynam ics

The inhibiton o f appetite, limitation o f meals quantity «
A decrease in the body weight.
Indications
Severe alimentary and endocrinal obesity.
Side-effects
For the Is' group: hypertension, tachycardia, arrhythmia, anxiety, insomnia, dry
mouth, tolerance, drug dependence.
For the 2,,d group: sleepiness, depression, euphoria, irritation o f the gastric
mucosa.

№1. The main mechanism by which amitriptyline increases the amount of catecho
lamines in CNS synapses is:
A. An increase in catecholamines release from the presynaptic membrane
B. An increase in catecholamines synthesis in the presynaptic membrane
C. The prevention of catecholamines degradation in the synapse
D. The inhibition of the neuronal re-uptake of catecholamines
E. The inhibition of MAO.
№2. All the statements concerning adaptogens are true, except:

A. They are taken orally
B. They modify the activity of hypophysial-pituitary-adrenal axis
C. They depresse immunity
D. They are used to improve non-specific resistance
E. They increase mental and physical work capacity.
№3. The MAO inhibitors are:

A. Among thymoerectics
B. Not influencing the emotional sphere
c. Causing dry mouth, blurred vision
D. Causing cheese syndrome
E. Without dangerous side-effects.
№4. Piracetam is effective in the treatment of:

A. The disturbance of movement in patients with cerebral stroke
B. The retardation of mental development in children
C. Disturbances of memory after stroke
D. Senile dementia
E. A memory impairment in alcoholics.
№5. 70-year^ old patient has vertigo and memory disturbances on the ground of
atherosclerosis. He is also suffering from the disturbances of blood flow in lower extremi
ties. Which ofthe listed drugs is necessary to include in the complex therapy ofthis patient?
A. Caffeine
B. Pentoxiphylline
C. Diazepam
D. Phenazepam
E. Amitryptiiine.
Answers:
№ 1 - D; № 2 - C; № 3 - A, C, D ; № 4 - B , C, D, E; № 5 - B.
16
<1>
Q.
as
O I W INOTROPIC DRUGS
CONGESTIVE H EAR T FAILURE

Congestive heart fa ilu re (CHF) is a decrease in the pump function o f the myo
cardium resulting from different causes (myocarditis, organic lesions of the heart,
hypertensive disease etc.). CHF may be acute and chronic. It is accompanied Jjy a
decrease o f cardiac output, the enhancing o f venous pressure and lowering of arterial
pressure. Such processes lead to a decrease in the renal blood flow, the stimulation
o f renin and aldosterone secretion, sodium and water retention in the body with the
development o f edema (fig. 16.1).
INOTROPIC DRUGS
Inotropic drugs are preparations, which increase the force o f myocardium
contraction and cardiac output without a significant increase in oxygen consumption.
They are divided into cardiac glycosides (steroidal inotropic drugs) and non
glycoside inotropic drugs (non-steroidal) (fig. 16.2).
Chapter 16. IN O T R O P IC D R U G S 187
Fig. 16.1. Pathogenesis o f congestive heart failure.
Fig. 16.2. T w o groups o f inotropic agents.
CARDIAC GLYCOSIDES
O rigin
Cardiac glycosides are inotropic drugs from medicinal plants (fig. 16.3). The
sources o f main glycosides are:
- Digitalis purpurea (Fox gloves) for digitoxin
- Digitalis lanata for digoxin
— Strophanthus Kombe for strophanthin-K
— Strophanthus gratus f o r S tro p h a n th in G ( Q u a b a in )
Fig. 16.3. Medicinal plants containing cardiac glycosides: A - Digitalis lanata,
B - Adonis vemalis, C - Strophanthus Kombe, D - Convallaria majalis.
A
- Convallaria majalis (lily of the vailey) for corglyconum

- Adonis vernalis for adonisidum, infusion from the herb of adonis.
H istory o f d evelop m e n t
The modern era o f the treatment with the digitalis glycosides began with the
work o f William Withering, who publised his famous book “An Account o f the
Foxglove and Some o f Its Medical Uses” in 1785. Withering was aware that digitalis
was only effective in certain forms o f dropsy or edema, and recognized that the drug
acted on the heart.
C h e m ica l stru ctu re

All cardiac glycosides have similar structure including glycone and aglycone.
This structure may be represented as follows: Cardiac glycoside=glycone + aglycone.
Glycone contains sugar moieties and determines pharmacokinetics. Aglycone contains
a steroid structure with lactone ring and determines pharmacodynamics (fig. 16.4).
DIGITOXIGENIN DIGITOXOSE
Fig. 16.4. Structural parts o f cardiac glycoside digitoxin:

digitoxigenin as aglycone (A) and digitoxose as glycone (B).
CLASSIFICATION
A c c o rd in g to the origin
1. Group o f Digitalis
- Digitoxin
- Digoxin
- Celanidum (Lantosidum C)
- Adonisidum
- Infusion from the herb o f adonis (Infusum herbae Adonidis vernalis)
2. Group o f Strophanthus
- Strophanthin-K
- Strophanthin-G (Quabain)
- Corglyconum
- Tincture o f Convallaria
A c c o rd in g to the duration o f action

1. Long-acting
- Digitoxin
2. Intermediate-acting
- Digoxin
- Celanidum
3. Short-acting
- Strophanthin
- Corglyconum.
M e ch a n ism o f action
M echanism o f a positive inotropic action
Lactone ring binds to SH-groups o f Na +/Kf ATP-ase that results in the revers
ible inhibition o f proton pump. Such inhibition leads to a decrease in Na+ transport
from the cell and a decrease in K+ entry. An increase in the intracellular Na+ content
causes the accumulation of Ca++ in the cell (fig. 16.5). Under the influence o f high
Ca++ concentration the interaction between actin and myosin is more active and the
force o f heart contractions increases.
Fig. 16.5. Mechanism of cardiac glycosides’ (CG) inotropic action (by H. Lullmann, 2000).
M echanism o f a negative chronotropic action

There are two parts in this mechanism: a vagal and an extravagal action. The
vagal action is due to the reflexive and direct stimulation o f the n.vagus center. The
extravagal action is due to the direct inhibition o f SA and the AV nodes and hyper
sensitization of SA node to acetylcholine.
P h a rm a co d y n a m ics
• a positive inotropic effect (an increase in the force o f systole, an increase
in the myocardial tone)
• a negative chronotropic effect (the prolongation o f diastole, slowing o f
heart rate)
• a negative dromotropic effect (deceleration o f conductivity)
• a positive bathm otropic effect (an increase in myocardium excitation,
manifests as extrasystoles in the overdose o f cardiac glycosides)
the improvement o f blood circulation
a decrease in venous pressure, normalization o f arterial blood pressure
• an increase in renal blood flow, which leads to an increase in diuresis and
a decrease in edema.
P h a s e s o f dig italis therapy

The phase o f digitalization is a saturation o f the organism by cardiac glyco
sides (1-7 days). The preparation is administered in a full therapeutic dose.
At the end of this phase the compensation o f heart failure should be obtained.
The phase o f supporting therapy is a long (durative) treatment by an indi
vidual small dose o f cardiac glycoside which is sufficient for heart com
pensation. Heart rate should not be less than 60 per 1 minute.
The pre-toxic phaseis the beginning o f overdose. The heart rate is less than
60 beats per 1 minute. The drug should be abolished.
The toxic phase (acute intoxication).
Digitalis toxicity
Signs (fig. 16.6):
- bradycardia, then tachycardia and arrhythmia (premature ventricular beats,
fibrillation)
- an increase in signs o f heart failure
- changes in ECG
- hypokalemia
- anorexia, vomiting, nausea
192 PH AR M ACO LO G Y. V. M. Bobyrov,T. 0. Devyatkina, 0. M.Vazhnicha, V. M. Khristyuk
- headache, fatigue, hallucinations

- vision disturbances (xantopsia, micropsia, macropsia).
Disturbance
of color vision
Digitalis
Digitalis
Excitation of
N. vagus:
Heart rate £
nausea, vomiting
Fig. 16.6. Signs of Digitalis toxicity (byH. Lullmann, 2000).
Treatm ent o f Digitalis intoxication:

- abolishing o f cardiac glycoside
- drugs containing potassium (potassium chloride; panangin)
- SH-group donator (Unithiolum)
- anti-arrhythmic agents (phenytoin, lidocaine, propranolol, atropine for AV
block)
- digoxin antibodies (digibind)
- glucose, vitamin preparations, oxygen inhalation.
Potassium preparations must be administered for prophylaxis of digitalis

toxicity.
PECULIARITIES OF PREPARATIONS
D igitoxin
• is a typical representative o f the Digitalis group
is lipid-soluble, non-polar
is administered orally orrectally, is well absorbed in the GI tract (90-100%),
binds to plasma proteins (95%), is metabolized in the liver; forms a hepatic-
intestinal cycle o f re-circulation, is excreted with urine and bile; begins to
act slowly in 2-4 hrs after the administration; has a long durative action with
a half-life o f 4-7 days, stays in the organism during 21 days, accumulates
has a negative chronotropic effect which exceeds inotropic and other effects
on its significance
is used in chronic heart failure o f 1-11 B stages, supraventricular tachyar
rhythmia
may cause hypokalemia, bradycardia, AV block, intoxication
is contraindicated in poisoning with cardiac glycosides, bradycardia, AV
block, acute myocardial infarction, severe aortal and mitral stenosis, potas
sium deficiency, childhood.
Digoxin
is water- and lipid-soluble
is an intermediate-acting glycoside from Digitalis lanata
may be administered orally and IV, is well absorbed in the GI tract (60-85%),
binds to plasma proteins less than digitoxin (20-25%), may re-circulate,
begins to act soon after the IV administration, has a half-life o f 36-48 hrs,
accumulates less than digitoxin
has less influence on AV conductivity than digitoxin
is used in chronic CHF, supraventicular tachyarrhythmia, acute CHF, an
attack o f arrhythmia (IV)
• is less toxic, may be used in children and in patients with a non-severe A V block.
Celanidum
The drug is similar to digoxin, but is absorbed worse in the GI tract and after
the IV administration starts to act faster than digoxin.
Strophanthin
is a typical preparation from Strophanthus group
is water-soluble, polar
is administered IV (as an exclusive case, may be administered IM together
with procaine or sublingually); is not absorbed in the GI tract (only 5% o f a
dose), does not bind to plasma proteins, has no re-cycling, is not metabolized
in the body, is excreted with urine, starts to act in 10-15 min after the ad
ministration, develops a maximal effect in 1,5-2 hrs after the administration;
has a half-life of 8 hrs; stays in the organism to 24 hrs; does not accumulate
• has a strong positive inotropic action which is the most significant among
other effects
is used to treat acute heart failure, attack of supraventricular arrhythmia as

well as for rapid digitalization
as a rule, does not cause intoxication.
Corglyconum
The drug is similar to strophanthin, but begins to act slower.
Infusion from the herb of adonis

is galenic preparation which contains glycosides from Adonis vernalis
is taken orally, does not accumulate
is weaker than all other preparations
has a sedative and direct diuretic action
is used for the treatment o f light forms ofCH F, cardioneurosis, neurosis (is
combined with valerian and bromides)
• has low toxicity.
NON-STEROIDAL INOTROPIC DRUGS

These inotrops improve cardiac pump function by adrenergic mechanisms or
the inhibition o f phosphodiesterase III.
CLASSIFICATION
1. Adrenomimetics
- Dobutamine (Pâdrenergic agonist)
- Dopamine (P(-adrenergic agonist)
- Isoprenaline (p,-, P2- adrenergic agonist)
- Ephedrine (a-, p* adrenergic agonist) s
2. Selective phosphodiesterase III (PDE III) inhibitors
- Amrinone
- Milrinone.
DOBUTAMINE
is a non-glycoside inotropic agent
is similar to dopamine by its chemical structure
is administered by IV infusion
is a selective agonist o f Pâdrenoceptors in the heart (fig. 16.7)
has a positive inotropic action, improves coronary circulation, reduces

peripheral resistance, redistributes blood flow in favor o f the heart and
lungs, increases the renal blood flow, does not act on heart rate; does not
cause hypertension
is used in acute heart failure, cardiogenic shock
may cause tachycardia, arrhythmia.
DOBUTAMINE
Stim ulation o f ß -adrenoceptors

in the heart
S' a In d u ctio n o f in tra ce llu la r reaction s:

activation o f adenylate cyclase and It o f cAMP
activation o f protein kinase, phosphorilatiolt o f Ca*~
________ channel and ft o f Coventry
AN IN C R E A SE IN F O R C E O F
M Y O C A R D IU M C O N T R A C T IO N S
Fig. 16.7. M e c h a n is m o f d o b u ta m in e ’s a c tio n .

№ 1. Only one inotropic drug has a non-glycoside structure:
A. Digoxin
B. Digitoxin
c. Dobutamine
I). Corglyconum
E. Infusion from the herb o f adonis.
№ 2. The main effects o f cardiac glycosides include all, except;

A. An increase in the strength o f myocardium contractions
B. A decrease in heart rate
196 PH AR M ACO LO G Y. V. M. Bobyrov.T. 0. Devyatkina, 0. M.Vazhnicha, V. M. Khristyuk
C. A decrease in the conductivity o f the heart

D. An increase in neurotransmission in CNS
E. The improvement o f blood circulation.
№ 3. Digitalis toxicity is characterized by the following:

A. Disturbances o f color vision
B. Hypokalemia
C. Heart block
D. Ventricular tachyarrhythmia
E. Hyponatremia.
№ .4. Acute heart failure may be treated by:

A. Strophanthin (ampoules)
B. Corglyconum (ampoules)
C. Digitoxin (rectal suppositoria)
D. Digoxin (tablets)
E. Celanidum (ampoules).
№ 5. Digoxin in tablets was prescribed to a patient with chronic CHF. After I

month o f treatment a decrease in heart rate was noted; the doctor advised to the patieul
to continue the treatment with a lower dose o f digoxin. In spite o f this, bradycardia
was soon transformed into AV block. Choose the necessary drug for the abolishing
of this manifestation o f glycoside toxicity.
A. Potassium chloride
B. Diphenin
C. Atropine
D. Lidocaine
E. Propranolol.
Answers:
№1 - C; №2 - D; №3 - A, B, C, D; №4 - A, B, E; №5 - C.
117
o i l ANTI ANGI NAL DRUGS
ANGINA PECTORIS
iHHlnu pectoris is one o f the forms of ischemic heart disease. Two other forms
| f f iiiym iniliiil infarction and cardiosclerosis (fig. 17.1).
Fig. 17.1. Is c h e m ic heart d is e a s e and it s f o r m s .
Atigimi pm Un is is characterized by a sudden, severe pressing or acute chest pain

HMlHltnK lu tlu- left arm and neck. Anginal pain occurs when the oxygen supply to
HimHitDuio is insufficient for its needs. The imbalance between oxygen delivery
HM iilllI / illh hi may result from a spasm or from the obstruction of heart blood ves-
sels (fig. 17.2). The coronary blood flow is insufficient to meet the heart’s metabolic
requirements. It causes the onset o f anginal pain.
Fig. 17.2. Pathogenic factors of angina attack

and myocardial infarction (http://www.picsearch.com).
ANTIANGINAL DRUGS
A ntianginal drugs are preparations which delay or prevent angina attack.
CLASSIFICATION
A. D ru g s th a t d e c re a se o x y g e n d e m a n d o f m y o ca rd iu m a n d in crea se o x yg en su p p ly
1. Organic nitrates
- Nitroglycerine (glyceril trinitrate, GTN)
- lsosorbide dinitrate
- lsosorbide mononitrate
- Sustac
Chapter 17. A N T IA N G IN A L D R U G S 199
2. Calcium channel blockers

- Verapamil
- Nifedipine
- Amlodipine
B. D ru g s th a t d e c re a se o x y g e n d e m a n d o f m y o c a rd iu m
1. ß-adrenoblockers
- Propranolol
- Metoprolol
- Talinolol
- Atenolol
D ru g s th a t in crea se o xy g e n su p p ly
1.Substances o f myotopic action
- Dipyridamole
- Papaverine
- Drotaverine (No-spa)
2. Substances o f the reflexive mechanism o f action
- Validolum
I). D ru g s a c tin g o n m y o c a rd ia l m eta b o lism
- Sodium adenosine triphosphate
- Trimethazide
- Tocopherol acetate.
DRUGS THAT D E C R E A S E OXYGEN

DEMAND AND INCREASE OXYGEN SUPPLY
“ORGANIC NITRATES
NITROGLYCERINE
The drug has a chemical structure o f glyceril trinitrate (fig. 17.3); is lipid- and
alcohol-soluble.
Pharmacokinetics
is taken sublingually
• is well absorbed from the oral cavity
• does not undergo hepatic first-pass m etabolism after the sublingual
administration
H2C — O — NOj
I
H2C — O — N02
I
H2C — o — n o 2
Fig. 17.3. Chemical structure of nitroglycerine.
starts to act in 15-30 sec, develops peak concentration in 3-5 min after the
administration
is metabolized in erythrocytes and in the liver with the formation o f active
metabolites (mono- and dinitrates)
finally is inactivated in the liver by conjugation
is excreted with urine and air
stays in the organism during 30-45 min.
N itrate (N 0 2) is transformed into nitrous oxide (= NO, endogenous endothe
lial-derived relaxation factor, EDRF).
It binds to SH-groups o f nitrate receptors.
That results in activation o f guanylate cyclase and leads to an increase in
the cGMP content in cells and a decrease in the C a^ entry.
Such processes lead to the dephosphorilation o f the myosin light chain and
relaxation o f vascular smooth muscles (fig. 17.4).
Pharm acodynam ics

the dilation o f venous vessels, pooling o f blood in the veins, as a result,
the redistribution o f blood in the body and a decrease in preload on the
myocardium
the dilation of arterial vessels, a decrease in total peripheral vascular resist
ance, as a result, a decrease in afterload on the myocardium
a decrease in load on the myocardium resulting in a decrease o f oxygen
dem and
the dilation of coronary vessels, redistribution o f the coronary blood flow
in favor o f the area o f ischemia and an increase in oxygen supply
the inhibition o f impulses from the vasomotor center
the relaxation o f the smooth muscles o f bronchi and the biliary system.
Fig. 17.4. Mechanism of nitroglycerine’s action.
Indications
Angina pectoris attack
Thrombosis of the central vein of the retina
Combined therapy o f hypertensive crisis
Paroxysmal nocturnal dyspnea
Myocardial infarction and edema of lungs (a special medicinal forni of
nitroglycerine for IV injections is used).
Side-effects
1. Headache (as a result o f the dilation o f blood vessels in brain tunics and
increasing o f intracranial pressure; may be diminished by the applying of
Validolum or non-narcotic analgesics)
2. Hypotension, postural hypotension, collapse (may be treated by Mesatonum)
3. Reflex tachycardia
4. Pain in eyes, an increase in intraocular pressure (as a result of dilation of
ocular blood vessels)
5. Flushing of the skin (as a result of the dilation of blood vessels in the skin)
6. Tolerance (as a result of the oxidizing o f SH-groups o f nitrate receptors;

may be overcome by the provision o f a daily “nitrate-free interval” and by
the use o f thiodrugs or antioxidants)
7. Overdose (the forming o f methemoglobin, hypoxia, collapse, respiratory
failure; needs the administration o f Methileni coeruleum as an antidote).
Contraindications
1. Hypersensitivity
2. Hypotension
3. Myocardial infarction accompanied by hypotension
4. Hypertrophic obstructive cardiomyopathy
5. Aortic and mitral stenosis
6. Cardiac tamponade
7. Constrictive pericarditis
8. An increase in intracranial pressure (trauma o f the brain, hemorrhagica! insult)
9. Glaucoma.
LONG-ACTING NITRATES
Sustac is tablets for the oral administration which contain microcapsules of
nitroglycerine; exists in two forms: sustac-niite with a lower dose and sustac-forte
with a higher dose o f nitroglycerine; is slowly absorbed from the gut; begins to act
in 30-60 min after the administration and acts during 4-6 hrs; is used for the preven
tion of an angina attack.
Isosorbide dinitrate (Nitrosorbidum) is used in the form o f tablets, spansules,
spray, injections; after sublingual administration begins to act in 3-20 min and acts
during 1-2 hrs; as an oral form, has an onset o f action in 30-60 min and duration of
action 2-10 hrs; may be administered in coronary blood vessels by special systems
in a clinic; is used for the prevention, as well as for the termination o f an angina
pectoris attack.
Isosorbide m ononitrate begins to act in 15-30 min and acts during 6-12 hrs; is
an active metabolite o f isosorbide dinitrate and has better bioavailability; is used for
the prevention o f an angina attack.
CALCIUM CH AN N EL B LO C K E R S
Calcium channel blockers (calcium antagonists) are preparations which block
calcium channels o f L-type and cause an antianginal, anti-arrhythmic and antihy
pertensive action.
CLASSIFICATION
A ccording to the chem ical structure
1. Phenylalkylamines
- Verapamil
2. Dihydropyridines
- Nifedipine (Phenigidinum)
- Amlodipine
3. Benzodiazepines
- Diltiazem
A ccording to generations
1. The first generation
- Verapamil
- Nifedipine
- Diltiazem
2. The second generation
- Nifedipine-retard
3. The third generation
- Amlodipine.
These drugs block voltage-gated “L-type” calcium channels and decrease
t 'a " entry in the cells of the myocardium and the smooth muscles o f blood vessels
(lig.17.5).
Reduction o f intracellular calcium concentration leads to a decrease in the ac
tivation o f Ca++-ATP-ase, a decrease in phosphate utilization, deceleration of slow
diastole depolarization of mpmbranes.
The result is a decrease in the contractility, excitability, and automaticity of
myocardium, relaxation o f smooth muscles and dilation o f blood vessels.
Pharm acodynam ics

• the dilation o f blood vessels, the reduction o f total peripheral resistance, the
redistribution of blood in the body, a decrease in the load on the myocardium
resulting in a decrease o f oxygen consum ption
the dilation o f coronary arteries and arterioles resulting in the an increase
o f oxygen supply
• a decrease in AV and SA node conduction, the prolongation o f the effective
refractory period within the AV node resulting in an anti-arrhythmic action
Vasodilation in arterial bed
0 ch 3
o CH3
h i
H3C - 0 - C / X X - 0 - C H 3
f
H3c H2C
o - ch 3
H C -Ç -C = n À -° "CHî
»Y Y»
oi Io H2Cs ,CH2
H,CA NA CH3
H2C CH2
h N
/ \
H2C H
Nifedipine Verapamil
(dihydropyridine derivative) (cationic amphiphilic)
Inhibition of cardiac functions
Fig. 17.5. Mechanism of action of calcium channel blockers (by H. Liillmann, 2000).
the dilation o f peripheral blood vessels resulting in a decrease o f BP and

an antihypertensive action
an anti-platelet action and a decrease in blood viscosity
• the relaxation o f the smooth muscles o f uterus, bronchi, and the gut.
Indications °
Angina pectoris
Hypertension
Tachyarrhythmia.
Verapamil is a calcium channel blocker from the first generation; is adminis
tered orally and IV; is well absorbed in the GI tract; develops a peak concentration
in 1-2 hrs; has a half-life of 3-6 hrs; undergoes first-pass biotransformation in the
liver; is excreted with urine; has a strong action on heart rate, as well as vasodilation;
is used for the treatment o f tachyarrhythmia, angina pectoris, hypertension, for the
termination of arrhythmia paroxysm; may cause AV block, heart failure, an increase
in digitalis toxicity when it is given together with digitalis preparations.
Nifedipine is a calcium channel blocker from the first generation; is adminis
tered orally and sublingually; begins to act in 10 min after sublingual administration;
displays peak level in 30 min; has a half-life of 3-6 hrs; has strong vasodilation and
weak action on heart rate; is used for angina pectoris, especially for Prinzmetal’s
angina, for the control o f hypertension; may cause reflexive tachycardia, hypoten
sion, peripheral edema.
A m lodipine is a calcium channel blocker from the third generation; is taken
orally; is absorbed in the GI tract more fully and slower than nifedipine; binds to
plasma proteins stronger; is metabolized minimally; has long period of half-excretion;
does not cause tachycardia.
DRUGS DECREASING OXYGEN

DEMAND OF MYOCARDIUM
p-AD REN O BLO CKER S

These preparations block p-adrenoceptors and limit adrenergic stimulation o f the
heart (fig. 17.6). In such a way, they decrease the heart rate, striking and minute vol
ume o f the myocardium. The result is a decrease in the consumption of oxygen by the
myocardium that leads to the limitation o f ischemia and hypoxia in the heart muscle.
Propanolol (Anapriltnum) is administered orally, IV; is absorbed in the Gl
tract; binds to proteins in blood serum; penetrates CNS; acts during 3-4 hrs; blocks
both P(- and p,-adrenoceptors; decreases the heart contractility, striking and minute
volume, as a result, decreases the consum ption o f oxygen by myocardium (an-
tianginal effect); decreases the excitability and conductivity o f the myocardium,
decreases the heart rate (an anti-arrhythmic effect)', decreases cardiac output and
renin’s secretion in the kidney, thus lowers BP (an antihypertensive effect)', also
decreases intraocular pressure; has a sedative action; is used to treat ischemic heart
disease (the prevention of an angina pectoris attack, myocardial infarction); supraven
tricular tachyarrhythmia; hypertension; hyperthyroidism; migraine; glaucoma; has
side-effects, such as: bradycardia, AV block, heart failure, hypotension, worsen of
peripheral blood circulation, a spasm of bronchi, gastric ulcer, hypoglycemia (when
insulin is co-administered), weakness, drowsiness.
Fig. 17.6. Antianginal action of P-adrenoblockers.

M etoprolol has a cardioselective action on p re c e p to rs; is taken orally for the
treatment o f hypertension, angina pectoris, and arrhythmia, may be administered
IV in acute cases, has less side-effects than propranolol, does not produce a spasm
o f bronchi and the stimulation o f gastric secretion, may be used in patients with
bronchial asthma, ulcerative disease, and diabetes mellitus.
Talinolol has a cardioselective action on P re c e p to rs, has inner sympathomi
metic activity and a membrane stabilizing effect (does not inhibits the heart contrac
tility and conductivity), has less side-effects and less contraindications connected
with the influence on p2-adrenoceptors.
A tenolol is a preparation o f a cardioselective action (on P recep to rs), is similar
to metopolol in the action, but acts longer, does not penetrate CNS.
DRUGS INCREASING OXYGEN

S U P P LY IN MYOCARDIUM
VALIDOLUM
is a menthol derivative
is taken sublingually
has a reflexive mechanism o f action: irritates sensitive nerve endings in the
oral mucous membrane and initiates reflex changes in the vasomotor center
activity, thus dilates coronary blood vessels, increases the oxygen supply
in the myocardium and terminates an angina attack
is less active than nitroglycerine
is used for the termination of an angina pectoris attack
has no significant side-effects; may cause glossitis if it is taken very often.
DIPYRIDAMOLE
is administered orally or IV
inhibits adenosine desaminase, decreases the re-uptake of adenosine by
myocardiocytes and erythrocytes, increases the concentration o f adenosine
in plasma resulting in the dilation of coronary vessels and an increase in
the oxygen supply
produces the dilation o f coronary vessels, an increase in the amount o f col
lateral vessels in the myocardium, the improving o f coronary blood flow;
an increase in coronary sinus oxygen saturation, anti-platelet action
• is used for the prevention o f an angina pectoris attack (is less effective than
nitrates and other drugs), fortheprevention of thrombosis and re-thrombosis
in patients with atherosclerosis or prosthetic cardiac valves; for the treatment
o f disturbances of cerebral and peripheral blood circulation
may cause side-effects, such as hypotension, flushing o f the skin, headache,
dyspepsia, a syndrome o f “stealing” in the myocardium (the dilation of
normal coronary vessels is more intensive than that o f vessels with athero
sclerotic lesions and the drug redistributes coronary blood flow in favor of
the normal areas o f the myocardium with the worsening o f blood supply in
the area o f ischemia) (fig. 17.7).
PAPAVERIN E
is an isoquinoline derivative, an opium alkaloid
is taken orally, 1M, IV; acts about 4 hrs
• is phosophodiesterase inhibitor, increases the cAMP concentration in cells by
which dilates coronary and systemic blood vessels, relaxes smooth muscles
produces the dilation o f coronary blood vessels and an increase in the oxy
gen supply; the dilation o f systemic vessels and a decrease in BP; a decrease
in a spasm of smooth muscles in the gut, biliary and urinary pathways
is used for the prevention o f an angina attack (the effectiveness is low),
hypertension, spasms o f smooth muscles, colic
may cause weakness, somnolence, constipation, disturbances of AV conduc
tion in high doses, a syndrome o f “stealing”.
DROTAVERINE (NO-SPA)
Drotaverine is a phosphodiesterase inhibitor. It is more potent and less toxic than
papaverine, but in angina pectoris is also used rarely, because the efficacy is low.
vessels results in redistribution of

blood from ischemic area to normal
one
Fig. 17.7. Mechanism of “stealing” syndrome.
DRUGS ACTING ON MYOCARDIUM METABOLISM

Drugs acting on metabolism in the myocardium are additional drugs in the
treatment of angina pectoris.
Pecu liaritie s o f preparation s

A TP-long is a complex compound o f ATP and metals (sodium and magne
sium); is taken orally; is well absorbed in the gut; enhances the ATP content in the
myocardium; limits ischemia; improves contractility; has an anti-arrhythmic action;
is the additional drug in the prophylaxis o f angina attack.
A ntioxidants (vitamin E, vitamin C) inhibit non-enzymic free-radical oxida
tion. protect cell membranes, decrease hypoxia, limit the area o f ischemia; are the
additional drugs in the treatment o f angina pectoris and infarction.
TREATM EN T OF ANGINA IN PATIENS

WITH CONCOMITANT DISEASES
The choice o f drugs for the treatment o f angina pectoris is grounded on the form
o f the disease (stable, non-stable, varient), as well as on the presence of concom itant
diseases (table 17.1).
Table 17.1. C hoice o f drugs for angina

pectoris with concom itant diseases
C on com itan t disease Drugs com m on ly used in treating angina

N one L ong-acting nitrates,
P-adrenoblockers,
calcium channel blockers
Recent m yocardial infarction L ong-acting nitrates,
P-adrenoblockers
B ronchial asthm a L ong-acting nitrates,
H ypertension L ong acting nitrates*,
P -adrenoblockers,
D iabetes Long acting nitrates,
C hronic renal diseases L ong-acting nitrates.
P-adrenoblockers*.
calcium channel blockers*
* - less effective drugs.
PRINCIPLES OF TR EATM EN T
OF MYOCARDIAL INFARCTION
Myocardial infarction is the formation o f the area of necrosis in the myocardium
due to local ischemia resulting from the obstruction o f blood vessel, most commonly
by thrombus or embolus. It manifests by persistent intense cardiac pain, diaphore
sis, pallor, hypotension, faintness, nausea, vomiting. Myocardial infarction may be
complicated by acute heart failure and cardiogenic shock.
M ain groups ofpreparations fo r treatm ent o f myocardial infarction and goals
o f tlteir administration:
For analgesia: narcotic analgesics, nitrous oxide
For a decrease in ischemia: organic nitrates (nitroglycerine), p-adrenoblockers
For a decrease in arrhythmia: anti-arrhythmics (lidocaine, amiodarone,

polarizing solution), p-adrenoblockers
For the inhibition o f blood coagulation: anticoagulants (heparin)
For the lysis o f thrombus: thrombolytics: (streptokinase, alteplase)
For a decrease in acute heart failure: inotrtopic drugs (dobutamine), va
sodilators.

№ 1. Nitroglycerine causes all the listed side-effects, except:
A. The delay o f AV conduction
B. Reflex tachycardia
C. Tolerance
D. Hypotension
E. Headache.
№ 2. The calcium channel blocker for the treatment of hypertension and angina
pectoris is:
A. Nitroglycerine
B. Nifedipine
C. Drotaverine
D. Papaverine.
E. Propranolol.
№3. The drugs for emergency help in an angina pectoris attack are:
A. Propranolol (Anaprilinum)
B. Verapamil
C. Validolum
D. Isosorbide dinitrate
E. Nitroglycerine.
№ 4. The following statements concerning antianginal drugs are true:

A. Isosorbide mononitrate is an active metabolite o f isosorbide dinitrate
B. Calcium channel blockers cause a “stealing syndrome”
C. Propranolol is a long-acting nitrate
D. Validolum has a reflexive mode o f action
E. Dipyridamol is a coronarolytic and anti-platelet drug.
Chapter 17. ANTI A N G IN A L D R U G S 211
№ 5. A patient with ischemic disease has not informed the doctor that he had had
attacks o f bronchospasm. The doctor prescribed a drug which has made the attacks
o f angina pectoris less frequent, but the attacks o f bronchospasm have become more
frequent. What medicine has been prescribed?
A. Atenolol
B. Propranolol
C. Verapamil
D. Diltiazem
E. Isosorbide dinitrate.
Answers:
№ 1 - A; № 2 - B ; № 3 - C, D, E; № 4 - A, D, E ; № 5 - B .
18
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■+■«
a
ro
O I W ANTI-ARRHYTHGMICS
CARDIAC RHYTHM AND ITS DISORDERS

Each heart beat originates as an electrical impulse from a small area o f tissue
in the right atrium o f the heart called the sinus node or Sino-atrial node (SA node)
(fig. 18.1). The impulse initially causes both o f the atria to contract, then activates
the atrio-ventricular (or AV) node which is normally the only electrical connection
between the atria and the ventricles or main pumping chambers. The impulse then
spreads through both ventricles via the His-Purkinje fibers causing a synchronised
contraction o f the heart muscle, and thus, the pulse.
The cardiac action potential is a s pecialized action potential (AP) in the heart.
There are 5 phases in cardial AP (fig. 18.2).
The resting membrane potential is caused by the difference in ionic concentra
tions and conductances across the membrane o f the cell during phase 4 o f the AP.
The normal resting membrane potential in the ventricular myocardium is about -85
to -95 mV. This potential is determined by the selective permeability o f the cell
membrane to various ions. The membrane is most permeable to K+ and relatively
impermeable to other ions. If the resting membrane potential becomes too positive,
the cell may not be excitable, and conduction through the heart may be delayed,
increasing the risk for arrhythmias.
Chapter 18. A N T I-A R R H Y T H G M IC S 213
Sinus node
Atrium
AV-node
Tawara's
node
Purkinje
fibers
Ventricle
Fig. 18.1. Electrical conduction system of the heart (http://www.picsearch.com).
F ig . 18.2. C ardiac action potential (Phases 0-4).

Phase 0 is the rapid depolarization phase. This phase is due to the opening o f
the fast Na+ channels causing a rapid increase in the membrane conductance to N a+
(table 18.1). Phase 1 o f the AP occurs with the inactivation o f the fast Na+channels.
The transient net outward current causing the small downward deflection o f the AP is
due to the movement o f K+and C f ions. Phase 2 (the “plateau” phase) of the cardiac
AP is sustained by a balance between the inward movement o f Ça** through L-type
calcium channels and the outward movement o f K + through the slow delayed recti
fier potassium channels. During Phase 3 (the “rapid repolarization” phase) of the
AP, the L-type C a^ channels close, while the slow delayed rectifier K+ channels are
still open. The delayed rectifier K+ channels close when the membrane potential is
restored to about -80 to -85 mV. Phase 4 is slow spontaneous depolarization during
diastole caused by an inward positive current o f N a' and Ca++.
Table 18.1. Ionic currents and states

o f N a+channels during cardiac action potential
Phase o f action Ionic currents States o f N a+ channels

potential
Phase 0 Fast Na+entry' Open (active)
Phase 1 K* and Cf movement Closed, opening impossible
(inactivated)
Phase 2 Slow Ca++ entry, outward K+ Closed, opening impossible
movement (inactivated)
Phase 3 K* efflux Closed, partly can be activated
Phase 4 Closed, opening possible
Cardiac arrhythm ia (also dysrhythmia) is a term for any from a large and het
erogeneous group o f conditions in which there is abnormal electrical activity in the
heart. They may occur due to the disturbances o f impulse formation, disturbances
o f impulse conduction, or both. %
Any part o f the heart that initiates an impulse without waiting for the SA node
is called an ectopic fo cu s. Premature beat caused by an impulse from the ectopic
focus is named extrasystole.
Re-entry arrhythm ias occur when an electrical impulse recurrently travels in
a tight circle within the heart, rather than moving from one end of the heart to the
other and then stopping. Re-entry circuits are responsible for atrial flutter, most
paroxysmal supraventricular tachycardias, and dangerous ventricular tachycardia.
When an entire chamber o f the heart is involved in a multiple micro-reentry
circuits, and therefore quivering with chaotic electrical impulses, it is said to be in
fibrillation.
There are many kinds of heart arrhythmias. The heart beat may be too fast or
too slow, and may be regular or irregular. Some arrhythmias are life-threatening
medical emergencies that can result in a cardiac arrest and sudden death. They are
divided into tachyarrhythmias with the heart rate of more than 80 beats per min
and bradyarrhytlimias when the rate is less than 60 beats per min. According to
the site o f initiation arrhythmias may by atrial and ventricular. Paroxismal atrial
tachyarrhythmia, atrial flutter, ventricular flutter, atrial fibrillation, extrasystolia,
ventricular fibrillation belong to tachyarrhythmias. Bradycardia is often associated
with AV block.
Restoration o f heart rate may be achieved by pharmacotherapy or cardioversion
(an electrical shock).
ANTI-ARRHYTHMIC DRUGS
Anti-arrhythm ics are a group of pharmaceuticals that are used to suppress fast
rhythms o f the heart (cardiac arrhythmias), such as atrial fibrillation, atrial flutter,
ventricular tachycardia, and ventricular fibrillation.
VAUGHAN WILLIAMS
ANTI-ARRHYTHMICS CLASSIFICATION
The Vaughan Williams classification is one o f the most widely used classifica
tion schemes for anti-arrhythmic agents. Anti-arrhythm ics designed fo r the treatment
o f tachyarrythmias are classified on the base o f their electrophysiological effects.
They are represented by 4 classes. Class 1 drugs exert their effect by the inhibition of
Na+ channels: subclass IA blocks Na+ channels which are in the open state; subclass
IB - both in activated and inactivated states; subclass 1C includes the most potent
agents with a more significant action on open channels. Class II drugs increase the
refractory period o f the AV node. Drugs of the class III block K+channels resulting in
the prolongation o f repolarization (Phase 1 and 3). Class IV blocks Ca^slow inward
movements during Phase 2, thus increasing the duration o f the refractory period.
This scheme classifies a drug based on the primary mechanism o f its anti-
arrhythmic effect. However, its dependence on primary mechanism is one o f the
limitations o f this classification, since many anti-arrhythmic agents have multiple
action mechanisms. Another limitation is the lack o f consideration within the clas
sification system for the effects o f drug metabolites. A historical limitation was that
drugs, such as digoxin and adenosine - important anti-arrhythmic agents - had no
place at all in the Vaughan Williams classification system. This has since been recti
fied by the inclusion of class V.
CLASSIFICATION
A . C la s s 1. M e m b r a n e s ta b iliz in g a g e n ts ( N a ‘ c h a n n e l b lo c k e r s )
1.Subclass IA
- Quinidine
- Procainamide
- Disopyramide
2. Subclass IB
- Lidocaine
- Phenytoin
- Mexiletine
3. Subclass IC
- Propafenone
- Flecainide
B. C la s s II. ß - a d r e n o b lo c k e r s
- Propranolol
- Metoprolol
C. C la s s III. K ' c h a n n e l b lo c k e r s
- Amiodarone
- Bretylium
- Sotalol
D . C la s s IV . C a * ' c h a n n e l b lo c k e r s ( a g e n ts a ffe c t th e A V n o d e )
- Verapamil
- Diltiazem
E . C la s s V. A g e n ts o f o th e r o r u n k n o w n m e c h a n is m s
1. Cardiac glycosides
- Digitoxin
- Digoxin
2. Potassium preparations «
- Pananginum.
3. Adenosine.
C L A S S I. M EM BRANE STABILIZING A G EN TS
S U B C L A S S IA
Mechanism of action
Class IA agents block the fast Na+channels and inhibit the Na+ influx.
Blocking o f these channels depresses the Phase 0 depolarization, which

prolongs the AP duration by slowing conduction (fig. 18.3).
• Agents in this class also cause decreased conductivity and increased re
fractoriness.
Fig. 18.3. Effect of class 1A anti-arrhythmic agents on cardiac action potential.
Indications
• Supraventricular tachycardia
Ventricular tachycardia
Symptomatic ventricular premature beats
The prevention o f ventricular fibrillation.
Qiunicline is an alkaloid, isomeric form o f quinine; is taken orally, has the
duration o f action o f 6-8 hr^; inhibits excitability, automaticity, and conductivity in
the atria, AV node, bundle o f His and Purkinje fibers, inhibits ectopic arrhythmias,
ventricular arrhythmias caused by increased normal automaticity, prevents re-entry
arrhythmias, decreases the contractility o f the myocardium, has M-cholinoblocking
properties and can induce tachycardia in normal individuals; is used in the treat
ment of atrial, AV junctional, and ventricular arrhythmias, is applied to maintain the
sinus rhythm after the direct current cardioversion; may cause the deformation of
the QRS complex, some kinds of ventricular tachyarrhythmia, heart block, asystole,
heart failure, hypotension, weakness, headache, vision disturbances, spastic pain in
the abdomen, nausea, vomiting, diarrhea, hemolytic anemia (as a manifestation of
idiosyncrasy), thrombocytopenia, skin rash, itch; is contraindicated to patients with
hypersensitivity, AV block, poisoning with cardiac glycosides, serious disturbances
of ventricular conduction, hypotension, hypokalemia, pregnancy.
Procainamide is a procaine derivative; is administered orally, 1M, IV, has a

half-life o f 2-3 hrs, is acetylated in the liver to N-acetylprocainamide which has
properties o f class III drug; is not toxic, does not inhibit contractility; may cause
side-effects, such as AV block, reversible lupus erythematosus-iike syndrome,
nausea, vomiting, seizures, asystole, and the induction o f ventricular arrhythmias
(in overdose). Procainamide can be used in the treatment o f atrial fibrillation in the
setting o f Wolff-Parkinson-White (WPW) syndrome, and in the treatment o f a wide
complex o f hemodynamically stable tachycardias. While procainamide and quinidine
may be used in the conversion o f atrial fibrillation to the normal sinus rhythm, they
should only be used together with an AV node blocking agent.
Disopyramide is similar to quinidine; is administered orally and parenterally
(IV); increases the refractory period in atria, inhibits conduction in the bundle of
His, produces a negative inotropic effect (which is greater than the effect of qui
nidine and procainamide), has M-cholinoblocking properties; is used in atrial and
ventricular premature beats, supraventricular tachyarrhythmia, is more effective in
the treatment o f ventricular arrhythmia; may cause worsening o f arrhythmia, heart
failure, hypotension, dry mouth, blurred vision, retention o f urination, headache,
allergic reactions; is contraindicated in AV block, denominated bradycardia, heart
failure, cardiogenic shock.
S U B C L A S S IB
Mechanism of action
Class IB antiarrhythmic agents are N a+channel blockers.
They increase membranes permeability for the influx of K+ and decrease
the permeability for the K+efflux.
Class IB agents have fast onset and offset kinetics, meaning that they have a
little or no effect at slower heart rates, and more effects at faster heart rites.
Class IB agents shorten the AP duration and reduce refractoriness (fig. 18.4).
Indications
Ventricular tachycardia
• Symptomatic premature ventricular beats
The prevention o f ventricular fibrillation.
Lidocaine is a local anesthetic; is administered IV, IM, by IV infusion, is widely
distributed in the body tissues, is metabolized in the liver, is excreted with urine, acts
during 6-8 hrs; blocks Na+ channels, increases the K+ efflux, accelerates repolariza
tion, inhibits Phase 2, inhibits Phase 4 in Purkinje fibers, that’s why decreases their
automaticity, decreases the re-entry; unlike quinine, lidocaine suppresses arrhythmias
caused by abnormal automaticity, does not influence the atria; is more effective in
ventricular tachyarrhythmia; is the drug o f choice for the emergency treatment of
cardiac arrhythmias; may cause vertigo, disturbances o f consciousness, seizures,
suppression of respiration, nausea, vomiting, hypotension, collapse, bradycardia,
arrhythmia, asystole, shock, allergy; is contraindicated in hypersensitivity, epilepsy,
AV block, bradycardia, weakness o f the SA node.
Fig. 18.4. Effect of class IB anti-arrhythmic agents on the cardiac action potential.
M exiletine is a stable preparation; is taken orally; is used for the chronic treat
ment of ventricular arrhythmias associated with previous myocardial infarction; may
cause nausea, vomiting, nistagmus, blurred vision.
Phenytoin is an anti-epileptic drug; is administered orally and IV; in the myo
cardium it decreases the K + loss caused by cardiac glycosides, inhibits premature
beats in acute poisoning by cardiac glycosides, improves blood circulation in the
heart, lowers BP; is used in acute poisoning with cardiac glycosides, heart surgeries,
arrhythmias o f central origin.
S U B C L A S S 1C
Mechanism of action
Class IC anti-arrhythmic agents markedly depress the Phase 0 repolariza
tion (fig. 18.5).
• They decrease conductivity, but have a minimal effect on the AP duration.
O f the sodium channel blocking anti-arrhythmic agents (the class I anti-

arrhythmic agents), the class 1C agents have the most potent N a+ channel
blocking effects.
/ A
/
/
/
\
i
/
/
\
1
V
Fig. 18.5. Effect of class IC anti-arrhythmic agents on cardiac action potential.
Indications
Life-threatening ventricular tachycardia or ventricular fibrillation
Refractory supraventricular tachycardia (atrial fibrillation).
Propafenone is administered orally, IV; has membrane-stabilizing properties, is
P-adrenoblocker and calcium antagonist, decreases automaticity, inhibits the conduction
o f excitement in the AV node, bundle o f His and Purkinje fibers; is used in ventricular
tachyarrhythmia, if other remedies are ineffective; may cause postural hypotension.
Flecainide is taken orally, undergoes minimal biotransformation, and has a
half-life o f 16-20 hrs; suppresses Phase 0 upstroke in Purkinje and myocardial fibers,
causes the slowing o f conduction in all cardiac tissue with a minor effect o f on tlje
duration of AP and refractoriness, reduces automaticity; is used in treating refractory
ventricular arrhythmias, is particularly useful in suppressing of premature ventricular
contractions; may cause dizziness, blurred vision, headache, nausea, aggravation of
CHF, induction o f some kinds o f dangerous ventricular arrhythmias.
C L A S S II. p-AD REN O BLO CKER S
Mechanism of anti-arrhythmic action

P-adrenobloLk^ block P:-adrenoceptors, prevent the action o f catechol
amines on the myocardium.
These drugs diminish Phase 4 depolarization.

• As a result, they prolong the refractory period and decrease conductivity.
They act by slowing conduction through the AV node.
They depress automaticity.
Thus p-adrenoblockers decrease the heart rate and contractility.
Indications
Tachyarrhythmia caused by increased sympathetic activity
Atrial flutter and fibrillation
AV nodal re-entrant tachycardia.
Side-effects
1. AV block
2. Bradycardia
3. Worsening in CHF.
A complete pharmacological characteristics of P-adrenoblockers is presented
in Chapter 8.
C L A S S III. K+CH AN N EL B LO C K E R S
Mechanism of acion
Class III agents predominantly block the K+ channels, thereby prolonging
repolarization (fig. 18.6).
Since these agents do not affect the N a+ channel, conduction velocity is
not decreased.
The prolongation<"of the AP duration and refractory period, combined
with the maintenance of nonnal conduction velocity, prevents re-entrant
arrhythmias.
Class III anti-arrhythmic agents exhibit reverse use dependent prolongation
o f the AP duration. This means that the refractoriness o f the ventricular
myocyte increases at lower heart rates. This increases the susceptibility
o f the myocardium to early after-depolarizations at low heart rates. Anti-
arrhythmic agents that exhibit reverse use-dependence are more efficacious
at preventing a tachyarrhythmia that converting someone into normal sinus
rhythm. Because o f the reverse use-dependence o f class III agents, at low
heart rates class III anti-arrhythmic agents may paradoxically be more ar-
rhythmogenic.
Fig. 18.6. Effect of class III anti-arrhythmic agents on cardiac action potential.
Am iodarone is a benzofuran derivative, contains iodine and is related structur
ally to thyroxine; is administered orally or IV; binds to plasma proteins (95% of the
drug), is metabolized in the liver (main metabolite is desethylamiodarone which
strengthens the anti-arrhythmic action o f the drug), is excreted with bile, has a half-
life of20-100 days; displays complex effects showing class 1 ,11, III, and IV actions,
blocks K+ channels, blocks C a^ and Na+channels; modifies the condition o f a- and
(3-adrenoceptors, as well as glucagons receptors (non-competitive antagonism);
increases the duration o f AP and the refractory period in the ventricular and atrial
muscle; has an anti-arrhythmic action; produces systemic and coronary vasodilation
resulting in antianginal action; is used for the treatment o f ventricular arrhythmia,
ventricular fibrillation in patients o f the risk group, supraventricular tachyarrhyth
mias, angina pectoris; myocardial infarction, for the prevention o f sudden coronary
death; may cause side-effects, such as pulmonary fibrosis (reversible), bradycardia,
AV block, phototoxicity, corneal microdeposits and blurred vision, hyper- and hy
pothyroidism, ataxia, tremor, myopathy and neuropathy, anorexia, nausea, vomitirig;
is contraindicated in patients with sinus bradycardia, AV block, syndrome o f sinus
node weakness, diseases o f the thyroid gland, pulmonary fibrosis, hypersensitivity
to iodine, pregnancy, lactation. The course o f treatment must have a provision o f
two days “drug-free interval” every week.
Bretylium tosilate is administered IV, IM, is excreted unchanged with urine; has
a potent anti-arrhythmic effect in ventricular arrhythmias; increases the duration of
the refractory period in Purkinje fibers, has a sympatholytic action, decreases BP; is
used for ventricular fibrillation, mainly in the acute period o f myocardial infarction
or in resistance to electrical defibrillation; may cause severe postural hypotension,
transitory tachycardia and ectopic beats, nausea, vomiting; is contraindicated in
pheochromacytoma, acute disorders ofbrain blood circulation, hypotension, collapse,

severe renal failure, aortal stenosis, pulmonary hypertension, pregnancy, lactation.
Sotalol is a p-adrenoblocker and anti-arhythmic o f class 111; is administered
orally and IV; is effective in many cases o f supraventricular tachyarrhythmia,
especially in atrial fibrillation, supraventricular tachycardia, the WPW syndrome,
ventricular tachycardia; is more effective than class 1 drugs in preventing o f arrhyth
mia recurrence and in decreasing o f mortality in patients with sustained ventricular
tachycardia has side-effects connected with p-adrenoblocking properties (bradycardia,
worsening in CHF).
C LA S S IV. Ca++CH AN N EL B LO C K E R S
Mechanism of anti-arrhythmic action

Ca^channel blockers block calcium channels o f L-type.
They inhibit Caêntry into the cells o f the conductive system in the heart.
Result is the inhibition o f automaticity and re-entry.
They do not the act on conductivity.
Indications
Supraventricular tachyarrhythmia
Fibrillation o f atria, atrial flutter
Paroxismal tachycardia.
Common properties of Ca” channel blockers and peculiarities of some prepara
tions are described in Chapter 17.
C LA S S V. A G EN TS OF OTHER
OR UNKNOWN MECHANISMS
CARDIAC GLYCOSIDES
Cardiac glycosides (e.g. digoxin) shorten the refractory period in atrial and
ventricular myocardial cells while prolonging the effective refractory period and
diminishing conduction velocity in Purkinje fibers.
They are used to control the ventricular response rate in atrial fibrillation and
flutter.
O ther pharm acological properties o f cardiac glycosides are described in
Chapter 16.
POTASSIUM PREPARATIONS
Potassium preparations (e.g. Pananginum) increase the speed o f spontaneous
depolarization in the SA and AV nodes, as well as in all conduction systems, thus
inhibits the automaticity. They also normalize Phase 0.
These drugs are used to treat tachyarrhythmias, especially caused by hypoka
lemia.
ADENOSINE
Adenosine is a nucleoside which is administered IV and have a very rapid and
short action, is uptaken by red blood cells. It stimulates Aâdenosine receptors in
the SA node. In high doses, adenosine decreases conduction velocity, prolongs the
refractory period, and decreases the automaticity in AV node. It is the drug of choice
for abolishing acute supraventricular tachycardia. Adenosine is not toxic, but may
cause flushing, chest pain, hypotension.
DRUGS FOR BRADYARRHYTHMIA AND AV B LO C K
CLASSIFICATION
1. M-cholinoblockers
- Atropine
2. Adrenomimetics
- Isoprenaline
- Ephedrine.
Atropine is a non-selected M-cholinoblocker, has a dose-dependent action on the
heart rate. At low doses, the predominant effect is a decreased heart rate (bradycar
dia) due to blockade o f M ,-receptors on the inhibitory pre-junctional neurons. With
higher doses o f atropine, the cardiac receptors on the SA node are blocked, and the
cardiac rate increases (tachycardia).
Isoprenaline is anon-selective P-adrenergic agonist, stimulates pâdrenoceptors
in the heart and increases the heart rate.
E phedrine is a indirect-acting adrenomimetic, has a presynaptic action, stimu
lates the norepinephrine release and its action on adrenergic receptors in the heart,
in such a way increases the cardiac rate and causes tachycardia.
All these drugs are described as autonomies in Chapters 6, 7.

№ I. All of the following correctly characterizes the drug, except:
A. Procainamide blocks Na+channels
B. Amiodarone blocks K+channels
C. Verapamil blocks Ca1“" channels
D. Bretylium blocks K+channels
E. Quinidine blocks Ca^ channels.
№ 2. Incorrect statement concerning lidocaine is:

A. It is administered parenteraly
B. It is class IA anti-arrhythmic
C. It is metabolized in the liver
D. It shortens an action potential
E. It is the drug of choice in ventricular fibrillation.
№3. The drugs for the maintenance of the cardiac rhythm after the cardioversion are:
A. Quinidine
B. Adenosine
C. Digoxin
D. Procainamide
E. Disopyramide.
№ 4. Adenosine:
A. Is given only IV
B. Has the shortest duration of action
C. Is class III anti-arrhythmic
D. Stimulates A.-adenosine receptors
E. Is used for the termination of acute supraventricular tachyarrhytmia.
№ 5. To maintain the normal sinus rhythm, a patient with atrial fibrillation was
prescribed with anti-arrhythmic drug containing iodine. This drug has very long duration
of action and may cause reversible pulmonary fibrosis and corneal microdeposits. What
preparation was prescribed?
A. Procainamide
B. Propranolol
C. Sotalol
D. Amiodarone
E. Mexiletine.
Answers
№ l - E ; № 2 - B ; №3 - A, D, E; № 4 - A, B, D, E ;№ 5 -D .
ANTIHYPERTENSIVE DRUGS.
HYPERTENSIVE AGENTS
HYPERTENSION
Hypertension is a sustained diastolic blood pressure greater than 90mrn Hg
accompanied by an elevated systolic blood pressure (more than 140 mm Hg).
Chronic hypertension leads to:
- congestive heart failure
- myocardial infarction
- renal damage
- cerebrovascular accidents. «
Arterial blood pressure (BP) is the sum of cardiac output and peripheral resist
ance. Cardiac output depends on the heart rate and contractility. Peripheral resistance
depends on the blood vessels tone and the volume o f circulating blood.
Regulation of blood pressure level

Increased sympathetic activity leads to the activation o f [3,-adrenoceptors in
the heart and results in the enhance o f cardiac output. It also causes stimulation of
o^-adrenoceptors and an increase in peripheral resistance.
The renin-angiotensin system takes part in the regulation o f vasoconstriction
and volume o f blood. The activation o f this system is caused by the stimulation of
C hapter 19. A N T IH Y P E R T E N S IV E D R U G S . H Y P E R T E N S IV E A G E N T S 227
angiotensin receptors by angiotensin II. It leads to vasoconstriction, an increase in

vascular peripheral resistance, retention o f sodium and water. These processes results
in the enhance o f BP and an increase in the load on the myocardium.
Main links of pathogenesis of hypertension

Hypertension is a result o f disregulation in the cardio-vascular system and
wnter-electrolytes balance. Its development is connected with:
Disturbances in the ratio between inhibition and stimulation in the cortex
o f the brain
Changes in activity o f the vasomotor center
• Activation o f sympathetic stimulation o f the heart and blood vessels
Changes in blood vessels wall
The activation o f renin-angiotensin system
An increase in the blood volume.
ANTIHYPERTENSIVE DRUGS
Antihypertensive drugs are drugs for the treatment o f hypertension.
Treatment strategies:
• mild hypertension can be controlled with one drug
• severe hypertension must be treated with the combination of drugs
• drugs for the combined therapy o f hypertension are selected to minimize
the side-effects of the combined regimen
• “first-lin e” drugs are diuretics, ß-adrenoblockers, inhibitors o f angiotensin
converting enzyme (ACE), calcium channel blockers, a-adrenoblockers.
CLASSIFICATION
A N e u r o tr o p ic a g e n ts
1. Drugs decreasing vasomotor center activity (centrally acting a2-adrenomimetics)
- Clonidine (Clophelinum)
- Methyldopa
2. Anti-adrenergic drugs
a) a-Adrenoblockers
- Prazosin
- Doxazosin
b) ß-adrenoblockers
228 PH ARM ACO LO G Y. V. M. ßobyrov,T. 0. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
- Metoprolol
- Propranolol (Anaprilinum)
c) a,ß-adrenoblockers
- Labetolol
- Carvedilol
d) Adrenergic neuron blocking agents (sympatholytics)
- Reserpine
- Guanethidine (Octadinum)
3. M -cholinoblocker
- Platyphylline
B M y o tr o p ic v a s o d ila to r s
1.Ca++ channel blockers
- Nifedipine
- Verapamil
2. Magnesium salts
- Magnesium sulfate
3. Phosphodiesterase inhibitors
- Papaverine
- Drotaverine (No-Spa)
- Bendazole (Dibazolum)
4. Potasium channel openers
- Appressin
- Minoxidil
- Diazoxide
5. Other vasodilators
- Sodium nitroprusside
C. D r u g s a c tin g o n r e n in - a n g io te n s in s y s te m
1. ACE inhibitors
- Captopril
- Enalapril
- Lisinopril
2. Angiotensin II receptor antagonist
- Losartan
D. D iu r e tic s
- Hydrochlorothiazide
- Furosemide.
I ') A N T IH Y P E R T E N S IV E D R U G S . H Y P E R T E N S IV E A G E N T S 229
DRUGS DECREASING VASO M O TO R

C EN TER ACTIVITY
CLONIDINE
Pharmacokinetics
is administered sublingually, orally, IV, 1M
is completely absorbed in the G I tract
niter IV or sublingual administration, begins to act in 5-10 min, after oral
administration - in 30-60 min
penetrates CNS
is metabolized in the liver and excreted with urine
a d s during 2-12 hrs.
Mechanism of action
I he drug stimulates a2-adrenoceptors in CNS.
Hie stimulation o f presynaptic a 2-adrenoceptors in the adrenergic synap
sis of the vasomotor center results in the inhibition o f the norepinephrine
iclease into the synaptic gap and a decrease in sympathetic impulsation to
peripheral blood vessels.
I liai leads to the dilation of blood vessels, lowering o f BP, and slow heart
i ale.
Pharm acodynam ics

n decrease in BP (antihypertensive action )
a decrease in heartrate and cardiac output
n decrease in renin activity
sedation
u decrease in pain
h decrease in intra-ocular pressure
llic potentiation of other drugs inhibiting CNS.
Indications
Acute hypertension (hypertension crisis)
( In on ic hypertension
i diiiicoma (eye drops)
Migiaine
230 PH AR M ACO LO G Y. V. M. Bobyrov.T, 0. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
Pain syndromes
Chronic alcoholism
The potentiation o f general anesthesia.
1. Weakness, somnolence 1. Severe atherosclerosis
2. Hypotension, postural hypotension 2. Job needed a quick reaction
3. Transitory elevation o f BP after the IV or 3. Should not be given
sublingual administration (resulting from together with alcohol and
the stimulation o f peripheral adrenoceptors) psychotropic drugs.
4. Constriction o f blood vessels in the brain
5. Dry mouth
6. Inhibition o f gastric secretion
7. Constipation
8. Retention o f sodium and water
9. Changes in glucose level in blood
10. Abolishing syndrome.
METHYLDOPA
is taken orally, is well absorbed in the GI tract, penetrates CNS, starts to
act slowly
• is similar to norepinephrine by chemical structure, that’s why acts as “a
false mediator” in CNS: stimulates a 2-adrenocepotors and decreases the
norepinephrine release in synapses o f the vasomotor center; by this mecha
nism it decreases the activity o f the vasomotor center, inhibits sympathetic
impulsation to blood vessels, dilates blood vessels and lowers BP (is a
centrally acting sympatholytic)
has an antihypertensive action, improves cerebral blood flow, increases
lactation
is used for the treatment o f hypertension
has side-effects which are similar to the same o f clonidine, also may cause
muscular and joint pains, a rise in the body temperature, skin rash, galac
torrhea
is contraindicated to patients suffering from depression, Parkinson’s disease,
liver diseases.
Chapter 19. A N T IH Y P E R T E N S IV E D R U G S . H Y P E R T E N S IV E A G E N T S 231
ANTI-ADRENERGIC DRUGS
a-A D R EN O B LO CK ER S
Prazosin and doxazosin selectively block cq-adrenoceptors, dilate blood vessels,
reduce peripheral vascular resistance and decrease BP. They are taken orally for the
Ireatment of mild to moderate chronic hypertension.
P-AD R EN O BLO CKER S

P-adrenoblockers (propranolol) are the “first-line” preparations for chronic
hypertension. They are taken orally to control hypertension. A full effect develops
in several weeks.
Mechanism of antihypertensive action

P-adrenoblockers lower BP due to blockage o f Pâdrenoreceptors in the
heart and a decrease in cardiac output.
They also block Pâdrenoreceptors in the kidney and inhibit renin secretion
resulting in a decrease of peripheral resistance and blood volume (fig. 19.1).
• Action on cardiac output develops quickly and leads to a decrease in sys
tolic pressure.
• Action on renin-angiotensin system develops in a few days and leads to a
decrease o f diastolic pressure and stable lowering o f BP.
Fig. 19.1. M echanism o f antihypertensive action o f ß-adrenoblockers.

232 PH ARM ACO LO G Y. V. M. Bobyrov,T. 0. Devyatkina, 0. M. Vazhnicha.V. M. Khristyuk
a,p-AD REN O BLO CKERS

Carvedilol is modem preparation which acts both on a- and (3-adrenoceptors, but
the action on |3-receptors is more significant. It is an antioxidant, has cardioprotective
properties (protects the myocardium from hypoxia).
SYM PATHOLYTICS
Reserpine acts in peripheral tissues, as well as in CNS (a sedative and neuroleptic
action); is used for mild forms o f hypertension; produces sodium and water retention;
is combined with thiazide diuretics; may cause disturbances o f sleep, depression,
and side-effects connected with prevanence o f PANS.
G uanetidine (Octadinum) is a potent peripherally acting sympatholytic; is used
for severe forms o f hypertension; begins to act slowly (in 2-4 days after the start of
treatment); may cause postural hypotension, and side-effects connected with PANS
prevalence in the body (bradycardia, a spasm o f bronchi, increased activity of the gut).
Adrenoblockers and sympatholytics belong to autonomic and are described in
detail in Chapter 8.
MYOTROPIC VASODILATORS
CALCIUM CH AN N EL B LO C K E R S
Calcium channel blockers (nifedipine, verapamil, amlodipine) have an anti
hypertensive action resulting from the dilatation of blood vessels and a decrease in
peripheral vascular resistance. They are suitable for chronic use in hypertension of
any severity. The choice o f calcium channel blockers is grounded on the effect of
the drug on cardiac pacemakers and contractility and coexisting diseases (angina
pectoris, bronchial asthma, peripheral vascular diseases). «
Detail description o f these agents is represented in chapter 17.
MAGNESIUM SA LTS
MAGNESIUM SU LFA TE
is administered IV, IM (after the oral administration acts as laxative)
is an antagonist o f calcium ions in cells
a sedative, hypnotic and narcosis action, the inhibition o f the vasomotor
center; an anti-seizure action, the dilatation o f blood vessels, and a decrease
in BP; an anti-arrhythmic action, the dehydratation o f tissues, a diuretic ac

tion, a decrease in intracranial pressure; a spasmolytic action; an antidote
in acute poisonings with compounds o f calcium
• is used in hypertensive emergency, chronic hypertension, seizures attack,
edema o f the brain, tachyarrhythmia, myocardial infarction, toxicosis of
pregnancy, overdose of calcium preparations
• may cause side-effects, such as pain and infiltrate in the site of administration
(IM), suppression o f respiration (IV). If the suppression o f respiration is oc
curred, calcium chloride (IV) and Carbogenum (inhalation) should be used.
PHOSPHODIESTERASE INHIBITORS
BEN D AZO LE (DIBAZOLUM)

• a synthetic preparation, an imidazole derivative
is administered IM, IV, orally; acts during 4-6 hrs
inhibits PDE III and increases the amount o f cAMP in cells, that’s why
produces the relaxation o f smooth muscles and dilation o f blood vessels
has antihypertensive and spasmolytic actions; stimulates functions o f the
spinal cord; is an interferon inductor
is indicated in hypertensive emergency, mild hypertension, spasms of blood
vessels, spasms o f smooth muscles in the gut, colic, neurological diseases
with lesions o f the spinal cord, non-specific prophylaxis o f viral infections,
is combined with papaverine to elevate antihypertensive activity.
POTASSIUM CH AN N EL O PEN ER S
APPRESSIN (HYDRALAZIN)
• is administered orally, IM, IV; begins to act slowly (even after IV ad
ministration); is well absorbed in the GI tract; is metabolized in the liver
by acétylation; the speed of acétylation in one patient differs from that in
another (rapid and slow acétylation); is excreted with urine and feces; acts
during 4-12 hrs
activates K+ channels, causes hyperpolarization and the blockage o f
Ca^channels, relaxes arteriolar smooth muscles and dilates arteriolar ves
sels; as a result, decreases peripheral vascular resistance and decreases BP
displays an antihypertensive action, increases the heart rate and car
diac output (resulting from reflexes, as well as from a direct action on
PH ARM ACO LOG Y. V. M. Bobyrov, T, 0. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
P-adrenoceptors in the heart); elevates pressure in the lung artery; increases

renin secretion
is used to treat moderate and severe hypertension, CHF
is combined with P-adrenoblockers and diuretics
causes side-effects, such as weakness, headache, tachycardia, worsen in
angina, flushing of skin, sweating, reversible lupus-like syndrome, reten
tion o f water and salts.
DIAZOXIDE
is administered orally, IV; begins to act in 2-5 min after IV administration;
has the duration o f action from 2-4 hrs (IV) to 12 hrs (orally)
is K+ channel opener, arteriolar vasodilator
produces a decrease in BP; a reflexive increase in the heart rate; a decrease
in tone of smooth muscles in the gut and uterus; inhibition o f insulin secre
tion, a decrease in renal filtration and ureic acid excretion
is used to treat hypertensive emergency and chronic hypertension
may cause tachycardia, worsening in angina pectoris and diabetes, urico-
semia, constipation.
MINOXIDIL
is the K+ channel opener, arteriolar vasodilator
is more potent than hydralazin
is used for severe hypertension, renal failure, alopecia (as ointment)
may cause hyrsutism as a side-effect.
O TH ER VASODILATORS
SODIUM NITROPRUSSIDE
is administered by IV infusion; begins to act within 1 min; stops to act in 5
min after the end o f IV infusion
contains group NO binding the Fe, that’s why the mechanism o f action is the
same as the mechanism o f nitroglycerine; exceeds nitroglycerine’s potency
in 1000 times; is a arteriolar and venous vasodilator
decreases BP; decreases the load on the myocardium; increases cardiac
output under the conditions o f heart failure; increases the secretion o f renin
* is used in hypertensive emergency, acute heart failure, edema of the lungs,

controlled hypotension in surgeries
may cause hypotension, nausea, headache, sweating, restlessness, retros
ternal pain.
DRUGS ACTING
ON RENIN-ANGIOTENSIN SYSTEM
A C E INHIBITORS
Mechanism of action
ACE inhibitors block ACE and disturb the transformation o f angiotensin I into
angiotensin II.
The result is a decrease o f output o f the sympathetic nervous system, vasodila
tion, a decrease in sodium and water retention, enhance in the bradykinin level in
blood (fig. 19.2).
Pharm acodynam ics

• vasodilation caused by diminishing o f angiotensin II contensandan increase
in the bradykinin level in blood
a decrease in the blood volume resulting from the inhibition of the secretion
o f aldosterone and reducing of its action on sodium and water excretion
• a decrease in BP resulting from the vasodilatation and a decrease o f blood
volume
• a decrease in the load on the myocardium
• an increase in cardiac output under the conditions o f heart failure
• a decrease in oxygen demand o f the myocardium
• the reduction o f pressure in blood vessels o f the lungs
• the retention o f potassium in the organism.
Indications
Hypertension
Chronic CHF
Myocardial infarction.
Kidney I A C E inhibitors
, ■ *•- RR|.
HOOC y
;4nn. ?// V -- Captopril

/ •"■)» vfe" ; / \ — 1 CH,
4 :. . T
HOOC
&
o ^ o '— 'CH,
Renin Enalaprilat Enalapril
Anglotenslnogen i j t ACE
(a,-globulln) \ Angiotensin I- ^
Ang I
converting- <g? Kinina
enzyme
Angiotensin I (Ang I) <g? Kininase

COOH ST II
i )
Degradation
products
Vascular i v
endothelium
Angiotensin II
H,N
Receptors
Fig. 19.2. Renin-angiotensin system and mechanism of action of ACE inhibitors

and angiotensin II-receptor inhibitors (by H. Lullmann, 2000). ,
Side-effects
1. Dry cough, spasm o f bronchi (resulting from an increase in the bradykinin
level)
2. Skin rash
3. Fever
4. Hypotension
5. Hyperkalemia
6. Disturbance in the renal function
7. Altered taste (dysgeusia).
Captopril is taken orally; reaches peak blood level in 60 min; has the duration
of action o f 6-8 hrs; is eliminated from the body within 24 hrs; the initial dose can
he increased in 1- to 2-week intervals.
Enalapril is more potent than captopril; has the duration of action which is twice
us long as that o f captopril; is taken orally once or twice a day.
Lisinopril is the active metabolite o f enalapril; is absorbed slowly and has a
slow onset o f action; is taken orally once a day.
ANTAGONISTS OF ANGIOTENSIN R ECEPTO R S
LO SARTAN
is taken orally and acts during 6-8 hrs
blocks angiotensin II receptors, dilates blood vessels, decreases BP and
load on the myocardium
is used for the monotherapy o f hypertension and CHF
has less side-effects than ACE inhibitors, does not cause dry cough and a
spasm o f bronchi.
DIURETICS
All the oral diuretics are effective in the treatment of hypertension, but thiazides
(hydrochlorothiazide, = dichlothiazide) have found the widest use. They act on the
cell basal membrane in proximal tubules and decrease the reabsorption of sodium
mid chlorides. As a result, they increase sodium, chlorides, potassium and water
excretion with urine, decrease the volume o f blood and edema of blood vessel wall
lhat leads to a decrease in peripheral resistance and lowering of BP.
Furosemide is a loop diuretic which is used parenterally in hypertensive emer
gency.
Potassium-sparring diuretics may also be used to treat hypertension. They
net in distal tubules, increase excretion o f sodium and water, cause the retention of
potassium in the body.
DRUGS FOR HYPERTENSION EM ERG EN CY

I'tir p a re n te ra l a d m in istra tio n :
sodium nitroprusside (by IV infusion in severe hypertensive crisis)
labetalol
- Pentaminum
- furosemide
- magnesium sulfate
- bendazole and papaverine
- diazoxide
F o r s u b lin g u a l a d m in istra tio n :
- clonidine
- nifedipine
- captopril.
HYPERTENSIVE DRUGS
To treat acute hypotension (collapse, shock) it is used a-adrenomimetics (no
radrenaline, phenylephrine), a, fi-adrenomimetics (adrenal ine, ephedrine), analeptics
(camphor, nikethamide).
To treat chronic hypotension it is used phenylephrine (in the form o f tablets),
analeptics (caffeine), adaptogens.
All the listed preparations are described in detail in Chapters 7, 14, 15.
T E S T S FOR SELF-CO N TR O L
№ 1. In hypertensive emergency the drugs o f the first choice are:
A. Clonidine + furosemide
B. Metyldopa + dichlothiazide
C. Reserpine + dichlothiazide
D. Guanetidine + dichlothiazide
E. Strophanthin + furosemide.
№ 2. Only one o f following drugs is a potent vasodilator realizing its effects

through the -N O group:
A. Papaverine
B. Drotaverine (No-spa)
C. Sodium nitropusside
D. Prazosin
E. Captopril.
№ 3. An antihypertensive action o f p-adrenoblockers is due to:

A. A decrease o f cardiac output
Chapter 19. ANTIHYPERTENSIVE DRUGS. HYPERTENSIVE AGENTS 239
B. The inhibition o f the conductivity in the heart

C. A decrease of the oxygen demand in the myocardium
D. A decrease of the renin synthesis in the kidney
E. A decrease o f intraocular pressure.
№4. The correct statements concerning antihypertensive drugs are:

A. Clonidine is the inhibitor of the vasomotor center activity
B. Diazoxide is K+-channel opener, arteriolar vasodilator
C. Guanethidine is sympatholytic for hypertensive emergency
D. Lisinopril is the active metabolite o f enalapril
E. Diuretics are not combined with other antihypertensive drugs.
№ 5. Hypertensive patient was treated with the drug that decreases the vascular
tone. His treatment was complicated by persistent dry cough. Which drug was most
probably used?
A. Papaverine
B. Phentolamine
C. Captopril
D. Prazosin
E. Clonidine (Clophelinum).
A n sw e rs
№ 1 - A; № 2 - C ; № 3 - A, D; № 4 - A, B, D; № 5 - C.
|
20
/ 1 1
O Êm \t
ANTI-ATHEROSCLEROTIC
DRUGS
ATHEROSCLEROSIS
Atheroscleosis is a chronic disease o f arteries which results in the forming of an
atheromatous plaque. An atheromatous plaque develops in such stages as the infil
tration o f the blood vessel wall by cholesterol, local forming o f fibrin, development
o f connective tissue and its calcinosis (fig. 20.1). An atheromathous plaque causes
disturbances in blood flow complicated by myocardial infarction, ischemic insult,
aneurism o f the aorta, and gangrene o f extremities.
M ain links o f p a th o g e n e sis

There are four main links in the development o f atherosclerosis:
hyperlipoproteinemia
• an increase in free-radical lipid peroxidation
hypercoagulation o f blood
lesions o f endothelium.
Hypcrlipoprotienemia
The main classes o f lipoproteins are:
- chylomicrones (Chy)
- low-density lipoproteins (LDL)
Chapter 20. ANTI-ATHEROSCLEROTIC DRUGS 241
Normal Mild Severe

Artery Atherosclerosos Atherosclerosis
Fig. 20.1. Atheromathous plaque in blood vessel (http://www.picsearch.com).
- very low-density lipoproteins (VLDL)

- high-density lipoproteins (HDL).
Chy, LDL, VLDL are atherogenic lipoproteins. HDL are anti-atherogenic lipo
proteins. According to laboratory findingds, there are 5 types of hyperlipoproteinemia.
Hyperlipoproteinemia o f type II—IV leads to the development o f atherosclerosis.
Lipids peroxidation
Lipids peroxidation is non-enzymic oxidation initiated by free radicals of
oxygen. It destroys cell membranes and leads to the forming of lipids peroxides. An
increase in lipids peroxidation and the inhibition o f antioxidant protection results
in the injuries of the blood vessels wall. Oxidized lipids are taken by macrophages
which are transformed into foam cells (components o f an atheromathous plaque).
H ypercoagulation o f blood
An increase in platelet aggregation and adhesion leads to an increase in blood
coagulation and to the sedimentation of fibrin on the site of injured inthima o f arteries
that is a prediction o f an atheromatous plaque.
E ndothelium lesions
Normal endothelium has no gaps through which atherogenous lipoproteins
and cholesterol can enter the blood vessels wall. The contraction of, endothelial
cells caused by bradykinin leads to the forming of such gaps and opens the way to
cholesterol infiltration o f the wall of arteries.
242 PH AR M ACO LO G Y. V. M. Bcbyrov,T. 0. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
Principles o f pharm acotherapy o f atherosclerosis

There are the following basic principles o f pharmacotherapy of atherosclerosis:
An early beginning o f treatment
A long-durative treatment
• Courses o f treatment in the periods o f worsening o f disease caused by the
season deficit o f antioxidants, stress, etc.
• The choice o f preparations according to a leading clinic-laboratory syndrome
The oral administration o f drugs and their minimal toxicity under the condi
tions o f long-lasting therapy
The laboratory control o f the effectiveness o f treatment.
ANTI-ATHEROSCLEROTIC DRUGS
Anti-atherosclerotic drugs are drugs for the treatment o f atherosclerosis. They
protect arteries from atherosclerosis and are angioprotectors (fig. 20.2).
A N T I-A T H E R O S C L E R O T IC
DRUGS
A n tih yperlipop rotein em ic drugs A
C (■G- hyperlip oproteinem ia)________ J
A ntioxidants
( 0 lipids peroxidation)
j f A n ti-p latelet drugs A

I _______ (0 platelet aggregation)_________ J
E nd otheliu m -tropic drugs

1 (1} perm eab ility o f endoth elium )
F ig. 20.2. M ain groups o f anti-atherosclerotic drugs.
ANTIHYPERLIPOPROTEINEMIC DRUGS
Antihyperlipoproteinem ic drugs are preparations for a decrease o f blood sesum
level o f atherogenous lipoproteins and cholesterol.
Chapter 20. ANTI-ATHEROSCLEROTIC DRUGS 243
CLASSIFICATION
1. Drugs interfering with intestinal absorption o f cholesterol
- Polysponinum
- Cholestiramine
2. Inhibitors o f de novo cholesterol synthesis
- Fenofibrate
- Lovastatin
- Nicotinic acid (niacin)
.1. Drugs increasing cholesterol catabolism
- Linaetholum
- Lipostabil
POLYSPONINUM
• is a plant preparation; contains saponins from Dioscorea (fig. 20.3)
• is taken orally 2-3 times daily; is not absorbed in the gut and acts in the
intestine
Fig. 20.3. D ioscorea is for Polysponinum.

binds to cholesterol, forms insoluble compounds which are excreted with

feces. This decreases the amount o f cholesterol received by the liver from
the gut and compensatorily increases the expression of hepatic LDL recep
tors. Such processes result in an increase o f capture o f LDL and cholesterol
from blood serum and the reduction o f serum LDL and the cholesterol level
is used for atherosclerosis with hyperlipoproteinemia o f II-IV types
may cause dyspepsia, rhinitis.
CHOLESTYRAMINE
is a synthetic preparation (resin)
is taken orally in a day dose o f 10,0-20,0
is a bile acid séquestrant: binds to bile acids in the intestine, forms insoluble
compounds which are excreted with feces. A loss of bile acids leads to an
increase in the conversion o f cholesterol into bile acids in the liver and a
compensatory increase in hepatic LDL receptors. That results in enhanced
capture o f LDL and cholesterol from blood serum and reduction in serum
LDL and the cholesterol level (fig. 20.4)
• is indicated in atherosclerosis with hyperlipoproteinemia o f II-IV types,
cholestasis, and elevated plasma bile acids
F ig . 20.4. Mechanism of cholestiramine’s action (by R. F inkel et al., 2008).

Chapter 20. A N T I-A T H E R O S C L E R O T IC D R U G S 245
causes side-effects, such as dyspepsia, constipation, a decrease in the ab

sorption o f fat-solubie vitamins and other drugs.
LOVASTATIN
belongs to statins; is a structural analog o f 3-hydroxy-3-methylglutaryl
coenzyme A (HMG CoA) (metabolite in cholesterol biosynthesis)
is taken orally once a day (in the evening); is a pro-drug (transforms into
the active form in the blood)
inhibits HMG CoA reductase and blocks the hepatic synthesis of cholesterol
on the stage o f the mevalonic acid, increases the expression o f hepatic LDL
receptors and activates receptor-mediated clearance o f LDL (fig. 20.5)
• decreases serum levels o f LDL, LDL-cholesterol, VLDL-cholesterol; el
evates serum level o f HDL-cholesterol
is used to treat atherosclerosis with hyperlipoproteinemia o f lla-IIb type,
atherosclerosis at a high risk of myocardial infarction; secondary hyperlipi-
demia resulting from diabetes mellitus or a nephrotic syndrome
may cause an increase in serunj level o f hepatic transaminases, dyspepsia,
diarrhea, myopathy, renal failure.
FENOFIBRATE
is a fibric acid derivative
is taken orally 2-3 times daily
has a complex mechanism o f action: 1) is an agonist o f the nuclear tran
scription regulator o f the genes coding enzymes o f lipid metabolism; 2) is
a stimulator o f peroxysome proliferator-activated receptor-a (PPAR-a); 3)
is an activator of lipoprotein lipase and increases the hydrolysis of triglyc
erides; 4) is an inhibitor of hepatic synthesis o f VLDL
reduces the serum level of Chy, VLDL, and triglycerides, lowers VLDL-
cholesterol, LDL-cholesterol and increases HDL-cholesterol (less than
triglycerides); also reduces plasma fibrinogen; activates fibrinolysis; inhibits
inflammation in the vascular wall
is indicated in atherosclerosis with the hyperlipoproteinemia of III or V type
may cause dyspepsia, myositis, myopathy, cholelithiasis, cholecystitis,
arrhythmia.
NICOTINIC ACID (NIACINUM)

is a water-soluble vitamin, but an anti-atherosclerotic action is not due to
vitamin activity
Fig. 20.5. The influence of statins on cholesterol synthesis (by H. Lullmann, 2000).
is taken orally in higher doses (3,0 per day)

inhibits lipolysis in fat tissue and hepatic triglyceride esterification; promotes
the activity o f lipoprotein lipase
reduces VLDL and triglycerides levels; elevates the level o f HDL; inhibits
platelet aggregation, increases fibrinolysis, and dilates blood vessels
is used in atherosclerosis with hyperlipidemia, especially o f V type
may cause a flush-syndrome, peptic ulcer o f the stomach, hepatic lesions,
glucose intolerance, hyperuricemia.
LINAETHOLUM
• is a plant preparation from oil of flax semen
contains unsaturated fatty acids
is taken orally (1 table-spoon per day)
• increases binding o f cholesterol to HDL; promotes the transformation of
cholesterol into its esters and their transport to the liver; stimulates trans
formation o f cholesterol into bile acids and reduces the serum level o f LDL
and LDL-cholesterol
is used for the treatment of atherosclerosis with hyperlipoproteinemia of
Il-IV types
may cause dyspepsia, an increase in lipids peroxidation (tocopherol acetate
should be given together with Linaetholum).
LIPOSTABIL
is a combined preparation containing essential phospholipids, vitamins,
AMP, and hydroxyethyltheophylline
is taken orally, may be administered IV under the conditions of hepatic
diseases or fat embolism
has the mechanism o f action similar to the mechanism o f Linaetholum, but
acts stronger, protects hepatic cells, can dissolve fat emboli
*. is used in atherosclerosis with hyperlipoproteinemia, liver diseases, fat
embolism.
ANTIOXIDANTS
A ntioxydants are natural or synthetic substances which inhibit free-radical
lipids peroxidation. »
CLASSIFICATION
1. Direct-acting antioxidants
- Tocopherol acetate
- Ascorbic acid
- Rutin
- Probucol
2. Indirect-acting antioxidants
- Glutaminic acid
- Methionine
- Cysteine.
248 PH AR M ACO LO G Y. V. M. Bobyrov,T. 0. Devyatkina, 0. M. Vazhnicha, V. M. Klwwlv»*
M e ch a n ism o f a n tih y p erlip o p ro te in e m ic action

D irect-acting antioxidants inhibit oxidation o f cholesterol resulting in lit*
ingestion o f the oxidized cholesterol laden LDL by macrophages. That’s why lit. t
inhibit the conversion o f macrophages into foam cells which are the basis for
formation (fig. 20.6).
Indirect-acting antioxidants do not interact with free radicals and p eim ulu
They are needed for the synthesis o f glutathion (natural direct antioxidanl whit It
supports the activity o f the ascorbic acid and takes part in detoxication proccv..-. in
the liver). In this process, the glutaminic acid takes out the carbon chain, melhyimin#
is a donator o f methyl group, cysteine is a donator of the SH-group.
Indications
Antioxidants are used for the treatment o f atherosclerosis accompanied by
enhanced lipids peroxidation. Their effectiveness is increased if antioxidanl pnpm*
tions are used in a combination.
Foam cells accumulate

ANTIOXIDANTS and release growth factors
that stimulate formation of
atherosclerotic plague
Fig. 20.6. Mechanism of antioxidants action in atherosclerosis

tfw p trr 20. A N T I-A T H E R O S C L E R O T IC D R U G S 249
Tocopherol acetate is a fat-soluble vitamin; is taken orally to treat athero-
l*rosis; is the most active low-weight antioxidant in the organism; is located in
Uihrane lipids; neutralizes all kinds o f free radicals and peroxides; decreases
I,-cholesterol, inhibits the destruction o f elastic fibers in the vascular wall and
lilng o f atheromathous plaque; decreases platelet aggregation.
Ascorbic acid is a water-soluble vitamin; is taken orally for the treatment o f
erosclerosis; is an active low-weight antioxidant which acts in the hydrophylic
*c o f membranes; it neutralizes free radicals and peroxides, as well as supports
activity o f tocopherol; takes part in cholesterol synthesis in the liver; inhibits
destruction o f vascular wall and forming o f atheromathous plaque, normalizes
tents of lipoproteins and cholesterol in blood serum.
Detail description o f antioxidants is represented in Chapter 27.
ANTI-PLATELET DRUGS
Aspirin and low doses of heparin (lM ,or by inhalation) are used for the treat-
lit til'atherosclerosis accompanied by hypercoagulation of blood.
Pharmacological properties of anti-platelets are described in detail in chapter 22.
ENDOTHELIUM-TROPIC DRUGS
PARMIDIN (PRODECTIN)
• is taken orally 2-3 times daily
• is an antagonist of bftadykinin. It decreases the influence of bradykinin on
endothelial cells and in such a way decreases contractions o f endothelial
cells. The absence o f gaps between endothelial cells makes impossible
the transport o f LDL-cholesterol into the vascular wall and decreases the
infiltration o f blood vessels wall by cholesterol (fig. 20.7)
• decreases the permeability ofthe blood vessels wall, stimulates endothelium
regeneration, inhibits inflammation, has an anti-platelet action
• is used to treat atherosclerosis (especially o f peripheral vessels or with
out any significant changes in laboratory analyses), diabetic angiopathy,
thrombosis o f veins in the retina, endarteritis obliterans, trophic ulcer o f
the lower extremities
• may cause headache, dyspepsia, skin rash.
F ig. 20.7. M echanism o f p a rm id in ’s action:

A - w ithout parm idin; B - u nder the influence o f parm idin.
Jftl. Cholestyramine lowers the level o f cholesterol by:
A. Sequestering bile acids in the intestine
B. The prevention o f bile acids reabsorption
C. An increase o f VLDL excretion
D. The inhibition o f lipids peroxidation
E. The activation o f lipoprotein lipase.
№ 2. The following statements concerning antioxidants are correct, except:

A. They inhibit free-radical lipids peroxidation
B. They inhibit the oxidation o f cholesterol and its uptake by macrophages
C. They slow the development o f atherosclerosis
D. They inhibit the synthesis o f cholesterol at the stage o f the mevalonic acid
E. Direct acting antioxidants are natural and synthetic substances.
№ 3. The drugs inhibiting de novo cholesterol synthesis are:

A. Lovastatin
B. Parmidin
C. Fenofibrate
D. Polysponinum
E. Tocopherol acetate.
№ 4. Fibrates decrease the lipoprotein level in blood serum by:

A. The activation o f lipoprotein lipase
B. Lowering o f circulating triglycerids
C. The prevention o f cholesterol absorption from the gut
D. The alteration o f LDL composition
E. All the above listed.
№ 5. A 60-year old patient visited her doctor for routine examination. Blood
sampling revealed an elevated level o f VLDL and triglycerides in blood plasma. Due
to this anti-atherosclerotic drug was prescribed. This drug belongs to vitamin prepa
rations and in higher dose enhances lipoprotein lipase synthesis and decreases the
level o f triglycerides in blood. It also dilatesTdood vessels and increases fibrinolysis.
What drug was prescribed?
A. Nicotinic acid
B. Ascorbic acid
C. Lovastatin
D. Fenofibrate
E. Cholestyramine.
A n sw e rs
№ 1 _ A; № 2 - D; № 3 - A, C; № 4 - A, B, D; № 5 - A.
21
m
f / I DRUGS ACTING ON
O M I HEMOPOIESIS (HEMATINICS)
HEMOPOIESIS
Hemopoiesis is the production o f blood cells from undifferentiated stem cells.
It is located in the bone marrow and divided into erythropoiesis and leukopoiesis.
Erythropoiesis is the production o f erythrocytes in the bone marrow. The de
velopment o f erythrocytes is accompanied by the reduction o f nuclei and saturation
by hemoblobin.
Pathology o f erythropoiesis displays as anemia or polycytemia.
A nem ia is blood disorder characterized by a reduction of erythrocytes count,
hemoglobin, and hematocrit, although not all three findings may be present.
Types o f anemia:
hypochromic iron-deficiency anemia (fig. 21.1)
hyperchromie megaloblastic anemia (fig. 21.1)
hemolytic anemia
• aplastic anemia.
Polycytemia is a disease with highly increased red blood cells mass and hemo
globin concentration caused by the pathological proliferation o f erythroid cells in
the bone marrow.
Chapter 21. D R U G S A C T IN G O N H E M O P O IE S IS (H E M A T IN IC S ) 253
Q
PNA Inhibition o(
sy n th e t hemoglobin synthesis
Vit. B,J deficiency

Iron deficency
.
Folate deficiency
A very few large A few small

hemoglobin-rich hemoglobin-poor
erythrocytes erythrocytes
(B ® C3 C) C3
Fig. 21.1. P athology o f e rythropoiesis (by H . L üllm ann, 2000).
Leukopoiesis is the production o f lymphocytes and granulocytes.

Pathology o f leukopoiesis is manifested as leukopenia or leukemia.
Leukopenia is a decrease in the amount o f leukocytes in blood resulting from
the inhibition o f their forming in the bone marrow.
Leukem ia (leukosis) is cancer o f blood characterized by malignant prolifera
tion o f white blood cells precursors in the bone marrow resulting in the increase of
the leukocytes amount.
&
DRUGS ACTING ON HEMOPOIESIS

Drugs acting on hemopoiesis (hematinics) are divided into agents acting on
erythropoiesis and agents acting on leukopoiesis. Stimulants and inhibitors are rep
resented in each group.
DRUGS ACTING ON ERYTHROPOIESIS

CLASSIFICATION
A . Erythropoiesis stimulants
1. Drugs used in hypochromic iron-deficiency anemia
254 PH AR M ACO LO G Y. V. M. Bobyrov,T. 0. Devyatkina, 0. M. Vazhnicha,V. M. Khristyuk
a) iron preparations
- Ferrous lactate
- Ferrous sulfate
- Ferrum-lek
b) cobalt preparations
- Coamid
c) combined preparations
- Ferovenum
- Ferroplex
- Hemostimulinum
d) adjuvant hematinics
- Erythropoetin (Epoetin a)
- Recormon (Epoetin p)
2. Drugs used in hyperchromie megaloblastic anemia
- Cyanocobalamin
- Folic acid
B. E r y th r o p o ie s is in h ib ito r s
- Sodium phosphate containing P32
- Imiphos.
DRUGS USED IN HYPOCHROMIC

IRON-DEFICIENCY ANEMIA
FER RO US L A C T A T E
The drug contains Fe++.
P h a rm a co k in e tics
is taken orally
is transformed into the ionic form with the participation o f HCL in the
stomach; is absorbed in the intestine (Fe‘ *binds to apoferritin and in the
form o f ferritin crosses intestinal epithelium) (fig. 21.2)
absorption in the GI tract is 10-20% of a dose and increases under the
conditions o f anemia
Fe++ absorption is stimulated by vitamin C and glucose and inhibited by
calcium, antacids, tetracycline, chloramphenicol
Fe++ binds to transferrin in blood serum and is transported in this complex
concentrates in the bone marrow and depo tissues (liver, spleen)
is excreted with urine, feces, epithelial cells, and menstrual blood in women.
Uptake into macrophages

spleen, liver, bone marrow
F ig . 21.2. Pharmacokinetics of iron (by II. Liillmann, 2000)

is used to form hemoglobin in erythrocytes
is used to form myoglobin in muscles
is used to form enzymes (cytochrome oxidase and others).
Pharm acodynam ics

an increase in the amount o f red blood cells
an increase in the saturation o f erythrocytes by hemoglobin
• the reduction o f symptoms o f anemia (weakness, paleness, tachycardia,
etc.) which begins in 5-7 days after the start o f treatment.
Indications
Hypochromic anemia o f various ethiology (anemia from an acute and chronic
blood loss, alimentary iron deficiency, pregnancy, etc.).
Side-effects C o n tr a in d ic a tio n s
1. Dyspepsia 1. Hemolytic anemia
2. Constipation (resulting from binding o f iron 2. Hemosiderosis, hemo
with H2S in the intestine and bowels) chromatosis
3. Teeth darkness (resulting from the binding of
iron to H,S in the oral cavity and forming of
black compound FeS)
4. Black color o f feces imitating intestinal
bleeding
5. Hemosiderosis
6. Allergy.
Acute poisoning with ferrous com pounds

Signs:
- The irritation and necrosis o f the gastric mucosa
- Lesions o f the liver and brain
- Collapse, coma.
Em ergency help:
- The lavage of the stomach with 1% solution of sodium bicarbonate
- Albumin solution (orally)
- D esferal (IV) as an antidote.

Ferrum -lek is a compound o f iron with maltose or saccharose; is made in two
forms: the 1st form - for IM administration (maltose-containing); the 2nd one - for
IV administration (saccharose-containing); is used for anemia resulting from iron
malabsorption or for severe anemia; may cause nausea, vomiting, allergic reactions,
hypotension (rarely).
Coam id contains cobalt; is administered IM, IV; accumulates the bone mar
row; increases the synthesis o f erythropoietin, promotes the including o f iron into
hemoglobin; is the additional remedy in the treatment o f hypochromic anemia, is
used together with iron preparations.
Fercovenum is a combined preparation containing ferrous saccharate, cobalt
gluconate, and carbonhydrates; is administered only IV in a dose which is calculated
according to color index and the patient’s body weight; is used for severe hypochromic
anemia (hemoglobin level may be restored during the 1st day o f the treatment) and
for anemia on the ground of iron malabsorption; may cause side-effects, such as face
hyperemia, retrosternal pain, hypotension, a shock-like reaction.
Ferroplex is a combined preparation in the form o f dragee which contains fer
rous sulfate and vitamin C.
H em ostim ulinum is in the form of tablets; contains ferrous lactate and copper
sulfate; stimulates erythropoiesis, as well as the synthesis o f oxido-reductases needed
for normal function o f CNS.
Epoetin p is glycoprotein, natural factor stimulating mitosis and proliferation
o f erythroid cells; is administered SC or IV; has half-elimination o f 4-12 hrs after
IV injection and 12-28 hrs after SC administration; is used for the treatment o f hy
pochromic anemia in patients with renal failure, for the prevention and treatment
o f anemia resulting from cancer chemotherapy, anemia accompaning myelomic
disease, before autohemotransfusion, and for the prevention o f anemia in premature
newborns; may cause side-effects, such as hypertension, hypercoagulation o f blood,
skin rash, allergy; is contraindicated in hypersensitivity, hypertension, myocardial
infarction, prone to thrombus formation.
DRUGS USED IN HYPERCHROMIC

M EGALO BLASTIC ANEMIA
The folic acid and cyanocobalamin (vitamin B |2) are necessary for the normal
formation o f red and white blood cells. The deficit o f cyanocobalamin or the folic
acid results from dietary factors, poor absorption, or therapy with folate antagonists
(metotrexate, sulfa drugs, trimethoprim). It leads to the development of megaloblastic
anem ia (= malignant, pernicious, Addison-Birmer’s anemia). Megaloblastic anemia

is characterized by the presence o f megaloblasts in blood, hyperchromic condition,
CNC disturbances, and glossitis.
CYANOCOBALAMIN
is a water-soluble vitamin
is taken orally, is administered IM, IV; binds to an intrinsic Castle factor in
the stomach and is absorbed in the intestine by endocytosis; concentrates
in the liver
is biotransform ed to cobalam in, co-factor o f the folic acid reductase
(fig.21.3), takes part in the synthesis o f purine and pyrimidine nucleotides
and transforms megaloblastic hemopoiesis into normoblastic one, normal
izes the blood film (the amount and qualities o f erythrocytes, leukocytes,
and thrombocytes);
takes part in the synthesis o f myelin and acetylcholine, decreases neurologi
cal disturbances connected with megaloblastic anemia
takes part in the function o f the epithelium and decreases disturbances in
tongue mucosa (Hunter’s glossitis)
is indicated in hypercromic megaloblastic anemia, hypoplastic anemia,
radiation sickness, neurological diseases, liver diseases, dystrophy in chil
dren, glossitis
may cause allergy, hypercoagulation, tachycardia, pain in the heart, worsen
in angina pectoris.
is contraindicated to patients with hypersensitivity, thrombosis, throm
boembolism.
FOLIC ACID
is a water-soluble vitamin
is taken orally; is absorbed in the small intestine and deposited in the liver
(fig. 21.3)
takes part in the synthesis o f purine and pyrimidine nucleotides, amino
acids and proteins
is the additional remedy in the treatment o f hyperchomic megaloblastic
anemia; is used together with cyanocobalamin; is also indicated in chronic
gastro-enteritis, sprue, in pregnancy for the prophylaxis o f neurological
pathology o f the fetus and newborn.
Fig. 21.3. Absorption and storage of folates and cyanocobalamin

(by H. Liillmann, 2000).
ERHYTHROPOIESIS INHIBITORS
Sodium phosphate with radioactive phosphor is administered IV in a special
clinic; is absorbed by erythoblasts and kill them due to radiation, that’s why inhibits
red blood cells forming, decreases the amount of erythrocytes and viscosity o f blood,
improves the condition o f patient suffering from polycytemia.
Im iphos is an anti-cancer drug; interacts with DNA and inhibits production o f
red blood cells in the bone marrow and in such a way improves the condition o f the
patient with polycytemia.
DRUGS ACTING ON LEUKOPOIESIS
CLASSIFICATION
A . L e u k o p o ie s is s tim u la n ts
1. Nucleic acid derivatives
- Sodium nucleinate
2. Pyrimidine derivatives
- Methyluracilum
- Pentoxilum
3. Colony stimulating factors
- Filgrastim
- Molgrastim
B . L e u k o p o ie s is in h ib ito r s a n d a n ti- c a n c e r d r u g s
1. Alkylating agents
- Mechlorethamide (Embichinum)
- Cyclophosphamide
- Dopanum
- Myelosanum
2. Antimetabolites
- Methotrexate
- Mercaptopurine
- Phtoruracil
3. Anti-cancer antibiotics
- Actinomycin (Dactinomycin)
- Rubomycin
4. Alkaloids
- Vinblastine
- Vincristine
- Demecolcine (Colchaminum)
5. Enzymes
- L-asparaginase
6. Steroid hormones
- Prednisolone
- Gonadal hormones and their antagonists
(Fosfestrol, Tamoxifen, etc).
LEUKOPOIESIS STIMULANTS
METHYLURACILUM
is a pyrimidine derivative
is administered orally, rectally, or applied topically (as ointment); is well ab
sorbed in the GI tract and completely metabolized in the body; acts during 4-6 hrs
is the substrate for the synthesis o f nucleic acids
• stimulates leukopoiesis and increases the amount o f white blood cells;
stimulates phagocytosis and immunity; improves tissues regeneration; ac
celerates the development and ending o f inflammation
is indicated in leucopenia, wounds and bone fractures with poor regeneration,
ulcers, bums, gastric ulcer, chronic inflammations with slow recovering,
radiation sickness, suppressed immunity, paradontitis
may cause dyspepsia, allergy
is contraindicated in severe disturbances o f leukopoiesis, aplastic anemia,
leukemia, cancer.

Pentoxylum acts similar to Methyluracilum, but irritates the skin and mucous
membranes; is not applied rectally or topically.
Sodium nucleinate is produced by hydrolysis o f nucleic acids; may be admi
nistered parenteraly; causes allergic reactions.
M olgrastim is glycoprotein, natural colony stimulating factor which stimulates
the proliferation and differetiation of granulocytes precursors in the bone marrow;
is administered IV for the treatment of agranulocytosis.
LEUKOPOIESIS INHIBITORS AND ANTI-CANCER DRUGS

Leukopoiesis inhibitors are drugs for the treatment o f leukemia and cancer.
They inhibit functions o f DNA at different stages o f a cell cycle and are cytostatics.
These drugs also are immunity depressants. They are also used in collagenosis and
autoimmune diseases.
MAIN GRO UPS OF LEUKOPOIESIS INHIBITORS

Mechanism of action and clinical use
Antim etabolites (methotrexate, 6-mercaptopurin) are structural analogs of
natural compounds and block enzymes participating in the synthesis of nucleic acids
262 PH ARM ACO LO G Y. V. M. Bobyrov, T. 0 . Devyatkina, 0 . M. Vazhnicha, V. M. Khristyuk
(fig. 21.4). Their maximal cytotoxic effects are S-phase specific. Methotrexate is used
to treat acute lymphocytic leukemia, B urkitf s lymphoma, chorioncarcinoma, breast
cancer, head and neck carcinomas. 6-mercaptopurine is used in the maintenance o f
remission o f acute lymphoblastic leukemia.
Purines
Dihydrofolate
Tetrahydro-
foiate
Thymine
Reductase \
Nucleotide Folic acid
h2ny m _ n
-
Inhibition by
Aminopterin
Methotrexate
Fig. 21.4. Mechanism of action of methotrexate (by H, Lullmann, 2000).
A lkylating agents (Chlorbutinum , Dopanunt, M yelosanum) are biotransfor

mated in anions interacting with nucleophylic centers of DNA (fig. 21.5). As a result,
they inhibit the reduplication o f DNA and m-RNA synthesis that is lethal for tumor
cells. They are used to treat lymphatic and solid cancer. Alkylating agents are highly
toxic for all rapidly divided cells. They are mutagenic and cancerogenic (may cause
secondary malignancy).
Antibiotics (dactinomycin, rubomycin) inhibit the reduplication o f DNA«by the
mechanism o f intercalation (fig. 21.5). Effects are maximal in the S and G2 phases
(cell-cycle specific agents). They are used for the treatment of acute lymphocytic
leukemia, lymphomas, sarcomas and a variety o f carcinomas.
Enzym e (L-asparaginase) destructs amino acid asparagine. L-aspraginase hy
drolyzes blood asparagine and thus deprives the tumor cells o f this nutrient required
for protein synthesis. It is used to treat childhood acute lymphocytic leukemia in
combination with vincristine and prednisolone.
Alkaloids (vinblastine, vincristine) are “mytotic“ poisons; they block mytosis
on the stage o f metaphase (cycle-specific agents). Vinca alkaloids are microtubule
inhibitors (fig. 21.6). Vincristine is used in the treatment o f acute lymphoblastic
Alkylation
e. g., by
mechlor-
ethamine
C I-C H -C H ,
N .
Insertion of
doxorubicin,
bleomycin,
actinomycin D, etc.
Streptomyces bacteria
Fig. 21.5. Mechanism of action of alkylating agents and anti-tumor antibiotics

(byH. Lullmann, 2000).
Vinca
alkaloids
Vinca rosea
F ig . 21.6. Mechanism o f action of alkaloids (by H. Liillmann, 2000).

leukemia in children, lymphomas, W ilm’s tumor, soft tissue sarcomas. Vinblastine

is used in the combined treatment o f lymphomas and metastatic testicular carcinoma.
Steroid horm ones. Glucocorticoids (prednisolone) inhibit the proliferation o f
lymphoid tissue. They are used in patients with acute lymphocytic leukemia and
lymphomas. Sex hormones and their antagonists are used in the treatment o f hormone-
dependent cancer o f breast (in women), prostate and testis (in men).
Com m on side-effects
1. The suppression o f hemopoiesis, leukopenia, anemia, thrombocytopenia
2. The suppression o f immunity
3. A toxic action on CMS (headache, vertigo, nausea, vomiting)
4. A toxic action on the GI tract (a loss o f appetite, dyspepsia)
5. Necrotic lesions in the skin and mucous membranes including necrotic
stomatitis
6. Alopecia.
All the listed side-effects are reversible, but some of them are dangerous
for the patient and must be treated.

№ 1. Only one drug inhibits leukopoiesis:
A. Fercovenim
B. Ferroplex
C. Pentoxilum
D. 6-Mercaptopurine
E. Methyluracilum.
№ 2. All the listed is correct, except:

A. Coamid is an additional drug for the treatment o f hypochromic anemia
B. Ferroplex is combined preparation containing the iron and the ascorbic acid
C. Folic acid inhibits DNA reduplication in erythrocytes precusors
D. Pentoxilum is used for the treatment o f leukopenia
E. Inhibitors o f leukopoiesis are cytostatics and immunity depressants.
№ 3. The main effects o f cyanocobalamin include:

A. The transformation o f megaloblastic erythropoiesis into normoblastic one
B. The improvement o f leukocytes forming
C. An increase in the amount of thrombocytes

D. An anti-platelet action
E. Reducing o f the neurological symptoms o f megaloblastic anemia.
№ 4. Inhibitors o f leukopoiesis are used to treat:

A. Acute leukemia
B. Cancer
C. Aplastic anemia
D. Psoriasis and some collagen diseases
E. Leukopenia.
№5. A patient has the pale skin and mucous membranes, weakness, tachycardia.
The total amount o f red blood cells is 3,5><10I2/L. Colored index is 0,76. It is known,
that he has gastritis with lower acidity of gastric juice. Point out a correct diagnosis
and the basic preparation for the therapy.
A. Iron-deficient anemia, ferrum-lek
B. Hemolytic anemia, prednisolone
C. Anemia due to chronic renal failure, epoetin
D. Hemochromatosis, desferal
E. Megaloblastic anaemia, cyanocobalamin.
Answers:
№ 1 - D; № 2 - C; № 3 - A, B, C, E; № 4 - A, B, D; № 5 - A.
5 f t A DRUGS ACTING ON
J= W W BLOOD COAGULATION
o mmmm a n d FIBRINOLYSIS
HEMOSTASIS AND FIBRINOLYSIS

Hemostasis is the arrest o f bleeding from damaged blood vessels. It is a complex
cascade o f enzymatic reactions.
The damage o f blood vessel causes vasospasm, platelet aggregation and ad
hesion. It results in the formation o f platelet plug, activation o f clotting factors,
conversion o f fibrinogen to insoluble fibrin, clot formation, and the stop of bleteding
(fig. 22.1). Natural clotting limitation factors are heparin and antithrombin III.
Fibrinolysis is the lysis o f thrombus for the restoration o f the blood flow:
plasminogen (pro-fibrinolysin) converts into plasmin (fibrinoiysin) and causes the
lysis o f fibrin clot.
Pathology o f hemostasis and fib rin o lysis:
A decrease in blood coagulation and (or) an increase in fibrinolysis result
in bleeding
An increase in blood coagulation and (or) a decrease in fibrinolysis result
in thrombosis, thromboembolism, syndrome o f disseminated intravasal
blood coagulation.
Chapter 22. D R U G S A C T IN G O N B L O O D C O A G U L A T IO N A N D F IB R IN O L Y S IS 267
Platelets Endothelial
defect
Tissue
thrombo-
kinase
Vessel
rupture
Fig. 22.1. Initial stage of blood coagulation (by H. Liillmann, 2000).
DRUGS AFFECTING BLOOD

COAGULATION AND FIBRINOLYSIS
Drugs affecting blood coagulation and fibrinolysis include coagulants, antico
agulants, anti-platelet drugs, fibrinolytic drugs, inhibitors o f fibrinolysis (fig. 22.2).
CO A G U LA N TS
Coagulants are preparations increasing blood coagulation.
CLASSIFICATION
1. Direct-acting (are active in vivo, as well as in vitro)
- Thrombin
- Spongia haemostatica
- Fibrinogen
- Calcium chloride
- Calcium gluconate
2. Indirect- acting (are active only in vivo)
- Vitamin K (Phytomenadion)
- Vikasolum.
( D R U G S A F F E C T IN G B L O O D
\ C O A G U L A T IO N A N D F IB R IN O L Y S IS
C o a g u la n ts J
Ç A n tic o a g u la n ts 1
( A n ti-p la te le t d ru g s
C F ib rin o ly tic s )
Ç In h ib ito r s o f fib rin o ly sis J
Fig. 22.2. G roups o f drugs acting on blood coagulation and fibrinolysis.
DIRECT-ACTING C O A G U LA N TS
Thrombin is an active compound o f the blood coagulation system, is used for
the bleeding from capillary 1vessels, is applied only topically (IV administration may
cause disseminated thrombosis).
Fibrinogen is a non-active compound of the blood coagulation system, is used
by IV infusion for the bleeding from bigger vessels, hypofiibrinogenemia, dissemi
nated intravasal blood coagulation.
C alcium chloride, calcium gluconate contain calcium ions which are the
components o f the blood coagulation system, stimulate the formation o f active
clotting factors, are used parenteraly for bleeding, for the prophylaxis o f bleeding,
for a decrease o f capillary permeability. Properties o f calcium salts are described in
detail in Chapter 28.
INDIRECT-ACTING CO A G U LA N TS
VIKASOLUM
is an indirect-acting coagulant, a water-soluble synthetic vitamin K
is administered orally, IM, rarely IV; develops a therapeutic effect slowly

in 12-18 hrs
takes part in the synthesis of clotting factors in the liver (fig. 22.3)
is used for the prophylaxis o f bleeding, for chronic and repeated bleedings,
radiation sickness, liver diseases, overdose of indirect-acting anticoagulants
is contraindicated to patients with hypercoagulation, thrombosis, throm
boembolism.
4-Hydroxy-
K derivatives Coumarin derivatives
Fig. 22.3. Mechanism of action of vitamin K derivatives (Vikasolum)

and their antagonists (coumarin derivatives) (by H. Lullmann, 2000).
ANTICOAGULANTS
Anticoagulants are drugs decreasing blood coagulation.
CLASSIFICATION
1. Direct-acting (are active in vivo, as well as in vitro)
- Heparin
- Fraxiparine
- Sodium citrate
2. Indirect-acting (are active only in vivo)
- Warfarin
- Neodicumarinum
- Phenylinum.
DIRECT-ACTING ANTICOAGULANTS
HEPARIN
Heparin is a natural substance produced by mast cells. High concentration of
heparin is observed in the lungs and in the wall o f the intestine. It belongs to acidic
mucopolysaccharides (fig. 22.4). A disaccharide component o f heparin shows nega
tive charges due to the carboxyl and sulfate groups.
C H 2O S O -
Fig. 22.4. Chemical structure of heparin (A) and its sources (B)
(by H.Lullmann, 2000).
Pharm acokinetics
is administered IV, IM, SC, topically
begins to act immediately after IV administration and acts during 4-6 hrs
begins to act in 15-30 min after IM administration and acts during 6-8 hrs
begins to act in 30-60 min after SC administration and acts during 8-12 hrs
• is metabolized in the liver by heparinase

is excreted with urine.
Mechanism of action
Heparin binds to anti-thrombin III, causes its conformational change that
leads to the rapid inactivation o f thrombin and some other clotting factors
resulting in the inhibition o f fibinogen conversion to fibrin (fig. 22.5).
Heparin has a negative charge, due to which it is absorbed on blood cells,
increases a negative charge o f platelets resulting in a decrease o f platelet
aggregation and adhesion.
• Heparin releases lipoprotein lipase from endothelial cells.
Æ/ÊêS ê^ 1
Fig. 22.5. Mechanism of action of heparin (by H. Lullmann, 2000)
Pharm acodynam ics

a strong rapid decrease in all stages o f blood coagulation
a decrease in platelet aggregation
• the improvement o f microcirculation and coronary circulation
a decrease in lipids concentration in blood serum

a decrease in inflammation
a decrease in immunity
an increase in the synthesis o f surfactant in the lungs
a decrease in blood pressure (in higher doses)
a decrease in glucose level in blood serum (in higher doses)
an increase in diuresis (in higher doses).
Indications
Acute thrombosis and thromboembolism
Myocardial infarction
Ischemic stroke
Prevention o f thrombus formation after surgeries
Hemodialysis or blood transfusion
Thrombophlebitis
A syndrome o f disseminated intravasal blood coagulation
• Atherosclerosis
Autoimmune diseases
Chronic non-specific diseases o f the lungs.
T h e tim e o f b l e e d i n g o r th e tim e o f b l o o d c o a g u la tio n s h o u l d b e c o n tr o lle d !
1. Bleeding 1. Hemorrhages
2. Hematomes 2. Hemorrhagic diathesis
3. Micro- and macrohematuria 3. Leukemia
4. Thrombocytopenia 4. Anemia
5. Allergy 5. Malignant diseases
6. Osteoporosis 6. Gastric ulcer
7. Silvering o f the hair. 7. Hypertension
8. Severe diseases o f the liver and kidney.
I n o v e r d o s e - in d u c e o f P r o ta m in e s u lfa te !
FRAXIPARINE
is a low molecular weight heparin
is administered SC once a day; has bigger bioavailability, a longer duration
o f action, less binding to plasma proteins
Chapter 22. D R U G S A C T IN G O N B L O O D C O A G U L A T IO N A N D FIB R IN O LY SIS 273
depresses activated Stuart-Prauers factor more than thrombin

is used for the treatment o f thromboflebitis, prevention of thrombus forma
tion after surgeries.
INDIRECT-ACTING ANTICOAGULANTS
NEODICUMARINUM
It is an indirect-acting anticoagulant, coumarin derivative (fig. 22.6).
Fig. 22.6. Chem ical structure o f N eodicum arinum .
Pharmacokinetics
• is administered orally
is absorbed in the G I tract
• binds to proteins m blood plasma
• begins to act in 2-3 hrs after the administration
• develops a maximal action in 12-30 hrs after the administration
• acts during 48 hrs after the end o f treatment
• is excreted by urine.
Mechanism of action
Mechanism o f action of Neodicumarinum, warfarin, and other indirect-acting
anticoagulants is the block o f epoxide reductase in the liver.
The inhibition of this enzyme leads to the block in the creation of vitamin K
active form and the inhibition of the synthesis of clotting factors (fig. 22.3).
274 PH AR M ACO LO G Y. V. M. B o b y ro v ,! 0. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
Pharm acodynam ics

• a decrease in blood coagulation
an increase in fibrinolysis
a decrease in lipids concentration in blood.
Indications
Acute thrombosis (together with or after heparin’s usage)
Myocardial infarction
Ischemic insult
Thromboembolism
Thrombophlebitis
The prevention o f thrombus formation after surgeries.
Index o f prothrombin should be controlled!
1. Bleeding 1. Hemorrhages
2. Forming o f hematomes 2. Hemorrhagic diathesis
3. Hematuria 3. Gastric ulcer
4. Dyspepsia 4. Malignant diseases
5. Suppression o f the liver function 5. Diseases o f the liver and kidney
6. Allergy. 6. Pregnancy.
For the treatment o f overdose - Vikasolum!
PHENYLINUM
is an indirect-acting anticoagulant; an indandione derivative
has the same mechanism o f action as Neodicumarinum
• starts to act slower, has a longer duration o f action than Neodicumarinum
• may cause pink discoloration o f urine resulting from the excretion o f the
drug and its metabolites.
ANTI-PLATELET DRUGS
Anti-platelets are preparations which inhibit platelet aggregation in blood.
CLASSIFICATION
1. COX-inhibitors
- Acetylsalicylic acid (Aspirin)
2. Inhibitors o f phosphodiesterase
- Dipyridamole
3. Inhibitors o f ADP-mediated aggregation
- Ticlopidine (Ticlide).
Anti-platelet action of aspirin

Aspirin irreversibly inhibits platelet COX-1. In such a way, it prevents the
synthesis o f thromboxane A2 and decreases platelet aggregation (fig. 22.7). This
effect occurs in lower doses (less than 0,5 per day) and lasts more than 48 hrs (till 7
days). In higher doses aspirin also inhibits the synthesis o f prostacycline. The drug
is completely described in Chapter 13 as a non-narcotic analgesic.
^ T hrom boxan e A 2
Fig. 22.7. Mechanism of anti-platelet action of aspirin.
Anti-platelet action of dipyridamole

Dypiridamole inhibits adenosine desaminase and phosphodiesterase in platelets,
increases cAMP concentration in the cells and inhibits thromboxane A2 synthesis that
leads to a decrease in platelet aggregation. It also increases the prostacycline level.
A detailed description of the drug is represented in Chapter 17.
276 PH ARM ACO LO G Y. V. M. Bobyrov,T. 0 . Devyatkina, 0. M.Vazhnicha,V. M. Khristyuk
A nti-platelet action o f ticlopidine

Ticlopidine irreversibly blocks purinergic receptors for ADP in platelet mem
branes. The inhibition o f ADP-induced expression of glycoprotein llb/llla receptors
in the platelet membrane decreases platelet aggregation.
Indications to anti-platelets usage

The prevention o f thrombosis and re-thrombosis (as the discontinuation o f
anticoagulant therapy)
The prophylaxis o f myocardial infarction and insult
The prophylaxis o f thrombosis after surgeries
Angioplasties
The prevention o f thrombosis in patients with prosthetic cardiac valves
Thrombophlebitis.
DRUGS AFFECTING FIBRINOLYSIS
CLASSIFICATION
A. F ib rin o ly tic d ru g s
1. Direct-acting
- Fibrinolysin
2. Indirect-acting (activators o f pro-fibrinolysin)
a) non-seiective
- Streptokinase
b) selective
- Alteplase
B. In h ib ito rs o f fib rin o ly sis
1. Direct-acting
- Contrykal ’
2. Indirect-acting
- Aminocaproic acid.
FIBRINOLYTICS
Fibrinolytics are drugs producing the lysis o f the blood clot.
FIBRINOILYSIN
is the protein from the donors’ plasma, the active factor of fibrinolysis
Chapter 22. D R U G S A C T IN G O N B L O O D C O A G U L A T IO N A N D FIB R IN O L Y S IS 277
has a direct action on fibrin and dissolves fibrin clot in the first hours after
thrombosis
is used for the treatment o f acute thrombosis, acute myocardial infarction,
thrombophlebitis
may cause bleeding resulting from an increase in fibrinolysis, allergy,
anaphylaxis, arrhythmia, hypotension
is contraindicated in bleeding, a cerebral vascular accident, recent trauma
o f the brain, surgery, uncontrolled hypertension.
STEPTOKINASE
is the proteolytic enzyme from hemolytic streptococcus
acts indirectly, promotes the conversion o f plasminogen to plasmin, causes
systemic activation o f fibrinolysis and degradation both of fibrin and fi
brinogen resulting in the dissolving o f thrombus (fig. 22.8)
has a plasma half-life of 23 min; is administered by IV infusion (intracoro
nary infusion in myocardial infarction)
is more potent than fibrinolysin
does not cause arrhythmia.
A L T E P L A S E (ACTILISE)
is a tissue plasminogen activator, product o f biotechnology
has a half-life o f 5 min, is administered by IV infusion
• has a high affinity for fibrin and acts selectively on plasminogen bound
with thrombus.
INHIBITORS OF FIBRINOLYSIS
Inhibitors o f fibrinolysis are drugs with anti-enzymic activity which decrease
fibrinolysis and proteolysis.
CO N TR YKAL
is a direct-acting inhibitor o f fibrinolysis and proteolysis
is administered IV slowly or by IV infusion
binds to plasmin and inactivates it, inhibits the activity o f trypsin (fig. 22.8)
inhibits fibrinilysis and stops bleeding caused by the activation of fibrinoly
sis; inhibits proteolysis and inflammation
is indicated in bleeding resulting from the activation o f fibrinolysis; myo
cardial infarction; acute pancreatitis; prophylaxis o f proteolytic complica-
Fibrin
r~ w
L— li. SL -.11— ..........
Streptokinase
Plasminogen
F ig . 22.8. M e c h a n ism o f a ctio n o f streptokinase

a n d p la s m in in h ib ito rs (by H. Liillmann, 2000).
Chapter 22. D R U G S A C T IN G O N B L O O D C O A G U L A T IO N A N D FIB R IN O L Y S IS 279
tions after surgeries on the pancreas, the thyroid gland, the bigger salivary
glands, and lungs
may cause allergy, nausea, vomiting, hypotension, tachycardia.
AMINOCAPROIC ACID
is an indirect-acting inhibitor of fibrinolysis
is administered orally and by IV infusion, acts during 4-6 hrs, is not me
tabolized, is excreted with urine
interacts with plasminogen and inhibits its transformation into plasmin,
partly inhibits plasmin; inhibits proteolytic enzymes
inhibits fibrinolysis and decreases bleeding caused by the activation of
fibrinolysis; suppresses proteolysis, decreases inflammation, has an anti
allergic action, stimulates the antitoxic function o f the liver
• has indications which are similar to that o f contrykal; is also used in a syn
drome o f disseminated intravasal blood coagulation, obstetrics pathology
(ablation placenta, uterine hemorrhages), liver diseases, hypoplastic anemia
may cause side-effects, such as*dizziness, hypotension, bradycardia, ar
rhythmia, skin rash, vomiting, nausea.

№1. Drug for the prevention o f bleeding is only:
A. Heparin
B. Vikasolum
C. Thrombin
D. Streptokinase -
E. Contrykal.
№2. Aminocapoic acid is:

A. Direct-acting anticoagulant
B. Indirect-acting anticoagulant
C. Fibrinolytic
D. Activator o f fibrinolysis
E. Inhibitor o f fibrinolysis.
№ 3. Therapeutic uses o f anti-platelet drugs include:

A. The prevention o f secondary thrombosis
280 PH AR M ACO LO G Y. V. M. B o b y ro v ,! 0. Devyatkina, 0. M.Vazhnicha, V. M. Khristyuk
B. Acute thrombosis
c. Use of prosthetic heart valves
D. Arteriovenous shunt for hemodialysis
E. Thrombophlebitis.
№4. Heparin is an anticoagulant which:

A. Is effective orally
B. Is effective in vivo, as well as in vitro
C. Is the antagonist o f vitamin K
D. Is bound with antithrombin and inactivates clotting factors
E. Is used to treat acute thrombosis.
№5. A patient with acute myocardial infarction was treated with intravenous
infusion o f streptokinase. What is the goal o f this drug administration?
A. To cause the lysis o f thrombus directly
B. To transform plasminogen into plasmin
C. To prevent further thrombosis
D. To prevent platelets activation
E. To decrease the area o f necrosis.
Answers:
№ 1 - B; № 2 - E; № 3 - A, C, D, E; № 4 - B, D, E; № 5 - B.
J
23
0)
1 / 1 DRUGS ACTING ON THE

O B i V RESPIRATORY SYSTEM
THE RESPIRATORY SYSTEM AND ITS PATH O LO G Y

The respiratory system is one o f the life-supporting systems of the body. The
main function o f respiration is to supply oxygen to the body and to remove carbon
dioxide. It also participates in the pH constancy control of inner medium and in
temperature regulation.
Many drugs in overdose may cause respiratory depression, but opioids cause
some depression even in therapeutic doses.
The main disorders o f the respiratory system are cough and bronchial asthma.
The emergent conditions result from a deep suppression o f the respiratory center,
status asthmaticus, and pulmonary edema.
Cough is a protective reflex which guards the respiratory passages against the
entrance o f foreign bodies and promotes their expulsion. Cough may be productive
and non-productive. Productive cough is useful. Non-productive cough is useless and
it should be stopped. If non-productive cough is due to thick secretion, it is reasonable
to transform it into productive one. Bronchial asthm a is a recurrent episodic short
ness of breath caused by bronchoconstriction arising from airway inflammation and
hyperreactivity.
Chronic asthm atic bronchitis is a persistent airway obstruction, chronic pro

ductive cough, and a major problem o f episodic bronchospasm.
C hronic obstructive disease is a disorder o f the respiratory tract resulting
from generalized bronchial narrowing and the destruction o f functional lung tissue
(emphysema). It is usually characterized by an impaired expiratory outflow that re
sponds poorly to therapy. The following respiratory disorders have a chronic airway
obstruction as a dominant feature.
DRUGS ACTING ON RESPIRATORY SYSTEM

Drugs affecting the respiratory system are divided into 5 groups:
Respiratory stimulants
Antitussives
Expectorants
Bronchodilators
Drugs used in pulmonary edema.
RESPIRATORY STIMULANTS (ANALEPTICS)

The frequency and depth o f breathing are regulated by the breathing center.
Respiratory stim ulants excite the respiratory center and then increase lung ventilation
and gas metabolism, enhsance the oxygen content and decrease the carbon dioxide
level. They improve the excretion o f metabolites with perspirated air, stimulate oxi
dative processes, and normalize acid-based equilibrium. They may increase arterial
pressure by the excitation o f the vasomotor center.
Respiratory stimulants (analeptics) are described in detail in Chapter 14.
CLASSIFICATION
1. Direct-acting
- Caffeine
- Aethimizolum
2. Reflexly-acting
- Lobeline
- Cytitonum
- Solution o f ammonia
3. Mixed-acting
- Nikethamide (Cordiaminum)
- Camphor
- Carbon dioxide (Carbogenum)
Chapter 23. D R U G S A C T IN G O N R E S P IR A T O R Y S Y S T E M 283
A ethim izolum is a purinergic direct-acting analeptic; increases the frequency
and depth o f respiration, dilates bronchi, promotes surfactant synthesis in the lungs;
stimulates the production of glucocorticoids, has an anti-inflammatory, anti-allergic,
and immunomodulative action, increases the tone o f cardiac and skeletal muscles. It
is used in overdose of general anesthetics, asphyxia, bronchial asthma, and asphyxia
o f newbons.
Camphor is an analeptic with a mixed mode of action and expectorant proper
ties which is used in the suppression o f the respiratory center caused by infections
and intoxications, as well as in pneumonia.
Sulfocam phocainum is a derivative o f the sulfocamphoral acid and procaine;
stimulates the respiratory and vasomotor centers; is used in cases o f poisoning with
narcotic drugs, carbon oxide, in asphyxia, cardiac insufficiency.
C ytitonum and lobeline stim ulate N -cholinoreceptors located in carotide
glomerules and excite the respiratory center reflexly. They are used as respiratory
stimulants very seldom, more often in the case o f poisoning with carbon oxide.
Solution o f am m onia irritates sensitive nerve endings o f nasal mucosa and then
the respiratory center by reflex in the case of dizziness.
Carbogenum excites the respiratory center as its physiological stimulant. It is
used in the case o f poisoning by narcotic agents and carbon oxide, during or after
inhalation general anesthesia, in asphyxia, different conditions with insufficiency
o f the respiratory system.
ANTITUSSiVES
Antitussives are drugs suppressing cough which are used in the case of dry cough.
CLASSIFICATION
A. D r u g s o f c e n tr a l a c tio n
1. Opioids
- Codeine phosphate
- Ethylmorphine hydrochloride
2. Non-opioid drugs
- Glaucine hydrochloride
- Oxeladin
B. D r u g s o f p e r i p h e r a l a c tio n
- Prenoxdiazin hydrochloride (Libexinum)
- Falimint.
284 PH AR M ACO LO G Y. V. M. Bobyrov,T.O. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
Codeine, ethylm orpine are alkaloids o f opium and have all the properties o f
narcotic analgesics, but in therapeutic doses they are less potent than morphine by
their analgesic activity and are highly effective in the suppression of the tussive center;
may cause tolerance and drug dependence. Codeine is described in Chapter 12 as a
narcotic analgesic.
Glaucine hydrochloride is an alkaloid; inhibits the medulla center o f cough
without tolerance and drug dependence; is taken by mouth to treat diseases o f the
lungs and bronchi accompanied by dry cough; may cause hypotension.
Prenoxdiazin Itydropcliloride (Libexinum ) has a broncholytic and local an
esthetic effect, realizes its action in bronchi; is administered orally; is used for dry
cough; may produce the sensation o f local anesthesia in the oral cavity.
F alim int has antitussive and antimicrobial effects.
EX PECTO R A N TS
Expectorants are drugs which transform non-productive cough into productive
one. Some of these drugs are described in Chapter 4. They are devided into bronchosec-
retor drugs which assist liquid mucus expelling and mucolytics which melt mucus.
CLASSIFICATION
A. Bronchosecretor drugs
1. Reflexly acting
- Infusion from the herb o f Thermopsis
- Decoction from the root o f Althea
- Mucaltinum
2. Directly acting
- Potassium iodide
- Sodium bicarbonate
B. Mucolytics
1. Synthetic
- Acetylcysteine
- Ambroxol
- Bromhexine
2. Enzymes
- Trypsin
- Chymotrypsin
- Ribonuclease.
AM BRO XO L
Ambroxol is a bromine-containing compound (fig. 23.1).
HO H
Br
Br
Fig. 23.1. Chemical structure of ambroxol.
Pharmacokinetics
• is taken orally
is completely absorbed in the G1 tract
binds with plasma proteins (90% o f absorbed drug)
develops maximal concentration in 0,5-3 hrs after administration
displays high concentration in the lungs
penetrates the blood-brain barrier and placental barrier
has T |/2=7-12 hrs
is excreted with uijine and nursing mother’s milk.
Mechanism of action
The drug stimulates serous cells o f the bronchial mucous membrane, regulates
the ratio between serous and mucous components in sputum (fig. 23.2).
It activates hydrolytic enzymes, increases the release of lysosomes from Clarck’s cells.
It stimulates production of surfactant in the lungs and activates the transport
function o f ciliated cells.
Pharm acodynam ics

an expectorant action
• a mucolytic action.
286 PH A R M A CO LO G Y. V. M. Bobyrov,T. 0. Devyatkina, 0. M.Vazhnicha,V. M. Khristyuk
AMBROXOL
D epolym erizing A A
ft production o f ft syn thesis o f
o f acid ic m u copoly-sac
lysosom al enzym es su rfactant
charides
■0 adhesia
■0- sputum viscosity )
exudation o f
ft sputum evacuation P-
plasm a into alveoli
Fig. 23.2. Ambroxol’s mechanism of action.
Indications
Acute and chronic diseases o f airways accompanied by the formation of
dense sputum and non-productive cough
Pneumonia
Bronchial asthma
Bronchoectasis
Respiratory distress-syndrome in newborns.
1. Dyspepsia 1. Ulcer of stomach
2. Headache 2. Seizures
3. Skin rash, urticaria. 3. Pregnancy
4. Hypersensitivity.
A CETY LC Y STEIN E
It is an amino acid derivative, contains SH- group (fig. 23.3).
Pharm acokinetics
is taken orally
is well absorbed in the gut
undergoes first-pass metabolism in the liver, that’s why bioavailability
is 10%
there is a dynamic balance between free acetylcysteine, protein bound drug,

and its metabolites in blood plasma
is distributed in the liver, kidney, lungs, and bronchial mucus
penetrates placenta
developes maximal concentration in 1 hr after the administration
• has plasma half-life o f 2 hrs
is excreted with urine and nursing mother’s milk.
O
II
H3C — C — NH
I
hs — CH 2 — CH — COOH
Fig. 23.3. Chemical structure of acetylcysteine.
Mechanism of action
SH-group o f acetylcysteine tears disulfide connections in acidic mucopoly
saccharides o f sputum that leads to the depolymerization o f mucoproteins
and reducing o f mucus viscosity.
• The drug has antioxidant properties.
It stimulates the synthesis of glutathion, is a glutathion substitute.
Pharm acodynam ics

a mucolytic action
• an antioxidant action
a
an antidote action in acute poisoning with paracetamol (as glutathion
substitute).
Indications
Diseases o f the bronchi and lungs accompanied by the formation o f dense
and serous-purulent sputum
Acute and chronic bronchitis
Tracheitis due to bacterial infection
Pneumonia
Bronchoectasis
Bronchial asthma
Synusitis
Mucoviscedosis
The evacuation o f viscous secretion from airways after surgeries or trauma
Overdose o f paracetamol.
1. Dyspepsia, nausea, vomiting, stomatitis 1. Ulcer o f stomach
2. Allergy (skin rash, itch, urticaria, rarely a spasm 2. Lungs bleeding
ofbronchi) 3. Hypersensitivity to
3. Nasal bleeding, hypotension, palpitation. preparation
4. The retention o f sputum if it is used together with 4. Age till 5.
antitussives.

Infusion fr o m the herb ofTlierntopsis, decoction fr o m the root o f Althea, and
M ucaltinum are reflexly acting expectorants. They irritate receptors o f the stomach
mucosa, initiate reflexes by which increase the secretion of bronchial glands, the
contractility o f the epithelium and muscles and help mucus expelling.
Sodium bicarbonate and potassium iodide are directly acting expectorants.
Potassium iodide excretes through glands, melts the mucus, and stimulates secretion.
Sodium bicarbonate changes pH to the base district and stimulates the secretion o f
liquid sputum in the bronchi.
Trypsin and chym otrypsin are mucolytics from the group o f proteolytic en
zymes which tear peptide connections, change physicochemical properties of mucus.
Desoxyribonuclease and ribonuclease produce the depolymerization of nucleic acids
and in such a way reduce sputum viscosity and promote its evacuation. Enzymes are
administered IM or by inhalation. They are used to treat purulent diseases of bçonchi,
the lungs, and pleura.
BRONCHODILATORS
BRONCHIAL ASTH M A AND ITS M ANAGEM ENT

Airflow obstruction in asthma is due to the inflammation o f the bronchial wall,
contraction o f bronchial smooth muscle, increased mucus secretion causing shortness
of breath and makes respiration difficult. An asthmatic attack may be precipitated by
the inhalation of allergens which interact with mast cells coated with immunoglobulin E,
generated in response to a previous sensitivity to allergen. The mast cells release

mediators, such as histamine, leukotrienes, and hemotaxic factors which promote
a bronchiolar spasm and mucosal thickening from edema and cellular infiltration.
Many asthmatic attacks are not related to a recent exposure to allergen, but
rather reflect bronchial hyperactivity o f unknown origin which is somehow related
to the inflammation o f the airway mucosa.
The symptoms o f asthma may be effectively treated by several drugs, but no
one o f the agents provides a cure for this obstructive lung disease.
T he m anagem ent o f bronchial asthm a includes:
• avoidance of asthma triggers
treatment o f allergic inflammation
dilatation o f bronchi (fig. 23.4).
Fig. 23.4. Bronchial asthma and its management (by H. Liillmann, 2000).
THEOPHYLLINE
Theophylline (Euphyllinum) is 1,3-dimetylxantine (fig. 23.5).
О H
H3C
H
о
C3H
Fig. 23.5. Chemical structure of theophylline.
Pharmacokinetics
is administered orally, IV, by IV infusion
begins to act in 5-15 min after IV administration
binds to plasma proteins (60% of drug)
is widely distributed in tissues
is metabolized in the liver with the participation o f cytochrome P-450
is excreted with urine; partially is excreted with nursing mother’s milk
has a half-life depending on the patient’s age and co-existing pathology (in
adult patients with bronchial asthma it is 6-12 hrs; in elderly patients with
C H F - more than 24 hrs).
• The drug blocks o f adenosine receptors.
It inhibits PDE resulting in an increase of cAMP concentration and in a
decrease o f C a^ contents inside the cells.
Pharm acodynam ics

the relaxation o f the smooth muscles o f the bronchi, GI tract, biliary system,
and uterus
the dilation o f coronary, cerebral, and pulmonary blood vessels
a decrease o f peripheral vascular resistance
an increase in the tone o f respiratory muscles, stimulation o f the respira
tory center in the brain medulla, the improvement o f lungs ventilation and
saturation o f blood by oxygen
a decrease in intracranial pressure and edema o f the brain tissue
an anti-platelet action, the inhibition o f thrombus formation, normalization
o f microcirculation
an anti-allergic action due to the inhibition o f mast cells degranulation

• a diuretic action due to a decrease o f tubule reabsorption.
Indications
Bronchial asthma
Spasm o f bronchi o f different origin
• Chronic obstructive bronchitis
Status asthmaticus
Emphysema o f the lungs
Noctural apnea
Apnea o f a new born
• Lungs hypertension
Disturbances of cerebral blood circulation, liquor hypertension, edema of
the brain caused by ischemic stroke.
Sid e-effects C on traind ications

1. R estlessness, insom nia * 1. H ypersensitivity
2. H eadache, trem or, seizures 2. A cute h eart failure
3. T achycardia, arrhythm ia, hypotension. 3. A ngina pectoris
an increase in the frequency o f angina 4. A cute m yocardial infarction
attacks 5. H eart arrhythm ia
4. D iarrhea, atony o f the gut 6. H ypotension, severe hypertension
5. A llergic reactions (skin rash, itch). 7. Prone to seizures
8. H yperthyroidism
9. Pregnancy, lactation
10. H epatic and renal failure
11. C hildren till 14 (for IV adm inistration).
PECULIARITIES OF OTHER BRONCHODILATORS

Adrenergic agents with (3-activity are the drugs o f choice for mild intermitted
asthma. These potent bronchodilators relax airway smooth muscle and inhibit the
release o f substances from mast cells which cause bronchoconstriction. The most
common agents are (3,-adrenomimetics: salbutam oljenoterol, terbutalin, salmeterol,
and clenbuterol.
Salbutam ol,fenoterol, terbutalin are the drugs o f short duration (4-5 hrs) and
are used for the treatment o f asthma attacks.
Salmeterol, clenbuterol have a prolonged action and are used for the preven
tion o f asthma attacks.
(31 adrenomimetics (Isadrinum and orciprenaline sulfate) are used seldom.
In an acute attack, adrenaline hydrochloride and ephedrine hydrochloride

may be administered.
M -cholinoblockers are less effective. Ipratropium bromide, atropine sulfate,
platyphylline hydrotartrate, M ethacinum are used as bronchodilators. They in
crease the cGMP concentration, decrease Ca++ concentration that leads to smooth
muscle relaxation. Inhaled ipratropium bromide is useful in patients unable to take
adrenergic agonists.
M yotropic broncholytics (Xantines). When asthmatic symptoms cannot be
controlled with adrenergic agents, addition of the methylxanthine derivatives may
be appropriate. Myotropic bronchodilators relieve an airflow obstruction in acute
asthma and decrease the symptoms o f chronic disease.
Anti-allergic drugs. Crontolyn-sodium is an effective prophylactic agent which
stabilizes the membrane o f mast cells and prevents mediator release by blocking the
calcium gate. The drug is not useful in the managing o f an acute asthmatic attack.
For the use in asthma cromolyn-sodium is administered by inhalation. Because it is
poorly absorbed only minor adverse effects are associated with it. The pre-treatment
with cromolyn-sodium blocks allergen-induced and exercise induced bronchocon-
striction. Not all the patients respond to a cromolyn-sodium therapy, but those who
do respond to the treatment show the improvement which is roughly equal to the
improvement obtained from th e o p h y llin e therapy.
Ketotiphen decreases histamine release and blocks H,-histamine receptors. It
is used for the prophylaxis o f bronchospasm.
There are also anti-leukotriene modulators (zafirlukast), leukotriene receptor
antagonists, and leukotriene synthesis inhibitors (zileuton). They are administered
orally or by inhalation, have a slow onset o f action, long duration of action (12-24 hrs)
and are used for the prophylaxis and chronic treatment of asthma.
Glucocorticoids. Prednisolone, dexamethasone, triamcinolone; and beclom-
ethasone are used for the prevention o f bronchial asthma attacks.
DRUGS USED IN PULM ONARY EDEM A

Edema o f the lungs is an urgent state characterized by an increase o f hydrostatic
pressure in lung vessels, exudation into alveoli, and disturbances in lungs ventilation.
Pulmonary edema accompanies CHF, infections, intoxications.
A gents used in the treatm ent o f pulm onary edema are:
1. Drugs decreasing hydrostatic pressure in lung vessels:
- S o d iu m n itr o p ru ss id e and organic nitrates (n itro g ly c erin e , iso so rb id e d in itra te )
- Ganglioblockers (P e n ta m in u m , B e n z o h e x o n iu m , H y g r o n iu m )
2. Broncholytics (E u p h y llin u m )
3. Drugs with a-blocking properties (c h lo r p r o m a z in e )

4. Opioid analgesics (m o r p h in e h y d r o c h lo r id e )
5. Corticosteroids (p r e d n is o lo n e , d e x a m e th a s o n e )
6. Drugs improving heart contractility:
— Cardiac glycosides (C o r g ly c o n u m , d ig o x in , s tr o p h a n th in )
— Non-glycoside inotropics (d o b u ta m in e )
7. Drugs decreasing circulating blood volume:
— Loop diuretics (fu r o s e m id e , to r a s e m id e )
— Osmotic diuretics in the conditions o f tolerance to f u r o s e m i d e (m a n n ito l,
U rea p u ra )
8. Drugs that restore norm al bronchial passage due to an antifoam action
( v a p o r iz e d a lc o h o l).

№ 1. All the following concerning glaucine is correct, except:
A. It is non-opiod antitussive
B. It has a central action
C. It suppresses cough
D. It decreases BP
E. It stimulates respiratory center.
№2. Long-acting P-adrenergic agonist for treatment of bronchial asthma is:

A. Adrenaline
B. Salbutamol
C. Fenoterol
D. Salmeterol "
E. Isoprenaline.
№ 3. Theophylline is:
A. Contraindicated in tachyarrhythmia
B. Synthetic catecholamine
C. Bronchodilator
D. PDE inhibitor
E. Expectorant.
№4. Ambroxol produces:

A. The stimulation o f surfactant synthesis
B. An expectorant action
C. The dilatation o f bronchi
D. An anti-allergic action
E. The stimulation o f respiration.
№ 5. A patient with bronchial asthma addresses to his doctor with complaints o f

unpleasant palpitations that occur after the usage o f an inhalation form of isoprenaline
(Isadrinum). The doctor advices him to use salbutamol. What is the mechanism of
salbutamol’s action?
A. The stimulation o f P,-adrenoceptors
B. The stimulation o f p2-adrenoceptors
C. The stimulation o f c^-adrenoceptors
D. The stimulation o f a,-adrenoceptors
E. The inhibition o f M-chlolinoreceptors.
Answ ers
№ 1- E; № 2 - D; № 3 -A , C, D ; № 4 - A , B ;№ 5 ~ B .
24
a>
+->
a
TO
O mm I GASTROINTESINAL DRUGS
FUNCTIONS OF THE Gl TR A C T
AND THE MAIN GASTOINTESTINAL DISEASES
The main GI tract functions are digestion and absorption o f food. It also plays
the role o f one o f the major endocrine systems in the body. Gastric exocrine cells
secrete pepsinogen, the hydrochloric acid, and an intrinsic factor. In addition to this,
the cells of the gastric mucous membrane secrete mucus and bicarbonates, forming
together a gel-like protecting layer. The most common disorders o f gastric secretion
are peptic ulcer and gastritis.
Under physiological conditions in the pancreatic gland most of digestive en
zymes are contained in granules in the inactive form (zymogen). These enzymes
are activated by enterokinase after they reach the duodenum. In acute pancreatitis
enzymes become activated inside the pancreatic tissue causing autodigestion. In
chronic pancreatitis enzyme insufficiency develops.
Disturbances o f gastric motility may be manifested by nausea, vomiting, a
gastroesophageal reflux, delayed gastric emptying. A vomiting reflex can be useful
in the case o f the ingestion o f toxic substances, but it is in most cases an unpleasant
side-effect accompaning administration o f many drugs.
Abnormalities of intestinal motility can be manifested mainly by constipation
or diarrhea.
GASTROINTESTINAL DRUGS
Drugs acting on the GI tract are divided into several groups (fig.24.1).
G A S T R O IN T E S T IN A L D R U G S
D
D rugs influencing appetite
D rugs influencing gastric secretion
D rugs affecting gastric m otility
D rugs influencing pancreatic secretion

J
D rugs affecting intestinal m otility
D rugs for hepatob iliary disorders

J
Fig. 24.1. Groups of gastrointestinal drugs.
Among them, there are agents influencing appetite, drugs used in disturbances
o f the gastric secretory function, drugs affecting gastric motility, agents used in
disturbances of pancreatic secretion, drugs used in hepatobiliary system disorders,
and drugs affecting intestinal motility.
DRUGS INFLUENCING APPETITE

Drugs influencing appetite are preparations for the regulation of appetite used
in gastrointestinal diseases, obesity, or anorexia.
CLASSIFICATION
A . S tim u la n ts o f a p p e tite ( A p p e tiz e r s )
1.Bitters
- Tincture o f A b s in th iu m
2. Hormonal preparations
- Insulin
— Retabolil
B . S u p p r e s s o r s o f a p p e tite ( A n o r e x ig e n s )
1. Adrenergic
— Amfepranone (Phepranonum)
Chapter 24. G A S T R O IN T E S IN A L D R U G S 297
- Chlorpheniramine (Desopimon)
- Mazindol
2. Serotoninerghic
- Fenfluramine.
Bitters are used as appetizers. They belong to drugs stimulating afferent nerve
endings and are described in Chapter 4.
Insulin andretabolilare hormonal preparations with anabolic properties applied
in cachexia. These drugs are described in Chapter 26.
Anorexigens are appetite suppressors for the treatment of severe obesity. They
have the central mechanism o f action, that’s why these preparations are character
ized in Chapter 15.
DRUGS REGULATING
GASTRIC S E C R ETO R Y FUNCTION
PEPTIC U LCER DISEASE AND GASTRITIS

Lesions o f the mucosal wall that occur in the stomach or duodenum are referred
to as peptic ulcer disease. Although certain drugs can cause ulcers (in particular
NSAIDs), the great majority o f cases of peptic ulcer disease stems from infection
with the bacterium Helicobacter pylori (H. pylori). Infection caused by H. pylori
produces chronic gastritis which is the inflammation o f the stomach lining.
Peptic ulcer disease takes two very different courses, depending on the predomi
nant location o f the gastritis in the stomach. Some individuals produce excessive
quantities o f acid (hypersecretion o f acid), and this leads to the development of
duodena! ulcer (fig. 24.2). This type o f response occurs when gastritis is localized
in the pyloric region.
If gastritis is located predominantly in the body of the stomach, the disease
progresses in the form o f atrophic gastritis. The inflammation induces apoptosis
of parietal cells, and there is eventual atrophy of the gastric glands. The result is
hyposecretion o f acid. Continued tissue damage may lead to the development of
gastric ulcer (fig. 24.2).
H.pylori is classified as a carcinogen because infection increases the risk o f the
developing ofcertain types of gastric cancer. This increased risk is almost exclusively
associated with atrophic gastritis and gastric ulcer.
298 PH ARM ACO LO G Y. V, M. Bobyrov,T. 0. Devyatkina, 0. M. Vazhnicha, V. M, Khristyuk
Fig. 24.2. Pathogenesis of peptic ulcer disease and gastritis:

A -duodenal ulcer and hyperacidic gastritis; B - gastric ulcer and hypoacidic gastritis
(http://www.picsearch.com).
T h e stra teg y o fp h a r m a c o th e r a p y o fp e p tic u lc e r d isea se a n d g a stritis in c lu d e s:

• Eradication o f H. pylori through the use of antibiotics
Reduction o f acid secretion (Reducing the acidity in the stomach lumen
promotes healing, and it also increases the effectiveness o f the antibiotics)
Protection o f gastric mucosa
Replacement therapy in the condition o f acid hyposecretion.
DRUGS USED IN PEPTIC U LC ER

DISEASE AND GASTRITIS
CLASSIFICATION
A . S tim u la n ts o f g a s tr ic s e c r e tio n
- Histamine
- Bitters
B . D r u g s f o r r e p la c e m e n t th e r a p y
- Pepsin
- Hydrochloric acid
C. S u p p r e s s o r s o f g a s tr ic s e c r e tio n
- Atropine
- Pirezepine
2. H2-histamine receptor blockers
- Ranitidine
- Famotidine
3. Inhibitors o f proton pump
- Omeprazole „
4. Prostaglandins
- Misoprostol
5. Gastroprotectors (mucosal protector agents)
a) Coverings
- Colloidal bithmus subcitrate (De-nol)
- Sucralfate
b) Ulcer healing drugs
- Misoprostol
- Carbenoxolone
I ) A n ta c id s
- Sodium bicarbonate
- Calcium carbonate
300 PH AR M ACO LO G Y. V. M. Bobyrov.T. 0. Devyatkina, 0. M .Vazhnicha,V. M. Khristyuk
- Magnesium hydroxide
- Aluminium hydroxide
E. Antimicrobial drugs fo r treatment ofpeptic ulcer
- Metronidazole
- Amoxicillin
- Clarithromycin
- Tetracycline.
O M EP R A ZO LE
Omeprazole is a benzimidazole derivative (fig. 24.3).
OCH,
Fig. 24.3. Chemical structure of omeprazole.
Pharmacokinetics
• is administered orally, IV, by IV infusion
after the oral administration, is absorbed in the small intestine with bio
availability o f 35-60% 8
begins to act in 60 min; develops a maximal effect in 2 hrs after the admi
nistration and acts during more than 24 hrs
binds to plasma proteins (90-95%)
is metabolized in the liver with the formation o f hydroxiomeprazole
has a half-life o f 40-60 min
is excreted with urine (80%) and feces.
It inhibits Na+, K+-ATPase (proton pump) which is necessary for the transport o f H+
from parietal cells o f the gastric mucous membrane to the lumen of the stomach (fig. 24.4).
Chapter 24. G A S T R 0 I N T E 5 IN A L D R U G S 301
N. vagus
Parietal cell
Proton Gastnn
pump inhibitors
Fig. 24.4. Mechanism of action of proton pump inhibitors, H2-antihistamines,

and selective M-cholinoblockers (by H.Lullmann, 2000).
the inhibition o f the final stage o f basal and stimulating acid secretion.
Indications
Peptic ulcer disease
Gasatroesophagal reflux disease
Chronic gastritis with the hypersecretion o f acid
Zolinger-Ellison syndrome.
1. Nausea, diarrhea,constipation, meteorism, pain in the 1. Pregnancy
stomach 2. Lactation
2. Headache, weakness, depression, vision disturbances 3. Childhood
3. Skin rash 4. Severe hepatic
4. Arthralgia, myalgia, eosinophilia. diseases.
RANITIDINE
Ranitidine is H2-antihistamine, an etylendiamine derivative (fig. 24.5).
H\ n -c h 2 'o '
/
ch2- s
\
H3C (CH2)2
I
NH
I
C - NHCH3
II
c h -n o 2
Fig. 24.5. Chemical structure of ranitidine.
is well absorbed in the GI tract: absorption is not disturbed by meals or
antacids
starts to act in 15 min, develops a maximal concentration in 2 hrs,3has a
duration o f action o f 8-12 hrs
is excreted with urine during 24 hrs (40% o f a dose).
It inhibits H 2-histamine receptors in parietal cells o f the gastric mucous mem
brane (fig. 24.4).
the inhibition o f gastric secretion
a decrease in the total volume of gastric juice

a decrease in pepsin activity.
Indications
Peptic ulcer disease

Reflux-esophagitis
Zolinger-Ellison syndrome
bleeding from the upper regions o f the GI tract
the prophylaxis o f bleeding in patients suffering from peptic ulcer
the prophylaxis o f gastric juice aspiration in surgery under general anes
thesia.
1. Headache, vertigo 1. Pregnancy
3. Skin rash 2. Lactation
4. An increase in the plasma concentration of 3. Childhood
hepatic enzymes 4. Severe renal and hepatic
5. Throm bocy topen ia diseases
6. Hypersensitivity. 5. Gastric malignancy.

M-cholinoblockers are the inhibitors o f acid production. Atropine is a non-
selective preparation rarely used in peptic ulcer disease. Pirenzepine is a selective
cholinoreceptor antagonist, unlike atropine, prefers the type o f cholinoreceptors.
These drugs are described in Chapter 6.
Antacid drugs are preparations for acid neutralization. Antacids are absorbable
(N aH C 03) and non-absorbable (C aC 03, Mg(OH)2, Al(OH)3) (fig.24.6).
They contain H+-binding groups, such as C 0 32', H C 0 3“or OH . Non-absorbable
agents are preferred. In this case, systemic absorption o f counter ions or basic resi
dues is minor. Antacid drugs are taken between meals (1 and 3 hrs after meals and at
bedtimej.They can cause a reduced absorption o f other drugs, the phosphate deple
tion o f the body with an excessive intake o f Al(OH)3. Because Mg (OH), produces a
laxative effect and Al(OH)3 produces constipation, these two antacids are frequently
used in combination.
Protective drugs are represented by coverings and ulcer healing drugs.
Sucralfate contains aluminium hydroxide residues. It is a suspension for oral admin-
Absorption
^ r .
Na* HCOTT
Fig. 24.6. Mechanism of action of absorbable (A)

and non-absorbable antacids (B) (by. H. Lullmann, 2000)
istration minimally absorbed from the gut. The drug is taken on an empty stomach.
Sucralfate forms an ulcer-adherent complex with proteinaceous exudate at the ulcer
site (fig. 24.7). A sucralfate-albumin film provides a barrier to diffusion o f hydrogen
ions, inhibits pepsin activity in gastric juice by 32%. The drug is indicated in the
short-term (up to 8 weeks) treatment o f active duodenal ulcer. It is well tolerated,
rarely may cause constipation, diarrhea, dry mouth, gastric discomfort, indigestion,
nausea, vomiting, pruritus, rash, dizziness, insomnia, sleepiness, vertigo.
Bism uth subcitrate forms a protective cover on the surface o f ulcers and ero
sions, stimulates regeneration by the accumulation o f an epidermal growth factor,
increases prostaglandin E, synthesis, promotes the production o f mucus and bicarbo
nates, inhibits the activity of pepsin, has an anti-helicobacter action. It is used to treat
peptic ulcer disease, chronic gastritis, peptic ulcers caused by NSAIDs, functional
dyspepsia. The drug has no significant side-effects (it causes black discoloration o f
feces, rarely nausea, vomiting, diarrhea, rash).
M isoprostol is a semisynthetic prostaglandin. It binds to Pg receptors, promotes
mucus production and inhibits acid secretion, improves the trophy o f the gastric
Chapter 24. G A S T R O ^ T E S IN A L D R U G S 305
Sucralfate
Fig. 24.7. Sucralfate’s mechanism of action (by H. Lüllmann, 2000).
Fig. 24.8. Chemical structure and mechanism of action of misoprostol

(by H. Lüllmann, 2000).
mucous membrane (fig. 24.8). Additional systemic effects (diarrhea, the risk of
precipitating contractions o f the gravid uterus) limit its therapeutic utility.
Antibiotics and metronidazole are used forthe eradication o f H.pylon (fig.24.9).
The properties o f these antimicrobial agents are described in Chapters 31, 33. They
are applied in the combination with omeprazole.
Fig. 24.9. Antimicrobial agents for eradication of H. Pylori (by. H.Lullmann, 2000).
DRUGS AFFECTIN G GASTRIC MOTILITY
MAIN DISORDERS OF GASTRIC MOTILITY

Vomiting is frequently occurred disturbance o f gastric motility. It is a reflex
regulated by the emetic center and central trigger zone (CTZ) in the brain medulla.
The emetic center may be activated by impulses from the vestibular apparatus, visual,
olfactory, and gustatory inputs. Psychic stimuli can also cause the stimulation o f
vomiting center. The main neurotransmitters involved in the control o f vomiting are
acetylcholine, histamine, serotonin, dopamine, and substance P (fig. 24.10).
CLASSIFICATION
A. P r o k in e tic s
- Metoclopramide
B. E m e tic s
- Apomorphine
- lpecacuanna
C. A n ti- e m e tic s
1. Cholinergic antagonists
- Scopolamine (hyoscine)
(Dopamine^Sfitalonin)
(Intrinsic:
Substance P.
Acetylcholine.
Histamine)
(Acetylcholine, Histamine,
(Acetylcholine, Histamine)
Serotonin, Substance P
& mechanoreceptors)
Fig. 24.10. Neurotransmitters participating in a vomit reflex (http://www.picsearch.com).
2. H2-antihistamines
- Promethazine
- Diphenhydramine
3. Neuroleptics
- Chlorpromazine
4. D2-dopamine receptor antagonists
- Metoclopramide
5. 5-HT4-antagonists
- Ondacetron.
M ETOCLOPRAM IDE
The drug is a synthetic centrally acting agent, an oxibenzamide derivative (fig. 24.11 ).
P h arm a co k in e tics
starts to act in 1-3 min after IV injection and in 10-15 min after IM admin
istration
• penetrates CNS and placenta
has a duration o f a prokinetic effect of 3 hrs, o f anti-emetic action - 12 hrs

is excreted with urine in an unchanged state (85% o f a dose).
Os
n c - nh - ch 2- ch 2- n
o ch 3 c2H5
nh 2
Fig. 24.11. Chemical structure of metoclopramide.
Metoclopramide is a specific blocker of D^-dopamine receptors.
It is 5-HT3-antagonist
• It inhibits chemoreceptors o f the trigger zone
The drug inhibits the sensitivity o f visceral nerves translating impulses from
the pylorus and duodenum to the emetic center.
a decrease in vomiting and nausea
an increase in the tone of the stomach and intestine
the promotion o f gastric evacuation
the prevention o f a esophagal and pyloric reflux
the stimulation of intestinal peristalsis
the normalization o f the tone of the bile bladder and bile secretion
the stimulation o f prolactin secretion.
Indications
Vomiting and nausea o f different origin
Disturbances o f the gut motility in dyspepsia, reflux-esophagitis, gastro-
duodenitis, peptic ulcer, meteorism, and postoperative atonia ofthe stomach
and intestine
X-ray investigations o f the gut.
1. Constipation, diarrhea, dry mouth 1. Hypersensitivity
2. Weakness, somnolence, headache, 2. Gastrointestinal bleeding
depression, akatasia, extrapy 3. Bowel occlusion
ramidal disturbances in children, 4. Ulcer perforation
hyperkinesis, a spasm of the face 5. Abdominal surgeries
muscles, parkinsonism 6. Pheochromacytoma
3. Allergic reaction (skin rash) 7. Epilepsy
4. An increase in the toxicity o f ethyl 8. Extrapyramidal disorders
alcohol and neuroleptics. 9. Pregnancy (during the first trimester)
10,, Childhood
11. Severe renal and hepatic diseases
12. Job needed a quick motor reaction.

Emetic drugs are the stimulants o f CTZ and the vomiting center. Ipecacuanna
is a reflexly acting agent nowdays applied rarely. A pom orphine is centrally acting
drug, a D2-dopamine receptor agonist. It is used in acute poisonings. These prepara
tions are described in Chapter 4.
Scopolam ine is a M-cholinoblocker (see Chapter 6) effective in the prophylaxis
o f motion sickness. The drug should be taken 30 min before the start of travel and
repeated every 4 to 6 hrs. Scopolamine applied transdermally can provide effective
protection for up to 3 days.
Diphenhydram ine is a H,-histamine receptor antagonist (see Chapter 8) is
used as an antiemetic to prevent kinetosis, cytotoxic drug-induced, or posoperative
vomiting, emesis due to radiation sickness.
Plienothiazines (e.g. chlorpromazine) may suppress nausea and vomit that
follow the surgery or are due to opiod analgesics, gastrointestinal irritation, uremia,
an elevated intracranial pressure.
DRUGS AFFECTING INTESTINAL MOTILITY
DISTURBANCES OF INTESTINAL MOTILITY

AND THEIR PHARM ACO LO GICAL MANAGEMENT
Smooth muscles of the gut are characterized by propulsive wave-like move
ments [peristalsis) (fig. 24.12). The activation o f intramural mechanoreceptors and
some humoral agents (cholecystokinin) induce ascending contraction and descending

relaxation, whereby the intraluminal bolus is moved in the anal direction.
Activation of opioid receptors in the enteric nerve plexus results in the inhibi
tion o f peristalsis. The stimulation o f M-cholinoreceptors also leads to an increase
in the tone and the motility o f the intestine.
Abnormalities o f intestinal motility can manifest by constipation, diarrhea, and
a spasm o f smooth muscles (spastic colitis, colic).
The pharm acological m anagem ent o f disturbances o f intestinal m otility
includes:
The use o f laxatives (purgatives) to treat constipation
The use o f antidiarrheal drugs (opioids, adsorbents, astringents) to treat
non-infectious diarrhea
The use o f antimicrobial drugs to treat diarrhea caused by infection
The apply o f cholinoblockers and myotropic spasmolytics to treat spastic
ity in the gut.
Contraction Relaxation
Fig. 24.12. Intestinal peristalsis as a target for drugs regulating motility of the gut
(by H. Lüllmann, 2000).
CLASSIFICATION
A. A g e n ts in c r e a s in g in te s tin a l m o tility (L a x a tiv e s a n d p u r g a tiv e s )
1. Bulk laxatives
a) Osmotic purgatives
- Magnesium sulfate
- Sodium sulfate
- Lactulose
b) Bulk-forming agents
- Laminaria saccharina
- Methylcellulose
2. Irritant laxatives (purgatives cathartics)
a) Small intestine irritant purgative
- Castor oil
b) Large bowel irritant purgatives
- anthraquinone derivatives (preparations from S e n n a , F r a n g u la , R h e u m )
- synthetic preparations (Bisacodyl, Sodium picasulfate)
3. Lubricant laxatives
- Liquid parafin
B. A g e n t s d e c r e a s in g in te s tin a l m o tility (S p a s m o ly tic s a n d a n tid ia r r h e a ls )
1.Cholinoblockers
- Atropine
- Plathyphylline
- Benzohexonium
2. A myotropic spasmolytics
- Papaverine
- Drotaverine
3. An opioid receptor agonist
- Loperamide (Imodium).
Laxatives promote and facilitate bowel evacuation by acting locally to stimulate
intestinal peristalsis or to soften bowel contents. They are described in Chapter 4.
B u lk laxatives are divided into osmotic purgatives and hydrophilic colloids
(bulk gels). Osmotically active laxatives (so-called saline cathartics) elicit bowel
discharge 1-3 hrs after the administration. They are used to purge the bowel before
the surgery or to hasten the elimination o f ingested poison. Bulk-form ing agents
consist o f the indigestible plant cell wall, take up water in the bowel and are used
for the prophylaxis o f constipation.
Irritant laxatives exert an irritant action on the enteric mucosa. According to the
site o f action they are divided into small bowel irritants (castor oil) and large bowel
irritants (antraquinone derivatives and diphenolmethane derivatives).
The oral administration of 10-30 ml o f castor oil is followed within 0,5-3 hrs by
discharge of watery stool. Because of its massive effect, castor oil is more suitable
for the treatment o f acute constipation or for a rapid elimination o f orally ingested
poison (except lipophilic toxins).
A ntraquinone derivatives are used in the form o f galenical preparations and
produce discharge o f soft stool in 6-8 hrs after administration. Synthetic preparations
also act after a latency o f 6-8 hrs. Indications to colon irritant purgatives are chronic
constipation, the prevention o f straining at stool following surgery, myocardial inf
arction, or stroke, and provision of relief in painful diseases o f the anus. They should
not be given in abdominal complaints o f unclear origin.
Lubricant laxatives (liquidparaffin) are non-absorbable and make feces softer
and more easily passed. They are used for chronic constipation and provision o f
relief in painful diseases o f the anus. Liquid paraffin may cause such side-effects
as a decrease in absorption o f fat-soluble vitamins, formation granulomas in enteric
lymph nodes, lipoid pneumonia (after the aspiration into the bonchial tract).
Antidiarreals. Loperam ide is an opioid antidiarrheal o f first choice. It is admin
istered orally; has a half-life o f 9-14 hrs; due to high affinity to the intestinal wall
and intensive first-pass metabolism, does not enter the systemic blood circulation.
Loperamide binds to opioid receptors in the wall of intestine that results in the inhi
bition o f the release of acetylcholine and prostaglandins. In such a way it decreases
peristalsis and increases the tone o f the anal sphincter. The drug is indicated in acute
and chronic non-infectious diarrhea. It may cause such side-effects as allergic reac
tions, weakness, headache, somnolence or insomnia, dry mouth, dyspepsia, nausea,
vomiting, ileus, meteorism, constipation, megacolon, disturbances o f defecation.
Loperamide must not be applied in infectious diarrhea.
M -cholinoblockers and spasmolytics are used to delay a spasm of intestinal
musculature and to relieve spasmotic pain in the abdomen. These preparations are
described in Chapters 6, 17, 19.
DRUGS USED IN DISTURBANCES

O F PANCREATIC SECRETION
MAIN PANCREATIC DISORDERS

The pathology o f pancreatic gland is displayed as acute or chronic pancreatitis.
An acute inflammation o f the pancreas is accompanied by the activation o f proteases
in gland tissue resulting in autolysis, pancreanecrosis, severe pain, and systemic
activation o f proteolysis and fibrinolysis.
Chronic pancreatitis leads to excretory insufficiency o f the pancreas and dis-
ruped digestion o f proteins, fats, and carbohydrates (creatorrhea, steatorrhea, etc.).
The pharm acological m anagem ent o f pancreatitis includes:

Use o f proteolysis inhibitors in acute pancreatitis and pancreonecrosis
• Replacement therapy with combined enzymic preparations in chronic
pancreatitis.
CLASSIFICATION
1. Drugs used in acute pancreatitis (inhibitors of proteolysis)
- Aprotinin
- Contrykal
- Aminocaproic acid
2. Drugs used in chronic pancreatitis (combined enzyme preparations)
- Pancreatin
- Mezym forte
- Festal.
Inhibitors o f pancreatic enzymes are most essential in the treatment o f acute
pancreatitis. Aprotinin and contrykal are directly acting inhibitors of proteolysis
and fybrinolisis. Am inocaproic acid has a mixed mechanism of action, inhibits
proteolytic enzymes, excerts anti-allergic and anti-toxic actions. These preparations
are described in Chapters 22, 28.
Enzym e replacement therapy is used in chronic pancreatitis (see Chapter 28).
Combined preparations containing protease, amylase, and lipase are suitable in
this case. With the oral administration o f pancreatic enzymes, allowance must be
made for their partial inactivation by gastric juice. Therefore, they are administered
in acid-resistant medicinal forms.
DRUGS USED IN HEPATOBILIARY SYSTEM DISORDERS
MAIN HEPATOBILIARY DISORDERS

The main liver functions are detoxication and bile secretion. Liver lesions are
manifested as acute hepatitis, chronic hepatitis, and cirrhosis.
Cholecystitis and cholelythiasis are also widely spread diseases o f hepatobiliary
system. Following its secretion from the liver into bile, water insoluble cholesterol is
held in solution in the form o f micellar complexes with bile acids and phospholipids.
When more cholesterol is secreted than can be emulsified, it precipitates and form
gall stones.
CLASSIFICATION
1. Agents stimulating bile secretion (choleretics)
- Oxaphenamidum
- Cholenzymum
- Allocholum
2. Agents promoting bile release (cholekinetics)
- Atropine
- Papaverine
- Drotaverine
- Magnesium sulfate
3. Gall stone dissolving drugs
- Chenodeoxycholic acid
- Ursodeoxycholic acid
4. Hepatoprotectors
- Essentiale
- Siliborum.
Choleretics stimulate the production and secretion o f dilute bile fluid. Among
them there are drugs containing bile or essential bile acids, as well as synthetic
preparations. Bile containing drugs are Cholenzymum and Allocholum.
C holenzym um contains dry bile, lyophilized tissues o f animals’ pancreas and
intestine. Due to the presence of bile acids and enzymes, the drug improves secretion
and motility o f the gut. It is indicated in gastritis, achilia, enterocolitis.
A llocholum is a combined preparation containing dry bile, dry extracts of
Allium and Urtica, and activated charcoal. Beside the influence on bile secretion, it
stimulates secretion and motility in the gut, normalized microbial state. The drug is
used in constipation, dyspepsia.
O xaphenam idum is a synthetic preparation with choleretic, spasmolytic, and
anti-inflammatory effects. It does not elevate the concentration of chelates, bilirubin,
and cholesterol in bile. The drug is used in chronic cholecystitis.
Cholekinetics stimulate the gallbladder to contract and empty (e.g. magnesium
sulfate, cholecystokinin). Some of them decrease spasm o f smooth muscles o f the
gallbladder and biliary pathways (atropine, papaverine, drotaverine) and in such a
way promote the release o f bile. Cholekinetics are employed to test the gallbladder
function for diagnostic purposes, as well as to treat colic, acute or chronic cholecystitis
(cholekinetics with a spasmolytic action).
Dissolving o f cholesterol-containing gallstones can be

achieved by a long-term oral administration o f chenode-
oxycholic a d d (CDCA) or ursodeoxycholic acid (UDCA).
They are stereoisomeric bile acids presented in a small
amount in bile. CDCA is absorbed in the small intestine,
undergone conjugation in the liver, and excreted into the bile
that leads to the elevation o f bile acids concentration in bile.
Under such condition the solubility of cholesterol increases
and cholesterol-containing stones can be dissolved slowly.
The daily dose is 8-10 mg, the course o f treatment - 1-2
years. UCDA is more effective and better tolerated than
CDCA. Both preparations may cause diarrhea, an elevation
of liver enzymes in plasma. Stone formation may recur after
the cessation o f a successful therapy.
Hepatoprotectors are preparations protecting hepatocytes
from different aggressive factors. They are divided into plant
preparations and drugs containing essential phospholipids.
Essentiale is a combined preparation containing es
sential phospholipids (phosphotidilcholine) and vitamins
(pyridoxine, cyanocobalamin, nicotinic acid, pantothenate).
Fig. 24.13. Silybum
It is administered orally or by IV infusion. The drug im mariarum contain
proves lipid metabolism, protein synthesis, and oxidative ing hepatoprotective
phosphorilation, inhibits lipids peroxidation, stabilizes flavonoids.
cell membranes. In such a way, it protects liver tissue
against hepatotoxic poisons, inhibits hepatic necrosis, promotes the restoration o f a
hepatocytes structure and functions. Essentiale is used in acute and chronic hepatitis,
cirrhosis, hepatic coma, fat embolism, poisoning with hepatotoxic agents, liver le
sions caused by diabetes mellitus, atherosclerosis, before and after surgeries in the
hepatobiliary system. It has no serious side-effects and contraindications.
Siliborum is a plant preparation containing flavonoids from Silybum mariaritm
(fig. 24.13). It demonstrates hepatoprotection grounded on antioxidant, membrane-
stabilizing, anti-inflammatory effects and is indicated in acute and chronic hepatitis,
cirrhosis, intoxications with hepatotoxic substances. The drug is well tolerated.

№ 1. Ranitidine inhibits gastric secretion induced by:
A. Histamine
ft.
316 PH AR M ACO LO G Y. V. M. B o b y ro v ,! 0. Devyatkina, 0. M.Vazhnicha, V. M. Khristyuk
B. Pentagastrin
C. Acetylcholine
D. NSAIDs
E. None o f the listed.
№ 2. The preparation which prevents the activation o f proteolytic enzymes in

the pancreas is:
A. Pancreatin
B. Festal
C. Aprotinin
D. Omeprazole
E. Atropine.
№ 3. An ulcer-healing effect o f bismuth subcitrate is based on:

A. Acid neutralization
B. An increase in prostaglandin synthesis
C. The irradication o f H.pylori
D. The inhibition of proton pump
E. The inhibition o f M-cholinoreceptors.
№ 4. The true statements concerning laxatives and antidiarrheals are:

A. Osmotic laxatives are used to remove the poison from intestine
B. Castor oil is applied for the elimination o f lipophilic toxins
C. Antraquinone derivatives act in 6-8 hrs after the administration
D. Loperamide is an antidiarrheal drug o f the first choice
E. Lopepamide is M-cholinoblocker.
№ 5. A patient has duodenal ulcer accompanied by the hypersecretion o f gastric

juice. He is prescribed with a potent inhibitor o f gastric secretion which belongs to
“proton pump” inhibitors. This drug is:
A. Pirenzepine
B. Omeprazole
C. Ranitidine
D. Bisacodyl
E. Metoclopramide.
A n sw e rs:
№ 1- A; № 2 - C; № 3 - B,C; № 4 - A,C,D; № 5 - B.
A
DIURETICS. ANTI-GOAT
DRUGS. DRUGS ACTING
ON THE MYOMETRIUM
NEPHRON AND ITS FUNCTION

Urine formation is the function o f the kidney. Nephron is the basic structural
and functional unit of the kidney (fig. 25.1). It includes vascular glomerulus, capsule,
proximal tubule, loop o f Henle, distal tubule, collecting tubule. Its chief function is
to regulate water and soluble substances by filtering the blood, reabsorbing necessary
substances and excreting tfie rest of urine. Nephrons eliminate wastes from the body,
regulate blood volume and pressure, control levels o f electrolytes and metabolites,
and regulate blood pH. Its functions are vital to life and are regulated by hormones,
such as antidiuretic hormone, aldosterone, and parathyroid hormone.
The cell o f the renal epithelium has apical and basal membranes.
On the apical membrane there is a passive transport ofN a+through pores with the
participation o f permeases. The synthesis of permeases is controlled by aldosterone.
On the basal m em brane there is an active transport o f ions by biological pumps.
Energy for this process is produced by K 7N a+-ATP-ase, succinate dehydrohynase.
Glucose, amino acids, inorganic phosphate, and some other solutes are reabsorbed
via secondary active transport through co-transport channels driven by the sodium
gradient out o f the nephron.
Carbonic anhydrase takes part in the forming of H* and H C 0 3', which are ex
changed on Na+on the apical membrane or reabsorbed together with it on the basal
membrane.
Because o f its importance in body fluid regulation, the nephron is a common
target o f drugs that treat high blood pressure a nd edema. These drugs, called
diuretics, inhibit the ability o f the nephron to retain water, increasing the amount o f
urine produced.
The m anagem ent o f urine form a tio n may be achieved by:
Increase o f glomerular filtration
• Decrease o f tubular reabsorption (the most preferable way: primarily the
reabsorption o f sodium and chloride is decreased; excretion of water is
secondary to excretion o f salts).
Bowman's
capsule
Aldosterone
Glomerulus
Glucose acids
Fig. 25.1. Structure and function of nephron (http://www.picsearch.com).
DIURETICS
Diuretics are drugs which increase water and salts excretion from the body by
a direct action on kidney functions.
Chapter 25. DIURETICS. ANTI-GOAT DRUGS. DRUGS ACTING ON THE M YO M ETRIU M 319
CLASSIFICATION
1. Thiazides
- Hydrochlorothiazide (Dichlothiazidum)
2. Loop diuretics
- Furosemide (Lasix)
- Ethacrynic acid
3. Carbonic anhydrase inhibitors
- Acetazolamide (Diacarbum)
4. Potassium-sparing diuretics
- Spironolactone
- Triamterene
5. Osmotic diuretics
- Mannitol
- Urea.
HYDROCHLOROTHIAZIDE
a
It is a thiazide diuretic (fig. 25.2).
Fig. 25.2. C h e m i c a l s tru c tu re o f h y d ro c h lo r o th ia z id e .
Pharmacokinetics
is administered orally
is quickly absorbed in the gut (60-80% o f the dose)
develops effect in 2 hrs after administration and acts during 12 hrs
is excreted with urine in an unchanged state
penetrates placental barrier and may be excreted with nursing mother’s milk.
Mechanism of action
Hydrochlorothiazide is secreted into the tubular fluid by proximal tubule cells.
320 PH A RM ACO LO G Y. V. M. Bobyrov, T. 0. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
In the distal convoluted tubule, it blocks K7Na+-ATP-ase and succinate

dehydrohynase and inhibits energetic metabolism (fig. 25.3).
Inhibition o f energy production blocks N a+, a Ch symporter that is associ
ated with the luminal (basal) membrane.
A decrease in an active transport o f Na+to the blood leads to the elevation of
N a+concentration in the cell and inhibition o f a passive transport o f Na+and
C l'through the apical membrane.
N a+, CL', K+, and water stay in primary urine and are excreted. The result
is a diuretic action.
Lumen- Interstitium-
urine blood
Fig. 25.3. Mechanism of action of hydrochlorothiazide.
Pharm acodynam ics

an enhance in N a+, Cl' excretion (the effect on Na* is small because most
o f the Na^has already been absorbed prior to reaching the distal tubule)
an enhance in K+ excretion
a reduce in uric acid excretion
a decrease in C a ^ excretion, enhance in the excretion o f Mgrt
an increase o f diuresis and a decrease in volume pf blood
the reduction o f peripheral vascular resistance and lowering o f BP
a decrease in diuresis in patients with diabetes insipidus
a decrease in intraocular pressure.
Indications
Hypertension
• Edema caused by CHF or hepatic cirrhosis
Treatment with corticosteroids and estrogens
Renal disturbances (nephrotic syndrome, acute glomerulonephritis, chronic
renal failure)
Diadetes insipidus
Glaucoma.
1. Electrolyte abnormalities: 1. Anuria
volume depletion, hypokalemia, hyponatremia, 2. Goat
hypochloremia, hypochloremic alkalosis, hypercal 3. Hepatic dysfunction
cemia, and hypomagnesemia 4. Hypercalcemia
2. Hyperuricemia 5. Pancreatitis
3. Hyperglycemia 6. Pregnancy.
4. Increased plasma levels o f LDL-ßholesterol, and
triglycerides
5. Sexual dysfunction (impotence)
6. Heart arrhythmias due to hypokalemia
7. Worsening o f renal and hepatic insufficiency
8. A variety o f drug interactions: a decrease in the
efficacy o f anticoagulants and uricosurics; an
increase in the toxicity o f cardiac glycosides and
anti-arrhythmic drugs.
PECULIARITIES OF OTHER DIURETICS
FUROSEMIDE
is a loop diuretic, or high ceilling diuretic
is administered IM, IV, orally; after IV injection, starts to act in 5-10 min,
develops a maximal effect in 20-60 min and acts during 1,5-3 hrs; after the
oral administration starts to act in 30-60 min and acts during 4-6 hrs; has
bioavailability o f 50-70%; binds to plasma proteins (95-99%); is metabolized
in the liver by conjugation with glucuronic acid; has T'A = 0,5-1,5 hrs; is
excreted with urine; is active under the conditions o f acidosis, as well as
under the conditions o f alkalosis
has the mechanism o f action similar to the mechanism o f thiazides, but the
site o f action is a thick ascending limb o f the loop ofH enle (fig. 25.4). This
limb has a high reabsorptive capacity and is responsible for the reabsorbing
25% o f the filtered load o f Na+. The loop diuretics act by blocking of Na+, K+,
a Cl" symporter. Because o f the large absorptive capacity and the amount of
Na+ delivered to the ascending limb, loop diuretics have a profound diuretic
action. Excretion o f Cl is greater than Na+one; large doses promote ureic
acid excretion. The osmotic gradient for water reabsorption is also reduced,
resulting in increased water excretion. The reduction in the cellular K+ also
results in a loss o f Ca++ and Mg++.
displays a potent and quick diuretic action with a significant increase in
Na+,K+and Cl" excretion; maintains the renal blood flow and does not inhibit
glomerular filtration
is indicated in edema o f the lungs, edema of the brain, forced diuresis in
acute poisonings, hypertensive emergency, acute glaucoma, chronic edemas
associated with CHF, cirrhosis, renal diseases, hypercalcemia
may cause side-effects, such as hypokalemia, disturbances in electrolytes
balance and renal ureac acid secretion, hypotension, vertigo, collapse, ar
rhythmia, thrombotic complications, dry mouth, nausea, vomiting, diarrhea,
pancreatitis, weakness, skin rash, ototoxicity, rarely aplastic anemia, leu-
copenia, hematuria
is contraindicated in acute glomerulonephritis, acute renal failure, anuria,
obturation o f urinary pathways, hepatic coma, pancreatitis, disturbances in
electrolyte balance, gout, diabetes mellitus, hypotension, lupus erhythema-
tosus, first half o f pregnancy, lactation.
ETHACRYNIC ACID
is a loop diuretic
is administered orally and IV; after the oral administration, starts to act in
30-60 min, develops maximal effect in 2 hrs, and acts during 6-9 hrs; after
IV injection, begins to act quickly and is suitable for emergency help
has the mechanism o f action and pharmacodynamics similar to that of
furosemide, but does not increase bicarbonate excretion
is indicated similar by furosemide, is effective in the treatment of bromides
accumulation in the body
has no significant influence on the electrolytes balance in blood, but is toler
ated worse than furosemide, especially in patients with renal insufficiency.
Thick
Lumen- ascending Interstitium-
urine limb blood
/
Na'
K*
2CI'
(+)
Potential
Mg2', Ca2'
Fig. 25.4. Mechanism of action of furosemide.
ACETAZOLAMIDE
is a carbonic anhydrase inhibitor with a sulfonamide structure
is the prototype for this class o f drugs
has the mechanism o f action connected with changes in the reabsorption of
H C 0 3\ H C O / is reabsorbed in the proximal tubule and requires the activity
o f carbonic anliydrase. H C 0 3’ reabsorption takes place in a circuitous way.
Intracellularly carbonic anhydrase converts H20 and C 0 2to the carbonic acid
(H2COj). H2C 0 3 dissociates into H+ and H C 0 3\ The H C 0 3‘ is transported
across the basal membrane. H+is secreted into the tubular lumen in exchange
for N a+. The H+ combines with a filtered H C 0 3' to form H2C 0 3 which
immediately dissociates into H20 and C 0 2, that is reabsorbed. Therefore,
filtered bicarbonate is reabsorbed for every H+secreted. Carbonic anhydrase
inhibitors, by blocking the enzyme, prevent the reabsorption of N aH C 03\
and hence diuresis occurs (fig. 25.5)
produces a H C 0 3' loss; increases Na+ and K+ excretion; decreases the renal
blood flow; lowers intraocular pressure and intracranial pressure due to the
inhibition o f carbonic anhydrase in these tissues
is not used for its diuretic properties; is used to reduce intraocular pressure
in glaucoma, to treat epilepsy, altitude and motion sickness
may cause side-effects, such as metabolic acidosis, sedation, and paresthe
sia; because o f the structural similarity to sulfonamides, acetazolamide can
cause bone marrow depression and allergic reactions.
SPIRONOLACTONE
is a potassium-sparring diuretic
is taken orally; is metabolized to canrenone which is the active drug mol
ecule; develops therapeutic effect in 2-5 days
is a competitive antagonist o f aldosterone in gene expression, inhibits
synthesis o f permeases that results in the inhibition o f a passive transport
o f N a+through the apical membrane in collecting tubules; does not act on
the excretion o f K.+; the diuretic and natriuretic effects of spironolactone
are modest (fig. 25.6)
Lumen- Interstitium-
urine blood
H,0 + C 0 2
Cf
Fig. 25.5. Mechanism of action of acetazolamide: CA - carbonic anhydrase.

is used as an adjunct to other diuretics to reduce a loss o f K+; in hyperaldos

teronism, CHF refractory to cardiac glycosides, myastenia
may cause hyperkalemia, G1 disturbances, diarrhea, somnolence, distur
bances in the menstrual function in women, ginecomastia and impotence
in men (due to anti-androgenic activity).
TRIAMTERENE
is potassium-sparring diuretic
is taken orally, has a weak slow action
by its chemical structure, is similar to hydrotating NaTand closes Na+pores
in the apical membrane of cells in collecting tubules (is a Na+channel in
hibitor); increases excretion o f Na+ and water; reduces K* loss (fig.25.6);
is used together with other diuretics for the treatment o f hypotension (This
//
WZ
Fig. 25.6. Chemical structure and mechanism of action

of potassium-sparring diuretics (by H. Liillmarm, 2000).
enhances the effects o f the more potent diuretics and counteracts the K+
loss seen with these diuretics)
may cause hyperkalemia, nausea, vomiting, dizziness.
OSMOTIC DIURETICS
are represented by m annitol a nd urea
are administered by IV infusion
have the mechanism o f action connected with an increase o f the osmolar-
ity o f blood, the extraction o f H20 from systemic body compartments, an
increase o f the extracellular fluid volume and the renal blood flow. Osmotic
diuretics are filtrated at the glomerulus, but are poorly reabsorbed, as a re
sult, they increase the osmolarity o f primary urine. These agents bind water
osmotically and retain it in the tubular lumen. When Na1" is taken up into
the tubule cell, H20 cannot follow in a usual amount. The fall in the urine
Ma" concentration reduces the Na+ reabsorption in the proximal tubules.
The result is a large volume o f dilute urine
are used for edema o f the brain (especially, mannitol), edema o f the lungs,
forced diuresis in acute poisonings, oliguria, anuria, the prophylaxis of acute
Fig. 25.7. Medicinal plants with diuretic action:

A -Equisetum ; B - Orthosiphonum.
renal failure in such situations as cardiovascular surgeries, traumatic shock,

hemolytic transfusion reactions
may cause headache, nausea, vomiting, chest pain, an increase in blood
volume resulting in heart decompensation, hyponatremia.
MEDICINAL PLAN TS WITH

DIURETIC PROPERTIES
they are Equisetum (the herb) and O rthosiphonum (leaves) (fig.25.7)
are taken orally as infusions
increase the excretion o f water with a minimal action on the electrolyte
balance, have an antimicrobial and anti-inflammatory action
are used for the treatment of renal diseases, diseases o f urinary pathways,
and chronic edemas
• have no significant side-effects.
DRUGS USED IN TR EATM EN T OF GOUT
GOUT AND PRINCIPLES OF ITS TH ER APY

Gout is a metabolic disease that results from hyperuricemia, an elevation in
the blood o f the uric acid, the end product of purine degradation. The typical gout
attack consists of a highly painful inflammation o f the first metatarsophalangeal
joint. Gout attacks are triggered by the precipitation o f sodium urate crtystals in the
synovial fluid o f joints.
The pharm acological m anagem ent o f gout includes:
treatment of the gout attack with colchicine, indomethacin, phenylbutazone,
glucocorticoids
prophylaxis o f gout attacks with the diet low in purines, uricostatics, uri-
cosurics.
CLASSIFICATION
A. U r ic o s ta tic s ( T h e y d e c r e a s e u r a te p r o d u c tio n )
- Allopurinol
B . U r ic o s u r ic s ( T h e y p r o m o te r e n a l e x c r e tio n o f u r ic a c id )
1. Drugs inhibiting reabsorption o f ureic acid
- Probenecid
- Aethamidum
2. Drugs increasing the solubility o f urates

- Urodanum
3. Drugs decreasing forming o f urate concrements
- Urolesanum.
ALLOPURINOL
is hypoxantine (purine) on chemical structure
is taken orally; is transformed into the active metabolite ailoxantine (oxy-
purinol)
inhibits xanthine oxidase and in such a way decreases the synthesis o f the
uric acid, prevents uricosemia, inhibits the development o f gout
is used for the prophylaxis a gout attack and urolythiasis
is well tolerated, rarely may cause skin reactions.
PECULIARITIES OF O TH ER PREPARATIONS
Probenecid is taken orally, saturates the organic acid transport system in the
proximal renal tubules, makes it unavailable for urate reabsorbion; is contraindicated
in patients with urate stones in the urinary tract.
A etham idum is a synthetic preparation which blocks an active reabsorption of
the uric acid in the proximal tubules and is used for the treatment of chronic gout.
U rodanum is a combined preparation in granules for the oral administration;
contains substances binding to urates and increasing their solubility.
U rolesanum is a combined preparation with plant ingredients; decreases form
ing o f urite concrements in the kidneys.
DRUGS ACTING ON THE MYOMETRIUM
UTERU S CONTRACTIONS AND THEIR

PH AR M ACO LO G ICAL M ANAGEM ENT
Uterus is a muscular organ o f the reproductive system capable to contrac
tions. Towards the end o f pregnancy uterine contractions increase in the force and
frequency and become fully coordinated in labor. Uterine motility is controlled by
the autonomic nervous system and hormones. The stimulation o f a-adrenoceptors
results in an increase o f uterus contractility, the stimulation o f (3-adrenoceptors
leads to the relaxation o f the uterus. The important factors of humoral regulation
o f contractile myometrium function are pituitary hormones, sex hormones, and Pg.
A pituitary hormone oxytocin stimulates uterus contractions on the ground o f the
increased level o f estrogens.
The m anagem ent o f m yom etrium contractility includes:
the stimulation of rhythmic contractions during labor
an increase in uterine tone for the arrest and prevention o f postpartum
uterine bleeding
• a decrease in the tone of the myometrium to prevent premature labor or
spontaneous abortion
a decrease in the uterine cervix tone during labor.
DRUGS ACTING ON UTERUS CONTRACTILITY
CLASSIFICATION
A. D r u g s s tim u la tin g m y o m e tr iu m
1. Stimulants o f rhythmic contractions
a) hormones
- Oxytocin
- Pituitrinum
b) prostaglandins
- Dinoprost (PgF2oi)
- Dinoprostone (PgE,)
c) other preparations
- Neostigmine
- Pachycarpine
- Serotonin adipinate
- Castor oil
2. Stimulants o f uterine tone
a) ergot alkaloids
- Ergometrine maleate
- Methylergometrine
B. Uterine relaxants (Tokolytics)
1. p-adenomimetcs
- Salbutamol
- Partusisten
- Methacinum
3. Other preparations
- Magnesium sulfate
- Nifedipine
- Aspirin
- Progesterone,
- Tocopherol acetate
C. D r u g s d e c r e a s in g u te r in e c e r v ix to n e
- Atropine sulfate
- Magnesium sulfate
- Drotaverine
- Lydasum.
OXYTOCIN
is octapeptide, hormone o f posterior pituitary (fig. 25.8)
is administered IM, IV, into the wall o f uterus, intranasally; starts to act in
'A -1 min after IV administration
Axons
Posterior lobe
Granules
containing
hormone
Anterior
lobe v
Hormones
Uterus
F ig . 25.8. Oxytocin as hormone of posterior pituitary (http://www.picsearch.com)

acts on oxytocin receptors on the cell membranes in the myometrium,

causes the depolarization of membranes and an influx o f calcium, increases
excitability, stimulates rhythmic contractions of the myometrium, promotes
labor activity; also stimulates milk production and ejection
• is used for the stimulation o f labor activity, the treatment o f postpartum
uterine bleeding, the stimulation of lactation
may cause nausea, vomiting, heart arrhythmia in the fetus, urine retention,
the elevation of BP, a thetanic contraction o f myometrium, the hyperstimula
tion o f labor activity resulting in the fetus hypoxia and a rupture of the uterus
is contraindicated in danger of a uterus rupture, hypoxia o f the fetus, ab
normal position o f the fetus.

Dinoprost (P gF ,J is administered IV, intravaginally, intra-amnionally; acts on
specific structures in the myometrium, increases the sen
sitivity to oxytocin, produces the stimulation o f rhythmic
contractions of the myometrium in any terms o f pregnancy,
relaxes the cervix of the uterus; is used for the stimulation
o f labor and initiation of artificial abortion; may cause side-
effects, such as nausea, vomiting, diarrhea, tachycardia, a
spasm o f bronchi, an increase in BP and an elevation of
intraocular pressure; is contraindicated in patients with
scars of the uterus, severe diseases of the cardio-vascular
system, liver, and kidney; bronchial asthma, glaucoma.
Dinoprostone (PgEJ is similar to dinoprost, but may
be taken orally; does not cause spasm o f smooth muscles
and an increase in BP. <•
Ergom etrine male ate is an ergot alkaloid (fig. 25.9);
is taken orally or administered IM, IV; increases the uterus
tone and terminates postpartum bleeding caused by a low
tone of the myometrium; realizes its effect through o^-
adrenoceptors and serotonin (5-HT) receptors; is used for
the treatment o f postpartum bleeding and slow postpartum
involution of the uterus; is not used for the stimulation of
labor; should not be used before the birth o f placenta; is
Fig. 25.9. Ergot
toxic; may cause acute and chronic poisoning (ergotismus) (Secale c o m u tu m )
connected with vasoconstriction, trophy disturbances, and containing
psychic disorders. ergometrine.
332 PH AR M ACO LO G Y. V, M. Bobyrov.T. 0. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
Many other drugs which are used as uterotonics and uterus relaxants belong
to different pharmacological groups and are described between autonomies, hormonal
preparations, spasmolytics, etc. in Chapters 5, 6, 7, 17, 19, 26, 27.

№ 1. A loop diuretic for forced diuresis in acute poisoning is:
A. Hydrochlorothiazide
B. Spironolactone
C. Ergometrine maleate
D. Furosemide
E. Triamterene.
№2. All the concerning dinopost and dinoprostone is true, except:

A. They are prostaglandins
B. They stimulate uterus contractions
C. They are effective only at the end of pregnancy
D. They relax the uterine cervix
E. They are used for the stimulation o f labor and induction o f abortion.
№3. Osmotic diuretics:

A. Are administered by IV infusion
B. Cause dehydratation of body tissues
C. Block carbonic anhydrase in the proximal tubules
D. Reduce N a+ reabsorption in the proximal tubules
E. Has a weak diuretic action.
№ 4. The correct statements concerning treatment o f gout are: 4

A. Colchicine is used to treat a gout attack
B. Allopurinol is a uricosuric agent
C. Allopurinol is the inhibitor o f xantine oxidase
D. Probenecid is uricostatic
E. Uricostatics are used for the prevention o f a gout attack.
№5. A patient has chronic cardiac insufficiency and essential hypertension.

The doctor advices him to include into the treatment regimen a potassium-sparing
diuretic. The drug is an antagonist o f aldosterone, but its therapeutic effect develops
slowly. Which o f the listed drugs is recommended to the patient?
A. Furosemide
B. Amiloride
C. Spironolactone
D. Mannitol
E. Urea.
Answ ers
№ 1 - D; № 2 - C; №3 - A, B, D; № 4 - A, C, E; № 5 - C.
26
0)
I / n HORMONAL
O M V PREPARATIONS
HORMONES AND HORMONAL PREPARATIONS

H orm ones are substances produced by endocrinal glands into blood which
achieve humoral regulation o f body functions.
H orm onal preparations are medicinal forms o f hormones used for treatment
o f diseases.
A nti-horm ones are drugs which decrease effects o f hormones by the inhibition
of their secretion or binding to hormonal receptors.
Hormonal drugs are divided into several groups by their origin and chnical
properties (fig. 26.1). They may be classified according to the mode o f action and
chemical structure.
C lassification o f hormones according to the

mode o f action
A. Kinetic hormones (oxytocin, vasopressin)
B. Morphogenous hormones (somatotropin, thyroid hormones)
C. Metabolic hormones
1. Anabolic (androgens, insulin)
2. Catabolic (epinephrine, glucocorticoids).
Chapter 26, H O R M O N A L P R E P A R A T IO N S 335
HORMONAL DRUGS )
— (_______ H y p o th a la m ic an d p itu ita ry h o rm o n e s_________ J
— ( T h y ro id h o rm o n e s a n d a n ti-th y ro id d ru g s j
— f P a r a th y r o id h o rm o n e p re p a ra tio n s J
——f A n ti-d ia b e tic d ru g s j
— C C o r t ic o ste ro id s J
— ^ G o n a d a l h o rm o n e s a n d re la te d su b sta n c e s______J
Fig. 26.1. M ain groups o f horm onal preparations.
Classification o f hormones according to the chem ical structure

A. A m in o a c id s d e riv a tiv e s -epinephrine,
L-thyroxine, Triiodthyronine hydrochloride
B. - Corticotropin, Somatotropin, Menopaustic gonadotropin, Chorionic
P e p tid e s
gonadotropin, Oxytocin, Adiurecrin, Calcitonin, Parathyroidin, Insulin
C. S te r o id s
1. Glucocorticoides - Hydrocortisone acetate, Prednisolone, Dexamethasone,
Triamcinolone, Flumetasone pivalate
2. Mineralcorticoides - Desoxycorticosterone acetate (DOCSA)
3. Estrogens - Estron, Estradiol benzoate, Ethinylestradiol
4. Progestins - Progesterone
5. Androgens - Testosterone propionate
6. A nabolic steroids - M ethandienone, N androlone phenylpropionate,
Nandrolone decanoate.
«9
Common mechanisms o f action

Hormones exert their effects through different mechanisms:
by binding to the cell surface receptors (oxytocin, vasopressin, corticotro
pin, insulin, etc.). Hormones acting on the cell membrane receptors realize
their effects by the alteration of the intracellular cAMP (e.g. hypothalamic
and anterior pituitary hormones), by Ca++and the generation o f inositol-
phospate / diacilglycerol (e.g. posterior pituitary hormones), or by a direct
transmembrane activation o f tyrosine kinase (e.g. insulin)
by binding to intracellular cytoplasmic receptors (glucocorticoids, mineral-
corticoids, estrogens, progestins, androgens)
by interaction with nuclear receptors (thyroxine, triiodthyronine).
The H o rm o n e’s level in blood is regulated according to the principle o f “back-

cross” (fig. 26.2).
Types of hormonal therapy

H orm onal therapy is the therapy by hormonal preparations.
There are such types o f hormonal therapy:
Replacement therapy, which is the use o f hormonal drugs for the hypofunc-
tion o f the endocrinal gland (e.g. insulin for diabetes mellitus)
Patogenesis therapy, which is the use o f hormonal preparations for diseases
unconnected with hormones deficit (e.g. insulin for cachexia)
Pharmacodynamic therapy is the usage o f non-hormonal properties o f
hormones (e.g. steroid Viadrilum for IV anesthesia)
Stimulation therapy is the usage o f hormones o f the anterior pituitary for
the stimulation o f peripheral glands (e.g. corticotropin after the withdrawal
o f corticosteroids).
Hypothalamus ® ■j r *1
f \
1J IX \
physis
f t |
Adrenal
' cortex
Ç J T
Cortisol Exogenous
30 mg/day administration
Fig. 26.2. Back-cross regulation of cortisol production:

A - cortisol production under normal condition; B - a decrease in cortisol
production with a cortisol dose < daily production (adapted by H. Liillmann, 2000).
Chapter 26 H O R M O N A L P R E P A R A T IO N S 337
Antihormonal therapy is the usage of anti-hormones (e.g. methimazole for

hyperthyroidism).
Principles of hormonal therapy

An individual selection o f the dose for each patient (e.g. 1IU o f insulin for
utilization o f 3-5g o f sugar excreted with urine per day)
• Taking into account o f biological rhythms (e.g. glucocorticoids are more
effective in the morning when it’s their peak concentration in the organism)
A long-term treatment, sometimes during the whole life (e.g. insulin for
type 1 diabetes mellitus)
Gradual abolishing
Stimulation therapy at the end o f treatment (e.g. corticotropin before the
abolishing o f glucocorticoids (fig. 26.2).
PITUITARY HORMONES
CLASSIFICATION
1. Anterior pituitary hormones and related substances
- Corticotropin
- Cosyntropin
- Somatotropin
- Human menopausal gonadotropin (hMG)
- Human chorionic gonadotropin (hCG)
- Prolactin
- Thyrotropin
2. Posterior pituitary hormones
- Oxytocin
- Vasopressin
- Desmopressin
3. Intermediate pituitary hormones
- Intermedin.
Corticotropin is a short peptide; stimulates the secretion o f corticosteroids by the
cortex o f the adrenal glands; has anti-inflammatory and anti-allergic effects resulting
from an increase in cortisol secretion; is administered IM to treat the hypofunction
o f the adrenal cortex, adrenocortical atrophy after the withdrawal o f corticosteroids,

rheumatism, collagenosis, bronchial asthma, and severe allergy, displays side-effects
which are similar to adverse reactions o f corticosteroids.
Cosyntropin is preferred for the diagnostics of the adrenal insufficiency.
Somatotropin is a large polypeptide from the anterior pituitary; is produced by the
recombinant DN A technology; stimulates protein synthesis and promotes bone growth;
is used to treat growth-hormone insufficiency in children, pituitary dwarfness; is con
traindicated to patients with closed epiphyses or with an increased intracranial mass.
H um an m enopausal gonadotropin (hMG) and hum an chorionic gonadotropin
(hCG) regulate reproduction. hMG contains follicle-stimulating hormone (FSH) and
luteinizing hormone (LH), causes ovarian follicular growth and maturation. hCG is a
placental hormone and LH agonist promoting ovulation. In men treatment with hCG
causes external sexual maturation, and treatment with hMG stimulates spermatogen
esis. Gonadotropins are used in hypogonadotropic hypogonadism, delayed puberty,
ovulation dysfunction and sterility in women, hypospermia and sterility in men.
Oxytocin stimulates uterus contractions and promotes contractions o f myoepithe
lial cells in mammary glands; is used in weak labor activity, hypotonic metrorrhagia,
for the promotion o f milk ejection; is contraindicated in abnormal fetal presentation,
fetal distress, and the risk o f uterine rupture development.
Adiurecrin (Vasopressin) binds to V2-receptors in the kidney to increase water
reabsorption in collecting tubules; stimulates V^receptors in vascular smooth muscles,
the Iver, and other tissues to regulate the vascular tone, the tone o f smooth muscles,
and blood coagulation; is used in diabetes insipidus, shock, hemorrhage, hemophylia,
atony o f the gut; may cause water intoxication, hyponatremia, enhanced BP, a spasm
o f bronchi, headache, tremor.
Desmopressin is a modified vasopressin with a long duration o f action and
low pressor activity; is now preffered for diabetes insipidus and nocturnal enuresis.
THYROID HORMONES AND ANTI-THYROID DRUGS
CLASSIFICATION
1. Thyroid hormones
- Levothyroxine (L-thyroxine)
- a-Triiodthyronine hydrochloride
2. Anti-thyroid drugs
- Methimazole (Mercazolilum)
- Iodides.
I
Chapter 26. H O R M O N A L PR E P A R A T IO N S 339
THYROID HORMONES
L-thyroxine, triiodthyronine hydrochloride have common effects and indica
tions. They are taken orally. Triiodthyronine is more active than other preparations.
Overdose o f thyroid hormones manifests as hyperthyroidism.
Pharm acodynam ics Indications

An increase in catabolism o f proteins, lipids, and Hypothyroidism
carbohydrates (myxedema, cretinism)
An increase in basal metabolism Diffuse non-toxic goiter
An increase in body temperature Thyroiditis.
An increase in the activity o f sympathetic nervous
system
Participation in growth and mental development in
children.
ANTITHYROID DRUGS
A nti-thyroid drugs are preparations for the treatment of hyperthyroidism (thy
rotoxicosis, Basedow’s disease).
METHIMAZOLE (MERCAZOLILUM)
is taken orally; concentrates in the thyroid gland
blocks peroxidase and suppresses thyrosine’s iodination. A result is a de
crease in the synthesis of thyroid hormones and the reduction o f symptoms
o f hyperthyroidism (fig. 26.3)
is used to treat hyperthyroidism
may cause side-effects, such as agranulocytosis, leucopenia, skin rash, fever,
joint pain, the depigmentation o f the hair, paradontitis, necrotic stomatitis.
IODINE PREPARATIONS
Preparations o f iodine are used:
- for the replacement o f iodine deficit in hypothyroidism
- for the prophylaxis o f hypothyroidism and goiter
- for hyperthyroidism (a back-cross decreasing of thyroid secretion, the de
creasing of size and vascularity of gland).
HORMONES REGULATING METABOLISM

OF CALCIUM AND PHOSPHATE
CALCITONIN (CALCITRINUM)
Calcitonin is produced by the thyroid gland (fig. 26.4). it is a protein, that’s
why it is not administered orally. Calcitonin’s preparations are administered IM or
intranasal ly.
P harm acodynam ics Indications

Suppression o f the décalcification Osteoporosis
ofbones Padget’s disease
An increase in the activity o f osteo Bone fractures
blasts Bone pain in neoplastic malignant diseases
A decrease in the activity o f osteo Caries, severe paradontitis
clasts Hypercalcemia
Suppression o f bone resorption Nephrocalcinosis.
A decrease in the calcium level in
blood serum.
Chapter 26. H O R M O N A L P R E P A R A T IO N S 341
PARATHYR01DIN
Parathyroidin is an antagonist o f calcitonin (fig. 26.4). It is a polypeptide pro
duced by parathyroid glands. It is only administered parenterally.

An increase in calcium absorption in the intestine Hypoparathyroidism (teta-
An increase in calcium reabsorption in the kidney nus, spasmophylia)
A decrease in phosphate reabsorption in the kidney Allergic diseases.
An increase in serum calcium and a decrease in
serum phosphate
An increase in resorption o f bone tissue due to acti
vation o f osteoclasts
A decrease in bone mineralization
Synergism to vitamin D.
Parafollicular | Parathyroid
cells of glands
thyroid
Fig. 26.4. Action o f calcitonin and parathyroidin on calcium metabolism

INSULIN AND HYPOGLYCEMIC DRUGS
DIABETES MELLITUS
Diabetes m ellitus is a heterogeneous group o f syndromes characterized by
a hyperglycemia caused by relative or absolute deficiency o f insulin. The classic
symptoms o f diabetes mellitus are polydipsia, polyphagia, polyuria.
There are two types of diabetes mellitus:
- insulin-dependent diabetes mellitus (IDDM) or type I
- non-insulin dependent diabetes mellitus (NIDDM) or type II.
Type I diabetes (10-20% o f all cases) is a result o f the destruction ofp-cells and
must be relayed on injected insulin.
Type I I diabetes (80-90% o f diagnosed diabetes) is a result ofp-cells inability to
produce an appropriate quantity o f insulin or insulin resistance in target organs. Blood
glucose level may be controlled by weight reduction, diet, and oral hypoglycemic drugs.
ANTIDIABETIC DRUGS
Antidiabetic drugs are hormonal preparations and synthetic drugs for the treat
ment o f diabetes mellitus.
CLASSIFICATION
A. In su lin p r e p a r a tio n s
1. Rapid action preparations
- Regular insulin
2. Intermediate action preparations
- Semilente insulin suspension
- Lente insulin ’
3. Prolonged action preparations
- Ultralente insulin
B. O ra l h y p o g ly c e m ic a g en ts
1. Suifonylureas
- Chlorpropamide
- Tolbutamide
- Glibenclamide
- Glyburide
2. Biguanides
- Metformin
3. a-glucosidase inhibitors
- Acarbose
- Miglitol
4. Thiazoiidinediones
- Rosiglitazone
- Pioglitazone.
INSULIN
Insulin is a short protein consisting of two chains that are connected by disulfide
bonds. It is synthesized by p-cells o f the pancreas.
Sources o f insuiin (fig. 26.5):
- pork and buff pancreas;
- special strain o f genetically modified E.coii.
Pharmacokinetics
is administered SC, IV (in hyperglycemic emergency)
starts to act in 15 min; has a duration o f action o f 4-6 hrs
is inactivated by insulinase in the liver and kidney.

An increase in glucose entry into cells Diabetes mellitus (type 1)
A decrease in gluconeogenesis Diabetic (hyperglycemic) coma
An increase in utilization o f glucose in Cachexia
the cells Furunculosis
An increase in glycogen synthesis in the Liver diseases
liver and skeletal musclçs Insulin-comatous therapy of schizo
Lowering o f the glucose level in blood phrenia
(hypoglycemic action) For better availability o f glucose du
An increase in protein synthesis ring IV infusion.
The promotion o f cells proliferation
(growth factor)
The regulation o f lipid metabolism
A decrease in ketoacidosis
Side-effects
1. Hypoglycemia (tachycardia, confusion, vertigo, sweating, hypoglycemic
coma)
2. Lypodystrophy in the site o f administration

3. Allergy.
LONG-ACTING INSULIN PREPARATIONS

Sem ilente insulin suspension is an amorphous precipitate o f insulin with zinc
ions in acetate buffer; has a duration o f action o f 12-16 hrs; is not administered IV.
Lente insulin is a mixture o f 30% o f semilente insulin and 70% ultralente
insulin; is administered only SC.
Ultralente insulin is a suspension o f zinc insulin crystals in the acetate buffer;
has a slow onset o f action and a long effect (36 hrs).
DIABETIC (HYPERGLYCEMIC) AND INSULIN

(HYPOGLYCEMIC) COM A
Diabetic (hyperglycemic) coma
Signs:
This coma develops due to a high blood sugar level and is characterized by
unconsciousness, hyperemia o f the skin, a low tone o f skeletal muscles and eyes,
specific odor from breathing air and urine, hyperglycemia and ketoacidosis.
Em ergency help:
— regular insulin (IV)
- 0,9% solution of sodium chloride fora decrease in hyperosmolarity o f blood
(IV infusion)
- 4% solution o f sodium bicarbonate for a decrease in acidosis (TV infusion)

- thiamine as synergist o f insulin (bigger dose).
Insulin (hypoglycemic) coma
Signs:
This coma results from a low blood sugar level caused by an overdose o f insu
lin. It is characterized by slow development, the pre-coma period, unconsciousness,
sweating, cold pale skin, a high tone o f skeletal muscles and eyes, seizures, the
absence of specific odor, hypoglycemia.
Emergency help:
- sweet tea and white bread by mouth during pre-coma
- 40% solution o f glucose (IV) in a comatous condition
- epinephrine, prednisolone, or glucagon as contra-insular hormones.
ORAL HYPOGLYCEMIC DRUGS

Oral hypoglycemic drugs are synthetic non-hormonal preparations which can
lower the glucose level in blood. Prepa'rations from each group are characterized by
a common mechanism o f action and pharmacological properties.
Mechanism of action
1. Sulfonylurea derivatives:
an increase o f insulin release from the pancreas
reduction of serum glucagon concentration
the potentiation o f insulin action on target cells.
2. Biguanides
an increase o f glycolysis in tissues
• the inhibition o f hepatic gluconeogenesis
a decrease in glucose reabsorption in the GI tract
the reduction o f the plasma glucagon level
a decrease in the absorption of lipids in the gut and the reduction of body weight
lowering o f hyperlipidemia.
3. a-glucosidase inhibitors
a competitive inhibition of a-glucosidase
• a decrease of monosaccharide absorption
a decrease in the blood sugar level
4. Thiazolidinediones
an increase in tissue insulin sensitivity.
346 PH AR M ACO LO G Y. V. M. Bcbyrov,T. 0. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
Indications
Type II non-insulin-dependent diabetes in patients after the age o f 35 years old.
Side-effects
1. Hypoglycemia
2. GI disturbances
3. Itch
4. Anemia
5. Hyponatremia, hypotension, disulfiram-like reaction (after the administra
tion of some drugs).
ADRENAL STEROIDS (CORTICOSTEROIDS)

Adrenal steroids are steroidal hormones produced by the adrenal cortex ortheir
synthetic analogs (fig. 26.6).
C O - C H 2- OH
- OH
H r. C O - C H 2- OH
OH
OH
o
Fig. 26.6. C hem ical structure o f som e adrenal steroids:
A - hydrocortisone; B - triam cinolone.
CLASSIFICATION
A . G lu c o c o r tic o id s
1.Short-acting (8-12 hours)
- Hydrocortisone acetate
2. Intermediate-acting glucocorticoids (18-36 hours)
- Prednisolone
- Methyiprednisolone
- Triamcinolone
3. Long-acting glucocorticoids (1-3 days)
- Dexamethasone
4. Topically active glucocorticoids
- Beclomethasone dipropionate
- Fluocinolone acetonide
B . M in e r a lo c o r tic o id s
- Desoxycorticosterone acetate.
GLUCOCORTICOIDS
Glucocorticoids are adrenal steroids with a prevalent action on metabolism
and inflammation. All glucocorticoids produce common pharmacological effects.
They have some common indications, contraindications, and side-effects. As a rule,
contraindications are not taking into acount if the drug is used for emergency help.
Pharmacokinetics
are administered IM, IV, topically, by inhalation; all drugs may be taken
orally
are well absorbedîn the GI tract
bind to plasma proteins (90% o f a dose)
• are metabolized in the liver
are excreted with urine in the form of metabolites (glucuronides and sulfates).

An increase in protein catabolism Collagenosis, severe rheumatism, arthri
tis, arthrosis
An increase in gluconeogenesis Bronchial asthma
An increase in glucose level in blood Allergic diseases o f the skin and mucous
membranes
The regulation o f lipids distribution, Autoimmune diseases
an increase in lipolysis
The retention o f sodium and water Transplantation o f organs

An increase in excretion of potassium Acute leukemia
and calcium
A decrease in all phases o f inflam Shock
mation
The suppression o f immunity Hypoglycemic coma
The suppression o f allergic reactions Anaphylactic shock
Changes in blood film (eosinopenia, Adrenal insufficiency (natural hormones
lymphopenia) are preferable)
The inhibition o f lymphoid tissue
proliferation
An increase in resistance to stress.
Glucocorticoids are among the most potent anti-inflammatory agents. They

inhibit all three stages o f inflammation. The inhibition o f alteration and exudation
is due to the reduction o f blood vessels permeability, the inhibition ofhyaluronidase
activity, the stabilizing o f mast cells membranes and a decrease in histamine liberation,
the stabilizing of lysosomal membranes and a decrease in the release of lysosomal
-0- histam ine

liberation
Blood
f phago
vessels perinea
cytosis
bility
G L U C O C O R T IC O ID S’
A N T I-IN FL A M M A T O R Y
A C TIO N
antibody
A rachidonate
synthesis
synthesis
F ig . 26.7. C om ponents o f glucocorticoids anti-inflam m atory action.

enzymes, the inhibition of leukocytes activity in the site o f inflammation (fig. 26.7).
In contrast to NSAIDs, glucocorticoids inhibit the synthesis o f arachidonate. Their
influence on the proliferation stage is based on the inhibition o f protein synthesis
and fibroblasts activity.
1. The suppression of the pituitary-adrenal function 1. Hyperfunction of
2. Immune suppression and an increase in susceptibil the adrenal cortex
ity to infection 2. Hypertension
3. Gastric ulceration 3. Severe CHF
4. Hypertension 4. Nephritis
5. An increase o f blood coagulation resulting in 5. Acute endocarditis
thrombosis 6. Ulcerative disease
6. Edema, retention o f sodium and water o f the stomach and
7. An increase o f appetite resulting in enhanced body duodenum
weight 7. Syphilis
8. Hypokalemia 8. Active forms of
9. Osteoporosis, severe caries tuberculosis
10. Hyperglycemia (steroid diabetes) 9. Diabetes mellitus
11. Dystrophy o f skeletal muscles 10. Osteoporosis
12. Disturbances in the function o f other endocrinal 11. Psychosis
glands 12. Pregnancy.
13.. Psychic disorders (depression, insomnia, somno
lence, “steroid psychosis”).
Hydrocortisone is in the form o f ointment, eye ointment, suspension for injec
tions; is used topically to treat allergic eye diseases, aseptic burns o f the eyes or after
eye surgeries (not earlier than 7 days after the operation); is also applied in allergic
skin diseases and administered in arthritis, arthrosis (into joint), bronchial asthma.
Prednisolone is a synthetic derivative o f hydrocortisone; is more potent than
hydrocortisone in 3-4 times; is administered orally, IM, IV, or applied topically in
the form of ointment or eye drops; has T'A o f 2-3 hrs.
Dexam etasone contains fluorine; is more active than hydrocortisone and pred
nisolone; has less side-effects; is administered orally, IM, IV or applied topically in
the form o f ointment or eye drops; has T'A o f 3-4,5 hrs; is characterized by 72 hrs
duration of an anti-inflammation effect after the oral administration.
L
Triamcinilone (Kenalog) contains fluorine; has a prolonged action; has T'A=

1,5-3,3 hrs which is not correlated with a duration o f action; develops maximal effect
in 24-48 hrs and acts during 6 weeks; is used to treat arthritis, arthrosis, joint lesions
caused by collagenosis, rheumatism; is injected in the site of lesion in psoriasis,
neurodermitis, lupus erythematoidis; is not administered IV; has less side-effects than
other preparations (less retention o f sodium and water, less diabetogenous action).
Fluocinolone acetonide (Flucinar) is a fluorine-containing preparation for a
topical application in dermatology; is used in the form o f ointment, penetrates the
upper layer o f epidermis and stays in the skin during 15 days; is indicated in allergic
and inflammatory diseases o f the skin, psoriasis, lupus erythematoidis; should not be
used for a long-time treatment or on the large area of lesion; may cause generalization
of infection if used without antimicrobial drugs.
B eclom ethasone d ipropionate is used in the form o f inhalations for the pre
vention o f a bronchial asthma attack; penetrates into the airway mucosa, but has a
short half-life in the body, so that systemic effects and toxicity are greatly reduced.
MINERALCORTICOIDS
D ESO XYCO R TICO STERO N E A C E T A T E

is administered IM and sublingually
regulates reabsorption o f sodium, promotes retention of phosphate, calcium,
carbonate, water, and sodium
supports BP and the muscular tone
is used to treat adrenocortical insufficiency and myastenia
may cause edema, hypertension, hypokalemia.
ANTAGONISTS OF A D R EN A L STEROIDS
M etyrapone inhibits the synthesis o f adrenal steroids; is used for the treatment
o f adrenal hyperfunction (Cushing’s syndrome).
A m inoglutethim ide reduces the synthesis of hormonally active steroids; is used
to treat breast cancer and adrenal cortex malignances.
Ketokonuzole is an antifungal drug; inhibits the synthesis o f gonadal and adrenal
steroids; is used to treat Cushing’s syndrome.
Spironolactone is an antagonist o f aldosterone; it binds to mineralcorticoid
receptor and inhibits sodium reabsorption in the kidney; antagonizes aldosterone and
testosterone synthesis; is used as diuretic and for the treatment of hirsutism in women.
G O N AD AL HORMONES AND RELA TED S U B STA N C ES

Gonadal horm ones are steroidal hormones produced by the male and female go
nadal glands which regulate the development o f sex characteristics and reproduction.
CLASSIFICATION
A. M a le g o n a d a l h o rm o n es a n d r e la te d su b sta n c e s
1. Androgens
- Testosterone propionate
- Methyltestosterone
2. Anti-androgens
- Flutamid
- Finasteride
- Cyproteron
3. Anabolic steroids
- Methandienone (Methandrostenolonum)
- Nandrolone phenylpropionate (Phenobolinum)
- Nandrolone deconoate (Retabolil)
B. F em a le g o n a d a l h o rm o n e s a n d r e la te d su b sta n c es
1. Estrogens
- Estradiol benzoate
- Ethinylestradiol
- Synoestrol
- Diethylstilbestrol
2. Anti-estrogens
- Clomiphene citrate
- Tamoxifen citrate
3. Progestins
- Progesterone
- Hydroxyprogesterone caproate
- Allilestrenol
- Levonorgestrel
4. Antiprogestins
- Mifepristone.
ANDROGENS
A ndrogens are male gonadal hormones produced mainly by testis or their
synthetic analogues.
T ES TO S T E R O N E PROPIONATE
is administered IM
takes part in the development o f primary and secondary sex characteristics,
maintains fertility in men; has an anabolic action; maintains normal bone
density
is used to treat hypogonadism in men; may be used in a combined therapy
o f certain anemias, wasting syndromes, senile osteoporosis, severe bums,
breast cancer in women before 60
may caue side-effects, such as masculinization in women, an altered bone
development in children, the inhibition o f gonadotropin release and reduc
tion o f spermatogenesis; gynecomastia in men, hepatitis, edema.

M ethyltestosterone is a synthetic analogue o f testosterone and has the same
androgenic properties; is not destroyed in the gut; is taken sublingually for better
bioavailability; is 3-4 times less active than testosterone propionate; is used for a
long-lasting therapy o f male hypogonadism, a pathological climax in men, impotence
connected with the hypofunction o f testis, climacteric disturbances and breast cancer
in women; displays side-effects similar to adverse effects o f testosterone.
ANABOLIC STEROIDS
Anabolic steroids are derivatives o f androgens with a strong anabolic effect
and residual androgenic activity.
P h arm acod yn am ics Indications

An increase in protein synthesis C achexia
T he retention o f nitrogen, phosphor, and A sthenia
calcium W ounds, ulcers
T he stim ulation o f tissue regeneration B one fractures, osteoporosis
An increase in m ass o f skeletal m uscles Ischem ic heart disease
T he im provem ent in trophy o f m yocardium M yopathy
A decrease in glucose level in blood D iabetes m ellitus (additional drug)
T he stim ulation o f hem opoiesis. A nem ia (additional drug)
P rolonged treatm ent w ith glucocorticoids
Side-effects
1. Edema
2. An increase in body weight
3. Liver disturbances
4. Masculinization in women.
The anabolics should not be used in sportsmen as a doping.
M ethandienone (Methandrostenolone) has an anabolic activity equal to the
same of testosterone, but is less active in 100 times as androgen than testosterone;
is taken orally 1-2 times a day
Nandrolonephenylpropionate (Phenobolin) is administered IM; has a duration
o f action o f 7-15 days.
Nandrolone decanoate (Retabolil) has a strong and long-lasting anabolic action;
develops therapeutic effect in 3 days, displays maximal effect for 7 days and acts
during 3 weeks; has a minimal androgenic and virilizing action.
ESTR O G EN S
Estrogens are female gonadal hormones produced by ovaries or their synthetic
analogues.
ESTRO N E (FOLLICULINUM))
is natural estrogen
• is administered IM, transdermally, vaginally; is metabolized in the liver
and excreted with urine
takes part in female sexual development, maintains the proliferation phase of
menstrual cycle, increases uterus sensitivity to oxytocin and acetylcholine,
has some metabolic effects (the inhibition o f bone resorption, stimulation
o f calcium transport, reduction o f the cholesterol level in blood), increases
blood coagulatiofi
is used for primary hypogonadism in young female, replacement therapy
in menopause (postmenopausal hormone therapy) (fig.26.8), a lack o f the
development o f the ovaries or castration, for osteoporosis, stimulation o f
labor (together with oxytocin)
• may cause side-effects, such as nausea, vomiting, edema, headache, hyper
tension, breast tenderness.

Estradiol dipropionate is a natural estrogen produced in female organism to
gether with estrone, but is more active; has a prolonged action and is administered
IM once in 3-5 days; has the indications similar to the indications o f estrone.
Ethinylestradiol is a synthetic estrogen similar to estradiol by its structure; is

taken orally, has slow metabolism, a prolonged action, and higher potency; is used
for primary amenorhea, the hyhofunction o f ovaries and secondary amenorrhea,
climacteric disturbances in women, breast cancer in women after 60, prostate cancer
in men; may cause feminization in men, nausea, vomitig, vertigo.
Synoestrol is a synthetic compound - a stilben derivative; has not a steroid
structure, but has estrogenic pharmacological properties and indications; is admin
istered orally, IM, SC
Diethylstilbestrol is a synthetic non-steroidal compound with estrogenic activity,
may be administered orally, IM; is more active than estrone and synoestrol.
ANTI-ESTROGENS
•5
Clom iphene interacts with estrogen receptors; by a feed-back mechanism it

stimulates the secretion o f gonadotropins, leading to ovulation; is used to treat in
fertility on the ground of anovulatory cycles.
Tam oxifen inhibits estrogens action by interfering with their access to receptor
sites; is used to treat breast cancer in postmenopausal women.
PROGESTINS
Progestins are female gonadal hormones produced by corpus luteum or their
synthetic analogues.
Chapter 26 H O R M O N A L P R E P A R A T IO N S 355
PR O G ESTER O N E
is native progestine
is given IM, orally (as a micronized form), intravaginally (vaginal cream)
• takes part in the development of sexual characteristics, maintains the luteal
phase o f a menstrual cycle, stimulates maturation o f the uterus endometrium
and provides implantation, decreases uterus sensitivity to oxytocin and
supports the normal development o f pregnancy, promotes the development
o f breast secretory tissue, acts on carbohydrate metabolism and stimulates
fat deposition
is used for the prevention o f spontaneous abortion, dysfunctional uterine
bleeding, dysmenorrhea, endometriosis, suppression o f postpartum lacta
tion, endometrial carcinoma
may cause side-effects, such as uterine bleeding, dyspepsia, edema, depres
sion, an increase in the cholesterol level, an increase in blood coagulation,
acne, hirsutism, weight gain.

Oxyprogesterone caproate is a synthetic analogue of progesterone, is more
stable in the body and has prolonged action during 7-14 days; is administered 1M;
is more suitable for a long-term therapy.
Allilestrenol is a synthetic progestin; is administered orally, is more stable to
first-pass metabolism; is used for the prevention o f spontaneous abortion.
ANTIPROGESTINS
M efipristone is a progestine antagonist, has antiglucocorticoid activity, is used
for the termination of gestation and for contraception.
O R A L AND INPLANTABLE CO N TRACEPTIVES

H orm onal contraceptives are hormonal preparations for the prevention of
pregnancy.
There are 4 main classes o f oral contraceptives (fig. 23.9).
• C om bination pills contain estrogen and progestin. The estrogen suppresses
ovulation. The progestin prevents implantation and makes the cervial mucus
impenetrable to sperm. They are taken in bi- or triphase regimen. Biphasic
preparation is atenovin. Triphasic preparations are triregol, triquilar,
tr is is ton.
Progestin pills contain a progestin only (norethindrone or norgestel). They

are less effective than the combination pills.
Progestin inplants are subdermal capsules containing levonorgestrel for
a long-term contaception (5 years).
Postcoital contraceptives contain a high dose o f estrogen (ethiny lestradiol,
diethylstilbestrol) or estrogen (ethinyl estradiol) and progestin (norgestret)
administered within 72 hrs o f coitus.
( ORALAND IMPLANTABLE CONTRACEPTIVES )
C om b in ation pills
1
P rogestin pills (m ini-pills)
P rogestin inplants
P ostcoital contraceptives
Fig. 26.9. C lasses o f oral contraceptives.
Side-effects of oral contraceptives

Breast fullness, depression, dizziness, nausea, vomiting, thromboembolism,
thrombophlebitis-, hypertension, increased incidents o f myocardial infarction and
cerebral thrombosis, abnormal glucose tolerance tests, changes in the serum lipo
protein profile, cholestatic jundice, skin pigmentation, acne, hirsutism, amenorrhea,
uterine bleeding.
№1. The hormonal preparation with mineralcorticoid activity is:
A. Prednisolone
B. Dexamthasone
C. Testosterone propionate
D. Desoxycorticostrone acetate
E. Estradiol caproate.
№ 2. Glucocorticoids may cause all the following side-effects, except:

A. Hypertension
B. Bronchospasm
C. Thromboembolism
D. Hypokalemia
E. Osteoporosis.
№ 3. Regular insulin:
A. Is produced by genetically modified E .c o li
B. Is administered SC, IV
C. Is used for replacement therapy o f I type diabetes mellitus
D. Is taken orally in II type diabetes mellitus
E. May cause hyperglycemia.
№4. Anabolic steroids:

A. Have high androgenic activity
B. Have high anabolic activity
C. May cause feminization in men
D. May cause masculinization in women
E. Are contraindicated to sportsmen.
№ 5. The patient suffering from the hypofunction o f the thyroid gland was
treated by hormonal preparation. Overdose o f this preparation causes restlessness,
insomnia, fever, headache, tachycardia, pain in the heart, palpitation, tremor. What
drug was used by this patient?
A. Insulin
B. Methimazole
C. L-thyroxine
D. Triamcinolone
E. Retabolil. <-
Answers
№ 1 - D; № 2 - B; № 3 - A, B, C; № 4 - B,D, E; № 5 - C.
27
o
1 / / VITAMINS
O mm I PREPARATIONS
VITAMINS AND THEIR PREPARATIONS

Vitamins are organic substances essential for normal metabolism. They are the
normal components o f diet and must be supplied in very small quantities.
H istory of vitam ins. A russian scientist N.I.Lunin discovered vitamins (1880).
Holand Ch.Echman supposed that rice husk contained substance for the prevention
and treatment of disease beri-beri (vitamin (1897). A polish scientist K.Funk
separated this substance from rice husk and proposed the name “vitamin” .
Vitamins preparations are medicinal forms o f vitamins used for the prophylaxis
and treatment o f diseases.
D is tin g u is h e s betw een m em brane-tropic

and enzym e-tro p ic vitam ins
Division o f vitamins into groups is based on their biochemical properties and
participation in biological processes. Some common characteristics make it possible
to speak about membrane-tropic and enzyme-tropic vitamins (table 27.1).
Chapter 27. V IT A M IN S P R E P A R A T IO N S 359
T able 27.1. D istinguishes between groups o f vitam ins
M em b ran e-tropic vitam in s E nzym e-tropic vitam ins

1. Are fat and water-soluble substances 1. Are only water-soluble substances
2. Have a requirement of 100 mg per day 2. Have a requirement of 1-10 mg per day
3. Are components of cell membranes 3. Are components of enzymes (co-en
4. Are not phosphorilized zymes)
5. Take part in the forming and protection 4. Are phosphorilized
of cells membranes 5. Take part in biochemical reactions
6. May cause hypervitaminosis 6. Don’t cause hypervitaminosis
Vitam in d e ficie n cy
Avitam inosis is a specific deficiency syndrome caused by the absence o f par
ticular vitamin. It is occurred very rarely.
Hypovitaminosis is a specific deficiency syndrome caused by the deficit of
particular vitamin. It is often occurred. There are two types o f hypovitaminoses:
cxogeneous and endogeneous (fig. 27.1). Exogeneous hypovitaminosis is caused
by factors outside the body, e.g. deficit o f vitamin in the diet or poor nutrition.
Endogeneous hypovitaminosis is caused by factors inside the organism and is divided
into physiological and pathological.
HYPOVITAMINOSIS
E xogenous Endogenous
(caused by (caused by
exogenic factors) endogenic factors)
Physiological P athological
(caused by pregnancy, lactation, (caused by diseases and their
quick growth, stress) treatment)
Fig. 27.1. Types of hypovitaminosis.
A ntivitam ins
A ntivitam ins are substances which decrease a vitamins action.
There are three groups o f antivitamins:
360 PH A R M A CO LO G Y. V. M. Bobyrov.T. 0. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
a n tim e ta b o lite s w h ich are c h em ical an alo g u es o f v itam in s (e.g.

Neodicumarinurn is an antivitamin o f naphthoquinon; isoniazid is an an
tivitamin o f pyridoxine; methotrexate is an antivitamin o f the folic acid)
enzymes which destroy vitamins (e.g. thiaminase, ascorbinase)
substances which increase the utilization o f vitamin (e.g. anti-atherosclerotic
drug Linaetholum increases the utilization o f vitamin E).
H yp e rv ita m in o sis
Hypervitaminosis is the overdose o f a vitamin preparation.
Most o f vitamins are comparatively safe, but vitamins A and D can cause seri
ous toxic effects. Hypervitaminosis may be acute and chronic.
V ita m in s therapy
Vitamins therapy is the therapy by vitamins preparations.
Vitamins therapy is divided into three types (fig. 27.2):
specific replacement therapy which is the use o f vitamins for the treatment
o f hypo- and avitaminosis (e.g. the ascorbic acid is for the treatment of
scurvy; thiamine - for beri-beri)
pharmacodynamic therapy which is the use o f vitamins for diseases non
connected with vitamins deficit (e.g. the use o f the ascorbic acid to treat
wounds and infections)
adaptation therapy which is the use o f vitamins for the improvement o f
non-specific resistance and adaptation (e.g. the use o f the ascorbic acid,
tocopherol acetate, and multivitamins preparations in healthy persons under
the conditions o f stress or physical overstrain).
VITAMINS THERAPY
Specific (replacement) therapy_______ j
Pharmacodynamic therapy ^
A d ap tatio n th e rap y ^
F ig. 27.2. T he types o f vitam ins therapy.

CLASSIFICATION
According to the solubility According to the biological activity
1. Water-soluble M em brane-tropic
- Thiamine chloride (B,) - V itam in A
- Riboflavin (B2) - V itam in E
- Nicotinic acid (B3 or PP) - V itam in D
- Calcium pantothenate (B5) - V itam in K
- Pyridoxine hydrochloride (B6) - V itam in C
- Cyanocobalamin (B|2) - V itam in P
- Folic acid (Bc) 2. E nzym e-tropic (co-enzym ic)
- Calcium pangamate (B15) - V itam in B !
- Ascorbic acid (C) - V itam in B2
- Rutin (P) - V itam in PP
2. Fat-soluble - V itam in B3
- Retinol acetate (A) - V itam in Bf
- Ergocalciferol (D) - V itam in B 12
- a-Tocopherol acetate (E) - V itam in B^.
- Naphthoquinon (K)
MEMBRANE-TROPIC VITAMINS PREPARATIONS

RETINOL A C E T A T E
Retinol has a polyenic structure (fig. 27.3). It is a fat-soluble vitamin.
CH2OH
Fig. 27.3. Chemical structure of retinol.
is taken orally, rarely IM, is applied topically
is absorbed in the intestine in the presence o f bile acids
binds to proteins in blood serum that protects retinol from renal excretion
concentrtes in the liver
exists in the body in such forms as retinol, retinal, and retinoic acid
is metabolized in the liver and excreted with bile and urine, has durative
elimination.
Active form o f retinol is a constituent o f visual purple (rhodopsin).
It takes part in the synthesis o f keratohyalin.
It takes part in the forming of bones and teeth.
Retinol activates synthesis o f im munoglobulins, antibodies, lysosome
enzymes.
• It activates glycogen deposit in the muscles, heart, and liver.
Retinol activates release o f STH, thyroid hormones.
It is an antioxidant.
supporting o f the normal function o f the retina (night vision)
stimulation o f the proliferation and regeneration o f the epithelium
the promotion o f growth o f the organism, prevention o f bones’ epiphyses
c a lc ific a tio n
an increase o f immunity
the improvement in the trophy o f the myocardium, skeletal muscles, liver,
the nervous system
supporting o f the reproductive function.
Indications
Hypovitaminosis (hemeralopia). A therapeutic dose for adult patients is
up to 10000 IU per day, a prophylaxis dose is 5000 IU per day (1 drop of
3,44% oil solution contains 5000 IU)
Eye diseases (cornea and retina diseases)
Hyperkeratosis, leukoplacia ,
Skin diseases, burns, frostbites
Chronic inflammations of the bronchi, urinary or bile pathways
Rickets (a complex therapy and prophylaxis)
Pregnancy
Diseases o f the mucous membrane o f the oral cavity, a complex therapy
o f severe caries.
Side-effects
A cu te hypervitaminosis: fatigue, headache, sleepiness, nausea, vomiting, pho
tophobia, convulsions (resulting from an increase in intracranial pressure).
Chronic hypervitaminosis: weakness, fatigue, sleepiness, nausea, skin pigmen

tation, hyperkeratosis, bone pains, the liver and spleen enlargement.
C o n tra in d ica tio n s

1. Acute diseases of the liver and kidney
2. Heart failure.
ER G O CA LCIFER O L
Vitamin D is a family o f substances with an anti-rachitic effect. They have
steroid structure and are fat-soluble. Ergocalciferol is vitamin Dr Cholecalciferol
is vitamin D}. Cholecalciferol is synthesized in the skin under the influence o f ul
traviolet rays (fig. 27.4).
Fig. 27.4. Vitamin D and its active forms (by H. Liillmann, 2000).
P h arm a co k in e tics
• is taken orally
is absorbed in the intestine with the participation o f bile acids
is transported to the liver by lymph
• is transported in connection with transcalciferrine in blood plasma
is transform ed into calcidiol in the liver and into calcitriol in kidneys

(fig.27.4)
is deposited in the liver, mucosa o f intestines, and bones
is excreted with bile and then is absorbed again
finally, is excreted with urine and feces
stays in the body for a long time
accumulates.
Vitamin D penetrates cell membrane, binds to the receptor in cytoplasma
and forms the complex “vitamin D -receptor” (fig. 27.5).
It is transported to nucleus and changes genes expression.
As a result, the synthesis o f proteins concerning calcium and phosphate
metabolism is increased.
Such events are similar to the mechanism o f action o f steroid hormones.
Fig. 27.5. Vitamin’s D mechanism of action (byH. Lüllmann, 2000).
Main task o f vitamin D is to regulate calcium-phosphor homeostasis and to
support calcium level in blood (fig. 27.6). According to this purpose, it causes:
an increase in calcium and phosphates absorption from the intestine
an increase in calcium and phosphates reabsorption in the kidney
an elevation o f the level o f calcium

in blood serum
Vit. D-Hormone
an increase in fixation of calcium in
bone tissue under the conditions of
the normal calcium level in blood
serum, but stimulation o f calcium
m obilization from bones if the
serum calcium level is low
• an increase in the calcium influx
into nervous cells
an increase in the calcium influx
into the cells o f skeletal muscles Ca2++ PO3" mm m "
• the stimulation o f immunity and
•
regeneration.
Indications
H y p o v itam in o sis: the p ro p h y
QO
laxis and treatm en t o f rick'ets.
A prophylaxis dose is 500-1000
IU per day; a therapeutic dose is
10000 IU and more per day and
depends on the severity o f vitamin Fig. 27.6. Vitamin D and regulation
deficiency (1 drop o f 0,125% oil of calcium homeostasis in the body
solution contains 1250 IU; 1 drop (by II. Liillmann, 2000).
o f 0,5% alcohol solution - 5000
IU o f vitamin D)
Osteoporosis
Bone fractures <.
Caries, disturbances o f teeth forming
Skin diseases
Tuberculosis.
Side-effects
A cu te hypervitam inosis: weakness, sleepiness, nausea, vomiting, dyspepsia,
hypotension, arrhythmia, an increase in body temperature, an increase in the calcium
concentration in blood serum, changes in urine (protein, cylinders, calcium salts,
erythrocytes, and leukocytes).
Chronic hypervitaminosis-. bone demineralization, calcium deposit in blood
vessels, the kidney, and other organs (calcinosis), CNS damage, heart insufficiency,
an increase in BP, an increase in the calcium level in blood serum and in urine.
Treatm en t o f D h y p e rvita m in o sis

- Abolishing o f drug
- Antioxidants (vitamins E, C, A)
- Glucocorticoides
- Other m edications: phénobarbital for the intensification o f vitamin D
biotransformation; solution of sodium bicarbonate for acidosis; prepara
tions o f potassium and magnesium; calcitrin for the prevention o f bone
demineralization.

1. Severe atherosclerosis
2. Elderly age.
a-TOCOPHEROL ACETATE
It belongs to quinons (fig. 27.7), is fat soluble.
CH,
H,
CH,
Fig. 27.7. Chemical structure of tocopherol. a
is taken orally and administered 1M; is applied topically
is absorbed in the small intestine in the presence o f bile acids
enters lymph, then blood and is transported with lipoproteins
is located in the membranes o f cells, the membranes o f mitochondria and
microsomes
concentrates in adrenal glands and fat tissue
is excreted in an non-transformed status with feces (more than 80% o f drug).
M e ch a n ism of a ctio n
• Tocopherol is the strongest bioantioxidant and protects cell membranes
from free radicals and peroxides
• It increases the activity o f creatinphosphokinase, cytochrome-C oxidase
and some other enzymes, stimulates the synthesis o f ubiquinon, improves
tissue respiration
• Tocopherol increases the secretion o f gonadotropines and sexual hormones
• It increases iron absorption, the synthesis o f hem and surphactant in the lungs.
• the regulation o f reproduction (the promotion o f follicles formation and
normal development of pregnancy in females; the stimulation of sperma
togenesis in males)
the improvement o f skeletal muscles trophy
a cardio-protective action
an increase in stability to hypoxia
the stimulation of erythropoiesjs
an improvement o f reological properties o f blood
an anti-atherosclerotic action
a stress-protective action
a hepatoprotective action
the stimulation of regeneration.
Indications
Spontaneous abortions, sexual glands function impairment, climax
Myodystrophy
Angina pectoris,.* omplex therapy o f myocardial infarction
Atherosclerosis
• Liver diseases
Complex therapy o f anemia
• Diseases o f blood vessels
Radiation sickness
Stress
Paradontitis, diseases o f the mucous membrane o f the oral cavity
• Hypervitaminosis D.
Si de-effects
Creatinuria
368 PH A R M A CO LO G Y. V. M. Bobyrov,T. 0. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
• Very rarely: hepatic disturbances, nausea, headache, an increase in BP (in

bigger doses).
ASCORBIC ACID
Ascorbic acid is a hexose, easily losses the atom o f hydrogen and transforms
into the dehydroascorbic acid (fig. 27.8). It is water-soluble vitamin.
O z = C -------- o = c —
I I
C -O H c=o
II I
C -O H c=o
I I
H - C -------- H -C —
I I
H O -C H HO-CH
I I
C H ,O H CH2OH
Fig. 27.8. Chemical structure of ascorbic acid.
is well absorbed in the intestine
vitamin C concentration in erythrocytes and leukocytes is more than that
in blood serum
• concentrates in gland tissue, especially in adrenal glands
is excreted with urine if the depo is complete.
The ascorbic acid is a donator and an acceptor o f hydrogen. That is why it takes
part in oxidation-reduction systems, is a direct-acting antioxidant.
• participation in the synthesis o f procollagen and collagen
providing o f the growth of bones, the formation o f cartilages and dentine
stimulation o f regeneration
• participation in the transformation o f the folic acid into the tetrahydrofolic

acid
an increase in the absorption o f iron and synthesis o f hem
• participation in the synthesis of adrenal steroids and thyroid hormones
participation in the synthesis o f catecholamines, activation o f sympathetic
nervous system
improvement of immunity and phagocytosis
a decrease in the permeability o f blood vessels
• participation in cholesterol metabolism and the inhibition o f the develop
ment of atherosclerosis
detoxication of xenobiotics in the liver
an increase in resistance to stress and radiation
the improvement o f adaptation.
Indications
Hypovitaminosis (scurvy)
Collagenoses
Rheumatism
• Wounds, bone fractures
Hemorrhagic diathesis
Atherosclerosis
Radiation sickness
Complex therapy o f anemia
Infections
Acute and chronic intoxications
• The stimulation o f protective powers of the organism and the improvement
o f adaptation
Bleeding gums, paradontitis, a complex therapy o f severe caries.
Side-effects
Side-effects only occure in bigger doses o f vitamin C:
1. A decrease in the secretion o f insulin
2. Renal concrements
3. An increase in BP
4. A decrease in permeability o f blood-tissue barriers
5. Hypercoagulation o f blood.
370 PH AR M ACO LO G Y. V. M. Bobyrov.T.O. Devyatkina, 0. M.Vazhnicha, V. M. Khristyuk
RUTIN
is a water-soluble membrane-tropic vitamin, a flavonoid
is taken orally
is an antioxidant; protects the ascorbic acid and epinephrine from oxidation,
participates in oxidation-reduction processes, inhibitshyaluronidase activity,
decreases the permeability of the blood vessels wall
is used together with the ascorbic acid in vasculitis, hemorrhagic diathesis,
rheumatism, collagenosis, radiation sickness, atherosclerosis, infections,
paradontitis.
CALCIUM PAN GAM ATE

is a water-soluble membrane-tropic vitamin, a derivative o f gluconic acid
and dimethylglycine
is taken orally
has the mechanism o f action connected with the ability to be a donator of
active methyl groups
improves lipids metabolism; enhances oxygen utilization in tissues; increases
the concentration o f creatin phosphate and glycogen in skeletal muscles and
the liver; decreases hypoxia; has neuroprotective, cardioprotective, antihy-
poxic, antidystrophic, hepatoproptective effects; decreases side-effects of
sulfa drugs and corticosteroids
is used to treat atherosclerosis, especially atherosclerosis o f arteria in the
lower extrem ities, em physem a o f the lungs, pneumosclerosis, chronic
hepatitis, chronic alcoholism, skin diseases; may be applied to improve the
tolerance to sulfa drugs and adrenal steroids
may cause allergy, abdominal pain.
CO-ENZYMIC VITANINS PREPARATIONS

Co-enzymic vitamins preparations are water-soluble ones. They are also named
“complex B vitamins” (fig. 27.9).
The main hypovitam inoses and avitaminoses caused by deficit o f co-enzymic
vitanins are:
Thiamine deficiency - beri-beri (polyneuritis, CHF, psychic disturbances;
in babies - heart failure, tachycardia, seizures, vomiting, anorexia, nervous
excitement)
Riboflavin deficiency-ariboflavinosis (cheilosis, angular stomatitis, perio
ral dermatitis, photophobia, conjunctivitis)
Nicotinic acid deficiency - pellagra (dermatitis, diarrhea, dementia, dys

trophy)
Pyridoxine deficiency - microcytic anemia, may be secondary pellagra,
neuropathy, depression, in babies - anemia, hypotrophy, seizures, meteorism
• Cyanocobalamin deficiency-m egaloblastic anemia (hyperchromie anemia,
crimson tongue, atrophic glossitis, parasthesia, ataxia).
( C O M PL E X B V IT A M IN S )
f T hiam ine chloride (or brom ide) J
( R ib o flav in
N icotin ic acid
( C alcium pan tothenate J
f P yridoxine hyd rochlorid e J
f C yan ocob alam in J
( Folic acid J
Fig. 27.9. Vitamins preparations of B complex.
THIAMINE CHLORIDE
It is co-enzymic water-soluble vitamin from B complex.
„ P h arm a co k in e tics
is administered orally, IM, SC, IV
is phosphorilized in the liver and transformed into cocarboxylase
• concentrates in the liver, heart, brain, and kidney
M e ch an ism o f action
Active form o f vitamin B, is a co-enzyme o f decarboxylase and takes part
in the oxidative decarboxilation o f a-ketoacids (fig. 27.10).
In such a way it stimulates the forming o f piruvic acid and decreases the
lactate level.
It is a co-enzyme o f transketolase and takes part in a pentosophosphaste

way of glucose metabolism.
B, stimulates synthesis o f acetylcholine.
0
H 1
I I£' 0 =P -0
I
R -C -O H
0
R -C - 1
. I -. .]
II H o=p-cr
O c— s
.c. ^ I I
N* n C - C H 2- N 0
I II \ 1
CH3— c CH C = C - C H 2- C H 2
Fig. 27.10. Active form of thiamine is for oxidative decarboxilation of a-ketoacids:

acid residue is shown on the left (by J. Musil et all, 1980).

Neurotropic effect: it improves impulses conduction in Hypovitaminosis (beri
nervous fibers, decreases pain, has ganglia blocking ac beri)
tion, decreases the action o f depolarized myorelaxants Polyneuritis, radiculi
Cardiotropic effect: it widens coronary vessels, im tis, neuralgia
proves the trophy o f the myocardium, increases contrac Chronic heart failure,
tility, normalizes the heart rate, improves the oxygena arrhythmia
tion o f the heart muscle, increases the action of cardiac Diabetes mellitus
glycosides Ulcer of the stomach
Hypoglycemic effect: it improves the utilization of and duodenum
glucose, is a synergist o f insulin. Skin diseases. ,
Side-effects
1. Allergic reactions, anaphylactic shock
2. Lethargy, ataxia, nausea, hypotension (in overdose).

Should not be used in allergy to B âs well as together with pyridoxine (resulting
in disorders o f phosphorilizing) or cyanocobalamin (resulting in allergy).
COCARBOXYLASE
Cocarboxylase is an active form o f vitamin B,; is a dry substance in ampoules for
IM and IV administration; is used for the treatment of acidosis, diabetes mellitus, diabetic
coma, hepatic coma, renal failure, chronic heart failure, arrhythmia, diseases o f CNS.
RIBOFLAVIN
It is a co-enzymic water-soluble vitamin from B complex.
Pharmacokinetics
is taken orally and applied topically as eye drops
is phosphorilized in the intestine, in the liver, and erythrocytes
• concentrates in the liver and kidneys
is excreted with urine and colored urine in light yellow color.
Mechanism of action
Active forms are FAD (flavin-adetiine-dinucleotide) and FMN (flavin-monu-
cleotide). They are co-enzymes o f flavin enzymes which take part in the H+transport
chain in tissue respiration (fig. 27.11).
NADH
[H ] + [c] = H NADPH
f j r c - NH’
1
- R
fadh 2
[H'l + [e] = H Y nY nY 0
1 ÏÏ fm nh2
IF?
Fig. 27.11. Active forms of vitamins B2 and PP participated

in tissue H+and e- transport (by J. Musil et all, 1980).

The improvement o f trophy o f the eye Hypovitaminosis (heilosis, glossitis,
and function o f vision photophobia)
The stimulation of the regeneration of Eye diseases (keratitis, conjunctivitis)
epithelium Skin diseases
The stimulation o f hemopoesis Radiation sickness
An increase in stability to hypoxia Anemia
The stimulation o f gastric secretion Asthenia
A decrease in cardiac glycosides Liver diseases
toxicity. Heilosis, angular stomatitis.
Side-effects
None recorded.
NICOTINIC ACID
It is a co-enzymic water-soluble vitamin from B-complex.
Pharmacokinetics
is taken orally and administered IM, SC, IV
is transformed into the active forms in the liver
Mechanism of action
The active forms are NAD (nicotine-amide-dinucleotide) and NADP (nicotine-
amide-dinucleotide phosphate). They take part in the electron transport chain in tissue
respiration (fig. 27.11), are acceptors o f H+
Vitamin PP active forms participate in the synthesis o f amino acids, neurotrans
mitters, cholesterol, bile acids, steroid hormones, etc.

Neurotropic effect: it inhibits CNS activity, inter Hypovitaminosis (pel
acts with benzodiazepine receptors, stimulates the lagra)
synthesis of neurotransmitters, has sedative and anti Diseases o f the skin and
epileptic properties mucous membrane
Cardiotrophic effect Liver diseases
The improvement of the skin trophy Atherosclerosis

The improvement o f the liver function Spasms o f blood vessels
Hypolipidemic action: it decreases triglycerids, cho - Gastritis, gastric ulcer
lesterol, and LDL level in blood (in a bigger dose) Radiation sickness.
Vasodilatation (in a bigger dose)
Activation o f fibrinolysis and an anti-platelet action
(in a bigger dose)
Stimulation o f the gut’s activity.
Side-effects
1. Skin hyperemia, itch, hypotension (flush-syndrome)
2. A loss of appetite, nausea, vomiting
3. Lipid liver infiltration.
CALCIUM PANTOTHENATE
is administered orally, parenteraly and applied topically
takes part in the formation o f co-enzyme A and acyl carrier protein. In such
a way it participates in the synthesis o f acetylcholine, corticosteroids, in the
metabolism o f fatty acids and the citric acid
improves neurotransm ission, increases skin trophy and regeneration,
stimulates the activity o f the intestine, increases the effectiveness of cardiac
glycosides, decreases the toxicity o f streptomycin
is indicated in neuritis, neuralgia, skin diseases, wounds, burns, allergic
reactions, bronchial asthma, diseases o f the upper respiratory pathways,
heart failure, atonia o f intestine, toxicosis o f pregnancy
• has minimal side-effects (nausea, vomiting).
PYRIDOXINE HYDROCHLORIDE
It is a co-enzymic water-soluble vitamin from B complex.
Pharmacokinetics
is administered orally, SC, IM
is absorbed in a connective status, is liberated from this status under the
influence of digestive juices and absorbed again
is phosphorilized in the tissues
is oxidized and excreted with urine.
Vitamin B6 exists in three forms: pyridoxine, pyridoxamine, pyridoxal.
Pyridoxalphosphate is the active form (fig. 27.12)
It takes part in the transamination, désamination, and decarboxylation of
amino acids.
Vitamin B6 participates in the synthesis o f dopamine, histamine, amino
levulinic acid, serotonin, GABA, glutaminic acid.
It promotes the transition o f linoleic acid into arachidonic acid.
: h \ c)
i| j d)
- n - c -j' r
il' «
a) CO O 0
1
O -P
a) C = 0 II
b) C 0 2 0
c) H
Fig. 27.12. Active form of pyridoxine and groups which are transported
by it (at left) (by J. Musil et all, 1980).

Neurotropic effect: increases synbthesis of Hypovitaminosis (normochromic
neurotransmitters in CNS, improves func microcytes anemia) *
tions o f the brain, decreases epileptic activ Neuritis, radiculitis
ity, interacts with anti-parkinsoian drugs Chorea, Parkinson’s disease, epilepsy
Cardiotrophic effect: it improves the M yocardiodystrophy, chronic heart
trophy o f the myocardium, has positive failure
inotropic and negative chronotropic effect Liver diseases
Hepatotrophic effect: it activates the Chronic alcoholism
secretion o f bile, biosynthesis o f glycogen Gestational toxicosis
and proteins, improves désintoxication in Anemia, leukopenia, aplastic anemia
the liver Radiation sickness
Stimulation o f hemopoiesis: it activates Prophylaxis and the treatment o f

the synthesis o f hem and forming o f side-effects of antimycobacterial
leukocytes. drugs, hormonal contraceptives and
some other drugs.
Side-effects
1. Allergy
2. A reduce o f prolactin secretion.
3. Damage o f sensor nerves and the liver.
CYANOCOBALAMIN
It is a water-soluble co-enzymic vitamin of B complex.
Pharmacokinetics
• is taken orally, administered IM, IV
after the oral administration, binds to the intrinsic Castle factor in the sto
mach and is absorbed in the intestine by endocytosis
• concentrates in the liver
• is biotransformated to deoxyadenosylcobalamine and methylcobalamine.
Mechanism of action
Active form o f cyanocobalam in is a co-factor o f the folic acid reductase
(fig. 27.13).
It takes part in the synthesis of purine and pyrimidine nucleotides and transforms
megaloblastic hemopoiesis into normoblastic one.
It takes part in the synthesis o f myeline and acetylcholine.
Cyanocobalamin participates in the synthesis of thiol compounds, methionine,
choline, as well as in lipid metabolism (it increases lipids fixation in children and
promotes lipids mobilization in adults).

The regulation o f hemopoiesis, the Hypovitaminosis (megaloblastic anemia,
transformation o f megaloblastic glossitis, myelosis)
hemopoiesis into normoblastic one; Radiation sickness
the improvement o f the formation o f Neuritis, neuralgia, radiculitis, neurologi
erythrocytes, leukocytes, and throm cal diseases o f the spinal cord and the
bocytes brain
378 PH ARM ACO LO G Y. V. M. Bobyrov.T. 0. Devyatkina, 0. M. Vazhnicha,V. M. Khristyuk
The regulation of the epithelium forming Liver diseases

The improvement o f the neurotrans- Hypotrophy in children
mission and functions o f nervous Glossitis, stomatitis,
system
The stimulation o f regeneration and
growth
[r , - C H 3 + e ]
Fig. 27.13. Active form of cyanocobalamin and methyl

group transported by it (on the left ) (by J. Musil et all, 1980).
Side-effects
1. Allergy
2. Hypercoagulation
3. Tachycardia, pain in the heart, the aggravation o f angina pectoris.
Contraindications
Hypersensitivity, thrombosis, thromboembolism.
The drug should not be administered together with vitamins B, and B6 due to
an increase in allergy.
FOLIC ACID
is water-soluble vitamin
is taken orally
• takes part in the synthesis o f purine and pyrimidine nucleotides, amino

acids and proteins
is an additional remedy in the treatment o f hyperchomic megaloblastic
anemia; is used together with cyanocobalamin; is also indicated in chronic
gastro-enteritis, sprue, in pregnancy for the prophylaxis o f neurological
pathology of the fetus and newborn.
MULTIVITAMIN DRUGS
are complexes o f fat- and water-soluble vitamins for the oral administration
contain doses o f vitamins which are equal their day requirement
are used for the prophylaxis o f hypovitaminosis and for the adaptation
therapy
may cause overdose due to the presence of vitamins A and D in multivitamin
drugs, if they are used uncorrectly.

JV» 1. All the statements regarding vitamins preparations are correct, except:
A. Ascorbic acid and tocopherol acetate are antioxidants
B. Riboflavin and the nicotinic acid take part in tissue respiration
C. Thiamine chloride regulates calcium homeostasis
D. Cyancobalamin and the folic acid transform megaloblastic hemopoiesis
into normoblastic one
E. Calcium panthotenate improves regeneration and skin trophy.
№ 2. Rutin is:
A. A multivitamin drug
B. A fat-soluble vitamin
C. A stimulant o f bone mineralization
D. An antioxidant which decreases blood vessels wall permeability
E. A constituent o f rhodopsin.
№ 3. Ergocalciferol has following effects:

A. Stimulates calcium absorption in the G1 tract
B. Stimulates calcium reabsorption in the kidney
C. Stimulates resorption o f bones
D. Inhibits bones resorption

E. Supplies calcium level in blood.
№ 4. Processes with the participation o f the ascorbic acid are:
A. The synthesis o f glucocorticoids
B. The synthesis o f catecholamines
C. The absorption of calcium
D. The synthesis o f procollagen
E. The resorption o f bone tissue.
JV® 5. A patient has disturbances o f vision (hem eralopia), xerophthalmia,

xerostomia, dry skin, and hypochromic anemia. Point a correct diagnosis and basic
preparation for the therapy.
A. Rickets and ergocalciferol
B. Megaloblastic anemia and cyanocobalamin
C. Malaria and chloroquine
D. Hyperthyroidism and methimazole
E. Hypovitaminosis o f vitamin A and retinol acetate.
Answers:
№ 1 - C; № 2 - D; № 3 - A, B, D, E; № 4 - A, B, D; № 5 - E.
ACIDS, ALKALIS, SALTS,
u. ENZYMES AND ENZYME
£ ^ Q INHIBITORS. GLUCOSE.
« / A PREPARATIONS FOR
o a V TRANSFUSION THERAPY
ACIDS
Acids are electrolytes which dissociate with the formation o f H+ ions. They are
non-organic and organic acids.
Hydrochloride acid (HCl) is a normal constituent o f gastric juice. It is neces
sary for a normal function o f pepsin, for the absorption o f iron, and the supporting
o f normal microbial status in the stomach. 2% solution o f HCl is used orally as a
replacing therapy in hypoacidic gastritis, achilia and together with iron preparations.
Boric acid is an antiseptic. It is used topically to treat purulent wounds, burns,
skin diseases, eye infections.
Salicylic acid is also an antiseptic. In high concentration, it has a keratolytic
action, in low concentration - a keratoplastic one; is used to treat skin diseases.
Acute poisoning with acids

Signs: the coagulation necrosis of the skin or mucous membrane, acute pain in
the mouth, gullet, the stomach, vomiting with admixtures of blood, acidosis, shock.
Em ergency help:
- lavage o f the stomach with cold water
- neutralization o f the acid and the protection of the gastric mucosa (magne
sium oxide, egg albumin, milk)
- neutralization o f the acid by weak solution o f alkali on the surface o f the
skin or mucous membrane
- IV administration o f sodium bicarbonate
- narcotic analgesics.
ALKALIS (BASES)
Bases are electrolytes dissociated the with formation o f OH' ions. They include
solution o f ammonia, sodium bicarbonate, and magnesium oxide.
SODIUM BICARBONATE
is administered orally, by IV infusion, by inhalation, rectally, or topically
causes the alkalinization o f body fluids, decreases the acidity
decreases the acidity of gastric juice (after the oral administration), decreases
acidosis, has expectorant, anti-arrhythmic and antihypertensive actions,
antiseptic and osmotic effects (locally)
is used to treat acidosis, hyperacidic gastritis, bronchitis, purulent diseases
in the oral cavity and throat, hypersensitivity of the teeth enamel
may cause side-effects, such as alkalosis, the formation o f C 0 2 during an
antacid action in the stomach that may produce a secondary stimulation
o f gastric secretion and a rupture o f the stomach wall in patients suffering
from peptic ulcer disease.
Peculiarities of other preparations

M agnesium oxide is taken orally for an antacid action in the stomach9(the
antacid effect is without CO, formation); is used to treat hyperacidic gastritis, may
cause a weak laxative action.
A solution o f am m onia is an antiseptic. It is used for the processing o f the
surgeon’s hands. It is an irritable agent and may cause the reflexive stimulation of
respiration in syncope. High concentration o f the vapor o f ammonia causes the ir
ritation and burn o f the upper respiratory pathways, provokes a respiratory arrest.
Acute poisoning with alkalis

Signs: a colliquation necrosis o f the skin or mucous membrane, acute pain in
the mouth, gullet, and stomach, vomiting with admixtures o f blood, excitation, shock.
Chapter 28. A C ID S , A L K A L IS , S A L T S . E N Z Y M E S A N D E N Z Y M E IN HIBITO RS... 383
Em ergency help:
- the avage o f the stomach with cold water
- coverings (egg albumin, milk)
- narcotic analgesics
- neutralization by a weak solution o f the acid on the surface o f the skin or
mucous membrane.
SALTS OF ALKALINE AND

ALKALINE-EARTH METALS
Salts are electrolytes which dissociate into the ions o f metal and acid (fig.28.1).
SALTS O F A L K A L IN E A N D A
A L K A L IN E -E A R T H M ETALS J
Salts o f sodium ^
Salts o f potassium ^
Salts o f calcium ^
Salts o f m agnesium ^
Fig. 28.1. Main groups of salts used in a clinic.
‘SODIUM CHLORIDE
ions ofNa* are the main extracellular ions in the body which influence osmotic
pressure, electrolyte balance, and volume of circulating blood, take part in
polarization and depolarization o f cell membranes, participates in the neu
rotransmission, contractions and tone of the muscles, synthesis o f hormones
isotonic (0,9%) solution of sodium chloride is administered by IV infusion
for the treatment o f dehydratation in cases o f vomiting, diarrhea, intoxica
tions, hemorrhages, for forced diuresis; is used to dissolve other drugs and
to irrigate wounds, cavities, eyes
hypertonic (2-10%) solution o f sodium chloride has an antiseptic and osmotic
action; is used topically for the treatment of purulent wounds or administered
IV for the stopping o f the lung and stomach bleeding.
384 PH A R M A CO LO G Y. V. M. Bobyrov, T. 0. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
POTASSIUM CHLORIDE
ions o f K + are the main intracellular ions which take part in polarization/
depolarization processes in cell membranes, neurotransmission, supporting
o f the heart rhythm and normal function o f skeletal muscles
is administered IV or by mouth, has a short duration o f action
is used to treat hypokalemia, arrhythmia, myastenia gravis, acute poison
ing with cardiac glycosides; to prevent hypokalemia caused by some drugs
(cardiac glycosides, glucocorticoids, diuretics)
may cause hyperkalemia.
Asparkam (Panangin) is a combined potassium preparation which contains
asparaginates o f potassium and magnesium; its properties and indications are the
same as the properties o f potassium chloride.
CALCIUM CHLORIDE
C a tio n s regulate the functions o f CNS and autonomic nervous system,
stimulate sympathetic activity, participate in blood coagulation, decrease
blood vessels permeability, inhibit allergic reactions and inflammation, take
part in the formation o f bones and teeth
is administered IV, rarely is taken by mouth in the form o f solution, in
dentistry is used topically (applications, electrophoresis)
is used for hypocalcemia, tetania and spasmophylia, allergic reactions, in
flammations, bleedings and their prophylaxis, vasculitis, acute intoxications
with fluorides, oxalates, magnesium salts
may cause the necrosis o f soft tissues if is administered SC or 1M, irritates
the gastric mucous membrane.
Peculiarities of other calcium preparations

(J
Calcium gluconate is similar to calcium chloride in its pharmacological activity,
but is administered IV, IM, and orally (in the form o f tablets), is often used to treat
bone fractures, osteoporosis, to prevent rickets and osteoporosis under the conditions
o f immobilization.
Calcium glycerophosphate contains calcium and phosphor, improves the min
eralization o f bones and teeth, has an anabolic action, is used orally for the treatment
o f bone fractures, osteoporosis.
MAGNESIUM SULFATE
is administered IV, IM, orally
Chapter 28. A C ID S , A L K A L IS , S A L T S . E N Z Y M E S A N D E N Z Y M E IN H IB IT O R S... 385
is an antagonist o f calcium ions in the cell

after parenteral administration, has sedative, hypnotic and narcosis actions;
inhibition o f the vasomotor center; an anti-seizure action; the dilation of
blood vessels and a decrease in BP; an anti-arrhythmic action; the dehyd-
ratation o f tissues; a diuretic action; a decrease in intracranial pressure; a
spasmolytic action; an antidote effect in acute poisoning with compounds
o f calcium
• after the oral the administration, acts as a laxative
• is used for hypertensive emergency, chronic hypertension, a seizures attack,
edema o f the brain, tachyarrhythmia, myocardial infarction, toxicosis of
pregnancy overdose o f calcium preparations, acute constipation
may cause side-effects, such as pain and infiltrate in the site of adminis
tration (1M); suppression of respiration (IV). If suppression o f respiration
occurs, calcium chloride (IV) and Carbogenum (inhalation) should be used.
ENZYMES AND INHIBITORS OF ENZYMES
ENZYMES
Enzym es are preparations which play the role o f the biological catalyzers of
metabolism in the organism. Enzymes, catallyzing the restriction o f different sub
strates (fig. 28.2), are of great importance for a clinic.
Classification
1. Peptidases and proteases
- Pepsin
- Trypsin
- Chymotrypsin
2. Nucleases
- Ribonuclease
- Desoxyribonuclease
3. Preparations o f hyaluronidase
- Lidasum
4. Fibrinolytic enzymes
- Fibrinolysin
- Streptolyase
5. Enzymes of another action
- L-asparaginase
386 PHARMACOLOGY. V. M. Bobyrov, T. 0. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
- Penicillinase
6. Combined preparations
- Pancreatin.
Fig. 28.2. Restriction of substrate by enzyme (http://www.picsearch com).
Pepsin is a normal constituent o f gastric juice; is active in an acidic pH and
tears peptide connections; is taken orally together with hydrochloride acid to treat
hypoacidic and anacidic gastritis, achilia, dyspepsia.
Trypsin is obtained from the pancreas o f horned cattle, is administered IM, in
cavities, by inhalation, or topically; splits peptones, that’s why decreases the density
of pus and exudation, improves the clean o f wounds and bronchi, decreases edema
and inflammation; is used to treat purulent wounds, purulent diseases o f the lungs,
bronchi, and pleura, osteomyelitis; may cause an allergic reaction, fever, chill.
Chymotrypsin is a protease similar to trypsin; is more stable in the body.
Ribonuclease is a nuclease obtained from the pancreas o f homed cattle; the
mechanism o f action is connected with the restriction of RNA to oligonucleotides;
in such a way it decreases the viscosity o f pus and exudation, improves the clean
o f wounds, cavities, and bronchi; has indications similar to indications of trypsin.
Desoxyribonuclease is also a nuclease, but its action is connected with the
depolymerization and restriction o f DNA.
Lydasum contains hyaluronidase; depolimerazes hyaluronic acid and decreases
the viscosity o f connected tissue, increases tissues permeability and the penetration
o f other drugs; is used to treat contractures o f joints, scars after burns and surgeries,
hematomas, chronic inflammation; may cause allergy.
Chapter 28. A C ID S , A L K A L IS , S A L T S . E N Z Y M E S A N D E N Z Y M E IN H IB IT O R S... 387
Pancreatin is an enzyme drug from the pancreas; contains iipase, amylase,

and trypsin; is used orally for a replacing therapy on an insufficient function o f the
pancreas, anacid gastritis, dyspepsia, enterocolitis.
INHIBITORS OF ENZYMES
Inhibitors o f enzymes are drugs inhibiting the activity o f different enzymes.
Among them there are inhibitors o f proteolysis and fhbrinolysis:
- Aprotinin
- Contrykal
- Aminocaproic acid.
Contrykal is a natural substance with short time o f action; is administered IV,
by IV infusion, or applied topically (in dentistry); inhibits the activity of trypsin
and plasmin, has a direct action on proteolytic enzymes, decreases proteolysis and
fibrinolisis, has anti-inflammatory properties; is indicated in acute pancreatitis, sur
geries on the pancreas, lungs, and glands, bleeding due to an increased fibrinolysis,
obstetrics pathology.
Am inocaproic acid is used orally, by IV infusion, and topically (in dentistry);
inhibits the activity o f trypsin and plasmin; has a direct + indirect action, decreases
proteolysis and fibrinolisis, has anti-inflammatory properties, decreases allergy and
intoxication; has the indications similar to the indications o f contrykal.
Both preparations areâlso described in Chapters 22, 28.
GLUCOSE
is administered IV,SC, orally
isotonic 5% solution o f glucose is used for an increase o f fluids volume, as
a energetic source, as a solvent for other drugs
• hypertonic 40% solution increases osmotic pressure, improves antitoxic
liver function, and contractility o f myocardium, decreases permeability of
blood vessels; is used to treat hypoglycemia, hypotension, asthenia, liver
diseases, heart failure, to dissolve some other drugs.
• is an ingredient of many tablets and dosed powders
may cause hyperglycemia
• is contraindicated in diabetes mcllitus.
DRUGS FO R TRANSFUSION TH ER APY

Drugs fo r transfusion therapy are solutions for IV infusions.
Classification
1. Low weight solutions
- 0,9% solution o f sodium chloride
- 4% solution o f sodium bicarbonate
- 5% solution o f glucose
2. Plasma substitutes and hemodynamic solutions
- Albumin
- Reopolyglucinum
3. Désintoxication drugs
- Neohemodesum
4. Drugs for IV nutrition
- Aminosterilum
- Lipofundinum.
Low weight solutions are used for rehydratation, the restoration o f the acid-base
balance, hemodilution under the conditions of acute poisoning, diabetic coma, etc.
Plasma substitutes and hem odynam ic solutions restore the volume of circulat
ing blood, support colloid-osmotic pressure, increase BP, improve reological blood
properties; are used in shock.
Désintoxication drugs increase the transport of toxic substances from tissues
into blood and their excretion, improve microcirculation. They are used to treat sepsis,
severe burns, endotoxic reactions, acute poisonings.
Drugs fo r I V nutrition contain amino acids, essential fatty acids and are used
for parenteral nutrition in patients after surgeries, unconsciousness patients, etc.
■i
T E S T S FO R SELF-CO N TR O L
№1. The following statements concerning Lidasum are correct, except:
A. It is hyaluronidase
B. It is used to promote drug absorption
C. It is used for replacement therapy
D. It is used for the treatment o f joint contractures
E. It is used for scar softening.
Chapter 28. A C ID S , A L K A L IS , S A L T S . E N Z Y M E S A N D E N Z Y M E IN HIBITO RS... 389
№ 2. The salt drug for the treatment o f purulent wounds is:

A. 0,9% solution o f sodium chloride
B. 5% solution o f glucose
C. 25% solution o f magnesium sulfate
D. 10% solution o f calcium chloride
E. 10% solution o f sodium chloride.
№ 3. The main indications for the calcium chloride use are:

A. Allergic reactions
B. Vasculitis
C. Thrombosis
D. Bleeding
E. Overdose o f vitamin D.
№ 4. Aminocaproic acid
A. Is proteolytic enzyme
B. Is the inhibitor of proteolysis
C. Is the inhibitor of fibrinolysis
D. Has anti-allergic and antitoxic properties
E. Is used to treat purulent diseases.
№5. A patient has bronchoectasia with purulent dense exudation. The physician
prescribes him inhalations o f an enzyme preparation. The drug suitable in this case is
A. Lydasum
B. Aprotinin
C. Trypsin
D. Parathyroidin
E. Pancreatinum.
Answ ers
№1 - C; № 2 - E; № 3 - A, B, D ; № 4 - B , C, D ; № 5 - C .
S’ 3M ANTISEPTICS
O Êm\J AND DISINFECTANTS
ANTIMICROBIAL AGENTS
A ntim icrobial agents are drugs for the treatment and prevention of infection
diseases. They are divided into disinfectants, antiseptics, and chemotherapeutics (fig.
29.1). D isinfectants realize their antimicrobial properties in the environment outside
the body. Antiseptics act on the surface o f the body. Chemotherapeutics produce an
antimicrobial effect inside the body.
A N T IM IC R O B IA L
AGENTS
Antiseptics
Disinfectants
(on the surface
(outside the body)
o f the body)
J
Fig. 29.1. M ain classes o f antim icrobial agents.
Chapter 29. A N T IS E P T IC S A N D D IS IN F E C T A N T S 391
Antimicrobial drugs may have a bactericidal or bacteriostatic type o f action

(fig.29.2). Antimicrobial drugs o f a bactericidal action produce death o f microbes.
Bacteriostatic drugs stop the growth and replication o f bacteria and then the immune
system destroys such microbes.
ANTIMICROBIAL
ACTION
. \ / Bacteriostatic \
C Bactenadal
(k,II bacteria) J
(arrest the growth and
^ repiicati‘n of bacteria) J
Fig. 29.2. Types of antimicrobial action.
ANTISEPTICS AND DISINFECTANTS

Good antiseptic and disinfectant should m eet such demands as:
Bactericidal action
Chemical stability
A rapid action
Lack o f absorption
Low toxicity
Efficacy in the presence of different organic substrates, such as pus, blood,
sputum
The absence o f allergic properties
The absence o f irritability.
There are 3 m ain m echanism s o f an antimicrobial action o f antiseptics and
disinfectants:
The dénaturation of bacterial proteins, including enzymes
The oxidation o f bacterial protoplasma (cytoplasma)
Changing o f bacterial membrane properties and an increase in its perme
ability
CLASSIFICATION
A. Inorganic substances B. Organic substances
1. Halogens 1. Aldehydes
- Iodine (5% alcohol - Formaldehyde (Formalinum)

solution) - Hexamethylentetraminum
— lodinolum (Methenamine)
- Lugol's solution 2. Alcohols
- Ioddicerinum - Ethyl alcohol (Spiritus aethylicus)
- Chlorinated lime 3. Phenol derivatives
(bleaching powder) - Phenol (Phenolum purum, Carbolic acid)
- Chloramine B - Cresol (Tricresolum)
- Halazone (Pantocidum) - Resorcinol
- Chlorhexidine (Hibitane) 4. Dyes
2. Oxidizing agents - Methylene blue (Methylenum
- Hydrogen peroxide coeruleum)
- Potassium permanganate - Brilliant green (Viride nitens)
3. Metallic salts - Etacridine lactate
- Mercury dichloridum 5. Detergents
- Yellow mercury oxide - Aethonium
- Silver nitrate - Decamethoxin
- Copper sulfate 6. Tar, resins, products of petroleum
- Zinc sulfate - Birch tar (Pix liquida Betulae)
- Zinc oxide - Ichthyol
4. Acids and alkalis - Liniment by Vishnevsky
- Salicylic acid 7. Nitrofuran derivatives
- Solution o f ammonia - Nitrofurasone (Furacilinum)
8. Antiseptics from medicinal plants
- Chlorophyliptum
- Novoimaninum
OXIDIZING AGENTS
HYDROGEN PEROXIDE
M echanism o f action and effects:
The drug’s effects are based on the destruction o f hydrogen peroxide with the
release o f oxygen atoms. They produce the oxidation and dénaturation of proteins.
The formation o f molecules o f 0 2 results in the foam formation and mechanical
cleaning o f the wound (fig. 29.3).
Fig. 29.3. Pharmacological effects of hydrogen peroxide.
Indications:
processing of wounds (3% solution)
processing o f impaired skin
gargling and mouthwash in diseases o f the throat and oral cavity
capillary bleeding
whitening o f teeth, the depigmentation o f skin.
The drug should not be used in deep wounds and injures o f bigger vessels.
POTASSIUM PERMANGANATE
M echanism o f action a nd effects:
The drug’s effects are grounded on the degradation o f the molecule of potassium
permanganate with the releasing o f oxygen atoms and manganum oxide (fig. 29.4).
Oxygen produces the oxidation and denaturation o f proteins resulting in a bactericidal
action. It also oxidizes some poisons. Manganum oxide causes an astringent action
on the macroorganism.
Indications:
the irrigation of purulent wounds (0,1 -0,5% solution)
gargling and mouthwash in diseases o f the throat and oral cavity (0,01 -
0,1% solution)
syringing in gynecology and urology (0,01-0,1% solution)
processing o f bums (2-5% solution)

the lavage of the stomach in acute poisoning with morphine, alcohol, alka
loids (0,1% solutions).
H ALO G EN S
IODINE A LC O H O L SOLUTION
Effects o f iodine are based on the interaction between atoms of halogen and
proteins resulting in halogenization and oxidation o f proteins (fig. 29.5). It has bac
tericidal, fungicidal and irritative actions.
Oxidazing of proteins
Bactericidal
action
Iodine (L) ^ Halogenizing of proteins
Irritation of skin
and mucous membranes
Fig. 29.5. Pharmacological effects o f iodine.
Indications:
processing o f small cuts o f the skin
processing o f the surgery skin area and surgeon’s hands
derm atomy coses

• diseases o f muscles and joints (the “ iodine network” on the skin).
Toxity:
Iodine may cause the irritation o f the skin, allergy, idiosyncrasy. On the surface
o f the skin or mucuos membrane it should be neutralized by sodium thiosulphate.
PECULIARITIES OF OTHER HALO G EN S

Solution o fL u g o l contains iodine, potassium iodide, and water or glycerin as a
solvent; is used for the processing o f the skin and mucous membranes (in tonsillitis,
atrophic pharyngitis, atrophic rhinitis).
Iodinol is an organic iodine preparation; contains iodine, potassium iodide, and
polyvinilic alcohol; is used for the processing o f the skin and mucous membranes,
ulcers, wounds, burns, chronic tonsillitis, purulent otitis, chronic rhinitis; has a less
irritative and more durative action in comparison with iodine alcohol solution.
Ioddicerinum is a combined preparation; contains iodine, Dimexidum, and
glycerin; due to Dimexidum, has an increased antiseptic activity and penetration
through the skin; is used for the treatment o f skin diseases, ulcers, wounds; may be
used on the mucous membranes due to less irritation (in otitis, tonsillitis, chronic
atrophic rhinitis, paradontosis, vaginitis).
Chlorinated lim e (bleachingpowder) contains active chlorine which interacts
with proteins and causes their denaturation; in water solution, forms active metabolites
o f oxygen oxidizing microbial proteins; has antimicrobial and deodorizing effects;
is used for disinfection.
Chloramine B is an organic compound containing chlorine; transforms into the
hypoclorite acid which decays into chlorine and oxygen: chlorine exerts irreversible oxi
dation of SH-groups of proteins and forms toxic N-chlorocompounds, oxygen oxidizes
proteins; has disinfectionântiseptic and deodorizing actions; is used for the disinfection
of the environment, clothes, non-metallic instruments (1 -5%); rarely for the treatment
of purulent wounds (1-2% solution) and processing of the skin (0,25-0,5% solution).
Chlorhexidine (Chlorhexidinum bigluconas) is an organic chlorine containing
preparation with detergent properties; has an antimicrobial, antifungal activity, im
proves regeneration; is used for the treatment of wounds, for gargling, for individual
prophylaxis o f sexually transmitted infections, for the processing o f the surgeon’s
hands, the surgical skin area, for a quick sterilization o f instruments.
ACIDS AND ALKALIS

M echanism o f action:
Acids and alkalis produce changes in pH leading to the inactivation o f enzymes
and denaturation of microbial proteins.
Salicylic acid has an antimicrobial action, an anti-inflammatory effect, a kera-
tolytic action in bigger doses (causes the reduction o f the upper skin layer) and a
keratoplastic action in lower doses (increases the development o f the upper skin
layer); is used in dermatology.
Solution o f am m onia (10%) has antimicrobial, weak detergent, irritative, and
reflexive actions; is used for the processing of the surgeon’s hands, but the main
indication is a reflexive stimulation o f respiration in syncope.
METALLIC SALTS
The action o f metallic salts on microbial cell results from their interaction with
SH-groups of proteins which leads to the inactivation of enzymes (fig. 29.6).
The metallic salts action on human tissues may be with the prevalence o f astrin
gent or caustic action. This phenomenon depends on chemical properties o f metallic
ions. On such activity, metals form Shmideberg’s line. In this line, mercury salts
have a caustic action, silver salts - caustic and astringent properties, salts of copper,
zinc - an astringent action only.
Salts of Binding to SH -groups
heavy metals
Inactivation
o f enzym es
and precipitation o f
proteins
A strin gen t and A n tim icrob ial

caustic action action
Fig. 29.6. P h a r m a c o lo g i c a l e f f e c ts o f h e a v y m e ta l s a lts .
Mercury dichloride has a bactericidal effect which is decreased at the presence of
proteins; is very toxic; is used for the disinfection of clothes, non-metallic instruments.
Yellow m ercury oxide is not soluble, is used in the form o f ointments for the
treatment o f pyoderma, blepharitis, seborrhea, pediculosis.
Silver nitrate rapidly kills microbes, but the action persists for a long period
because of a slow release o f silver ions from silver proteinates formed by interac
tion with tisue proteins; is used to cauterize erosions, ulcers, surplus granulations;
in past, it was used for the prophylaxis of blenorrhea in newborns. Organic silver
preparations (Proturgol, Collargol) are indicated for the treatment o f conjunctivitis,
diseases o f the throat, urological and gynecological diseases.
Copper and zinc sulfates are used in the forms o f solutions for external use, eye
drops, ointments, pastes; are applied for the treatment of wounds, burns, diseases of
the oral cavity, eye infections, for the washing o f the urethra and urinary bladder.
Copper sulfate is used in chemical burns caused by white phosphor.
Zinc oxide is an insoluble substance; has antimicrobial, astringent, and ab
sorbing properties; is used as an ingredient o f aspersions, ointments, and pastes to
treat wounds, burns, skin diseases.
Toxicity:
Metallic salts can cause acute and chronic poisoning. Such poisoning is mani
fested by vomiting, abdominal pain, metallic aftertaste, renal failure, CNS problems,
and hypochromic anemia. UnUliiolum is an antidote in poisoning with salts o f heavy
metals. Solution of sodium chloride is'used for the neutralizing o f silver nitrate.
ALIPHATIC A G EN TS (ALCO H OLS AND ALDEHYDES)
A LC O H O L (SPIRITUS AETHYLICUS)
The alcohol’s mechanism o f action is connected with the inhibition o f oxido-
reductases, dehydratation and precipitation o f proteins. The result is a bactericidal
action (an antiseptic effect and disinfection). It also has an irritating and tannic action.
Indications:
processing o f the surgeon’s hands and surgical area (70%)
processing of instruments (95%)
compresses (40%).
FORM ALDEHYDE
It acts on spores o f bacteria and fungi (bactericidal action), dehydrates proteins
and tissues (mummifying action), has deodorizing properties (fig.29.7). Standard
40% solution o f formaldehide is called Formalinum.
Fig. 29.7. Pharmacological effects of formaldehyde.

Indications:
freet sweating (0,5-1% solution)
syringing in gynecology (in ratio 1:2000)
disinfection (0,5% solution)
the conservation o f vaccines and serums
the conservation o f anatomic preparations.
Toxity:
Formaldehyde irritates the skin and mucous membranes of the upper respiratory
pathways. It can cause acute poisoning. A weak solution o f ammonia or ammonia
chloride is an antidote in this case.
HEXAM ETHYLENTETRAM INE (UROTROPINUM)

H exam ethylentetram ine is a derivative of formaldehyde; is administered IV
and orally; transforms into formaldehyde in the organism; is used for the treatment of
infections o f urinary pathways, cholecystitis, as well as for a decrease in intracranial
pressure in meningitis or encephalitis. ,
AROMATIC COM POUNDS (PHENOLS, TARS, RESINS)
PHENO L (CARBOLIC ACID)

It blocks dehydrogenases, denaturates proteins and damages the membranes
o f bacteria. Bonds between phenol and protein are not strong and one molecule of
phenol can interact with few protein molecules by turn. Phenol has a bacteriostatic
action in a low concentration and bactericidal action in a bigger concentration. The

action o f aqueous solutions o f phenol is stronger than the effect o f oil solutions. It is
a reference preparation for the comparison with other antiseptics.
Indications:
disinfection (3-5% soluions)
• the conservation o f serums and drugs
external otitis (0,5-0,1% oil solutions)
some forms o f rhinitis (ozena)
infections of the oral mucosa and throat (spray).
Toxity:
Phenol is very toxic. It can penetrate through the skin and mucous membranes
and cause acute poisoning. A specific therapy is absent in this case.
PECULIARITIES OF OTHER AROMATIC ANTISEPTICS

Resorcinol is used for the treatment o f skin diseases (eczema, seborrhea, itch,
fungal diseases).
Tricrezol is used for the disinfection and conservation o f injection solutions
(0,25%).
Ichthyol is a dense liquid o f dark color; belongs to the group o f “tars and
resins”; is a product of processing o f some minerals; contains aromatic compounds
and sulfur; has an antimicrobial action, decreases inflammation and pain, improves
regeneration; is used in burns, erysipelas.
Birch tar (Pix liquida Betulae) is a product o f sublimation o f birch bark; is a
dense oil-like liquid o f black color; contains aromatic compounds; has antiseptic
properties, an insecticide action, an irritating and keratoplastic action; is used in skin
diseases; is an ingredient o f balsamic liniment by Vishnevsky.
DYES
Dyes inhibit bacterial enzyme systems. Cations of dyes replace anions in natural
compounds with the formation of insoluble complexes. By an antimicrobial action,
dyes are less active than other antiseptics. The spectrum o f action is not so wide as
in other antiseptics: they act mainly on Gram (+) cocci.
M etylene blue (Methylenum coeruieum) is used for the processing o f burns,
pyoderma, diseases o f the mucous membrane o f the oral cavity (1-2 % aqueous and
alcohol solutions), for the washing o f the urethra and urinary bladder (0,02% water
solution), is an antidote in poisoning with cyanids, nitrites, and aniline derivatives
(IV as the preparation Chromosmonum)
Brilliant green (Viride nitens) acts mainly on staphylococci; is used for pyo
derma, skin pustules, small cuts, blepharitis (1-2% water and alcohol solutions).
Etacridine lactate (Aethacridini lactas) acts mainly on streptococci; is non
toxic, does not irritate tissues; is used for the processing and treatment o f wounds
(0,05-0,1%), the washing of cavities (0,05-0,1%), in conjunctivitis (0,1% eye drops)
and for gargling (0,1-1%).
DETERGENTS
These agents have a bactericidal action due to a decrease of the surface tension
o f substances and to an increase of the permeability of cell membranes (fig. 29.8).
Fig. 29.8. Pharmacological effects of detergents.
A ethonium is a quaternary ammonium compound, cationic detergent; has an
antiseptic action, stimulates regeneration, causes local anesthesia and decreases
intoxication; is used for the treatment o f wounds, trophic ulcers, radiation injures
(0,02-1% solution), eye diseases (0,1% eye drops), otitis, tonsillitis, burns, dermatitis
(ointment).
D ecam ethoxinum is a quaternary ammonium compound, cationic detergent;

by its pharmacological activity is similar to Aethonium; may be also used for the
processing o f the surgeon’s hands, surgical area, disinfection of surgical instruments
and nursing items, for the irrigations of bronchi, and washing of cavities.
NITROFURAN DERIVATIVES
NITROFURASONE (FURACILINUM)
It inhibits carbohydrates metabolism and tissue respiration in bacteria; has a
bactericidal and bacteriostatic action.
Indications:
the washing and the treatment o f purulent wounds, ulcers, burns (0,02%
water solution)
the irrigation of cavities (0,02% water solution)
gargling (0,02% water solution)
otitis (alcohol solution 1: 1500)
skin pustules (alcohol solution 1:1500)
conjunctivitis (0,02% eye drops).
ANTISEPTICS FROM MEDICINAL PLANTS
Chlorophylliptum is a mixture of chlorophylls from eucalypt (fig. 29.9) used in
the form of alcohol or oil solution; acts mainly on cocci, especially on staphylococci; is
applied for the treatment o f wounds, bums, trophic ulcers, erosions o f the uterus cervix,
irrigations o f the cavities (alcohol solution should be dissolved before application);
may be used IV in sepsis or pneumonia caused by staphylococcus; causes allergy.
N ovoim aninunt is an antiseptic from the herb o f Hypericum (st. John’s wort),
acts on Gram (+) cocci, is used topically for treatment of wounds, burns, abscesses, etc.
APPLICATION OF ANTISEPTICS
AND DISINFECTANTS
There are many potent antiseptics and disinfectants, but some preparations or
group o f preparations air most suitable in the eases pointed at lip, n> It)
alcohol solutions), for the washing o f the urethra and urinary bladder (0,02% water
solution), is an antidote in poisoning with cyanids, nitrites, and aniline derivatives
(IV as the preparation Chromosmonum)
Brilliant green (Viride nitens) acts mainly on staphylococci; is used for pyo
derma, skin pustules, small cuts, blepharitis (1-2% water and alcohol solutions).
Etacridine lactate (Aethacridini lactas) acts mainly on streptococci; is non
toxic, does not irritate tissues; is used for the processing and treatment of wounds
(0,05-0,1%), the washing of cavities (0,05-0,1%), in conjunctivitis (0,1% eye drops)
and for gargling (0,1-1%).
DETERGENTS
These agents have a bactericidal action due to a decrease of the surface tension
o f substances and to an increase of the permeability of cell membranes (fig. 29.8).
Fig. 29.8. Pharmacological effects of detergents.
A eth o n iu m is a quaternary ammonium compound, cationic detergent; has an
antiseptic action, stimulates regeneration, causes local anesthesia and decreases
intoxication; is used for the treatment o f wounds, trophic ulcers, radiation injures
(0,02-1% solution), eye diseases (0,1 % eye drops), otitis, tonsillitis, burns, dermatitis
(ointment).
D ecam ethoxinum is a quaternary ammonium compound, cationic detergent;

by its pharmacological activity is similar to Aethonium; may be also used for the
processing o f the surgeon’s hands, surgical area, disinfection o f surgical instruments
and nursing items, for the irrigations o f bronchi, and washing o f cavities.
NITROFURAN DERIVATIVES
NITROFURASONE (FURACILINUM)
It inhibits carbohydrates metabolism and tissue respiration in bacteria; has a
bactericidal and bacteriostatic action.
Indications:
the washing and the treatment o f purulent wounds, ulcers, burns (0,02%
water solution)
the irrigation o f cavities (0,02% water solution)
gargling (0,02% water solution)
otitis (alcohol solution 1: 1500)
skin pustules (alcohol solution 1:1500)
conjunctivitis (0,02% eye drops).
ANTISEPTICS FROM MEDICINAL PLANTS
Chlorophylliptum is a mixture of chlorophylls from eucalypt (fig. 29.9) used in
the form of alcohol or oil solution; acts mainly on cocci, especially on staphylococci; is
applied for the treatment of wounds, burns, trophic ulcers, erosions of the uterus cervix,
irrigations of the cavities (alcohol solution should be dissolved before application);
may be used IV in sepsis or pneumonia caused by staphylococcus; causes allergy.
A'ovoim aninum is an antiseptic from the herb o f Hypericum (st. John’s wort),
acts on Gram (+) cocci, is used topically for treatment of wounds, bums, abscesses, etc.
APPLICATION OF ANTISEPTICS
AND DISINFECTANTS
There are many potent antiseptics and disinfectants, but some preparations or
p.roup ol'prepaiations me most suitable in the cases pointed al lip. 10
Fig. 29.9. Eucalypt as a source of antiseptics.

№ 1. The antiseptic from the oxidizers group is only:
A. Silver nitrate
B. Hydrogen peroxide
C. Aethonium
D. Phenol
E. Iodine solution.
№ 2. For the processing o f the surgeon’s hands all the drugs are used,'except:
A. Alcohol
B. Mercury dichloride
C. Chlorhexidine bigluconate
D. Solution o f ammonia
E. Solution o f iodine.
№ 3. Nitrofurasone is:
A. Disinfectant
B. Antiseptic
C. Bactericidal to gram positive and gram negative pathogens
D. Inhibiting enzymes participating in carbohydrate metabolism o f bacteria

E. Used for wound irrigation.
№ 4. Phenol is:
A. An organic antiseptic
B. Used for the irrigation o f wounds
C. Protoplasmic poison
D. A chemotherapeutic agent
E. A standard for comparing of other germicides.
Disinfection of floors Disinfection

or excrement of instruments
Phemîls ÔCI surfactants
Catibnic
surfactants
Skin disinfection Skin disinfection

Regular e.g., hands Acute,
e.g., before local procedures
Alcohi )is ' Phenols
Ü tié lE surfactants
o>
Disinfection
of mucous membranes Wound disinfection
Fig. 29.10. Summary o f application of antiseptics and disinfectants (by. H. Lullmann, 2000).
№ 5. A patient is admited to the clinic with severe abdominal pain and vomiting.
The copper-colored shade o f the mucosa in the oral cavity and m etallic aftertaste are
observed. Three days after that, the symptoms o f acute renal failure and the defeat of
CNS are appeared. What is the cause o f the poisoning? What must antidote therapy
include?
A. Iodine and solution o f sodium thiosulfate
B. Formaldehyde and solution o f ammonia chloride
C. Mercury' dichloride and Unithiolum
D. Strong acid and sodium bicarbonate
E. Alcohol and sodium permanganate.
Answ ers
№ 1 - B; № 2 - B; №3 - B, C, D, E; № 4 - A, C, E; № 5 - C.
'i
COMMON PRINCIPLES
OF CHEMOTHERAPY.
SULFONAMIDES.
CHEMOTHERAPEUTICS
30
O
OF DIFFERENT
ro CHEMICAL STRUCTURE.
sz
O ANTIFUNGAL DRUGS
MAIN CONCEPTS OF CHEMOTHERAPY

Chemotherapeutic drugs are anti-infective drugs realizing their action inside
the body. They are divided into antibiotics, sulfonamides, fluorquinolones and anti
microbial drugs o f different chemical structure, antifungal drugs, antimycobacterial
drugs, antiviral drugs, antiprotozoal drugs, antihelminthics (fig. 30.1).
TYPES OF ANTIMICROBIAL ACTION

There are two types o f antimicrobial action: bactericidal and bacteriostatic (fig.
30.2). The drug with bactericidal action produces the death o f microbes. The drug
o f bacteriostatic action inhibits the growth and reduplication o f microbial cells and
after that the immune system destroys such organisms.
( CHEMOTHERAPEUT1CS )
A ntib iotics
Su lfon am ides
F lu orq uinolones
A n tifu ngal drugs
A n tim ycobacterial drugs
A n tiviral drugs
A n tip rotozoal drugs
A n tih elm inthics
Fig. 30.1. Main classes ofchemotherapeutics.
Fig. 30.2. Types of antimicrobial action.

Chapter 30. C O M M O N P R IN C IP L E S O F C H E M O T H E R A P Y 407
SPECTRUM OF ACTION
The spectrum o f action is the list o f species o f microbes affected by this chemo
therapeutic (fig. 30.3).
A single species or
limited amount of
microbes' species Many species of microbes
including both cocci and
bacilli
Fig. 30.3. Spectrum of antimicrobial action.
G E N E R A L PRINCIPLES OF ANTI-INFECTIVE THERAPY

The selection o f an appropriate chemotherapeutic agent: 1) should be
grounded on the spectrum o f action; 2) should be based on the laboratory
identification o f the infecting microorganism; 3) if the infecting organism
is unknown, a wide spectrum drugs (or drugs combination) should be used.
The selection o f the optimal route of administration and dose
The maintenance o f a constant chemotherapeutic concentration
The discontinuation o f chemotherapy during 2-3 days after the normaliza
tion o f body temperature
A rational combination o f drugs
Taking into account the patient’s sensitivity to the drug (an allergic test
before the start of treatment)
Taking into account the site of infection, the immune competence, the age,
and physiological status
The clinical and laboratory monitoring o f a therapeutic response to drug

therapy
SULFONAMIDES (SULFA DRUGS)

Sulfonam ides and trimethoprim belong to folate antagonists. They are synthetic
antimicrobial drugs inhibiting folate synthesis. Sulfonamides are sructural analogs
o f para-aminobenzoic acid (PABA) (fig. 30.4). All sulfas have common pharmaco
logical properties.
H OH H O R
Fig. 30.4. Chemical structure of PABA (A) and sulfonamides (B).
CLASSIFICATION
A H ig h ly a b s o r b e d s u lfo n a m id e s
1. Short-acting
- Sulfamethazine (Sulfadimezinum)
- Aethazolum
2. Intermediate-acting
- Sulfamethoxazole
- Sulfaphenoxazole
3. Long-acting
- Sulfamethoxypyridazine (Sulfapyridazinum)
- Sulfadimethoxine
4. Ultralong-acting
- Sulfamethoxypyrazine (Sulfalenum)
B. P o o r ly a b s o r b e d s id fo n a m id e s
- Phthalylsulfathiazole (Phthalazolum)
C. S u lfo n a m id e s f o r a lo c a l u se
- Sulfacetamide sodium (Sulfacylum natrium, Albucid)
- Sulfonamide (Streptocidum)
D. D e r iv a tiv e s o f s u lfo n a m id e a n d th e s a lic y lic a c i d o r s ilv e r

- Sulfasalazine (salazosulfa)
- Salazopiridazine
- Silver sulfadiazine
E . C o m b in a tio n s o f s u lfo n a m id e s a n d tr im e th o p r im
- Co-trimoxazole (Bactrim).
Pharmacokinetics
are taken orally, sometimes are administered IV or applied topically
are absorbed in the small intestine
bind to serum albumen
• penetrate CNS and placenta
are metabolized in the liver: most sulfas undergo acétylation accompanied
by a decrease o f their solubility that results in the crystals formation in
renal tubuli
are excreted the with urine.
Mechanism of action
Structural similarity to PABA provides competitive antagonism of sulfona
mides to PABA and the blockade o f dehydropteroid synthase (fig. 30.5).
Fig. 30.5. The role of PABA in folate synthesis (at left)

and its blockade by sulfonamides (at right) (http://www.picsearch.com).
This leads to the inhibition o f stage 1 of the synthesis of the folic acid active
form in a microbial cell.
The absence of tetrahydrofolate results in disturbances in the synthesis of
nucleic basis and then in the synthesis o f nucleic acids.
The reduplication and growth o f microbes are inhibited (bacteriostatic
action).
Sulfonamides act only on the organisms using PABA in their life cycle.
Sulfas are inactive in the purulent environment rich in PABA.
They leak antimicrobial activity in the presence o f ester local anesthetics
which are hydrolyzed to PABA.
The affinity o f enzymes to sulfonamides is less than to a natural substance,
that’s why a strike dose o f the drug is necessary at the start o f treatment.
Drugs, inhibiting the second stage o f folate synthesis (e.g. trimethoprim),
are synergic to sulfas.
Spectrum of action
Sulfonamides have a broad spectrum o f action. They are effective against Gram
(+) cocci (S tr e p to c o c c i, S ta p h y lo c o c c i), Gram (-) cocci { N e is s e r ia g o n o r r h o e a e ), Gram
(-) bacilli (H e m o p h ilu s in flu e n za e , E .c o li, S h ig e lla , Y e r s e n ia e n te r o c o litic a , P r o te u s
m ir a b ilis ), N o c a r d ia , A c tin o m y c e te s , C h la m id ia , T o x o p la s m a , P la s m o d iu m m a la ria e .
Indications
Respiratory infections
Gastrointestinal infections
Urinary tract infections
Genital infections (gonorrhea)
Trachoma
Nocardiasis
Toxoplasmosis 4
Infections o f the skin and mucous membranes
Infections o f the eyes
Schem es of treatment
For short-acting drugs: 4 tablets (2,0) for the 1st administration, then 2 tablets
(1.0) 4 times a day, after the normalization o f body temperature 1 tablet (0,5) 4 times
a day during 3 days. (Total dose is 20-30 g).
For long-acting drugs: 4 tablets (2,0) for the 1st administration, then 2 tablets
(1.0) once a day, after the normalization o f body temperature 1 tablet (0,5) once a
day during 3 days. (Total dose is 8-10 g).
For ultra-long-acting drugs: 5 tablets (1,0) for the Is' administration, then 1
tablet (0,2) once a day (Total dose is 2 g). The total dose may be taken once a week.
Side-effects
1. Crystalluria
2. Allergy
3. Hemopoietic disturbances
4. Dermatitis and phototoxicity
5. Stevens-Johnson syndrome
6. Hepatitis
7. Kernicterus (in newborns)
8. Idiosyncrasy (hemolytic anemia in patients with the deficiency o f glucose-
6-phosphate dehydrogenase).
Sulfacetam ide sodium is a well-soluble substance, is used as eye-drops in con
junctivitis, trauma of the eyes, the prophylaxis o f eyes gonorrhea in newborns.
Plitalylsulfathiazole is inactive in vitro, but active in the intestine because of
norsulfazole’s liberation; is used for gastrointestinal infections.
Aethazolum is rapidly absorbed in the gut and rapidly excreted; is used in urinary
tract infections and nocardiasis.
Sulfadim ethoxine is a long-acting sulfonamide, is rapidly absorbed, but slowly
excreted, has a half-life o f 24-48 hrs, is concentrated in bile, thus is suitable to treat
cholecystitis.
Sulfalene is an ultralong-acting sulfonamide, has a half-life o f more than 48hrs
due to strong bonds with serum albumins and reabsorption in the kidney; is used orally
for all infections se n sitiv e ^ sulfa drugs; is suitable to treat long-durative infections.
C o-Trim oxazalole is a combined preparation containing sulfamethoxazole
together with trimethoprim. Sulfamethoxazole inhibits dehydropteroide synthase
(stage I of the synthesis o f the active form o f the folic acid). Trimetoprim inhibits
dehydrofolate reductase (stage II o f the synthesis o f an active form o f the folic acid).
A result is a bactericidal action. The antimicrobial spectrum of trimethoprim is similar
to that o f sulfonamide, however the combination is in 20-50 times more potent than
sulfonamide. Pharmacokinetics o f trimethoprim is similar to that o f sulfamethoxazole.
Co-trimoxazole is used to treat Pneumocystis Carrini pneumonia, respiratory infec
tions, gastrointestinal infections (shigellosis, non-typhoid salmonella infections, the
carrierity o f Salmonella typhi), genital infections (gonorrhea), prostate and urinary
tract infections. It may cause side-effects, such as skin lesions, nausea, vomiting, sto
matitis, anemia, folate deficiency, special adverse reactions in HIV infected persons.
Salazopyridazine and sulfasalazine are the combinations o f sulfonamides with

the acetylsalicylic acid; have antimicrobial and anti-inflammatory effects; are used
for ulcerative colitis.
SYNTHETIC ANTIMICROBIAL
DRUGS WITH DIFFERENT CHEMICAL STRUCTURE
This group o f preparations is represented by nitrofuran derivatives and quinolone
derivatives.
CLASSIFICATION
A. N itr o fu r a n d e r iv a tiv e s
- Furozolidone
- Nitrofurantoin (Furadoninum)
B. Q u in o lo n es a n d flu o rq u in o lo n e s
1. Quinolones
- Nitroxoline (5-NOK)
- Nalidixic acid
2. Fluorquinolones
a) the Is' generation
- Ciprofloxacin
- Ofloxacin
b) the 2nd generation
- Lomefloxacin
c) the 3rd generation
- Fleroxacin
d) the 4,h generation
- Moxiflacin. i
FUROZOLIDONE
is taken orally 3-4 times a day, is metabolized in the liver and inhibits liver
enzymes, is excreted with urine
disturbs proton transport during cell respiration
• has a wide spectrum o f action; Gram (-) bacilli, Gram (+) bacteria (against
which the drug is less effective), T r ic h o m o n a s , L a m b d a g ia r d ia s is
is used in urinary tract infections, intestinal infections, bacillary dysentery,
giardiasis, trichomoniasis, infected wounds and burns (topically)
may cause allergy, dyspepsia, a disulfiram-Iike reaction, an increase in BP

if the diet is reach in tyramine.
NITROXOLINE
is an oxiquinoline
is taken orally, is excreted with urine and produces high concentration in
urine
• disturbs reduplication o f nucleic acids, forms complexes with metals ions
and inhibits oxidative-reductive processes
has a broad spectrum o f action: Gram (-) cocci and bacilli, Gram (+) cocci,
C a n d id a a lb ic a n s, T r ic h o m o n a s v a g in a le
has a bacteriostatic type of action
is used in urological infections (so-called uroseptic) and for the prevention
o f infection before urological surgeries
may cause allergy, dyspepsia, neurological problems (ataxia, paresthesia,
neuropathy), an orange discoloration o f urine.
NALIDIXIC ACID
isaquinolone
is taken orally, partly is metabolized in the liver and excreted with urine
inhibits topoisoinerase II (DNA gyrase), in such a way disturbs DNA
reduplication
the antimicrobial spectrum is narrow (only Gram (-) bacilli) and resistance
emerges rapidly
is used in urinary tract infections, cholecystitis, otitis media
may cause side-effects, such as gastrointestinal irritation, glucosuria, skin
rash, phototoxicity, CNS and visual disturbances.
FLUORQUINOLONES
are fluor-containing quinolones divided into 4 generations
are administered orally or IV, are widely distributed in the body, produce
high concentrations in the bones, urine, prostate, kidney, are concentrated
in phagocytes and act on intracellular microbes, are excreted with urine or
bile, have a half-life o f from 3-8 hrs to 10-20 hrs
inhibit DNA gyrase, disturb the normal transcription and duplication of
bacterial DNA (fig. 30.6), have a bactericidal type o f action
the spectrum o f action is wide: Gram (-) bacilli { E n te ro b a c te r, P se u d o m o n a s,

H a e m o p h ilu s in flu e n za e , M o x za re lla , L e g io n e lla ), C h la m id ia , M y c o b a c te ria ,
some Gram (+) cocci
are indicated in urinary tract infections, gonorrhea, gastrointestinal infec
tions, infections o f the bones, joints, skin, and soft tissues, resistant respira
tory infections, tuberculosis
may cause nausea, headache, dizziness, crystaluria, phototoxicity, cartilage
lesions
are contraindicated to pregnant women, nursing mothers, and children
younger than 18 years old.
M iM
4-Quinolone-
xxxx Twisting by
opening, underwinding,
and closure
of DNA strand
DNA-doubie helix
Fig. 30.6. Mechanism o f action of tluorquinolones (by II. Liillmann, 2000).
ANTIFUNGAL DRUGS
A ntifu n g a ts are the preparations for the treatment of infections caused by
pathogenous fungi (mycoses).
Like mammalian cells, fungi are eukaryotes with DNA organized into chromo
somes. This homology to mammalian cells also extends to biosynthetic pathways. The
similarity o f fungal and mammalian cells creates a number of problems for designing
drugs that are selectively toxic to fungal cells, but not the human host.
Both fungi and mammalian cells contain a cell membrane. The sterol contents
between mammalian cells and fungal cells is different. Ergosterol is the predominant
sterol in many pathogenic fungi. This difference in sterol content has been exploited
as the target of an antifungal drug action by several classes o f antifungal agents
CLASSIFICATION
A. Antibiotics
1. Polyenes
- Nystatin
- Amphotericin B
2. Heterocyclic benzofurane
- Griseofulvin
B. Azotes
1. Imidazoles
- Clotrimazole
- Miconazole
- Ketokonazole
2. Triazoles
- Fluconazole
- Itraconazole
C. Antimetabolites
- Flucirosine
D. Allylamines
- Terbinafine.
<*
POLYENES
Polyene antifungals, such as amphotericin B and nystatin, act by binding to
ergosterol in the fungal cell membrane (fig. 30.7). This results in the depolarization
o f the membrane and formation o f pores that increase permeability to proteins and
monovalent and divalent cations, eventually leading to cell death. Amphotericin B
may also induce oxidative damage in fungal cells and has been reported to stimulate
o f host immune cells.
Amphoterricin B has a wide antifungal spectrum o f action including Histoplasma
capsulala, Cryptococcas neoforenans, Coccidioides immitis, Blastomyces dermati-
tidis, Candida albicans, Aspergilus, Sporotrichum. It is used in systemic mycoses.
Toxicities of polyene antifungals are an extension of their mechanism o f action.
The stimulation o f the host immune cells by amphotericin B causes the release of
416 PH AR M ACO LO G Y. V. M. Bobyrov.T. 0. Devyatkina, 0. M, Vazhnicha, V. M. Khristyuk
inflammatory cytokines by circulating monocytes resulting in fever, chills, rigor,

nausea, vomiting, myalgias, arthralgias, and headache during IV infusions. In higher
concentrations, amphotericin B binds to cholesterol in mammalian cel! membranes
leading to various organ foxicities.
Nystatin has a narrow antifungal spectrum. It is only effective against Candida
fungi and is used for the treatment o f Candida infections of the skin and mucous
membranes, as well as for the prevention o f candidiasis under the therapy o f wide-
spectrum antibiotics.
Both polyenes are described in detail in Chapter 31.
Am photericin 8
Ergosterol
Cell membrai
Binding to ergosterol, v Ca~

intercalation of cell membrane . . «. Na*
\ Na
Leakage of intracellular cations
Fig. 30.7. Mechanism of action of polyenes (http://www.picsearch.com).
GRISEOFULVIN
is an antibiotic, heterocyclic benzofurane
is taken orally, is absorbed in the small intestine, concentrates in the infected
newly synthesized keratin-containing tissue (skin, nails, hair), is metabo
lized in the liver, is the inducer o f cytochrome P-450, is excreted with urine
interferes with the microtubule function, disturbs the mitosis of fungal cells,
inhibits the synthesis o f nucleic acids, has a fungistatic action
• has the spectrum o f action represented by dermatophytes (Microsporon,
Epidermophyton, Trichophyton)
is used for the treatment o f dermatomycoses, mycoses o f the scalp and nails
may cause headache, CNS problems, hepatotoxicity, gastrointestinal distress,
leukopenia, skin rash, phototoxicity.
• is contraindicated in pregnancy, malignant diseases; should not be used in
patients whose job needs a quick motor reaction.
AZOLES
• are imidazole or triazole derivatives (fig. 30.8)
are taken orally and applied topically; are absorbed in the gut; absorption
is impaired by food, cimetidine, rifampim; are widely distributed in body
tissues; penetrates into CNS poorly; are metabolized in the liver and inhibit
cytochrome P-450
inhibit the fungal cytochrome P-450-dependent enzyme 14-a-demethylase
(fig. 30.9), thereby interrupting the synthesis o f ergosterol. Inhibition o f this
critical enzyme in the ergosterol synthesis pathway leads to the depletion of
ergosterol in the cell membrane and the accumulation o f toxic intermedi
ate sterols causing increased membrane permeability and the inhibition of
fungal growth
have a wide antifungal spectrum o f action
are indicated in mucocutaneous candidiasis, prophylaxis o f candidiasis,
dermatomycoses, cryptococcal infection, infections due to Blastomyces,
Sporotrix, Coccidioides, Histoplasma
may cause side-effects, such as nausea, vomiting, allergy, hepatotoxicity,
blockade of the synthesis o f testosterone and adrenal steroids, gynecomastia,
changes in the pharmacokinetics of other drugs.
© ® F
Fig. 30.8. C hem ical structure o f ketokonazole (A ) and fluconazole (B).

P e cu liarities o f preparations
Ketoconazole is used for systemic mycoses caused by Blastomyces, Coccidioides,
Histoplasma, for dermatomycoses, and chronic candidiasis; has antihormonal activity,
blocks cytochrome P-450-enzymes and changes the metabolism o f co-administered
drugs; may cause gynecomastia, impotence, menstrual irregularities; may accumulate
in patients with hepatic dysfunction; antagonizes amphotericin B antifungal effect
and should not be given together with amphotericin.
Fluconazole is administered orally and IV; does not bind to plasma proteins;
penetrates into CNS; is eliminated by the kidney in an unchanged form; is used in
oropharyngeal candidiasis, Coccidioides infection, vaginal candidiasis, for the pre
vention and the treatment o f cryptococcal infection; is less toxic than ketoconazole
or amphotericin; has no endocrinal side-effects.
Itra co n a zo le is the drug o f choice for the system ic m ycoses caused by
Blastomyces and Sporotrix; is an alternative drug in the treatment o f aspergillosis,
coccidiomycosis, cryptococcosis, and histoplasmosis; is used to treat dermatomy
coses, to prevent superinfection during the therapy by wide-spectrum antibiotics.
Cell membra
^ Squalene
A ccum ulation of
toxic sterols In
cell membrane
Toxic sterols
Inhibition
14-alpha-c- demethylase
Fig. 30.9. Mechanism o f action o f azoles (http://www.picsearch.com).

ALLYLAM INES
Allylam ines (terbinafine) work in a conceptually similar fashion to azole anti-
fungals by inhibiting the synthesis of ergosterol. However, allylamines act at an earlier
step in the ergosterol synthesis pathway by inhibiting the enzyme squalene epoxidase.
ANTIMETABOLITES
This class has only one exam ple, flu c y to s in e (5-fluorocytosine, 5-FC).
Flucytosine was developed as a potential anti-cancer agent. Although ineffective
against tumors, it was later found to have antifungal activity. This small molecule is
transported into susceptible fungal cells by a specific enzyme cytosine permease and
converted in the cytoplasm by cytosine deaminase to 5-fluorouracil, a pyrimidine
anti-metabolite. A result is the inhibition o f nucleic acid synthesis in fungal cells.

№ 1. The following is the bases for sulfamethoxazole and trimethoprim com
bination:
A. The both drugs act at the same stage of folates metabolism
B. The both drugs are bacteriostatic agents
C. The combination o f these drugs has less side-effects
D. The combination has a long duration of action
E. The both drugs have nearly similar plasma half-life.
№ 2. The mechanism o f a sulfonamides’ action is:

A. Competitive antagonism with PABA
B. The inhibition o f the synthesis of microorganisms’ membrane
C. An increase in permeability of microorganisms’ membranes
D. The inhibition of the synthesis of microorganisms’ proteins
E. The blockade of the sulfhydric groups o f enzymes.
№ 3. Drugs with antifungal activity belong to:

A. Sulfonamides
B. Polyenes
C. Imidazoles
D. Fluorquinolones
E. Allylamines.
№ 4. The correct statements concerning antifungals are:

A. Nystatin has a narrow spectrum o f action
B. Amphotericin B is never used to treat systemic mycoses
C. Griseofulvin concentrates in the skin, hair, and nails
D. Itraconazole is antibiotic for the treatment of Candida infection only
E. Ketoconazole has antihormonal activity.
№5. A patient with acute cystitis was prescribed a highly active antimicrobial
drug. It has a wide spectrum. The mechanism o f its action is connected with the
depression o f DNA-gyrase. This drug influences negatively cartilaginous tissue.
What drug was prescribed?
A. Sulfalene
B. Furozolidone
C. Ciprofloxacine
D. Nalidixic acid
E. Nystatin.
Answers
№ 1 - E; № 2 - A; № 3 - B,C,E; № 4 - A,C,E; № 5 - C.
H1
o W l ANTIBIOTICS
ANTIBIOTICS
Antibiotics are substances produced by microbes for their antagonism with other
microorganisms. Antagonism o f microbes is named antibiosis.
The history o f antibiotics. Antibiosis was studied by L.Paster and I.Mechnikov.
The first antibiotic was penicillin. It was discovered by A.Fleming in 1928. The
second antibiotic streptomycin was discovered by Vaxman. He also proposed the
name “antibiotics” .
Antibiotics are divided:
1. A c c o r d i n g to th e ty p e o f a c tio n
- bactericidal
- bacteriostatic.
2. A c c o r d in g to th e s p e c tr u m o f a c tio n
- antibiotics of a wide spectrum (with Gram (+) and Gram (-) coverage
including Gram (-) bacilli)
- antibiotics o f a narrow spectrum o f action (with a limited list o f microbes,
Gram (+) and Gram (-) coverage without Gram (-) bacilli, only Gram (+),
or only Gram (-) coverage).
3. A c c o r d in g to th e c lin ic a l u s e
- basis antibiotics (antibiotics o f choice) (the most effective antibiotics which
are used at the start o f treatment)
- alternative antibiotics (preparations which are used for the replacement
o f basis antibiotics in the case o f m icrobial resistance or p atien t’s
hypersensitivity).
MAIN PRINCIPLES OF THE TH ER APY BY ANTIBIOTICS

Therapy with antibiotics must be put into practice according to some common
rules concerning both microorganism and macroorganism. These rules (principles) are:
• An early beginning o f treatment
• The choice o f an antibiotic according to its spectrum o f action
• The choice o f an antibiotic according to the sensitivity o f microbes in a
definite patient
The use o f a wide spectrum antibiotic if the cause o f infection is unknown
The duration o f the treatment no less than 5-7 days
The usage o f big doses o f antibiotics
The supporting o f the therapeutic concentration o f the drug in the organism
Combination o f antibiotics with one another, as well as with drugs from
other groups
The discontinuation o f the treatment after the normalization of a clinical
status and body temperature
Allergic test at the start o f treatment
Attention to the age, physiological status of the patient, concomitant diseases,
the location and severity o f infection.
COMMON ANTIBIOTICS SIDE-EFFECTS

Allergy, an anaphylactic shock. For prevention - an allergic test before the
first administration o f the drug
A direct toxic influence
Endotoxic reactions. They display as an increase in body temperature and
intoxication resulting from the liberation o f endotoxins from microbes
destroyed by antibiotic
Dysbacteriasis. It is the inhibition o f normal microflora in the human body
accompanied by activation o f Candida fungi. For prevention - to take
antifungal drugs (nystatin, itraconazole) together with a wide spectrum
antibiotics.
Chapter 31. A N T IB IO T IC S 423
CLASSIFICATION
A. I n h ib ito r s o f c e ll w a ll s y n th e s is
1. Penicillins
2. Cephalosporins
3. Carbapenems and monobactams
4. Glycopeptides
B. P r o te in s y n th e s is in h ib ito r s a c tin g o n r ib o s o m a l s u b u n its 3 0 S
1. Aminoglycosides
2. Tetracyclines
C. P r o te in s y n th e s is in h ib ito r s a c tin g o n r ib o s o m a l s u b u n its 5 0 S
1. Macrolides and azalides
2. Chloramphenicols
3. Lincosamides
I). A n tib io tic s w h ic h d is tu r b f u n c t i o n s o f n u c le ic a c id s
1. Rifampicins
/i. A n tib io tic s w h ic h d is tu r b th e s tr u c tu r e a n d f u n c t i o n s o f c e ll m e m b r a n e s
1. Polyenes
2. Cyclic polypeptides (polymyxins).
ANTIBIOTICS-INHIBITORS OF C E L L W A LL SYNTHESIS
The most important antibiotics o f this group are the ß-lactam antibiotics, named
after the ß-lactam ring which is essential to their activity (fig. 31.1).
PENICILLINS
Penicillins are derivatives o f the 6-aminopenicillanic acid. The members o f
this family differs from one another in the substituent attached to the amino group
o fthe 6-aminopenicillanic acid.
CLASSIFICATION
•1. N a tu r a l p e n ic illin s (b e n z y lp e n ic illin , p e n ic i ll i n G )
1. A short acting
- Benzylpenicillin sodium (penicillin G)
- Benzylpenicillin potassium
- Penicillin V
2. A long acting
- Penicillin G procaine
- Benzathine penicillin (B icillin-1)

- Bicillin-3
- Bicillin-5
B. S e m is y n th e tic p e n ic i ll i n s
1. A penicillinase resistant
- Oxacillin
2. A wide spectrum
- Ampicillin
- Amoxicillin
- Carbenicillin
3. Combined penicillins
- Ampiox
- Amoxiclav (Augmentin).
Methicillin (semisynthetic)
Penicillins Cephalosporin Monobactam
Fig. 31.1. Chemical structure of ß-lactam antibiotics.
BENZYLPENICILLIN SODIUM
Benzylpenicillin sodium (penicillin G) is a natural substance produced by
fungus Penicillium notatum.
Pharm acokinetics
• is destroyed by gastric juice (fig. 31.2), that’s why is administered IM, IV,
endolumbally
is widely distributed through the body

• penetrates CNS only in the conditions o f meningitis; penetrates placenta
without negative influence on the fetus
• acts during 4-6 hrs.
Fig. 31.2. Site of cleavage of penicillin by acid or by

bacterial penicillinase (by. H. eeeLullmann, 2000).
In bacteria, there are several integral proteins in the cell membrane that
provide numerous functions: 1) transpeptidase activity —this permits cross-
linking in the formation of the cell wall; 2) contribute to the shape o f the
bacteria; 3) contribute to septum formation during replication/division; 4)
the inhibition the action o f autolysin (an enzyme that causes the destruction
o f the bacteria). These proteins are the target for penicillin. They are referred
to penicillin binding proteins or PBPs.
426 PH ARM ACO LO G Y. V. M. Bobyrov.T. 0. Devyatkina, 0. M. Vazhnicha,V. M. Khristyuk
• Penicillin G binds directly to PBPs and inhibits the enzyme transpeptidase,

thus inhibiting cell wall formation. The inhibition o f this action will reduce
the structural and functional integrity o f the cell wall. The cell bursts from
osmotic pressure because the integrity of peptidoglycan is not maintained
(= a bactericidal action) (fig. 31.3).
Benzylpenicillin only acts on organisms in the stage o f growth and division.
Bacteria may be resistant or develop resistance to penicillin by a variety of
mechanisms: the structure of the cell wall may provide resistance to a drug
effect; the PBP may undergo modification, decreasing the binding affinity
for the antibiotic; the production o f p-lactamase (penicillinase) provides
destruction o f the antibiotic before it may exert its effect.
Bacterium hi ass-linked
&
t 1 transpeptidase
Inhibition of
i cell wall synthesis wall
1 r~~y----- building block
Fig. 31.3. Mechanism of bactericidal action of penicillins (by H. Lüllmann, 2000
Spectrum o f action
It has a narrow spectrum o f action: Gram (+) and Gram (-) cocci (s tr e p to c o c c i,
s o m e s ta p h y lo c o c c i, g o n o c o c c i, m e n in g o c o c c i), c lo s tr id ia , c o r y n e b a c te r ia , liste ria ,
s p ir o c h e ta s , le p to s p ir a .
Indications
Infections caused by streptococci (angina, scarlet fever, rheumatism)
Meningitis (caused by Meningococcus)

Pneumonia (caused by Pneumococcus)
Gonorrhea
Syphilis
• Gangrene
Diphtheria
Infections o f the skin and soft tissues
Listeriosis
Leptospirosis.
Side-effects
1. Allergic reactions which occur in 0.7-20% o f patients taking penicillin and
may range from rash, fever, through broncospasm, vasculitis, serum sick
ness, exfoliative dermatitis, and Steven-Johnson syndrome to anaphylaxis
2. Neurotoxicity (in a bigger dose).
Contraindications
Hypersensitivity to penicillin.

Benzyl penicillin potassium is a short-acting natural penicillin similar to ben-
zylpenicillin sodium , but is not administered IV or endolumbally due to toxic action
o f potassium on CNS and the heart.
Benzathine penicillin (Bicillin-1) is a long-acting natural penicillin, has a
spectrum o f action similar to that of benzylpenicillin sodium, is administered only
IM once a week to treat chronic infections (syphilis, rheumatism).
Bicillin-5 is a long-acting natural penicillin, contains 'A o f benzylpenicillin pro
caine and 3/< of Bicillin-1; has a spectrum of action similar to benzylpenicillin sodium,
is administered only IM once a month to treat chronic infections (syphilis, rheumatism).
Oxacillin is semisynthetic penicillin, is an acid resistant and may be taken by
mouth, is penicillinase-resistant and is effective against Staphylococcus spp.\ is not
as effective against the other organisms that older penicillins are effective against.
Oxacillin and other penicillinase-resistant penicillins (Meticillin, Nafcillin) are only
topically used in the skin infections caused by susceptible organisms. There are nu
merous strains that are now resistant to these agents - so-called methicillin-resistant
staphylococci (MRSA).
Am picillin is semisynthetic penicillin, is an acid resistant and may be taken by
mouth, as well as IM and IV, is destroyed by penicillinase of staphylococci; has a wide
spectrum o f action: is more effective against Gram (-) organisms than the older drugs
o f the class (These include H a e m o p h ilu s in flu e n z a e , E s c h e r ic h ia coli, a n d P r o te u s
m ir a b ilis ) \ is most often used in the treatment o f urinary tract infections, respiratory
tract infections, and otitis media caused by susceptible organisms
Am oxicillin is a wide spectrum penicillin, is an active metabolite of ampicil|jn
has a better bioavailability in comparison to ampicillin.
Carhenicillin, piperacillin are extended spectrum penicillins, are more active
against Gram (-) and anaerobic organisms including P s e u d o m o n a s sp p ., E n te r o b a c ter
sp p ., a n d P r o te u s spp.-, are used primarily in the treatment o f infections caused by
susceptible organisms, often associated with bacteraemia and burns. Piperacil|jn
shows the greatest activity against P s e u d o m o n a s and K le b s ie lla spp.
A m piox is a combined preparation containing ampicillin and oxacillin, that’s
why it has a wide spectrum and acts on staphylococci.
A m oxiclav is a combined preparation containing ampicillin and clavulanic
acid (P-lactamase inhibitor), may be used to treat infections caused by penicillin
resistant microbes.
CEPHALOSPORINS
Cephalosporins are derivatives o f the 7-aminocepalosporanic acid and contain
P-lactam ring (fig.31.1).
They are wide spectrum antibiotics with a bactericidal action. Mechanism 0f
action is similar to that of penicillins.
CLASSIFICATION
1. The Is' generation
- Cefazolin (Kefzol)
- Cephaloridine
Cephalexin «
2. The 2nd generation
- Cefamandole
- Cefuroxime
- Cefaclor
3. The 3,d generation
- Cefotaxime
- Ceftriaxone
- Cefixime
- Cefazidime
4. The 4th generation

- Cefpirome
- Cefepime
Spectrum of action
Cephalosporins o f the 1 " generation act on Gram (+) cocci including s ta p h y
lo c o c c i resistant to penicillins, Gram (-) cocci, some Gram (-) bacilli. They are not
effective against MRSA.
C ephalosporins o f th e 2"J g eneration act on Gram (-) bacilli including
E n te r o b a c te r , K le b s ie lla , H a e m o p h ilu s , and P r o te u s spp., but they are less active
against Gram (+) cocci. Some preparations (cefoxitin, cefmetazole) are effective
against B a c te r o id e s sp p .
Cephalosporins o f the 3rd generation act on Gram (+) cocci, Gram (-) cocci,
as well as on Gram (-) bacilli; they are more resistant to the effects of (3-lactamase.
Ceftazidime and Cefoperazone are also effective against P s e u d o m o n a s .
Cephalosporins o f the 4"' generation have the spectrum similar to the 3rd
generation, they are also effective against P s e u d o m o n a s a e r u g in o s a and anaerobic
bacteria. They are alternative antibiotics.
Indications
Severe respiratory infections
Urinary tract infections
• Gynecologic infections
Osteomyelitis
Infections of the skin and soft tissues
Sepsis
Peritonitis "
The prophylaxis o f infectious complications o f surgeries
Side-effects
1. Allergy (there is some cross-sensitivity with the penicillins: 1-20% of pa
tients exhibit sensitivity to both classes o f antibiotics)
2. Dyspepsia
3. Renal disturbances (cephaloridine is the worst offender)
4. Changes in the blood film, the suppression of the bone marrow resulting in
granulocytopenia (relatively rare)
5. A decrease in the prothrombin amount in blood
6. Dysbacteriasis (for drugs administered orally).
Cefazolin is from the 1st generation; is administered IM, IV; acts during 8-12
hrs, is excreted unchanged with urine; is used to treat infections o f the respiratory
pathways, urinary pathways, bones, skin and soft tissues, may be used for the preven
tion o f infection before the surgery; has low nephrotoxicity.
Cephalexin is less active than other preparations o f the Is' generation, but it is
taken orally.
Cefotaxim e is the 3rd generation cephalosporin; is administered IM 2-3 times a
day, well penetrates CNS, tissues, and liquids o f the body; is used in severe infec
tions o f the respiratory and urinary pathways, sepsis, meningitis, osteomyelitis; is the
antibiotic o f choice in infections caused by non-identified microbes, may be applied
for prophylaxis o f infection before the surgery.
Ceftriaxone is more active than other preparations of the 3rdgeneration; is admin
istered IM or IV 1-2 times a day; has indications similar to indications o f cefotaxime.
C A R B A P EN EM S
lm ipenem a nd M eropenem are carbapenems (fig. 31.1):
act in a manner identical to the penicillins and cephalosporins
lmipenem is given with the agent cilastatin. lmipenem is rapidly metabo
lised by renal dehydropeptidases. Cilastatin inhibits this renal metabolism,
promoting renal reabsorption and an extended half-life o f the drug
Meropenem demonstrates a long half-life with higher blood levels and
therefore does not require the co-administration o f cilastatin
• have the broadest spectrum of action: Gram (+), Gram (-) microorganisms,
anaerobs, Pseudomonas aerugirosa. They are extremely resistant to the
actions o f P-lactamase
are used in the treatment o f urinary tract infections, lower respiratory tract
infections, gynecological infections, and soft tissue infections caused by
susceptible organisms 1
may cause nausea, vomiting, and rarely, seizures in high doses (meropenem
is less likely to cause seizures).
M ON O BACTAM S
A ztreonam is an antibiotic from the monobactams group:
has the mechanism o f action similar to other p-lactams
has a narrow spectrum o f action; is highly effective against Gram (-) organ
isms, especially enterobacteria; is resistant to the action o f p-lactamases
is well tolerated with minimal side effects: there is no cross sensitivity with
the p-lactam antibiotics.
GLYCOPEPTID ES
Vancomycin is an antibiotic from the glycopeptides group:
binds to the D-alanyl-D-alanine terminus o f the glycopeptide polymer, in
hibiting a loss o f the terminal D-alanine, inhibits cross-linking and weakens
the cell wall o f the microorganism
• is bactericidal in action
• has activity against Gram (+) organisms including those that produce
penicillinase, some Gram (-) and anaerobic bacteria; is effective against
methicillin-resistant staphylococci
is used for the parenteral administration in serious infections and orally in
the treatment o f pseudomembranous colitis; may be applied in patients with
serious allergy to p-lactams; is used prophylactically in dental patients, as
well as in patients with the prosthetic heart valves
may cause vancomycin flush syndrome (after rapid IV infusion) character
ised by flushing, hypotension, tachycardia due to histamine release. Other
adverse effects include hypersensitivity, chill, fever, rash, and, in high doses,
ototoxicity and nephrotoxicity.
p-LACTAM ASE INHIBITORS

Clavulanic acid, sulbactam, tazobactam are p-lactamase inhibitors. The spec
trum o f penicillins may be extended to include p-lactamase producing bacteria by
the addition o f agents which inhibit the lactamase enzyme and preserve the structural
integrity o f the p-lactam antibiotic. These will allow the use o f penicillins in peni-
cillase producing resistant organisms, but will not be beneficial in organisms with
altered PBP characteristics.
ANTIBIOTICS - INHIBITORS OF PROTEIN SYNTHESIS
AMINOGLYCOSIDES
Aminoglycosides are compounds containing amino sugars joined to a hexose
nucleus in glycosidic linkage (fig. 31.4). They are polar compounds o f polycationic
structure and are used in the form o f sulfates.
OH
HNS I
NH
/
NH— С
II
NH
OH
OH NHCH
Fig. 31.4. C h e m ic a l s tr u c tu re o f s tr e p to m y c in .
CLASSIFICATION
/. T he 1“ g e n e ra tio n
— S tre p to m y c in
— N e o m y c in
— K a n a m y c in
2. The 2"J g e n e ra tio n
— G e n ta m ycin
3. The 3rJ g e n e ra tio n
— A m ika cyn .
Pharmacokinetics
are not absorbed after oral administration 0
must be given parenterally for a systemic effect
have limited tissue penetration
are distributed in all extracellular fluids, but tissue concentrations are low,
except in the kidney and ear
cross the blood-brain barrier only in meningitis
are excreted with urine.
Mechanism of action
Aminoglycosides bind irreversibly to the 30S subunit of bacterial ribosomes
(fig. 31.5).
wrong amino acid
misreading of
codon by tRNA
G A U
aminoglycoside . , .
codon for Arg
Fig. 31.5. Aminoglycosides’ mechafiism of action (http://www.picsearch.com)
They prevent the formation o f an initiation complex with the messenger RN A

They reduce the rejection rate for tRNAs that are near matches for the co
don. This leads to the misreading o f the codons or premature termination
o f protein synthesis.
Aminoglycosides inhibit protein synthesis.
They increase membrane leakage.
They have bactericidal type o f action.
They are capable o f exerting such a postantibiotic effect that their killing
action continue?when their plasma levels have declined below measurable
levels.
Aminoglycosides have greater efficacy when administered as a single large
dose than when given as multiple smaller doses.
Aminoglycosides transport into the cell can be enhanced by cell wall syn
thesis inhibitors that may be the basis o f antimicrobial synergism.
Spectrum of action
The antibacterial spectrum is broad. It includes only aerobic organisms because
anaerobes lack the oxygen requiring the transport system. Aminoglycosides act
on Gram (-) bacilli: P ro te u s , P s e u d o m o n a s , S e r r a lia , E. coli, K le b s ie la p n e u m o
n ia e , F r a n c is e lla tu la r e n s is , Y e r s in ia p e s tis , s o m e G r a m (+ ) c o c c i: E n te r o c o c c i,
S tr e p to c o c c i ,
some strains o f S ta p h y lo c o c c u s . Kanamycin, amikacin, streptomycin
have some activity against M tu b e r c u lo s is .
Resistance is connected with decreased uptake o f the drug, an altered receptor
for the binding o f aminoglycoside to the SOS ribosomal subunit, and the plasmid
associated synthesis o f enzymes that modify and inactivate the antibiotic.
Indications
Pneumonia
Chronic urinary tract infections
• Infections due to P s e u d o m o n a s a e r u g in o s a
Tularemia
Tuberculosis.
Streptom ycin is effective against the organisms which cause plague, tularemia
and, in combination with penicillin, against Gram (+) enterococci and streptococci;
suppresses tubercle bacilli; is used very seldom in tuberculosis, subacute bacterial
endocarditis, tularemia, and plague, severe cases of brucellosis.
Neom ycin is effective against many Gram (-) species and several Gram (+)
bacteria (e.g. S. a u re u s)', because o f its serious toxic effects, it is used topically to
treat wounds, infected burns, skin diseases; can be used orally for the prevention of
infection before gastrointestinal surgery or for the treatment o f enterocolitis.
Gentamycin is bactericidal against a wide variety o f Gram (-) organisms, includ
ing P ro te u s , P s e u d o m o n a s , S e r r a tia , and some strains o f S ta p h y lo c o c c u s ; is used
1M, IV, and topically in the treatment of many infections caused by: P .a e r u g in o s a ,
S e r r a tia , E n te r o b a c te r , K le b s ie lla ; methicillin-resistant staphylococci; is the most
nephrotoxic among the aminoglycosides.
A m ikacin has a spectrum o f activity similar to that o f gentam ycin, but is often
reserved for situations in which resistance to gentamycin emerges; is active against
M. tu b e r c u lo s is and is an alternative preparation in this disease.
Kanamycin has a more limited spectrum o f activity than gentamycin. It is inef
fective against P s e u d o m o n a s and most Gram (-) organisms.
Side-effects
1. Ototoxicity
2. Nephrotoxicity
3. Neurotoxic effects, including dysfunction o f the optic nerve, neuromuscular

junction blockade when an aminoglycoside is given at high doses or in combination
with antidepolarizing drugs.
4. Allergic reactions.
TETRACYCLINES
Tetracyclines contain 4 heterocyclic rings in their molecules (fig.31.6).
Fig. 31.6. Chemical.structure of tetracyclines.
CLASSIFICATION
1. Natural
- Tetracycline
2. Semisynthetic
- Doxycycline
- Methacycline.
Pharmacokinetics
are absorbed from the GI tract, particularly from the stomach and the Upper
small intestine: oral absorption is variable and may be impaired by foocj and
multivalent cations (calcium, iron, aluminium)
penetrate CNS, but the levels are insufficient for therapeutic efficacy
have a wide tissue distribution
cross the placental barrier and concentrate in fetal bones and dentition
undergo entero-hepatic cycling
concentrate in bones and dental bone, in the liver, and some malignant tu
mors. The drugs are deposited in the teeth and bones because of their chelat
ing properties and form a tetracycline-calcium orthophosphate comp)ex
are eliminated primarily in the urine; doxycycline is excreted mainly in feces.
436 PH ARM ACO LO G Y. V. M. Bobyrov, 1 .0. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
Tetracyclines are transported into the microbial cell by transport proteins
unique to the bacterial inner cytoplasmic membrane.
The drugs bind to 30S ribosomal subunits.
They block access o f the amino acyl-tRNA to the mRNA-ribosome complex
at the acceptor site and inhibit protein synthesis (fig. 31.7)
Tetracyclines
Insertion of
incorrect
amino acid
Peptide chain Aminoglycosides
Fig. 31.7. Mechanism of action of tetracyclines in comparison with

the mechanism of action of aminoglycosides (by. H. Lullmann, 2000).
They interact with ions o f bivalent metals and disturb tissue respiration in
microbes; are the antagonists of riboflavin. !
They are bacteriostatic.
Resistance to tetracyclines is due to the inability ofm icrobes to accumulate
the drug, as well as to the modification o f the tetracycline binding site.
Spectrum of action
Tetracyclines are broad-spectrum antibiotics with activity against Gram (+) bac
teria ( C o r y n e b a c tr iu m a c n e s ), Gram (-) enteric rods, Gram (-) bacilli ( H a e m o p h y lu s
in flu e n z a e , V ib r io c h o /e r a e ) , rickettsiae, chlamydiae, mycoplasma, spirochetes
( B o r r e l ia b u r g d o r fe r i, T r e p o n e m a p a l li d u m ) , actinomyces, and some protozoa
(Amoebae).
Indications
Rickettsial infections including: Rocky M ountain spotted fever, Brill's
disease, murine and scrub typhus
Chlamydial infections (lymphogranuloma venereum, psittacosis, trachoma)
Mycoplasmal infections
Bacillary infections (brucellosis, tularemia, cholera, some S h ig e lla and
S a lm o n e lla infections)
Venereal infections
Amebiasis
Lyme disease.
Side-effects
1. Gastrointestinal disturbances
2. Hepatic dysfunction
3. Dermatitis, phototoxicity
4. Teratogenic action (“tetracycline teeth”)
5. Yellow-brown discoloration o f the teeth and depressed bone growth if
tetracyclines are given to children
6. A pseudotumor of the brain
7. Dysbacteriasis and superinfection which can result in staphylococcal en
terocolitis, candidiasis, and pseudomembranous colitis.
8. Stomatitis, gingivitis.
Contraindications
1. Diseases of the liver and kidney
2. Pregnancy
3. Children younger than 8 years old.
Tetracycline is administered orally 3-4 times daily or applied topically (oint
ment), has the bioavailability o f 66%, binds to plasma proteins (65%), penetrates
different tissues and body fluids, crosses the blood-brain barrier and placenta, is not
metabolized, is excreted with urine (60%) and feces (20-30%),
Doxycycline is administered orally and by IV infusion, binds to plasma proteins
(90%), is metabolized in the liver, has a half-life o f 18-24 hrs thus the preparation
may be given once a day; developes high concentration in the eye, prostate, testis,
uterus, urinary bladder, bile, liver, bones, teeth, lungs, lymphoid tissue; is excreted
with urine (40% o f the dose).
CHLORAMPHENICOLS
CHLORAMPHENICOL
Laevomycetin (Chloramphenicol) is a nitrobenzene derivative (fig.31.8).
N H C O C H C I,
_
0 ,N — V y CHOH —
J ~ \ ^
CH —
1C H ,O H
Fig. 31.8. Chemical structure of chloramphenicol.
Pharmacokinetics
is administered orally, applied topically (ointment, eye drops)
is absorbed rapidly from the GI tract
undergoes entero-hepatic cycling
is widely distributed in body fluids and reaches therapeutic levels in the
cerebrospinal fluid; is also present in bile and milk
is metabolized in the liver by glucuronyl transferase
is excreted with urine in the form o f metabolites.
Mechanism of action
Chloramphenicol binds to the 50S ribosomal subunit, blocks peptide syn
thetase and disturbs elongation'of peptide chain (fig. 31.9).
The drug is primarily bacteriostatic although it may be bactericidal to some
strains.
Spectrum of action
Chloramphenicol has a wide spectrum o f antimicrobial activity, including: many
Gram (-) organisms; anaerobic organisms (Bacteroides species,)/ Meningococcus,
some strains o f Streptococcus and Staphylococcus (at a high antibiotic concentration);
spirochetes, Clostridium, Chlamydia, Mycoplasma; rickettsiae.
Indications
Typhoid fever and salmonella infections
Bacterial meningitis
Anaerobic infections
Rickettsial diseases
Brucellosis;
• Infections o f the skin and soft tissues
Bacterial conjunctivitis
Clamidial infections (trachoma).
Fig. 31.9. Mechanism of action of chloramphenicol (by. H. Lullmann, 2000).
Side-effects
1. Allergic reactions
2. The inhibition o f leukopoesis and erythropoesis
3. Superinfections including candidiasis and acute staphylococcal enterocolitis.
4. A gastrointestinal upset
5. The gray-baby syndrome (this condition is seen in neonates, especially
premature infants, who have been given relatively large doses o f chloram
phenicol. Cyanosis, respiratory irregularities, vasomotor collapse, abdominal
distention, loose green stools, and an ashen-grey color characterize this often
fatal syndrome. The condition develops because o f the immature hepatic
conjugating mechanism and the inadequate mechanism for renal excretion
in neonates)
6. Endotoxic reactions.
MACROLIDES AND AZALIDES

Macrolides and azalides are the antibiotics that have a large lactone ring struc
ture. These may be 14- or 16-membered rings.
CLASSIFICATION
1. The 1st generation
- Erythromycin
2. The 2nd generation
- Azithromycin
- Clarithromycin.
ERYTHROMYCIN
Erythromycin is the first generation macrolide (fig. 31.10). It was the first drug
in this family.
Fig. 31.10. Chemical structure of erythromycin.
Pharmacokinetics
is taken by mouth and applied topically (ointment)
is destroyed by gastric juice, that’s why erythromycin doses are given as
either enteric coated or as more stable salts or esters
is very rapidly absorbed

is diffused into most tissues and phagocytes; due to the high concentration
in phagocytes, it is actively transported to the site o f infection where large
concentrations o f erythromycin are released during active phagocytosis
is metabolised by demethylation in the liver
is excreted with bile (mainly) and with urine (a small portion)
has a half-life o f 1,5 hrs.
Mechanism of action
• Erythromycin binds to the 50S ribosomal subunit and inhibits peptidyl
transferase activity.
It blocks the translocation o f peptidyl-tRNA from the acceptor site to the
donor site. The incoming charged tRNA cannot access the occupied acceptor
site, so the next amino acid cannot be added to the peptide chain (fig.31.11).
It is usually bacteriostatic, but can be bactericidal in certain situations.
Resistance is connected with the inability of microbes to take up the anti
biotic, decreased affinity o f 50S ribosomal subunit for the antibiotic, and
the presence o f erythromycin esterase.
Spectrum of action
Erythromycin has activity against many species o f Campylobacter, Chlamydia,
Mycoplasma, Legionella, spirochetes, Gram (+) cocci, and some Gram (-) organisms.
Its antimicrobial spectrum is similar to the spectrum o f penicillin.
This drug is an alternative antibiotic to penicillin in patients who are allergic
to (3-lactam antibiotics.
F ig . 31.11. Mechanism of action of erythromycin (http/www.picksearch.com).

Indications
Non-severe infections o f the respiratory system, synusitis, otitis
Pneumonia due to M y c o p la s m a
Legionnaires' disease
Diphtheria
Urogenital infection due to U r e a p la s m a
• Chlamidial infections
Syphilis
Acne.
Side-effects
Erythromycin has a very low incidence o f serious side-effects:
1. Cholestatic hepatitis, jaundice
2. Epigastric distress
3. Ototoxicity (transient deafness).
Contraindications
1. The decreased liver function.

Clarithromicin is taken by mouth; is absorbed in the gut on 55% that does not de
pend on meals, is widely distributed in the body except CNS, is metabolized in the liver
with the formation of active metabolite, is excreted with urine, has a half-life of 4 hrs;
has an increased activity compared to erythromycin; is active against S tr e p to c o c c u s
a g a la c tia e , S .p y o g e n e s , S .v ir id a n s , S .p n e u m o n ia e , H a e m o p h ilu s in flu e za e , N e is s e r ia
g o n o r r h o e a e , L i s t e r i a m o n o c y t o g e n e s , L e g i o n e l l a p n e u m o p h i la , M y c o p l a s m a
p n e u m o n ia e , H e lic o b a c te r p y lo r i, C a m p ilo b a c te r j e j u n i , C h la m y d ia p n e u m p n ia e ,
C. tr a c h o m a tis , M o r a x e lla c a ta r r h a l is, B o r d e te lla p e r tu s s is , P r o p io n ib a c te r iu m acnes,
M y c o b a c te r iu m a v iu m , M y c o b a c te r iu m le p r a e , S ta p h y lo c o c c u s a u re u s, U r e a p la s m a
is used to treat bronchitis, pneumonia (including
u r e a ly tic u m , T o x o p la s m a g o n d ii.;
mycoplasmial atypical pneumonia), infections o f the nose, ear, and throat, synusitis,
infections o f the skin and soft tissues, the eradication o f H .p y lo ri.
A zithrom ycin is administered orally with bioavailability o f 37% due to first-
pass-metabolism; develops maximal concentration in 2,5-3 hrs, displays tissues
concentration exceeding that in blood plasma in 10-100 times; concentrates in
phagocytes; has a half-life o f 14-20 hrs, is metabolized in the liver; is excreted with
urine unchanged (50%) and in the form o f metabolites; has an increased activity
compared to erythromycin; has a broad spectrum o f action which is similar to the

spectrum o f clarithromycin; does not act on microbes resistant to erythromycin; has
indications like clarithromycin; is well tolerated.
LINCOSAMIDES
The lincosamides include lincom ycin (fig. 31.12) and clindamycin.
CH3
HC/
H ,c
T
ow
H
N. H CH'
SCH,
OH
Fig. 31.12. Chemical structure of lincomycin.
are administered orally and parenterally, penetrate most tissues, including

bone, concentrate in phagocytic cells, pass through the placental barrier,
are metabolized in the liver and excreted with urine
bind to the 50S ribosomal subunit and block peptide bond formation; have
bacteriostatic type o f action
are very activé"against staphylococci, streptococci, and obligate anaerobic
pathogens
are used to treat infections o f bones (osteomyelitis), respiratory organs,
the urinary tract, anaerobic abdominal infections caused by Bacteroides.
Clindamycin is also used in ulcer disease
may cause side-effects, such as pseudomembranous colitis resulting in
diarrhea, abdominal pain, fever, and admixtures o f the mucus and blood in
the stool; allergic reactions.
STEROIDS
Fusidic acid (Fusidin-sodium) is an antibiotic o f steroid structure.
• is a protein synthesis inhibitor, acts by the preventing the translocation of

peptidyl tRNA
influences Gram (+) microbes (Staphylococcus and Streptococcus)
is osteotropic
is an alternative antibiotic to treat Gram (+) infections
is usually administered in combination with another antibiotic, because o f
easily selected resistant mutants during monotherapy with the fusidic acid.
ANTIBIOTICS WHICH DISTURB

FUNCTIONS OF NUCLEIC ACIDS
RIFAMICINS
Rifam pin (Rifam picinum ) belongs to the group o f complex macro cyclic an
tibiotics (fig. 31.13).
nu nu I
H3C O О OH
COCH,
Fig. 31.13. Chemical structure of rifampin.
Pharmacokinetics
is given orally
is well absorbed in the G1 tract
is distributed to most body tissues, including CNS
undergoes entero-hepatic cycling and is partially metabolized in the liver:

is the inducer of microsomal oxidation
is eliminated mainly in feces (both free drug and metabolites).
Mechanism of action
It inhibits the RNA synthesis in bacteria and chlamydiae by binding to DNA-
dependent-RNA polymerase (fig. 31.14).
RIFAMPIN - — ^ DNA-dependent-RNA polymerase
I
RNA
synthesis
Fig. 31.14. Mechanism of action of rifampin.
Spectrum of action
Most Gram (+) and many Gram (-) microorganisms are sensitive to rifampin.
It is highly effective against Mycobacterium tuberculosis, Mycobacterium leprae.
Prolonged administration o f the drug as the single therapeutic agent promotes the
emergency o f highly resistant organisms.
Indications
Tuberculosis (^co m b in atio n with other agents)
Atypical mycobacterial infections
Leprosy
Bacterial infections caused by sensitive microbes: pneumonia, cholecystitis,
osteomyelitis, etc. (as an alternative antibiotic).
Side-effects
1. Red discoloration o f urine, sweat, tears, and contact lenses
2. Proteinuria and impaired antibody response
3. Changes in the half-life o f a number o f co-administered drugs metabolized
by cytochrome P-450 system
4. Rash
5. Gastrointestinal disturbances
6. Renal damage
7. Jaundice and severe hepatic dysfunction.
ANTIBIOTICS INFLUENCING
STR U C TU R E OF M EM BRANES
PO LYEN ES
Nystatin a nd A m photericin B are polyene antibiotics. Their chemical structure
is like that o f unsatureted fatty acids (fig. 31.15). These antibiotics are antifungals
and decribed also in Chapter 30.
The drugs are fungistatic and fungicidal
They bind to sterols, especially ergosterol which is present in the membrane
o f fungi. As a result, the drugs appear to form channels in the membrane
which allow small molecules to leak out o f the cell. This disturbs the chemi
cal intracellular contents.
Nystatin is poorly absorbed from the GI tract; is used orally and topically; has
a narrow spectrum o f action; influences Candida albicans; is used to treat Candida
447
Chapter 31. A N T IB IO T IC S
infections o f the skin, mucous membranes, and intestinal tract: thrush (ora^
diasis) and vaginitis are treated by topical application, whereas intestinal carf oacj_
is treated by oral administration; is well tolerated. /1 /1p' v W u
Am photericin B is administered by IV infusion and applied topically; is “f ome
spectrum antifungal agent effective against H is to p la s m a c a p s u la tu m , C r y p tft ' |-Qr
n e o fo r m a n s , C o c c id io id e s im m itis, C a n d id a species, B la s to m y c e s d e r m a titid l' f t ■
strains o f A s p e r g illu s and S p o r o tr ic h u m ; it is the most effective drug avail*4 ( (a n e _
systemic fungal infections; it is frequently used for the treatment o f life-thr^y ■
fungal infections in patient with impaired defence mechanisms; pulmonary, r em \.
ous, and disseminated forms o f blastomycosis; acute pulmonary coccidioidortV^ ■
pulmonary histoplasmosis; C. n e o fo r m a n s infections, candidiasis, including % ' ^
nated forms; may cause side-effects, such as hypersensitivity reactions, anapf1. ^ , ^
fever, chill, headache, gastrointestinal disturbances; decreased renal func*^*
over 80% of patients treated with amphotericin B), anemia and thrombophK
POLYPEPTIDES (POLYMYXINS)
Polymyxins M and B are polypeptides used in the form of sulfates.
Mechanism of action ^fthe

Polymyxins interact with a specific lipopolysaccharide component
cell membrane. ft
• The membrane lipid structure is distorted with an increase in penn^
to polar molecules resulting in marked changes in cell metabolism-
Spectrum of action jn o s a ,
The spectrum o f action is narrow and includes Gram (-) bacteria (P. a e r d f t
etc.)
S a lm o n e lla , S h ig e lla , E. coli, P a s te u r e lla , B r u c e lla , H. in flu e n za e ,
ac-
Peculiarities of preparations A
* âses,
Polym yxin M is not absorbed in the GI tract; is administered orally (fof\ft jcaj
tion in the gut) and topically, is used to treat infected burns, wounds, skin
intestinal infections, for the sterilization o f bowels before surgeries; the / f t ^
administration o f polymyxin M is not accompanied by denominated side-ef' ^tjons
Polymyxin B is administered parenterally; its clinical usage is li m i t e y tê
therapy o f resistant Gram (-) infections. Polymixin B is used in severe >n^ / * j ness
caused by Gram (-) bacilli: meningitis, sepsis, peritonitis; if it is absorbed ' /"tion)"
systemic circulation, adverse effects include neurotoxicity (paresthesias, d i^ f t
ataxia) and acute renal tubular necrosis (hematuria, proteinuria, nitrogen re t^

№1. The most long acting cephalosporin o f 3rd generation is:
A. Cefalexin
B. Cefasolin
C. Ceftriaxone
D. Cefaclor
E. Cefpirome.
№2. All the concerning the mechanism of action of penicillins is true, except:
A. They inhibit cell wall synthesis
B. They inhibit transpeptidase
C. They have a bactericidal action
D. They cause disturbances o f the structure and function of the cell membrane
E. They act on microbes in the growth phase.
№3. Erythromycin is:

A. Destroyed by the gastric acid
B. Destroyed by intestinal enzymes
C. Entered the phagocytes
D. The crossing blood-brain barrier
E. Mainly excreted with bile.
№4. Tetracycline is stored in the body in:

A. The liver
B. Some malignant tumors
C. Hairs, nails, skin
D. Bones and dentition
E. Fat tissue.
№5. A 6-year old boy was admitted to hospital with pneumonia. The treatment
with amoxicillin was not effective. Bacterial analysis revealed mycoplasmial pneumonia.
Choose the most suitable drug for the treatment of this child.
A. Tetracycline
B. Azithromycin
C. Bicillin-5
D. Nystatin
E. Oxacillin.
Answ ers
№ 1 - C; № 2 - D; №3 - A, C, E; № 4 - A, B, D; № 5 - B.
B ANTISPIROCHETAL DRUGS,
w \ y ANTIMYCOBACTERIAL
O W M DRUGS. ANTIVIRAL AGENTS
SPIROCHETAL INFECTIONS AND THEIR TREATM EN T

Syphilis is one o f the most widely spread spirochetal infections caused by
It is a chronic infection developed in a few stages from the
T r e p o n e m a p a lid u m .
primary tissue affect to the systemic disorders in CNS and other organs.
ANTISPIROCHETAL DRUGS
Drugs for the treatment o f syphilis and other spirochetal infections are named
antispirochetal drugs.
CLASSIFICATION
A. A n tib io tic s
1. Basis antibiotics
- Benzylpenicillin sodium
- Bicillin-1
- Bicillin-5
2. Alternative antibiotics
- Cefaloridine
- Erythromycin
- Chloramphenicol (Laevomicetinum)
B. B is m u th p r e p a r a tio n s
- Bijochinolum.
ANTISPIROCHETAL ANTIBIOTICS
Benzyl penicillin sodium is the inhibitor o f the cell wall synthesis with short
duration o f action and a narrow spectrum. It is effective against Treponemapalidum
and used as the basis antibiotic in syphilis.
Bicillins are long-acting natural penicillins which have a narrow spectrum o f
action and are administered IM once a week (Bicillin-1) or once a month (Bicillin-3)
for the treatment o f syphilis.
Cefaloridine is the Is1generation cephalosporin. It is the inhibitor o f the cell wall
synthesis with a wide spectrum o f action. It is an alternative preparation in syphilis.
Erythromycin is a macrolide antibiotic. It is a protein synthesis inhibitor whose
spectrum o f action is similar to the spectrum o f benzylpenicillin. It is used as an
alternative antibiotic in patients hypersensitive to basis antibiotics.
Chloram phenicol is a wide spectrum antibiotic, a protein synthesis inhibitor.
It may be used as an alternative antibiotic in syphilis.
BISMUTH PREPARATIONS
BIJOCHINOLUM
is a compound between bismuth and quinine suspended in Oleum Persicorum
is administered IM once per 3 days, accumulates in the body; is excreted
with urine and saliva
interacts with SH-groups o f enzymes and has a bacteriostatic action on
Treponema palidum
is indicated for all stages o f syphilis (together with benzylpenicillin), non
syphilitic encephalitis and myelitis
may cause grey spots on gums, stomatitis, renal disturbances
is contraindicated in patients with renal failure and diseases of the oral mucosa.
TUBERCULO SIS AND ITS TH ER APY

Tuberculosis is a chronic infection caused by Mycobacterium tuberculosis.
The treatment o f tuberculosis is a serious problem due to some peculiarities of
mycobacteria, such as:
a slow growth
the ability to be dormant and completely resistant to many drugs
the impermeability o f cell wall to many agents
persistence in macrophages
the development o f resistance to any single drug.
Chapter 32. ANTISPIROCHETAL DRUGS. ANTIMYCOBACTERIAL DRUGS. ANTIVIRAL AGENTS 451
General principles of chemotherapy of tuberculosis

To begin the therapy with the Is1 line drugs
To use the 2nd line preparations after the development o f drug resistance
in microbes
• To apply 2-3 preparations together to delay or prevent the emergency of
resistant strains
• To carry out a long lasting treatment (6-24 months)
To continue the regimen after the disappearance o f clinical disease to eradi
cate any persistant organisms
To carry out laboratory monitoring o f the efficacy o f treatment.
ANTIMYCOBACTERIAL DRUGS
Antim ycobacterial drugs are preparations to treat tuberculosis. Some o f the
most active drugs are effective in leprosy.
CLINICAL CLASSIFICATION
OF ANTIMYCOBACTERIAL DRUGS
There are 2 groups o f antimycobacterial drugs: the Is' line and the 2nd line
preparations (fig. 32.1). The Is’ line preparations have high efficacy and low toxic
ity. The efficacy o f the 2nd line preparations is lower, but they act on resistant strains
o f mycobacteria.
Ç Antimycobacterial drugs J
( T h e 1“ line preparations ) ( T he 2*1 line preparations J
c Isoniazid
J - f A m in osalicylic acid J
Rifam pin -( C ycloserine )
E tham butol
-c E thionam ide
J
P irazinam ide
J t E thionam ide
Fig. 32.1. C lassification o f antim ycobacterial drugs according to their activity.

ISONIAZID (INH)
It is the hydrazide o f the isonicotinic acid, a synthetic analog o f pyridoxine
(fig. 32.2). Isoniazid is the most potent anti-tubercular agent.
Fig. 32.2. C hem ical structure o f isoniazid.
Pharm acokinetics
is administered orally, IM, IV; absorption after the oral administration is
impaired by food and antacids
diffuses into the whole body: infected tissues tend to retain the drug longer
penetrates CNS
is metabolized in the liver by acétylation and hydrolysis; acétylation is
genetically regulated: the fast acetylator trait is an autosomal dominant
(fig. 32.3)
is excreted with urine, parthialy with saliva, sputum, and milk.
N -acetylation
Rapid acetylators: ^ Slow acetylators: A

half-life o f isoniazid is half-life o f isoniazid is
about 1 hr . about 3 hrs
Fig. 32.3. G roups o f patients according to speed o f isoniazid’s acétylation.
Mechanism of action
• It disturbs the synthesis o f the mycolic acids which are an important con
stituent o f the mycobacterial cell wall.
• It competes with vitamins B6, B (, PP.

For bacilli in the stationary phase, isoniazid is bacteriostatic; for dividing
bacilli, it is bactericidal.
Isoniazid is effective against extracellular, as well as intracellular bacteria.
When it is used alone, resistant organisms rapidly emerge.
Spectrum of action
Mycobacterium tuberculosis
Indications
It is used for all forms of diagnosed tuberculosis.
Side-effects
1. Hypersensitivity
2. Peripheral neuritis (paresthesia)
3. Mental abnormalities, psychotic episodes, euphoria, convulsions
4. Optic neuritis
5. Hepatitis
Neurological side-effects are due to competition to B6 and pyridoxine deficiency.
RIFAMPIN
It is a wide-spectrum antibiotic produced by Streptomyces. The drug interacts
with the DNA-dependent-HNA polymerase, suppresses the initiation step of tran
scription in procaryotes. It is bactericidal for both intracellular and extracellular my
cobacteria. Rifampin is the P' line preparation in tuberculosis and the most effective
anti-leprosy drug. For detail information - see Chapter 31.
PYRAZINAMIDE
is a pyrazine analog o f nicotinamide
is taken orally and widely disrtributed in the body, penetrates into CNS
• is transformed into the active form (the pyrazinoic acid)
has an unknown mechanism o f action (probably the inhibition of oxygen
dependent mycolic acid synthesis); acts on extra- and intracellular myco
bacteria
• ' is the Is*line anti-tubercular preparation; is widely used in the multi-agent

short-term therapy o f uncomplicated pulmonary tuberculosis
may cause the liver dysfunction and urate retention.
ETHAM BUTO L
• is taken orally and widely disrtributed in the body, penetrates into CNS
is ethylenimine derivative, blocks nucleic acids synthesis and inhibits arabi-
nozyl transferases involved in the synthesis of arabinogalactan, a component
o f the mycobacterial cell wall
is a bacteriostatic anti-tubercular agent
• is the 1st line anti-tubercular preparation
• may cause optic neuritis, a loss o f ability to discriminate between red and
green.
ALTERN ATIVE SECO N D LINE DRUGS

Am inosalicylic acid is a competitive inhibitor of PABA in folate metabolism, is
bacteriostatic, is taken in a high dose (10-15g per day) and causes many side-effects
(dyspepsia, crystalluria, the enlargement o f the thyroid gland), is used rarely.
E thionam ide is a structural analog o f isoniazid, inhibits acetylation, may cause
side-effects, such as hepatotoxicity, gastric irritation, peripheral and optic neuritis.
Cycloserine is an antibiotic—inhibitor o f the cell wall synthesis, is toxic; may
cause CNS and peripheral neurological disturbances.
Streptom ycin is an aminoglycoside antibiotic, the inhibitor o f protein synthesis,
is used in drug combination for the treatment o f life-threatening tuberculosis disease
(meningitis, miliary dissemination, severe organ tuberculosis).
A m ikacin is an aminoglycoside antibiotic, is used for the treatment of tuber
culosis caused by streptomycin-resistant strains, is applied in the combination drug
regimen.
Ciprofloxacine, ofloxacine are fluorquinolones, block DNA gyrase, are used
as the 2nd line preparations in the combination drug regimen.
VIRAL INFECTIONS AND THEIR CH EM O TH ER APY

Viruses are obligate intracellular parasites. They are small particles the main
structure elements o f which are the nucleic acid (DNA or RNA) and the protein coat
(capsid), require the active participation o f cell metabolism to survive.
A life cycle o f virus consists o f adsorption and penetration, uncoating, early
protein synthesis, nucleic acid synthesis, assembly and budding (release o f virions).
Viruses have some specific enzymes which are the targets for antiviral drugs (reverse
transcriptase, HIV-specific protease, DNA polymerase).
In the body there are natural antiviral substances interferons produced by im
mune competent cells.
ANTIVIRAL AGENTS
Antiviral drugs are preparations for the treatment of viral infections.
CLASSIFICATION
1. Inhibitors o f attachment to host cell or penetration into host cell
- Amantadine
- Reman tad ine
2. Inhibitors o f DNA polymerase
- Acyclovir
- Gancyclovir
- Famcyclovir
- Vidarabine
3. Reverse transferase inhibitors
- Zidovudine (azidothymidine, AZT)
- Didanosine
- Zalcitabine
4. HIV protease inhibitors
- Saquinavir
- Ritonavir
- Nelfinavir
- Amprenavir
5. Neuroaminidase inhibitors
- Zanamivir
- Oseltamivir
6. Interferons
- Laferonum (IFN-a-2p)
According to the clinical usage

1. For influenza and respiratory virus infections
- Amantadine, Remantadine
- Ribavirin
- Zanamivir and other neuroaminidase inhibitors

2. For herpes and cytomegalovirus infection
- Acyclovir and other inhibitors o f DNA polymerase
3. For HIV infection
- Zidovudine and other reverse transferase inhibitors
- Sanquinvir and other HIV protease inhibitors
4. Preparations with a wide antiviral spectrum
- Laferonum and other interferons
PREPARATIONS FOR TREATMENT OF INFLUENZA
REMANTADINE
It is a midantan derivative, structurally related to amantadine.
Pharmacokinetics
is taken orally
does not penetrate into CNS
* is excreted by the cells o f the epithelium o f the upper respiratory pathways
is excreted with urine as a parent drug and metabolites.
Mechanism of action
The drug blocks the viral membrane matrix protein M2 which functions as an
ion channel (it is required for the fusion o f the viral membrane with the cell mem
brane) (fig. 32.4)
It also inhibits the release of new virions. 1
Spectrum of action
The virus o f influenza A 2, the virus o f encephalitis.
Indications
The treatment o f influenza A2
The prevention o f influenza
The prophylaxis o f epidemic encephalitis.
/' j Influenza
;r^ */ A-virus
Fig. 32.4. Mechanism of action ofmidantan derivatives (by II. Liillmann, 2000).
Side-effects
1. Headache
2. Hallucinations
3. Ataxia
4. Disturbances o f speesh
5. Insomnia
6. Confusion
7. Seizures.
PECULIARITIES OF OTHER DRUGS

A m antadine is structurally similar to remantadine, crosses the blood-brain
barrier; does not metabolized in the body; has antiparkinsonian action; displays
side-effects associated with CNS; should be employed cautiously in patients with
psychiatric problems, epilepsy, cerebral atherosclerosis, renal failure, pregnancy.
PREPARATIONS FOR TR EATM EN T OF HERPES

AND CYTOM EGALO VIRUS INFECTION
ACYCLOVIR
It is a synthetic purine nucleoside analog (acycloguanosine) (fig. 32.5).
G uan in e
Acyclovir
Fig. 32.5. Structural resemblance between acyclovir and guanine-containing nucleotide

(http://www.picsearch.com).
Pharm acokinetics
is administered orally, IV, or topically
penetrates into CNS
is partially metabolized and excreted with urine.
A ciclovir transform s into triphosphate, interferes with the viral DNA
polymerase and inhibits the viral DNA replication (fig. 32.6)
• It is also incorporated into DNA and leads to premature chain termination
• Acyclovir inhibits only actively replicating viruses.
Chapter 32. ANTiSPIROCHETAL DRUGS. ANTIMYCOBACTERIAL DRUGS. ANTIVIRAL AGENTS 459
Phosphate
Incorporated into DNA
® Phosphate
DNA polymerase
blocked by false
nucleotide. Assembly
of DNA stops.
False nucleotide
(acyclovir triphosphate)
Acyclovir
Fig.32.6. Mechanism of acyclovir’s action: A - synthesis of normal viral

DNA guanine nucleotide; B - synthesis of false viral DNA nucleotide with acyclovir
(adapted from http://www.picsearch.com).
Spectrum of action
Herpes simplex virus types I and II, varicella-zoster virus, Epstein-Barr virus,
cytomegalovirus.
Indications
Primary mucocutaneous herpes infection
Recurrent mucocutaneous herpes infection
• Herpes genitalis
Herpes simplex encephalitis
• Prophylaxis o f herpes infection before and after tissue transplantation (in
seropositive patients).
Side-effects
1. Local discomfort, itch (after the topical application)
2. Nausea, vomiting
3. Headache, encephalopathy (after IV administration)
4. Nephrotoxicity.

Gancyclovir is a nucleoside analogue, blocks DNA-polymerase o f cytomegalo
virus, is used for the treatment o f cytomegalic retinitis in immune suppressed patients.
Famcyclovir is an acyclic analogue of deoxyguanosine, is only used for the
treatment of acute herpes zoster.
Vidarcibine (ara-A) is adenine arabinoside, is one o f the most effective nucle
oside analogues, is the least toxic, is used for the treatment of herpes infection and
herpes zoster.
A G EN TS OF WIDE ANTIVIRAL SPECTRUM OF ACTION
INTERFERONS
They are glycoproteins produced by leukocytes (INF-a), fibroblasts (INF- P)
and immune cells (INF-y). Nowdays they are synthesized by the recombinant DNA
technology.
Interferons interact with receptors on the host cell membrane and induce the
formation of protein kinase that leads to the phosphorilation and blockage
o f peptide chain initiation
They also induce phosphodiesterase activation that leads to the degradation
o f terminal nucleotides o f tRNA.
Spectrum of action
Interferons have a wide antiviral spectrum o f action. They also have anti-cancer,
anti-toxic and immune stimulating properties.
'1
Indications
INF-a is used to treat viral hepatitis A and B, Kaposi’s sarcoma, papillo
matosis, hairy cell leukemia.
INF- p is applied for the treatment o f multiple sclerosis.
• INF-y is used for chronic granulomatous disease.
Side-effects
1. Fever
2. Lethargy
3. Bone marrow suppression

4. Heart failure
5. Hypersensitivity.
PREPARATIONS FOR TREATMENT OF HIV INFECTION
ZIDOVUDINE {AZT)
It is a nucleoside analogue (fig. 32.7).
Pharmacokinetics
• is taken orally
• has bioavailability o f 60%
penetrates CNS
• is excreted with urine in the form of metabolites
has a half-life o f 1-3 hrs.
AZT is a nucleoside reverse transcriptase inhibitor (NRTI). Its mechanism of
action includes:
the phosphorilation o f AZT by host cell kinases
the formation of nucleotide analog AZT-triphosphate
• AZT-triphosphate incorporation into the growth chain o f the viral DNA by
the reverse transcriptase
the immature chain termination and inhibition o f viral replication (fig. 32.7).
Spectrum of action
HIV-1, HIV-2.
Indications
• AIDS
The prophylaxis of HIV infection through accidental needle sticks
The prevention o f vertical HIV transmission from the mother to the neonate.
462 PHARMACOLOGY. V. M. Bobyrov,T. 0. Devyatkina, 0. M.Vazhnicha, V. M. Khristyuk
Envelope
Matrix protein
Reverse
transcriptase
Inhibitors of
reverse
transcriptase
HOCH
e.g., zidovudine
A A /V Inhibitors of
Viral RNA Polyproteins HIV protease
♦ Protease
Cleavage of
polypeptide
precursor
Mature virus
Fig. 32.7. Chemical structure and mechanism of action o f N R 'll

and H I V protease inhibitors (by H. Liillmann, 2000).
Chapter 32. ANTISPIROCHETAL DRUGS. ANT1MYCOBACTERIAL DRUGS. ANTIVIRAL AGENTS 463
Side-effects
1. Anemia, neutropenia
2. GI distress
3. Headache, agitation, insomnia
4. Myalgia
5. Hepatitis and cholestasis.
PECULIARITIES OF OTHER NRTI

Didanosine is used for AZT-resistant HIV-infection.
Zalcitahine is used in a combination with AZT or as monotherapy in patients
who can not tolerate AZT.
HIV PROTEASE INHIBITORS

Saquinavir, ritonavir, indinavir, nelfinavir, amporenavir belong to this group.
Protease inhibitors act in the stage o f late protein synthesis (fig.32.7). At this stage,
HIV-specific protease cleaves biochemically inert polypeptides to produce the final
structural and functional proteins of virus. They are used in a combination with AZT,
reduce opportunist infections and prolonge the lives o f patients.

№1. Bijochinolum:
A. Is a synthetic anti-tubercular drug
B. Is the basis antibiotic for treatment o f syphilis
C. Is the bismuth preparation for the treatment of syphilis
D. Is administered orally
E. Is used only in syphylis.
№ 2. Antiviral agents that inhibit viral nucleic acid synthesis do not include:
A. Remantadine
B. Acyclovir
C. Gancyclovir
D. Famcyclovir
E. Vidarabine.
464 PH ARM ACO LO G Y. V. M. Bobyrov,T, 0. Devyatkina, 0. M.Vazhnicha,V. M. Khristyuk
№ 3. Isoniazid:
A. Is highly effective against tuberculosis
B. Inhibits the synthesis o f mycolic acids
C. Is the 2nd line preparation for the treatment o f tuberculosis
D. Does not act on intracellular mycobacteria
E. Is less neurotoxic if given together with pyridoxine.
JY®4. Zidovudine has such properties as:

A. Inhibits HIV reverse transcriptase
B. Is taken orally
C. Can be used for the treatment o f herpes and cytomegalovirus infection
D. Significantly reduces mortality and morbility from AIDS
E. Is used in a combination with HIV protease inhibitors.
№ 5. A patient came to a doctor with complaints o f urine and lacrimal liquid

painted red. It is known from the patient’s anamnesis, that he was treated for pulmo
nary tuberculosis. What anti-tubercular drug became the cause o f such complications?
A. Isoniazid
B. Rifampin
C. Ethionamide
D. Streptomycin sulfate
E. Ethambutol.
A n sw e rs
№ 1 - C; № 2 - A; № 3 - A,B,E; № 4 - A,B,D,E; № 5 - B.
1
| 4 4 ANTIPROTOZOAL
O W % / DRUGS
MALARIA AND CO N TR O L S TR A TE G Y FOR IT

Malaria is an acute infectious disease caused by the parasites called plasmodia.
There are 4 species o f plasmodia; PI. falciparum, PI. vivax, PI. malariae, PI. ovale.
PI. falciparum is the most dangerous species causing acute disease characterized by
high fever, orthostatic hypotension, and massive hemolysis. This infection can cause
capillary obstruction and death.
The life cycle o f parasite consists o f sexual and asexual stages (fig.33.1). The
1st stage takes place in female anopheles mosquito. At this stage, parasite exists as
gametocyte. The 2nd one develops in the human body. Here it may reside in the liver
(pre-erythrocytic schizogoni) and in erythrocytes (erythrocytic shizogoni).
The control o f this dreaded menace would therefore involve three living be
ings: M an (The host), Plasmodia (The agent), and Anopheles m osquito (The vec
tor) (table 33.1) The control o f malaria is a complex chain o f measures that often
complement one another.
The control strategy for malaria, concerning the human, includes an early di
agnosis and treatment:
• Presum ptive treatm en t. Tests for malarial parasite should be done in all
cases o f fever, and presumptive treatment with the first full dose o f chlo-
Table 33.1. C ontrol strategy for m alaria
HUMAN (Host) PARASITE (Agent) MOSQUITO (Vector)
Kill the asexual forms

Prevent the progression of
disease Prevent breeding
Treat the affected
Kill the sexual forms Prevent entry
Protect the unaffected
Prevent the spread to mos Prevent bites
quitoes
Ensure full treatment
Problems: Resistance to
Problem: Compliance Problem: Drug resistance
insecticides; compliance
Fig. 33.1. Transmission cycle o f malaria (http://www.picsearch.com).

Chapter 33. A N T IP R O T O Z O A L D R U G S 467
roquine should be administered. Chloroquine is highly effective as schi-

zonticidal drug against all species of malaria and is also gametocytocidal
against all except P. f a lc ip a r u m . Thus, by administering chloroquine to all
cases o f fever, it is possible to sterilize the gametocytes and thus prevent
the spread to mosquitoes.
• R a d ical treatm ent. All confirmed cases o f fever should be administered
with primaquine. A single dose o f primaquine must be administered in
P. f a lc i p a r u m malaria to sterilize the gametocytes. A 14 days course of
primaquine should be administered in P. v iv a x infection to destroy the pre-
erythrocytic shizontes in the liver and thus to prevent relapse.
• Ensure com pliance. A complete treatment should be ensured. If the patient
vomits the drugs within an hour o f ingestion, the same should be repeated.
Many patients fail to complete the treatment due to either negligence, the
lack o f proper education or sometimes due to adverse effects.
• Personal protection: A human should be encouraged to protect himself (or
herself) against malaria. Personal protection measures include protection
against mosquito bites and chemoprophylaxis against malaria.
• C hem oprophylaxis: Travelers to endemic areas and high risk individuals
living in endemic areas (pregnant, elderly, patients with organ failure)
should start on chemoprophylaxis against malaria. This involves taking
antimalarial drugs every week (some drugs must be taken every day) so as
to suppress malaria.
CLASSIFICATION
According to the chem ical structure
1. 4-Aminoquinolines
- Chloroquine
2. Quinoline-methanols
- Quinine
- Mefloquine
3. 8-Aminoquinolines
- Primaquine
4. Sulfonamides and sulfone
- Sulfadoxine
- Sulfamethopyrazine
- Dapsone (pyrimethamine + sulfonamide)
5. Diaminopyridines
- Pyrimethamine (Chloridinum)
468 PHARMACOLOGY. V. M. ßobyrov.T. О. Devyatkina, О. M. Vazhnicha, V. М. Khristyuk
6. Biguanides
- Chloroguanide (proguanil)
7. Hydroxynapthoquinone
- Atavaquone
8. Other preparations
- Halofantrine
- Artemisin.
According to the antimalarial action

1. Hemato-shizonticidal agents
- Quinoline-methanols
- 4-Aminoquinolines
- Sulfonamides and sulfone
- Hydroxynapthoquinone
- Diaminopyridines
2. Tissue-shizonticidal agents
- 8-Aminoquinolines
3. Gameticidic agents
- 4-Aminoquinolines
- 8-Aminoquinolines
- Diaminopyridines.
CHLOROQUINE
Choroquine is the most potent antimalarial agent, 4-aminoquinoline derivative
(fig. 33.2).
Cl N
Fig. 33.2. C hem ical structure o f chloroquine.

Pharmacokinetics
is administered orally and 1M
is rapidly and completely absorbed after oral administration; concentrates
in the erythrocytes, liver, spleen; has a very large volume of distribution
is metabolized in the liver: some metabolic products retain antimalarial
activity
• is excreted with urine.
Mechanism of action
The food vacuole is a lysosome-like organelle in which the breakdown of
hemoglobin and the detoxification of heme occur. Chloroquine concentrates
up to several 1000-fold in the food vacuole of the parasite.
This accumulation may involve ion trapping following protonation, specific
transport, and/or binding to a receptor.
The major action of chloroquine is to inhibit the formation o f hemozoin
from the heme released by the digestion of hemoglobin (fig.33.3).
Mechanism of action of chloroquine: CQ - chloroquine,

F ig . 33.3.
Hb - hemoglobin, Hz - hemozoin (http://www.picsearch.com).
The free heme then lyses membranes and leads to the parasite death.
Chloroquine resistance is due to a decreased accumulation of chloroquine
in the food vacuole.
Spectrum of action
Erythrocytic shizontes o f PL falciparum, PI. vivax (less effective), gametocytes
o f PL falciparum , Entamoeba histolytica.
The drug also has an anti-inflammatory, weak cytostatic action, suppresses
immunity, excerts anti-arrhythmic effect in the human body.
Indications
An acute attack o f malaria
Malarial coma
The prevention of the spread o f malaria
Individual chemoprophylaxis
Extra-intestinal amebiasis
Rheumatoid arthritis
• Discoid lupus erythematosus.
Side-effects
1. A gastrointestinal upset
2. Headache
3. Skin rash, itch
4. Visual disturbances
5. Depigmentation o f nails beds, hair, and mucous membranes
6. A quinidine-like effect in the heart.
Contraindications
Hepatic dysfunction, severe gastrointestinal diseases, neurological and blood
disorders, psoriasis, porphyria.

Q uinine is an alkaloid o f the bark o f a cinconha tree; is administered orally, is
widely distributed in the body, penetrates CNS, crosses placental barrier, is blood
shizonticide, realizes its action by complexes with double-stranded DNA to prevent
strand separation resulting in block o f DNA replication and transcription of RNA; is
used to treat an attack o f Pl. falciparum malaria resistant to chloroquine; in humans,
inhibits CNS, has a M-cholinomimetic action on the smooth muscles, stimulates

uterus contractions, suppresses the conduction system o f the heart (a quinidine-like
effect) and the contractility o f the myocardium; may cause cinchonism, a syndrome
including gastrointestinal distress, headache, vertigo, blurred vision, tinnitus, AV
block, heart incompetence; also causes hemolytic anemia (blackwater fever); is
fetotoxic and contraindicated in pregnancy.
M efloquine is structurally relative to quinine; is administered orally, is well
absorbed in the GI tract, concentrates in the liver and lungs, has a long half-life (17
days), is excreted with feces; is blood shizonticide o f the unknown mechanism of
action (fig. 33.4); is an effective single agent for suppressing and curing multi-drug
resistant forms o f PI. fa lc ip a r u m ', is less toxic than quinine, but may cause nausea,
vomiting, dizziness, disorientation, depression, ECG disturbances a heart arrest if is
given together with anti-arrhythmics.
P rim aquine
A to v a q u o n e
GAM ETOCYTES ©
fv ©
©Q
M E R O Z O IT E S
C h lo ro q u in e
M efiooquine
Fig. 33.4. Stages in the plasmodium life-cycle

when antimalarial drugs act (http://www.picsearch.com).
Prim aquine is a 8-aminoquinoline derivative; is administered orally, is well

absorbed in the gut, rapidly oxidized, and excreted with urine; has the mechanism
o f action connected with an oxidative damage o f parasite cell; is tissue shizonticide
(fig. 33.4); acts on pre-erythrocytic forms o f PL f a lc ip a r u m , PL v iv a x . PL o v a le , as
well as on gametocytic forms o f all four plasmodia; is used to eradicate liver stages of
PL v iv a x and PL o v a le (in conjugation with blood shizonticides); is also used for the
interruption o f malaria transmission; is well tolerated, but may cause gastrointestinal
disturbances, methemoglobinemia, headache, itch, hemolysis in patients deficit in
glucose-6-phospate dehydrogenase.
Sulfonam ides a nd sulfone are blood shizonticides active mainly against Pl.
fa lc i p a r u m . The malaria parasite synthesizes folates de novo, whereas the human
host must obtain preformed folates and cannot synthesize folate. The inability o f the
parasite to utilize exogenous folates makes folate biosynthesis a good drug target.
One ofthese enzymes, dihydropteroate synthase (DHPS), is inhibited by sulfa-based
drugs. Sulfadoxine anddapsone are two common antimalarials that target DHPS. The
sulfa drugs are structural anlalogs of PABA and are converted into non-metabolizable
adducts by DHPS. This leads to a depletion o f the folate pool and thereby reduces
the amount o f thymidylate available for the DNA synthesis.
Pyrimethamine andproguanil are the two most common dihydrofolate reductase
(DHFR) inhibitors used as antimalarials. Inhibiting DHFR prevents the formation of
thymidylate and leads to the arrest in the DNA synthesis and the subsequent parasite
death. P yrim etham ine alone is blood shizontocide and strong sporonticide in the
mosquito’s gut, is effective against Pl, f a lc i p a r u m in a combination with a sulfona
mide, is used against P L m a la r ia e and T o x o p la s m a g o n d ii. It may cause deficit o f the
folic acid and megaloblastic anemia, has teratogenic action. Proguanil has similar
targets o f action (fig. 33.4).
DRUGS FOR TREATM EN T OF AMEBIASIS
AMEBIASIS
Am ebiasis is a disease caused by a one-celled parasite called E n ta m o e b a h is
It is more common in people who live in tropical areas with poor sanitary
to ly tic a .
conditions. In European countries and the USA amebiasis is most often found in
travellers to and immigrants from these areas, as well as in people who live in insti
tutions with poor sanitary conditions.
Only about 10% to 20% o f people who are infected with E. h is to ly tic a become
sick from the infection. The symptoms often are quite mild and can include loose
stools, stomach pain, and stomach cramping. Amebic dysentery is a severe form o f
amebiasis associated with stomach pain, bloody stools, and fever. Rarely, E. his
tolytica invades the liver and forms an abscess. Even less commonly, it spreads to
other parts o f the body, such as the lungs or brain.
Life cycle o f E. histolytica includes ingestion o f cysts, the formation of tropho
zoites, the penetration o f intestinal wall, the multiplication o f trophozoites within
the colon wall, excretion of cysts with feces. If amoebas enter the blood and travel
to another organs, they cause systemic invasion.
CLASSIFICATION
1. Mixed amebicides (for all localizations)
- Metronidazole
2. Tissue amebicides
- Metronidazole
- Tinidazole
- Emetine hydrochloride
- Chloroquine
3. Luminal amebicides
- lodoquinol
- Tetracyclines
- Diloxanide furoate
- Quiniodochlor.
METRONIDAZOLE
It is a nitroimidazole derivative (fig. 33.5).
C H 2C H 2OH
Fig. 33.5. C h e m i c a l s tru c tu re o f m e tro n id a z o le .
Pharmacokinetics
is administered orally, IV, rectally, vaginally, applied topically as gel or
ointment
474 PHARMACOLOGY. V. M. Bobyrov,T. 0. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
is well absorbed in the gut

binds to plasma proteins (about 10% of a drug)
has the volume o f distribution o f 70-95% o f body mass
penetrates CNS and placenta; develops therapeutic levels in vaghinal and
semenal fluids, saliva, breast milk, cerebro-spinal fluid
concentrates in the liver
is metabolized in the liver (30-60%), has entero-hepatic circulation, is
excreted with bile to the intestine and is absorbed again, produces a high
concentration in the bile
is the inhibitor o f liver enzymes
is excreted with urine, bile, and feces
has a half-life o f 8-10 hrs, completely leaves the body during 2-3 days.
The drug is activated by a reduction of the nitro group to an anion radical
(fig. 33.6)
Ferrodoxin
reduced
Ferrodoxin
oxidized
DNA
fragmented^/
Fig. 33.6. Mechanism o f action of metronidazole.

In the case o f metronidazole, reduced ferredoxin appears to be the primary

electron donor responsible for its reduction.
The anion radical is highly reactive and forms adjunctions with proteins
and DNA leading to a loss o f the function. In particular, the reactions with
DNA result in the strand breakage and inhibition o f replication and will
lead to the cell death.
• There is a good correlation between the presence o f the pyruvate-ferredoxin
oxidoreductase (PFOR) and sensitivity to metronidazole. All three o f the
protozoa ( G iaridia, E ntam oeba, and T richom onas) affected by metroni
dazole lack mitochondria and have PFOR similar to that found in many
anaerobic bacteria. Aerobic microbes use other electron transport systems
and are not sensitive to metronidazole.
Sp ectru m o f action
Protozoa ( G ia rd ia L am blia, E n ta m o eb a h istolytica, T richom onas vagin alis,
Leishm ania), anaerobic cocci, anaerobic Gram (+) and Gram (-) bacilli (B acteroides
spp., E ubacterium spp., F usobacteriunt spp., Clostridium spp., H elicobacter pylori, etc).
Indications
• Amebiasis
Trichomoniasis
• Giardiasis
• Cutaneous leishmaniasis
Sepsis, peritonitis, m eningitis, brain abscess caused by sensitive m i
crobes (IV)
• Respiratory infections, infections of the intestine and urinary pathways
caused by sensitive microbes
Pseudomembranous colitis
Prophylaxis o f anaerobic infection before abdominal surgery
Peptic ulcer associated with H. p y lo r i
Infections o f the skin (perioral dermatitis) and soft tissues (topically)
Paradontitis, ulcerative stomatitis (topically).
1. A loss of appetite 1. Hemopoiesis disturbances
2. An unpleasant taste in the mouth 2. Organic lesions o f CNS
3. Nausea, vomiting 3. Pregnancy
4. Diarrhea 4. Lactation
5. Headache, reversible polyneuropathy 5. Should not be used togeth-

6. Skin rash, itch er with alcohol drinks due
7. Leukopenia to disulfiram-like reaction.
8. Red-brown discoloration o f urine
9. Changes in pharmacokinetics o f some other
drugs (e.g.; ethyl alcohol, lithium salts).

Tinidazole is a nitroimidazole derivative; similarto metronidazole; is only taken
orally; is not used in leishmaniasis.
C hloroquine is an antimalarial preparation with amebicidic properties. It is a
systemic amebicide; is used in a conjugation with metronidazole and diloxanide to
treat and prevent amebic liver abscesses.
Em etine is an alkaloid from ipecacuanna; is administered IM, SC, concentrates in
the liver, is metabolized slowly, can accumulate, has a half-life of 5 days; inhibits pro
tein synthesis at the stage o f elongaion; is the alternative drug in the treatment of tissue
amebiasais; is toxic and causes nausea, vomiting, cardiotoxicity, weakness, dizziness.
D iloxanidefuroate is a luminal amebicide; is used to treat intestinal amebiasis; is
well tolerated, but may cause flatulence, dry mouth, itch, urticaria; is contraindicated
to pregnant women and children younger than 2 years o f age.
DRUGS FOR TREATM EN T OF TRICHOMONIASIS

Trichomoniasis is the most common curable sexually transmitted disease in
young women. As estimated, 7.4 million new cases occur each year in women and
men. Trichomoniasis is caused by the single-celled protozoan parasite, Trichomonas
vaginalis. The vagina is the most common site of infection in women, and the urethra
(urine canal) is the most common site o f infection in men.
Trichomoniasis can usually be cured with nitroimidazole derivatives (metro
nidazole or tinidazole) and nitrofuran derivatives (furozolidone). These drugs are
described in Chapter 30 and as amebicides in presented Chapter,
DRUGS FOR TREATM EN T OF GIARDIASIS

Giardiasis is an intestinal illness caused by infection with the parasite Giardia
lamblia which lives in contaminated water. Although the illness most frequently
occurs in developing countries, giardiasis is also one o f the most common causes
o f waterborne illness in the United States. G. lamblia parasites are found in the
feces o f infected people. Two-thirds o f persons infected with the organism do not
have any symptoms. When symptoms occur, they typically start one to three weeks
after exposure and include a sudden onset of watery diarrhea, abdominal cramping,
bloating, nausea, gas.
Although most people will recover from giardiasis without treatment, medica
tions, such as metronidazole, quinacrine hydrochloride (Mepacrine) orfurazolidone
(furoxone), are used to treat giardiasis.
Pecu liaritie s o f preparations

Quinacrine is an acridine derivative that is effective in the treatment of giardiasis,
malaria, leishmaniasis, and tapeworm invasion; is taken orally, concentrates in the liver,
skin, brain tissue, accumulates; binds to membrane phospholipids, blocks phospholipase
A2, disturbs functions o f DNA, also binds to acetylcholine receptor; may cause diz
ziness, headache, vomiting, liver lesions, yellow pigmentation of the skin, psychosis.
M etronidazole and fu razolidone are described in detail as amebicides and
chemotherapeutics of different chemical structure.
DRUGS FOR TREATM EN T OF TOXOPLASMOSIS

Toxoplasmosis is caused by a microscopic parasite Toxoplasma gondii that
can live inside the cells o f humans and animals, especially cats and farm animals.
Toxoplasmosis passes from animals to humans, sometimes without causing any
symptoms. When kids have symptoms, they vary depending on the child’s age and
the immune system’s response to the infection.
Toxoplasmosis infections in people fall into three basic patterns:
1) congenital toxoplasmosis, in which a child becomes infected before birth; 2) toxo
plasmosis in otherwise healthy kids (with the same symptoms a pregnant woman
may have); 3) toxoplasifiosis in kids with weakened immune systems.
Toxoplasmosis is treated with pyrim etham ine which is described as an antima-
larial agent and its combinations with sulfonamides (sulfadiasine).
DRUGS FOR TREATM EN T OF LEISHMANIASIS
LEISHMANIASIS
Leishm aniasis is a parasitic disease that is found in the tropics, subtropics, and
southern Europe. It is caused by infection with Leishmania parasites which are spread
by the bite o f infected sand flies. There are several different forms of leishmaniasis
in people. The most common forms are cutaneous leishmaniasis which causes skin
sores, and visceral leishm aniasis which affects some o f the internal organs o f the
body (e. g. the spleen, liver, and bone marrow).
CLASSIFICATION
1. The drugs for the treatment o f cutaneous leishmaniasis
- Quinacrine
- Metronidazole
- Monomycine
- Amphotericin B
2. The drugs for the treatment o f visceral leishmaniasis
- Sodium stibogluconate
- Pentamidine.
SODIUM STIBO GLUCO NATE

is the compound o f pentavalent antimony
is administered IV; has minimal metabolism; is excreted with urine
is not active in vitro
has an unclear mechanism o f action: probably it is connected with the inhibi
tion o f glycolysis and blockade o f SH-groups in the parasite
is used in visceral leishmaniasis as a preparation o f choice
• may cause asthenia, headache, anemia, hepatitis.
Some other preparations for the treatment o f leishmaniasis (quinacrine,

metronidazole, am photericin B) are presented in other parts o f this Chapter
and in Chapter 30. i
№ 1. The blood shizonticides are all the drugs, except:
A. Chloroquine
B. Primaquine
C. Quinine
D. Pyrimethamine
E. Mefloquine.
№ 2. The mechanism o f the action o f chloroquine is connected with:

A. The conversion o f the nitro-group into the toxic anion radical
B. B lockade o f SH-groups
C. Prevention ofhem oglobin digestion
D. Disturbances in DNA reduplication
E. Folate antagonism.
№ 3. The indications for the use o f metronidazole are:

A. All forms o f malaria
B. All forms o f amebiasis
C. Giardiasis
D. Trichomoniasis
E. Visceral leishmaniasis
№4. The correct statements concerning antiprotozoals are:

A. Quinine is used for the radical cure of malaria
B. Chloroquine is used for malaria and amebiasis
C. Metronidazole may cause disulfiram-like adverse reaction
D. Sodium stibogluconate is antimony compound for leishmaniasis
E. Sodium stibogluconate is a folate antagonist for toxoplasmosis.
№ 5. A patient with an acute attack o f malaria was presctibed with an erythro

cytic shizonticidal fast acting drug. In addition to antimalaial effect, this drug has
anti-inflammatory properties and is used in the treatment of rheumatoid arthritis and
lupus erythematosus. This preparation is:
A. Pyrimethamine
B. Chloroquine ,
C. Quinine
D. Metronidazole
E. Emetine.
A n sw e rs
№ 1 - B; № 2 - C; № 3 - B, C, D; № 4 - B,C D; № 5 - B.
5 l f l ANTIHELMINTHIC
O %/ I DRUGS
HELMINTHIASIS AND ITS CO N TROL

H elm inthic infection (helminthiasis) is caused by pathogenic worms and may
be localized in the alimentary tract or in other tissues. There are several main spe
cies o f parasitic worms causing human helminthic infections. They are tapeworms
(cestodes): Taenia sagin ata, T aenia solium , H ym en olepis nana, a n d E ch ion ococcu s
sp ecies; roundworms (nematodes): A sca ris lu m bricoides, E n terobiu s verm icu laris,
A n cilo sto m a du oden a le, N e c a to r a m erican u s, T rich in ella sp ira lis; trematodes:
S ch isto so m a m ansoni, S ch isto so m a haem atobiu m . Helminthiases are divided into
groups by their etiology (fig. 34.1).
( H E L M IN T H IA S E S )
N em atodoses
C estodoses
T rem atodoses
Fig. 34.1. Main classes of helminthiases.

Chapter 34. A N T IH E L M IN T H IC D R U G S 481
Intestinal helminthiasis is an infestation with one or more intestinal parasitic

worms. It is more often than tissue helminthiasis. Infected people excrete helminth
eggs in their feces which then contaminate the soil in areas with inadequate sanitation.
Other people can then be infected by ingesting eggs or larvae in contaminated food,
or through the penetration of the skin by infective larvae in the soil (hookworms).
Infestation can cause m orbidity, and sometimes death, by compromising
nutritional status, affecting cognitive processes, inducing tissue reactions, such as
granuloma, and provoking intestinal obstruction or rectal prolapse.
Control o f helm inthiasis is based:
on drug treatment
improved sanitation
• health education.
ANTIHELMINTHICS
Antihelm inthics are drugs that expel parasitic worms (helminths) from the body
by either stunning or killing them. They may also be called vermifuges (stunning)
or vermicides (killing).
CLASSIFICATION
1. The drugs for the treatment of nematodoses
- Pyrantel pamoate
- Piperazine adipinate
- Levamisole
- Mebendazole
- Ivermectin
2. The drugs for the treatment of cestodoses
- Niclosamide (Phenasalunt)
3. The drugs for the treatment o f trematodoses
- Diethylcarbamazine
- Praziquantel.
M EBEN D AZO LE
Mebendazole is a benzoimidazole derivative (fig. 34.2).
• is taken orally
is poorly absorbed in the gut (10%); absorption is increased in the presence

o f fatty meals
is rapidly metabolized
is excreted with urine and bile within 24-48 hrs.
Fig. 34.2. Chemical structure of mebendazole.
It inhibits the polymerization of helminth tubulin.
Thus, the drug interferes with microtubule-dependent functions, such as a
glucose uptake.
The effect takes time to develop and the worms may not be expelled for
several days.
The cure rates are 60-100% with most parasites.
Sp e ctru m o f action
Pinworm (E nterobius verm icu la ris), roundworm (A scaris lu m bricoides), guinea
worm (D racu n cu lu s m ed in en sis), T rich in ella sp ira lis, hookworm (A n cilosto m a
duodenale, N e c a lo r a m erica n u s), whipworm (T richuris trichiura).
Indications
Infection caused by pinworm
Infection caused by roundworm
Infection caused by guinea worm
Trichiniasis
Infection caused by hookworm
Infection caused by whipworm.
Is given as a single dose for threadworm, and twice daily for 3 days for hook
worm and roundworm infestations.
Side-effects
Gastrointestinal disturbances.

Should not be given to pregnant women and children under 2 years old.
PIPERAZINE
is taken orally, has poor absorption in the gut, is partly metabolized and
excreted with urine
acts as GABA on GABA-gated chloride channels in nematode muscles,
causes paralysis of worms which are expelled alive by normal intestinal
peristaltic movements
is effective against Ascaris lumbricoides and Enterobius vermicularis
• is used in a single dose to treaLroundworm and in the form of 7-days course
to treat threadworm
may cause gastrointestinal disturbances, urticaria, spasm o f bronchi, rarely
dizziness, paraesthesias, vertigo, incoordination
is contraindicated in pregnancy, renal and hepatic diseases.
LEVAMISOLE
is taken by mouth, is quickly absorbed and widely distributed in the body,
crosses the blood-brain barrier, is metabolized in the liver and excreted with
urine,7has a half-life o f 4 hrs
has a nicotine-like action, blocks neuromuscular transmission in nematodes,
thus causes paralysis o f worms and their expelling
is effective against Ascaris lumbricoides and less active against other
nematodes
is used to treat roundworm (a single-dose therapy)
stimulates immunity in the humans, especially T-dependent processes and
phagocytosis, that’s why is used in the complex treatment o f collagenoses,
chronic non-specific diseases o f the lungs
• if a single-dose therapy is used, side-effects are few and soon subside; when
the drug is used as an immune stimulant, it may cause fever, an influenza
like syndrome, leukopenia.
PYRAN TEL
is taken orally, is poorly absorbed and acts in the gut
is the depolarizing neuromuscular blocking agent causing the paralysis of
nematode musculature and their expelling from the intestine
is effective against A s c a r is lu m b r ic o id e s , E n te ro b iu s v e r m ic u la r is ,
A n cilo sto m a duodenale, N eca to r am erican u s
is used to treat infections caused by roundworms, pinworms, and hookworms
may cause nausea, vomiting, diarrhea.
IVERMECTIN
is safe and highly effective antihelminthic o f a broad spectrum o f action
is a semisynthetic agent obtained from actinomycete organism
is given orally; has a half-life o f 11 hrs
acts probably by opening glutamate-gated chloride channels and increasing
the CL' influx, by the stimulation o f N-cholinoreceptors and motor paralysis
o f worms, or by binding to GABA-receptors
• is effective against S tr o n g ilo id e s s te r c o la r is , W u c h e re ria b a n c ro fti.
O n ch o cerca vo lv u lu s , roundworms, whipworms
is the first choice o f the drug for filarial infection, onchocerciasis (river
blindness), infestation by W uchereria b a n crofti caused elephantiasis
is well tolerated, but may cause skin rash, fever, headache, pain in muscles
and joints.
NICLOSAMIDE
is taken orally
causes paralysis o f muscles o f tapeworms and damages their covering tunic,
thus provides the damage of tapeworms by intestinal enzymes, their separa
tion from the intestinal wall and expelling of damaged parasites
• is effective against T aenia sagin ata, T aenia solium , H ym en o lep is nana
is used to treat infestations by tapeworms: for Taenia soliu m the drug is
given in a single dose after a light meal followed by a purgative 2 hrs later
for the evacuation of ova and prevention of cysticercosis
may cause nausea and vomiting.
PRAZIQUANTEL
is a highly effective broad-spectrum antihelmintic
• is administered orally, is well absorbed, is quickly metabolized and excreted

with urine, has a half-life o f 1-1,5 hrs
binds to protein kinase C, increases the Ca ' influx into the muscular
cells of parasites, thus produces a rapid and prolonged contracture of
m usculature, paralysis, and death of the worm; also disrupts the tegu
ments o f the parasite and make it more susceptible to the host’s normal
immune responses
is effective against blood flukes {S ch istosom a mansoni, S ch istosom a h aem a
tobium , Sch istoso m a ja p o n icu m ), D racu n cu lu s m edinensis, E ch in ococcu s
granulosus, la rva o f Taenia soliu m
is used to treat schistosomiasis, cysticercosis, hydated disease; is commonly
used in national disease control programmes
• has minimal side-effects, may be used in pregnant and lactating women.
DIETHYLCARBAMAZINE
is a piperazine derivative
is administered orally, is widely distributed in the body, is partly metabolized
and excreted with urine, stays in the organism during 48 hrs
is active in filarial infections, rapidly removes microfilariae from the blood
circulation and has a limited effect on the adult wonns in the lymphatics
is used to treat filarial infections, whipoworm, wisceral larva migrans
may cause gastrointestinal disturbances, arthralgias, headache, weakness,
toxic and allergic reactions due to dying filariae.
ANTIHELMINTHICS
FROM MEDICINAL PLAN TS
There are many medicinal plants with antihelminthic properties which are used
in traditional and folk medicine in different countries. Examples o f naturally occur
ring anthelmintics include: Tobacco {N icotia n a ta b a cu m ), black walnut (Juglans
n ig ra ), wormwood (A rth em isia absyn th iu m , A rth e m isia cin a), clove {S yzygiu m
a rom aticu m ), tansy tea (T anacetum vu lg a re ), hagenia {H a g en ia a b yssin ica ), garlic
{A llium sativu m ), pine-apple {A nanas co m o su s), kalonji {N ig ella sa tiv a ) seeds, male
fern {D ryo p teris filix -m a s), plumeria {P. acu tifolia o r P. ru bra), pumpkin {C u cu rbita
p e p a ) seeds (fig. 34.3).
Many natural anthelminthics are poisonous and, in improper dosages, dangerous
for humans, as well as for parasites.
486 PH ARM ACO LO G Y. V. M. Bobyrov.T. 0. Devyatkina, 0. M .Vazhnicha,V. M. Khristyuk
Fig. 34.3. Some medicinal plants used as antihelmmthics: A - Dryopteris filix-mas;

B -Allium sativum, C -Arthemisia cina, D - Cucurbitapepa.
T ES TS FOR SELF-CO N TR O L
№1. All the listed drugs are antihelminthics, except:
A. Mebendazole
B. Metronidazole
C. Niclosamide
D. Pyrantel pamoate
E. Piperazine adipinate
№ 2. The antihelminthic affecting microtubular function in nematodes is:

A. Praziquantel
B. Niclosamide
C. Piperazine adipinate
D. Mebendazole
E. Ivermectin.
№3. The correct statements concerning the mechanisms o f action o f antihelmin

thics are:
A. Mebendazole disturbs parasite’s microtubules and glucose uptake
B. Niclosamide causes paralysis o f microfilariae
C. Pyrantel is depolarizing neuromuscular blocking agent for nematodes
D. Ivermectin interferes with receptors of parasite’s chloride channels
E. Praziquantel stimulates GABA receptors in parasitic worms.
№ 4. The true indications for to the use o f antihelminthics are:

A. Roundworm disease is treated by pyrantel pamoate or mebendazole
B. Pinworm disease is treated by niclosamide
C. Filariasis is treated by diethylcarbamazine
D. Tapeworm disease is treated by niclosamide
E. Whipworm disease is not treated with mebendazole.
№ 5. A patient with roundworm disease was prescribed with antihelminthic

preparation for a single-dose therapy. This drug also stimulates T-dependent immune
reactions, increases the activity o f phagocytes, and is used to regulate the immune
balance in collagenosis. What antihelminthic was prescribed?
A. Mebendazole «7»
B. Pyrantel pamoate
C. Niclosamide
D. Piperazine
E. Levamisole.
A n sw e rs
№ 1 - B; № 2 - D; № 3 - A, C, D; № 4 - A, C, D; № 5 _ E.
1" 1 ■ PHARMACOTHERAPY
O \ / W OF ACUTE POISONINGS
POISONINGS
Poisoning is the result o f the action o f a toxic agent or a toxic dose o f the drug
on the organism.
Poisonings may be acute and chronic. They are divided into household, envi
ronmental, industrial, pharmacological.
Poisoning with pharmacological agents results from:
• an absolute overdose (administration o f a toxic dose o f the drug)
a relative overdose (caused by a therapeutic dose under the conditions of
drug accumulation, hepatic and renal insufficiency, etc.).
M ain s y n d ro m e s a cc o m p a n ie d acute p o iso n in g s

Acute poisonings may be accompanied by:
CNS disturbances: coma, unconsciousness, seizures
cardiovascular disturbances: heart failure, collapse, arrhythmia
respiration disorders: a spasm o f bronchi, pulmonary edema, a respiratory
arrest, asphyxia
G1 disorders: vomiting, nausea, diarrhea, constipation, a loss o f appetite
• liver lesions: hepatic necrosis, hepatic insufficiency
Chapter 35. P H A R M A C O T H E R A P Y O F A C U T E P O IS O N IN G S 489
• renal insufficiency
lesions o f the skin and mucous membranes: necrosis, irritation, exfoliation,
rash.
P rin cip le s o f p o is o n in g s treatm ent

There are four basic principles o f poisoning treatment:
• the termination o f poison exposure
• the fa sten in g o f the elimination o f a toxic agent fro m the body
• antidote administration
• general supportive and symptomatic therapy.
According to this principles, the treatment o f poisoning includes:
detoxication therapy (non-specific)
symptomatic therapy (non-specific)
antidote therapy (specific).
DETOXICATION TH ER APY
The main purposes of detoxication’therapy are to reduce poison absorption and
to enhance the removal o f poison.
For the reduction o f absorption the follow ing is used:
1. The irrigation of the skin and mucous membranes with cold water, an isotonic
solution of sodium chloride, in some cases with special antidotes (e.g. a
weak solution o f ammonia for the neutralizing o f formaldehyde; oil for the
washing out o f phenol; 2% solution of sodium chloride for the neutralizing
o f silver nitrate)
2. The lavage of the stomach with potassium permanganate (in poisoning with
alkaloids), cold water (in poisoning with acids or alkalis), etc.
3. Emesis induced with apomorphine (parenterally), a solution o f ammonia
(dissolved in water, per os), or mechanically
4. The use of adsorbents (activated charcoal, enterosgel)
5. The use o f astringents (tannin, milk, egg-white)
6. The use of osmotic purgatives (magnesium sulfate) which form high osmotic
pressure in the lumen o f the intestine and bowel and in such a way inhibit
absorption of the toxic agent
F or the enhancem ent o f poison rem oval the follow ing is used:
1. Forced diuresis with furosemide or mannitol
2. The altering of urinary pH (alkalinization for acidic substances and acidi
fication for alkaline drugs)
490 PH ARM ACO LO G Y. V. M. Bobyrov,T.O. Devyatkina, 0. M. Vazhnicha, V. M. Khristyuk
3. Peritoneal dialysis, hemodialysis, hemosorbtion

4. The use o f osmotic purgatives (magnesium sulfate, sodium sulfate)
5. The administration o f drugs stimulating enzymes activity in the liver forthe
fastening o f poison metabolism (e.g. phénobarbital; glucose, and vitamins
in poisoning with ethanol)
6. Analeptics for the stimulation o f respiration and an increase of the excretion
o f poison through the lungs (Carbogenum, Aethimizolum).
SYMTOMATIC TH ER APY
It is a therapy aimed at the supporting o f damaged functions o f the organism
and resuscitation. General supporting and symptomatic therapy are needed in most
cases o f poisonings. It is achieved according to the main syndromes o f intoxication
and is the same in different poisonings.
A seizures attack is treated by:
- anxiolytics: diazepam (IV, IM)
- neuroleptics: chlorpromazine (IV, IM)
- IV general anesthetics: sodium oxybutyrate (IV, IM)
- magnesium salts: magnesium sulfate (IV, IM).
A respiratory arrest needs:
- N-cholinergic agonists: Cytitonum (IV), lobeline hydrochloride (IV).
The inhibition o f respiration should be treated with:
- analeptics: niketamide (IV, SC), camphor (SC), Sulfocamphocainum (IV,
IM, SC), Bemegridum (IV), Aethymizolum (IV, IM), Carbogenum (carbon dioxide
.+ oxygen, by inhalation).
Pulmonary edema needs emergency help, such as:
- diuretics: furosemide (IV), mannitol (IV infusion), Urea pura (IV infusion)
- drugs caused the redistribution o f blood: ganglia blockers (Hygronium,
IV infusion; Pentaminum, IV, or IM); peripheral vasodilators (nitroglycerine, IV;
sodium nitroprusside, IV infusion) i
- cardiac glycosides: strophanthin (IV), Corglyconum (IV)
- glucocorticoids: prednisolone (IM, IV)
- narcotic analgesics: morphine hydrochloride
- surfactants: exosurf, curosurf
- oxygen with anti-foam agents (vapor o f ethanol).
Collapse is overcome by the administration of:
- a- and a,(3-adrenergic agonists: phenylepiphrine (IM, SC, or IV), noradrena
line hydrotartrate (IV infusion), adrenaline hydrochloride (SC)
- analeptics: niketamide (SC, IV), camphor (SC), Sulfocamphocainum (IV,
IM, SC).
A cu te heart fa ilu re is treated by:

- c a rd ia c g ly c o sid e s from S tro p h a n th u s group: sto p h a n th in (IV ),
Corglyconum (IV)
- non-glycoside inotropic agents: dobutamine (IV infusion).
ANTIDOTE TH ER APY
Antidotes are drugs specifically interacting with some poisons. They act either
by the preventing o f absorption or by inactivating or antagonizing the action o f the
poisons. Specific antidotes are not available for all poisons (e.g. acute poisoning
with phenol).
G EN ER A L MECHANISMS OF ANTIDOTE ACTION

Antidotes exert an antitoxic effect by a variety o f mechanisms:
binding to receptors (e.g. atropine, naloxone)
acting on enzymes (e.g. Cholinesterase reactivators)
displacement from tissue binding sites (e.g. ethanol under the conditions
o f poisoning with methanol)
exchanging with poison, binding to poison (e.g. chelating agents)
• the replenishment o f depleted essential substances (e.g. sulfur containing
agents)
CLASSIFICATION OF ANTIDOTES
1. Sulfur containing compounds
- Unithiolum
- Sodium thiosulfate
- Acetylcystein^'
2. Chelating agents
- Sodium edeteate (trilon B, EDTA-Natrium)
- Tetacin-calcium (Calcium-EDTA)
- Deferoxamine (desferral)
- Penicillamine
3. Cholinesterase reactivators
- Pralidoxim (PAM)
- Alloxim
- Dipiroxim
- Isonitrosine
4. Antagonists o f opioids
- Naloxone
- Naltrexone
- Atropine sulfate
6. Anticholinesterases
- Neostigmine (Proserinum)
7. Preparations o f other groups
- Cromosmonum (Methyleni coeruleum)
- Ethanol (Spiritus aethylicus)
- Potassium permanganate
- Activated charcoal (Carbo activatus).
SULFUR-CONTAINING A G EN TS
UNITHIOLUM
is a mercaptide by its chemical structure
• contains two SH-groups and forms two bonds with metal ions
• is an analogue o f the drug British anti-lewisite (BAL, dimercaptoprol)
is administered IM, orally (in chronic poisonings)
has a complex mechanism of action: 1) it forms bonds between SH-groups
and metal ions with the formation o f inactive complexes which are excreted
with urine; 2) it prevents metals binding to tissue proteins; 3) it restores the
activity o f SH-groups o f enzymes as a donator o f SH- groups (fig. 35.1)
is indicated in poisonings with arsenic compounds, mercury, lead, in cardiac
glycosides poisoning, streptomycin poisoning, hepatocerebral dystrophy,
the treatment o f alcoholism
may cause nausea, tachycardia, dizziness, paleness, 1
SODIUM THIOSULFATE
is administered orally or IV
contains sulfur and forms non-toxic compounds with ions o f metals, the
cyanic acid, bromides and iodides; converts cyanomethemoglobin to thio-
cyanate which is excreted
has antitoxic, anti-inflammatory, and anti-allergic properties
is used in poisonings with heavy metals, cyanides, iodine and bromine salts,
as well as for allergic diseases, arthritis, neuralgia.
A CETYLCYSTEIN E
is known as mucolytic for the treatment o f diseases of the lungs and bronchi
is administered IM and orally (for intoxication)
contains one SH-group
is used in poisonings with metals and acetominophen (paracethamol). In
the last case it is used for the replacement o f depleted essentia! substance
(as glutathion substitute).
proteins
Fig. 35.1. M echanism o f action o f sulfur-containing drugs.
CHELATING A G EN TS
Chelators are organic compounds which can form stable covalent-coordinate
bonds with cationic metal ions excreted from the body (fig. 35.2).
SODIUM ED ETEA TE
• forms complex compounds with different metal ions, especially with calcium
is used in poisonings with metal salts, cardiac glycosides, as well as in
pathological calcification
can cause hypocalcemia and tethany in a quick administration.
494 PHARMACOLOGY. V. M. Bobyrov.T. 0 . Devyatkina, 0 . M. V azhnicha, V. M. Khristyuk
Fig. 35.2. Mechanism of action of chelators (by H. Lulltnann, 2000).
TETACIN-CALCIUM
is administered IV and orally (in chronic intoxication)
is used for the treatment o f poisonings with compounds o f thorium, lead,
cobalt, mercury, uranium, yttrium
may cause gastrointestinal disturbances, toxic nephrosis, a decrease in the
contents o f hemoglobin, ferrous, and vitamin B |2
is contraindicated for patients with diseases o f the liver and kidney.
PENICILLAMINE
is a synthetic preparation similar to the fragment o f penicillin’s molecule
is taken orally
forms complex compounds with metal ions (copper, lead, mercury, iron, calcium)
• is used in acute and chronic poisonings with heavy metals, as well as in
hepapocerebral dystrophy (W ilson’s disease) and some collagen diseases
(rheumatoid arthritis, scleroderma)
• may cause leukopenia, thrombocytopenia, hematuria, proteinuria, myalgia,

arthralgia, itch, utricaria, gastrointestinal disturbances.
DEFEROXAMINE
• is administered 1M, IV, orally, or used for the lavage of the stomach
binds to free ions of iron and to iron from ferrous-containing proteins (fer
ritin and hemosiderin); does not interact with iron from hemoglobin and
enzymes; does not influence the content of other ions
is used for the treatment o f acute poisoning with ferrous compounds, he-
mochomatosis, hemosiderosis
may cause skin rash, collapse (after a quick IV injection).
CH OLIN ESTERASE REACTIVATORS

Cholinesterase reactivators (alloxim, dipiroxim, isonitroside, obidoxime) are
drugs for the restoration o f acetylcholine esterase activity in acute poisonings with
organophosphate compounds (fig. 35.3).
They interact with phosphor and split o ff phosphor from the etheric site o f
cholinesterase, cause the reactivation o f enzyme.
They interact with poison and neutralize it.
They are the most effective if are used for the prophylaxis of poisoning or
at the beginning o f poisoning.
• Cholinesterase reactivators are administered together with atropine.
ANTAGONISTS OF OPIOID R ECEPTO R S

N aloxone is an antidote o f narcotic analgesics. It displaces drugs from opioid
receptors (fig. 35.4).
M -CH O LIN O BLO CKER S

Atropine is an antidote to M-cholinergic agonists. It is also used in poisonings
with anticholinesterases and morphine.
ANTICHOLINESTERASES
Neostigmine, physostigmine, galantham ine are antidotes to M-cholinoblockers
and antidepolarizing myorelaxants.
Opioid
O rg a n o p h o sp h a te s agonists
Naloxone
e.g., Paraoxon
~ ° “ CH “ “O " mH
B in d in g o f naloxone d o e s
N N
2 Cl' not activate the receptor;
OH OH therefore, naloxone re v e rse s
the effe cts o f o p io id a g o n ists ,
s u c h a s morphine a n a heroin.
Reactivator:
o b id o xim e
Fig. 35.3. Reactivation of acetylcholine Fig. 35.4. Competition between

esterase with obidoxime morphine and naloxone
(by H . Liillm ann, 2000). (by R. F in k el e t al., 2000).
M ETH YLEN E BLUE

■J
is an antiseptic with the properties o f a donator and acceptor o f hydrogen
is administered IV in the form of sterile solution (C hrom osm onum )
is used for the treatment o f acute poisonings with cyanides, carbon oxide,
hydrogen sulfide. Under the conditions o f cyanide poisoning Methylenum
coeruleum converts hemoglobin into methhemoglobin which interacts with
cyanides and transforms them into non-toxic compounds.
ETHAN O L
is an antidote to m ethyl alcohol
replaces methanol in metabolic systems and in such a way prevents methy-

laldehyde forming.
POTASSIUM PER M AN GAN ATE

is an antiseptic from oxidazers group
is an antidote in poisonings with morphine, some alkaloids, and phosphor
is used for the lavage o f the stomach as 0,1-0,5% solution
* is not effective in poisonings with atropine, cocaine, and barbiturates.
ACTIVATED C H A R C O A L
is an adsorbent containing pores which absorb low weight molecules of
toxic agents
is taken orally in the form o f aqueous suspension or tablets (in light intoxi
cation or in chronic toxicity) |
• is an universal antidote.
SOM E INTOXICATIONS AND THEIR TREATM EN T

Acute poisoning w ith organophosphates
(irreversible anticholinesterases)
Signs:
hypersalivation, nausea, vomiting, spasm of the bronchi, then edema o f lungs,
convulsions, unconsciousness.
Em ergency help:
1. Reactivators o f cholinesterase (dipyroxim, alloxim, izonitrozin), IM
2. Atropine, IM.
Acute poisoning with ethanol

Signs:
specific odor; excitement, then sleeping and coma; hyperemia o f the face, then
paleness; a decrease in BP; suppression o f respiration; hyporeflexia; hypotermia;
involuntary urination and defecation.
Em ergency help:
1. Lavage o f the stomach with the solution o f potassium permanganate
2. Analeptics (Bemegridum)
3. Glucose, insulin, and vitamins preparations (IV)
4. Nootrops (piracetam, IV).
Acute poisoning with morphine

Signs:
sleep or unconsciousness, normal or increased reflexes, a normal muscles tone,
miosis, bradycardia, Chain-Stocks breath, the retention o f urination, a spasm o f the
intestine and bowel.
Em ergency help:
1. The lavage o f the stomach with 0,5% solution o f potassium permanganate
2. Naloxone, IV ( an antagonist o f narcotic analgesics)
3. Atropine (for a decrease in the vagal action o f morphine).
Acute poisoning w ith cardiac glycosides

Signs:
bradycardia, then tachycardia and arrhythmia (premature ventricular beats, fibr-
tillation); changes in ECG; an increase in signs o f CHF; anorexia, vomiting, nausea;
headache, fatigue, hallucination; vision disturbances (xantopsia, micro- and macropsia).
Em ergency help:
1. The abolishing o f cardiac glycoside
2. Drugs containing potassium (potassium chloride, panangin)
3. SH-group donator (Unithiolum)
4. Anti-arrhythmic agents (phenitoin, lidocaine, propranolol, an atropine for
AV block)
5. Digoxin antibodies (digibind)
6. Glucose, vitamins preparations, oxygen inhalation.
Acute poisoning w ith hypnotics (barbiturates)

Signs
sleeping, unconsciousness, hypotonia, the lowering of reflexes, the suppression
o f respiration, a decrease in BP.
Em ergency help:
1. The lavage o f the stomach
2. The alkalinization o f urine and forced diuresis
3. Hemodialysis
4. Salt purgatives (magnesium sulfate).
Acute poisoning w ith acids and alkalis

Signs:
necrosis o f the skin and mucous membranes (coagulation necrosis caused by
acid or coliquation necrosis caused by alkali); metabolic acidosis (if an acid is a
toxic agent); severe pain.
Chapter 35 P H A R M A C O T H E R A P Y O F A C U T E P O IS O N IN G S 499
Em ergency help:
1. The neutralizing o f the acid by solution o f sodium bicarbonate and the
neutralizing o f the alkali by weak solution o f the acid (acetic acid, citric
acid) on the surface o f skin
2. The lavage of the stomach with cold water
3. The administration o f covering drugs, astringents, and local anesthetics into
the stomach
4. In poisoning with acids - sodium bicarbonate (IV) for the correction o f
metabolic acidosis
5. Narcotic analgesics for a decrease in pain.
Acute poisoning with salts o f heavy metals (e.g. mercury)

Signs:
severe pains in the abdomen, vomiting and diarrhoea with admixtures o f blood,
metal aftertaste, hypersalivation, bleeding gums, 2-3 days after - acute renal failure,
hypochomic anemia, irritateability.
Emergency help:
1. The lavage of the stomach
2. The administration of activated charcoal and astringents in the stomach
3. Unithiolum, tetacin-calcium, or sodium thiosulfate
4. Atropine for a decrease in a spasm o f the GI tract
5. Morphine
6. Hemodialysis.

№ 1. All the statements regarding the treatment o f acute poisoning are correct,
except:
A. Activated charcoal binds to many toxins
B. Gastric lavage decreases the absorption o f poison
C. Potassium permanganate is used for the lavage o f the stomach
D. Apomorphine is an ideal emetic in poisonings with acids and alkalis
E. Specific antidotes are not available for all poisons.
№ 2. Deferoxamine is:
A. A sulfur-containing compound
B. An acetylcholine esterase reactivator
C. A chelating agent used in poisoning with ferrous compounds
D. An antidote in mercury poisoning

E. A drug for the treatment o f hepatocerebral dystrophy.
№ 3. The treatment o f mercury poisoning includes:

A. Deferoxamine
B. Unithiolum
C. Penicillinamine
D. Atropine
E. Hemodialysis.
№ 4. Forcsed diuresis is:

A. Specific antidote therapy
B. Realized by the hydratation and further administration o f furosemide
C. Non-specific detoxication therapy
D. Used to hasten the elimination of poison from blood through the kidney
E. Realized by the dehydratation and use o f potassium-sparing diuretics.
№ 5. A patient with symptoms of the phosphororganic poisoning was admited

to the emergency department. Which combination o f drugs must be used as fist aid?
A. Naloxone and atropine
B. Unithiolum and potassium chloride
C. Neostigmine and chlorpromazine
D. Unithiolum and EDTA
E. Alloxim and atropine.
Answers
36
Q)
5 i n GENERAL
O \ / \ / PRESCRIPTION
STRUCTURE OF PRESCRIPTION
AND MAIN RU LES OF PRESCRIBING
The prescription of medicinal preparations is a practical skill in Pharmacology.
A prescription is a written doctor’s appeal to a pharmacist about the making,
delivery and marks of medicinal form. A prescription is a juridical document for
which a doctor bears justifiable responsibility.
The com ponent parts o f the prescription (in Latin):
• In scrip tio
P rep o sitio
• D e sig n a tio m a teria ru m :
- adjuvans
- corrigens
- constituens
• S u b scrip tio
• S ig n a tu ra
• N o m e n m edici.
A prescription is written according to the current decree with an ink or ball-point
pen clearly without corrections.The names o f medicinal substances in Designatio
m ateriarum are written with a capital letter in a column in Latin and in Genitive
Case. The word “gram” is not written, it is replaced with a comma.
Basis is the main substance which removes a cause or a leading symptom of
illness;
A djuvans is an auxiliary substance which strengthens or adds the action o f the
main substance or lessen side-effects.
Corrigens improves the taste, color, or smell o f medicine. They use sugar, syrup,
essential oils as corrigens.
Constituens is a forming inert substance that gives medicine consistence and
mass.
Signature is filled in the native language o f a patient. In this part o f prescrip
tion taking a dose for one administration is shown (a tablespoon, one powder, etc.),
the time o f taking (for the night, after meal), the number o f daily takings (3 times a
day, in an hour, etc.), the way o f taking (inside, a gargle, for injections and etc.). It
is impossible to use unclear expressions: “inside”, “taking is known”.
Abbreviation in a prescription is possible according to a generally used one and
it must not attribute to the substances which have similar names. Marking the amount
o f substances which are taking in equal dose, a doctor must use the word “ana ” and
hand mark the dose only once at the last ingredient.
At the beginning o f the urgent prescription it is necessary to make a note "C ito ! ”,
“C itissim e ” o r “Statim !" The recurring making of medicine according to a prescrip
tion is made with the help o f “R e p e ta tu r !”
Prescribing poison or drastic substance in the dose which exceeds the maximum
one a doctor must write out a dose o f this substance in words and put an exclama
tion mark.
Units o f mass measuring of medicinal substances which are supplied to patients
are: gram —1.0; decigram —0.1; centigram -0.01; milligram - 0.001. A prescrip
tion is written out as a special fonn. For the majority o f medicinal forms we use
“Form № 1” (fig. 36.1). Form №2 is for the prescribing o f drugs which are free o f
charge. Form №3 is for narcotic and poisonous drugs.
MEDICINMAL FORM S AND THEIR CLASSIFICATION

M edicinal fo r m is a shape o f medicine in which it is supplied to a patient.
Medicinal forms are divided into dosed and non-dosed forms. Forms for internal
use and injections are prescribed with the indication o f a dose and are called dosed
medicinal forms. Forms for external use are prescribed with the total amount o f drug
and are dosed by patient. Dosed medicinal forms are divided into non-liquid (solid),
Chapter 36. G E N E R A L P R E S C R IP T IO N 503
Code of
Hospital...
establishment
Medical documentation. Form F1
PRESCRIPTION
(adult, children's - underline that's necessary)
“ ___________________ 2009
(Patient’s family-name, initials and age)
(Physician's family -nam e and initials)
Gr. Cop. Rp.:
Gr. Cop. Rp.:
Gr. Cop. Rp.:
(Physician's signature and stamp)

Prescription is real during 10 days, 1 month - underline that's necessary
Fig. 36.1. Form №1 for prescribing of most of drugs.
liquid, soft, and sterile forms (fig. 36.2). Non-dosed medicinal forms may also be
non-liquid (solid), liquid, and soft.
NON-LIQUID DOSED MEDICINAL FORMS

N on-liquid dosed m edicinal fo r m s are represented by powders, capsules,
dragee (coated tablets), and tablets (fig. 36.3). The positive qualities are: stability, a
convenient taking, the exactness o f dosage, protection from the action o f destroying
enzymes for some forms. For dragee, it is an opportunity of incompatible medicinal
substances’ combinations. The defects are: a slow action, the impossibility to prescribe
to little children, to patients in faint state, etc.
Dosed powders are non-liquid medicinal forms with the exact dosage o f the
medicine for one taking. The mass o f powders is minimum - 0.1 g, maximum - 1.0
g, average - 0.3-0.5 g.
The classification is: 1) simple powders which contain only one substance; 2)
complex powders which have two and more ingredients.
To prescribe a simple powder with the mass o f more than 0,1 are written the
name of drug, the dose, then the sentence “ D a ta le s d o s e s n u m e r o 10", and “S i g n a ”
after which there are instructions about drug taking.
Powders which have a less mass than a minimal one need the addition o f filling
(sugar, glucose) and are written in full form with the list o f all the ingredients and
indication “ M is c e lit f i a t p u l v i s ” in the subscription.
Capsules are the covers for packing powders or some liquid medicines in
them for taking inside. The rules o f the prescribing capsules differ from the rulek of
prescribing o f simple powders with the mass exceeding 0,1 only that in S u b s c r ip tio
after showing the amount o f supplying doses the name o f capsule form is written:
“in c a p s u l e s " (in c a p s .).
Tablets and dragee are industrial medicinal forms. The positive qualities of
them are: the exactness o f dosage, portability, the convenience o f preservation and
delivery. Tablets and dragee mask unpleasant taste, protect the teeth and mucous
membrane o f the oral cavity from the destruction. In dragee it is possible to combine
substances which are incompatible for different reasons (e.g. vitamins o f B complex).
Their negative quality is slow action; sometimes they don’t dissolve.
Drug -0.5 - 500 mg
Filler 30-250 mg
/Z257 O
D isintegrating 20 - 2 0 0 m g
Tablet
ablet
Capsule
Other 30-15 mg
excipients
m in 100-1000 m g max
p o ssib le tablet size Coated tablet
Fig. 36.3. N on-liquid (solid) m edicinal form s (by H. Liillm ann, 2000).
The rules oftablets prescribing are the same as the ways of prescribing capsules,
but in S u b s c r ip tio it is written “in t a b u le t ti s ” (in ta b .).
The rules o f dragee prescribing are similar to tablets prescribing, but the word
“D r a g e e ” is written before the drug’s name. In this case, there is no name o f me
dicinal form in S u b s c r ip tio .
Combined tablets and dragee with a commercial name (trade mark) are pre
scribed in another way: T a b u le tta r u m (o r D r a g e e ) , the drug’s name, the amount of
doses (n u m e r o 10), then “D a " , “S ig n a ” and instructions how to use this medicinal
form. In such prescriptions, drug’s name is given in the Nominative Case and in
inverted commas.
The main abbreviations used for prescribing of non-liquid dosed medicinal forms
are: Rp. (R ec ip e ), D. t. d. N. 1 0 (D a ta le s d o s e s n u m e r o decern); M . f p u lv . (M is c e ut
f i a t p u l v i s ) ; in c a p s (in c a p su lis ); in tab. (in ta b u le ttis ); drag, (d ra g e e ); S. (S ig n a ).
Exam ples o f prescribing o f non-liquid dosed m edicinal form s:
P o w d e r (pulvis) T a b le t (tabuletta)
1. A sim ple pow der w ith a w eight m ore than 0,1 1. Sim ple and com bined tablets
Rp.: A m idopyrini 0,25 Rp.: Reserpini 0,0001
D. t. d. N . 10. D. t. d. N .10 in tab.
S. T ake 1 pow der 3 tim es S. T ake I tablet tw ice a day.
a day. #
#
2. A powder with a weight less than 0,1 (Sugar 2. Tablets with a commercial name
should be added in the dose of 0,2-0,3) Rp.: Tab. ’’Biseptolum” N. 10
Rp.: Pyridoxini hydrochloridi 0,005 D. S. Take 2 tablets twice daily.
Acidi nicotinici 0,05 #
Riboflavini 0,01 Dragee (dragee)
Sacchari 0,2 1. Simple dragee
M. f. pulv. Rp.: Drag. Diazolini 0,05
D. t. d. N. 10. D. t. d.N.10.
S. Take 1 powder twice a day. S. Take 1 dragee 2 times a day.
# k>
#
Capsule (capsula) 2. Dragee with a commercial name
1. Capsules containing a powder Rp.: Drag.’TJndevitum” N. 10
Rp.: Rifampicini 0,15 D. S. Take 1 dragee once a day.
D. t. d. N. 10 in caps.
S. Take 1 capsule 3 times daily.
#
2. Capsules containing oil solution
Rp.: Sol. Tocopheroli acetatis
oleosae 20% - 0,5 ml
D. t. d. N. 10 in caps.
S. Take 1 capsule 2 times daily.
MEDICINAL FORMS FOR INJECTIONS

Injections may be intravenous (IV), intramuscular (1M), subcutaneous (SC),
etc. The positive qualities o f injections are: the exactness o f dosage, the quickness
o f acting, the convenience o f use for patients in a faint state (in the state o f uncon
sciousness). The negative qualities are: pain, the necessity o f sterility, the possibility
o f vessel damage, the transmission o f infection, etc.
For injections, drugs are often given as solutions and, less frequently, in crys
talline suspension for IM and SC injection. An injectable solution must be free o f
infectious agents (sterile), pyrogens (apyrogenic) and suspended matter (homogenic).
It should have the same osmotic pressure and pH as body fluids in order to avoid
tissue damage at the site o f injection.
Solutions f o r injections are preserved in an airtight glass or plastic sealed
containers (ampoules and flacons) (fig. 36.4; 36.5).
From ampoules and flacons the solution is aspirated via a needle into a syringe
(fig. 36.4). If injectable solutions are instable, ampoules or flacons contain dry sub
stances dissolved aseptically before use. The cartridge ampoule is fitted into a special
injector that enables its contents to be emptied via a needle (fig. 36.4).
l:feÉ Sterile, iso-osmolar
Ampule Cartridge
1-20ml ampule 2 ml
With and without Often with

fracture ring preservative
Fig. 36.4. Ampoules with sterile medicinal forms (by H. Liillmann, 2000).
An infusion refers to a solution being administered over an extended period

o f time (fig. 36.5). The solution for infusion must meet the same standards as the
solution for injection.
Medicinal forms for injections are o f industrial manufacture (ampoules, flacons)
and o f chem ist’s making (flacons).
M edicinal fo rm s f o r injections o f industrial m anufacture (officinal) are pre
scribed in a short form of prescription by the method o f a single dose. If a dose for
one occasion has its packing (an ampoule), in Subscriptio after the amount o f doses
“in ampu/lis"(in ampu/l.) is written.
Infusion
1 " solution
Multiple-dose
500-1000 ml
vial 50-100 ml
F ig . 36.5. F la c o n s containing sterile so lu tio n s (adapted fro m H. Liillmann, 2000).

The rules o f prescribing of the officinal sterile forms in flacons are similar, but
the name o f medicinal form is not indicated.
M e d i c i n a l f o r m s f o r i n je c ti o n s o f c h e m i s t ’s m a k i n g (m a g is tr a l) can be pre
scribed in a short as well as in a full form o f prescription. In subscription, except
usual marks, a note about medicine’s sterility must be done: “S te rilisetu r! ” (S te ril.!).
M a i n a b b re v ia tio n s'. Sol. (solutio), in am pull. (in am pullis), S te ril.! (Sterilisetur),
1M (in tra m u scu la rly), S C (su b cu ta n eo u sly), IV (in tra ven o u sly).
E x a m p le s o f p r e s c r i b in g o f t h e s te r ile m e d i c i n a l f o r m s ( a m p o u le s a n d b o ttle s ):
Ampoule (ampulla) Bottle (flacon)

Rp.: Sol. Promedoli 1 % - 1 ml Rp.: Heparini 5 ml (5000 1U)
D. t. d. N.10 in ampull. D. t. d. N,10.
S. Administer 1 ml 1M, for pain. S. IV.
# #
Rp.: Sol. Retabolili oleosae 5%~ 1 ml Rp.: Kefzoli 0,5
D. t. d. N. 5 in ampull. D. t. d.N. 10.
S. Administer 1 ml IM, once S. Dissolve, administer IM every
a month. 8 hrs.
# #
Rp.: Cordiamini 2 mi Rp.: Sol. Glucosi 5% - 200 ml
D. t. d. N. 10 in ampull. Sterif.!
S. Administer 2 ml SC. D. S. By IV infusion
#
Rp.: Cocarboxilasi 0,05
D. t. d. N. 10 in ampull.
S. Dissolve in 2 ml of solvent,
administer IM twice a day.
SOFT DOSED MEDICINAL FORMS

The application o f a drug via the rectal or vaginal route is achieved by means
o f s u p p o s ito r ie s a n d v a g in a l ta b le ts (fig. 36.6). On rectal application, absorption
into the systemic circulation may be intended. With vaginal suppositories or vaginal
tablets, the effect is generally confined to the site of application. Suppositories contain
cacao oil (O leum C acao) or some other C o n stitu e n s, which are solid at usual tem
perature, but become liquid at body temperature. The weight o f rectal suppositories
is 1,0-4,0 (the average - 3,0). The weight of vaginal suppositories is from 1,5 to 6,0
(the average weight - 4,0).
S u p p o s i t o r i e s may be prescribed in a full form, as well as in a short form. They
may be written out by the method o f a single dose, as well as by the method o f a total
dose. As a rule, a full form is used and the method o f a single dose. A short form
is suitable for suppositories o f industrial manufacture (officinal) and for combined
suppositories with commercial name.
To prescribe r e c ta l s u p p o s ito r ie s in a full form, are written the name of B a s is

and A d ju v a n s , their doses, then —”O le i C a c a o 3 , 0 ”. In subscription it should be
indicated: “M is c e u t f i a t s u p p o s ito r iu m r e c ta le . D a ta le s d o s e s n u m e r o 10. ”
<35 °C
Vaginal
tablet
Suppository
>15°C Melting point
Fig. 36.6. Suppositories as soft dosed medicinal form (by H. Liillmann, 2000).
Prescribing o f v a g in a l s u p p o s ito r ie s is similar and differs in the dose o f 01.

C acao (4,0) and the indication “in s u p p o s ito r iu m v a g in a le " .
To prescribe suppositories in a short form, “S u p p o s ito r io r u m ”, the name o f the
drug, the dose and the amount of suppositories (N. 10), are written then “D a . S i g n a ”
and instructions how to use this medication. The suppositories with a commercial
name are prescribed without the dose. The drug’s name (a trade mark) is given in
the Nominative Case with inverted commas.
M a i n a b b r e v ia tio n s ; su p p . r e d . (s u p p o s ito r iu m re c ta le ), su p p . v a g in . (s u p p o s i
to r iu m v a g in a le ), M. f . su p p . r e d . ( M is c e lit f i a t s u p p o s ito r iu m re c ta le ), M . f . su p p .
v a g in . ( M is c e u t f i a t s u p p o s ito r iu m v a g in a le ).
E x a m p le s o f s u p p o s ito r ie s p r e s c r ib in g :
Rectal suppository Vaginal suppository

(su p p o sito riu m rectale) (su p p o sito riu m vaginale)
I. A full form, the method of a single dose 1. A full form, the method of a single dose
Rp.: Digitoxini 0,00015 Rp.: Metronidazoli 0,5
01. Cacao 3,0 01. Cacao 4,0
M. f. supp. rect. M. f. supp. vagin.
D. t. d. N. 10. D. t. d. N. 10.
S. Administer rectally once a day. S. Administer vaginally twice a day.
2. A full form, the method of a total dose 2. A full form, the method of a total dose
Rp.: Digitoxini 0,0015 Rp.: Metronidazoli 5,0
01, Cacao 30,0 01. Cacao 40,0
M. f. supp. rect. N. 10. M. f. supp. vagin. N. 10.
D. S. Administer rectally once a day. D. S. Administer vaginally twice a day.
# #
3. A short form 3. A short form
Rp.: Supp. cum Digitoxino 0,00015 Rp.: Supp. cum Metronidazolo 0,5
N.10. N. 10.
D. S. Administer rectally once a day. D. S. Administer vaginally twice a day.
# #
4. Suppositories with a commercial name
Rp.: Supp. “Anaesthezolum” N 10.
D. S. Administer vaginally twice a day.
LIQUID DOSED MEDICINAL FORMS

The advantages o f liquid dosed m edicinal fo rm s are:l) they are sucked and
act quicker; 2) they are convenient for children; 3) they are suitable for prescribing
hygroscopic substances. The disadvantages are: less portability, unsteadiness, the
difficulty o f dosage.
All liquid dosed medicinal forms for taking inside are prescribed by the method
o f a total dose. This is a method when after the name o f a substance its total dose
and the whole volume o f medicine are noticed. The dose o f the medicine for one
administration (a tablespoon, 10 drops, etc.) is noticed in signature (fig. 36.7).
All liquid medicinal forms which are prescribed for taking inside and are measu
red by spoons are only prepared with distilled water.
Solution is a liquid dosed medicinal form that consists of a solvent and a soluble
substance. The concentration o f solutions prescribed in a short form can be expressed
in mass-volume correlation, in p e rc e n t, but by strong diluting it is expressed in the
ratio (1:500, 1:1000, etc).
The generally used volume units of dosage are: a tablespoon - 15 ml, a des
sertspoon - 10 ml, a teaspoon - 5 ml. Solutions can be prescribed in a short or full
form. They are prescribed for 3-4 days of the treatment in the volume o f 100-200 ml
(average - 180 ml for 12 administrations). If the solution for internal use is written
out in a short form, after "Recipe” it is indicated "Solutionis", the name o f the dis
solved substance in the Genetive Case and with the capital letter, the concentration
o f solution, its volume, “Da. Signa", and instructions about usage.
Chapter 36 G E N E R A L P R E S C R IP T IO N 511
Solutions o f drastic and poisonous substances are dosed in drops. They are
named drops fo r internal use. These medicinal forms are prescribed for 10-30
administrations (average 20 takings). Drops are made on the account that 1 ml o f
water solution has 20 drops. Drops for taking inside are prepared from poisonous or
drastic substances and are prescribed to a patient in a little amount (5-10 ml). The
total dose o f acting substance and the total amount o f solution are also calculated
proceeding from doses for one administration multiplied by the amount o f takings.
Dosage:
in drops
Dosage:
in spoon
Fig. 36.7. Dosage of liquid medicinal forms for taking inside

(adapted fr o m H . Liillm ann, 2000).
Infusions and decoctions are aqueous extractions from medicinal plants. They
are galenic preparations containing ballast substances. Infusions and decoctions are
only prescribed in a short form of prescription. Prescribing infusions and decoctions,
after "Recipe ” the name o f medicinal form is written, then the name of a plant part,
the name of a plant itself, its total dose and the volume o f fluid. A total dose is cal
culated proceeding from a dose for one administration. As infusions and decoctions
are unstable forms and even in a refrigerator they are kept not more than 3-4 days,
they are usually prescribed for 12 doses. The amount o f medicinal raw materials
and acting substances in infusion, decoctions, and mixtures are prescribed in grams.
M ixtures, mixings of medicinal and correction substances in water, infusions
or decoctions, are written in a full form o f prescription.
512 PH ARM ACO LO G Y. V. M. Bobyrov,T. 0. Devyatkina, 0, M. Vazhnicha, V. M. Khristyuk
Tinctures, liquid extracts, and neogalenic preparations are alcohol-containing

preparations from medicinal plants. They are taken by mouth and are dosed in
drops. How many drops o f such a medicinal form the patient must take inside for
one administration, so many milliliters o f tincture or extract should be prescribed.
Tinctures, liquid extracts, and neogalenic preparations are prescribed in a short form.
M a in a b b r e v i a t i o n s : S o l.(s o lu tio ), inf. (in fu sio ), d e c .(d e c o c tio ), tinct. (tin c tu ra ),
extr. (extr a c tu m ) .
Exam ples ofprescribing o f liquid dosed m edicinal form s:
Solution (solutio) T incture (tinctura)

Rp.: Sol. Natrii bromidi 3 % - 180 ml Rp.: Tinct. Valerianae 30 ml
D. S. Take 1 tablespoon 2 times a day. D. S.Take 30 drops 3 times daily.
# #
D rops for internal use Liquid extract
Rp.: Sol. Atropini sulfatis 0,1% - 10ml (extractum flu id u m )
D. S. Take 5 drops 2 times a day. Rp: Extr. Viburni fluidi 40 ml
# D. S. Take 40 drops twice a day.
Infusion (infusio) #
or decoction (decoctio) N eogalen ic preparation
Rp. Dec. cort. Quercus 10,0 -2 0 0 ml Rp: Adonisidi 20 mi
D. S. Take 1 tablespoon 2 times a day. D. S. Take 20 drops twice a day.
# #
M ixture
Rp:. Inf. herb. Thermopsidis 0,6 - 180ml
Natrii hydrocarbonatis 3,0
M. D. S. Take 1 tablespoon 2
times a day.
NON-DOSED MEDICINAL FORMS

N on-dosed m edicinal fo r m s are forms for external use. They are prescribed
without the dose. The total amount o f the drug is indicated and the patient take^ so
much medication, as it’s necessary. Non-dosed medicinal forms are divided into 3
groups: non-liquid (powders for external use, aspersions), liquid (solutions, eye
drops, drops for ear or a nose, infusions, decoctions, tinctures, liquid extracts and
mixtures for external use), soft (ointments, liniments, pastes).
The pow der f o r external use is a very fine powder ( P u lv is s u b tillis s im u s ) ,
containing only medicinal substances. Aspersion (A s p e r s io ) is a very fine powder
containing medicinal substance (or substances) and inert substances. As inert sub
stances, they use T a lc u m , Z i n c i o x y d u m , A m y lu m . Powders for external use and
aspersions are prescribed in a short form, as well as in a full form. Their amount
may be from 5,0 to 100,0. I f aspersion is prescribed in a short form, after “R p " it
is indicated " A s p e r s i o n i s ”, the name o f the drug, the percent concentration and the
total amount o f such a medicinal form.
Solutions (Solutio) for external use may be aqueous, oil, or alcohol. The amount
o f solution depends on the purpose o f its application.
A queous solutions for processing o f dental root channels, drops for eyes, nasal
drops, ear drops are prescribed in the amount o f 10-20 ml, solutions for processing
wounds - 50-500 ml, solutions for gargling - 200 ml, solutions for the lavage o f the
stomach and for disinfection - 500-1000 ml. As a rule, these solutions are prescribed
in a short form, and their concentration is expressed in percent.
Oil solutions are prescribed in the total amount o f 10,0 -100,0. We can use
“grams,” as well as “ml” to prescribe such medicinal forms. As a rule, they are pre
scribed in a short form with the term " o l e o s a ” after the name o f the drug.
The volume of alcohol solution should be less than 100 ml. More often, they are
prescribed in a short form with the word “s p i r i t u o s a ” after the medication’s name.
E ye drops are the kind of solutions for external use, but they must be sterile.
That is why eye drops are prescribed with the indication " S te r ilis e tu r ! ” or abbrevia
tion " S te r il. / ’’(fig. 36.8).
Sterile
isotonic
pH-neutral
F ig . 36.8. Eye drops and nasal drops as liquid non-dosed medicinal forms
(by II. Lullmann, 2000).
Infusions and decoctions f o r external use are always made in the correlation
o f 1:10, so they are prescribed without the indication o f the weight o f the dry me
dicinal plant. Only the total amount o f such liquid form is indicated according to the
purpose o f its application.
Tinctures and liquid extracts as non-dosed medicinal forms are prescribed in
the total amount less than 100 ml because o f alcohol contents.
M ixtures also may be prescribed for external use. In this case we use a full
form o f prescribing in which list all the ingredients o f the drug and point “M isce”.
O intm ent (Unguentum) is a soft non-dosed medicinal form. It is characterized
by plasticity and always contains medicinal substances and ointment basis (fig. 36.9).
Ointment basis is represented by different lipids (Vaselinum, Lanolinum, Adeps
suilis depuratus, etc.). Ointments may be prescribed in a short and full forms. As a
rule, it is used a short form: after “Rp. ’’ it is written “Unguenti" or the abbreviation
“Ung. ”, then the name o f the drug, the percent concentration, and the total amount
o f ointment (from 10,0 to 100,0). Combined ointments with a commercial name and
some simple officinal ointments are prescribed without their concentrations.
There are liquid ointments (liniments) and dense ointments (pastes). Linim ents
(Linimentum) are made on liquid oils (e.g. Oleum Vaselini, Oleum Persicorum, Oleum
Helianthx).They are prescribed similar to ointments.
Pastes (Pasta) contain a lot o f dry substances (more than 25%) (fig. 36.9). To
form paste such inert substances as Talcum, Zinci oxydum, etc. are added to medicinal
substances and ointment basis.
Fig. 36.9. Soft non-dosed medicinal forms (adapted from H. Lullmann, 2000).
Some combined ointments, liniments, and pastes may be prescribed in a full

form. In this case, all the ingredients o f the medicinal form are listed with the fol
lowing indication “ M is c e u t f i a t u n g u e n tu m (p a sta , lin im e n tu m ) ”.
M a in abbreviations used to prescribe non-dosed m edicinal form s are:
A s p .( A s p e r s io ) , s u b til, ( s u b tillis s im u s ) , S o l. ( S o lu tio ) , U ng. ( U n g u e n tu m ) , L in .
( L in im e n tu m ), M . f . u ng. ( M is c e u t f i a t u n g u e n tu m ), M .f . p a s t a (M is c e u t f i a t p a s ta ) ,
M . f . lin. (M is c e u t f i a t lin im e n tu m ).
Exam ples ofprescribing o f non-dosed m edicinal form s:
A pow der for external use Infusion and decoction

Rp.: Sulfadim ezini subtil. 5,0 for external use
D. S.A pply on the wound. Rp.: D ec. cort. Q uercus 200m l
# D. S. For gargling.
A spersion (aspersio) #
Rp.: Asp. A naesthesini 5% - 50,0 T incture and liquid extract
D. S. A pply on the wound. Rp.: Tinct. C alendulae 50ml
# D. S. D issolve 50 drops in
Solution for external use 100 ml o f w ater, use for gargling.
Rp.: Sol. K alii perm anganatis 0 , 1 % - 200 ml #
D. S. For gargling. Eye drops
# Rp.: Sol. A tropini sulfatis 1 % - 10 ml
Rp.: Sol. Kalii perm anganatis 0 , 5 % - 1000 ml Steril. 1
D. S. For the lavage o f the stom ach. D. S. Eye drops.
# #
Rp.: Sol,. A naesthesini oleosae 5 % - 50 ml O in tm en t (unguentum )
D. S. Oil m ucous m em brane Rp.: Ung. Prednisoloni 1 % - 10,0
o f the oral cavity D. S. A pply on the skin.
# #
Rp.: Sol. V iridis nitentis spirituosae 1 % - 10ml Rp.: Ung. “ Synalar"10,0
D. S. For the processings o f sm all D. S. A pply on the skin.
cuts o f the skin. #
# L inim ent (linim entum )
Rp.: Lin. Synthoinycini 1 0 % - 5 0 ,0
D. S. A pply on the w ound.
#
P aste (pasta)
Rp.: Pastae Z inci 10,0
D. S. A pply on the injured skin.
O f course, nowadays there are many modern medicinal forms (e.g. aerosols,
dissolved tablets, spansules, micronized forms, etc), but the forms described above
stay the most spread.
TASKS FOR SELF-CONTROL

Prescribe the following medicinal forms:
1. Powders o f Thyreoidinum (0,02). Take 1 powder 3 times a day.
2. Tablets o f Pentoxylum (0,2). Take 1 tablet 3 times daily.
3. Tablets “Ascorutinum” . Take 1 tablet twice a day.
4. Capsules o f Celecoxibum (0,1.). Take 1 capsule 3 times daily.
5. Dragee o f Aminazinum (0,025). Take 1 dragee 2 times a day.
6. 5% solution o f Natrii salicylas for internal use. Take 1 tablespoon 3 times a day.
7. 4 % solution o f Dibazolum as drops for internal use. Take 10 drops 2 times
a day.
8. Tincture o f Arnica. Take 30 drops 3 times daily.
9. Ampoules each containing 1 ml o f 50% solution of .Analginum. Administer IM.
10. Flacons each containing Insulinum in a dose o f 5 ml (1 m l- 4 0 IU). Administer
SC.
11. 200 ml o f sterile 5% solution o f Glucosum for IV infusion.
12. 10 suppositories “Betiolum”. Use 1 suppository rectally 2 times a day.
13. 3% aspersion o f Octathionum. For applying on the skin.
14. 5% ointment o f Iodoformium. For the treatment of the wound.
15. 0,5% solution o f Atropini sulfas as eye drops. Apply 2 drops into each eye.
16. 2% paste o f Acidum salicylicum. For applying on the skin.
SELEC TED R EFEREN CES 517
SELECTED REFERENCES
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8. Геортієвський В
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зі син тезувати колаген , неспособности
Пб., 1 9 9 6 .- 18 с
н е о б х ід н и й д л я п о б у д о в и
11. Клигуненко Е.Н.
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3. П репарат « П р опес» ,
песом. Гіперпроліферація епідермісу з формуванням сосочків. 15. Ф едорова Т.К.,
Інтенсивно фуксинофільний колаген в сосочковому шарі. п р и в н у т р іш н ь о м ’ я з о в о м у 16. Якушев B.C., Ли
Фарбування пікрофуксином за Ван-Гізоном. 36. х400. в в е д е н і, призводи ть до 17. Методы о п р ед е
зн и ж ен н я п р о ц е с ів ПОЛ 18. Костюк В.А., По
та а к т и в а ц ії ф е р м е н т ів
19. Кулаичев А.П. U
рер. и д о п .- М.:
АО с и с т е м и б іл ь ш в и р а з
н о м у , н іж п р и з а с т о с у в а н Т .В .З в я ги н ц є в і
ні м азі « М е ти л у р а ц и л о - Ф арм акотерап
ва». К р ім т о г о , у в о г н и щ і хронического [
ф орм ується новий кола В п атогенезе хрон
ген, що д о в о д и ть висока си е. На м одели м ест
о п т и ч н а щ іл ь н іс т ь , о д н а к д ей стви е пропеса, с
у гл и би н і дерми з б е р іг а рогатого скота. Прог
м азь «Метилурацило
ю ться г о м о г е н н і д іл я н к и
невом п р оц ессе приї
некр озу, які є ознакою
очаге на 2 1 -е сутки,
х р о н іч н о ї р а н и . зован ие толстого слс
4. П репарат « П р опе с» , на, близкого по свое
п р и п ар ав у л ь н ар н о м у вве женном ранозаживлг
д е н н і, м ає н а й б іл ь ш ви пропеса.
р азну ф арм акотерапев-
Т. V.Zvyagintse\
Рис. 8. Д ілянка рани морськоі свинки після лікування про- тичну е ф е к т и в н іс т ь , що
The pharmacot
песом, що загоїлася з наявністю значної макрофагально- п ід т в е р д ж у є н о р м а л із а ц ія
лімфоцитарної інф ільтрації в субепітеліальному шарі. wound in the e>
п р о о к си д ан тн о -а н ти о кси -
Фарбування гематоксиліном т а еозином. 36. хІОО. The pro oxydant-a
д ан тн ої систем и: зн и ж ен m odel of local skin ra
н я р ів н ів п р о д у к т ів П О Л and polypeptides con
Висновки
т а п ід в и щ е н н я а к т и в н о с ті ф ермен muscular and paravul
1. Х р о н іч н и й п е р е б іг р а н о в о г о п р о ц е
т ів А О систем и. В ід н о в л е н а ш к ір а under chronic wound
су суп р ов од ж ується а к т и в а ц іє ю oxydant-antioxydant t
має е п ід е р м іс і колаген, анало
П О Л т а з н и ж е н н я м а к т и в н о с т і ф ер epithelium with basal
г іч н и й таком у ж у ін т а к т н и х тва
ture, that confirm moi
м е н т ів А О с и с т е м и . Д е ф е к т не л із у - рин. Паравульнарне введення про
ється й н е в ід ч у ж у є т ь с я , але п р о цесу за б е з п е ч у є повне загою вання
д о в ж у є с п р и ч и н я т и м е т а б о л іч н і п о рани'*, щ о я к іс н о п е р е в и щ у є з а г о ю
руш ення. К ол аген є н екротичною в а н н я м а зз ю «М е т и л у р а ц и л о в а » т а Контактна особа:
в н у т р іш н ь о м ’ я з о в и м введенням рецептури, Харків
м асою , що доводить т а к о ж і й о го
Тел. (057) 7 0 7 -7 2
н и з ь к а о п т и ч н а щ іл ь н іс т ь . п роп есу.
1. Раны и раневая инфекция. Руководство для врачей / Под р ед. М.И.Кузина, Б.М .Костючонок,-
М.: М едицина, 1 9 9 0 .- 5 9 2 с.
2. Harding K.G., MorrisH.L., Patel G.K. //B M J .- 2 0 0 2 , - V. 3 2 4 ,- P .1 6 0 -1 6 3 .
3q Фармакологія та лікарська токсикологія, № 5-6(6-7)/2008 Фармакологія та лікар

ГГ + М & Е с'2008
Исследование проведено на половозрелых крысах-самках линии Вистар массой 200-260 г,

исследованы 3 группы животных: 1 группа - облученный контроль, 2 группа - облученные жив
получавшие альтан, 3 группа - интактный контроль. Местные лучевые повреждения моделировали пу
локального рентгеновского облучения бедра крыс в дозе 80 Гр. Условия облучения: аппарат ТУР-60 ( I :
мА, и=50 кВ, фильтр 0,3 мм, Б облучения 20 мм2). «Альтан» вводили внутрижелудочно в дозе 1 мг/кг в в
взвеси препарата в 3 % крахмальной слизи за 1 час до облучения и в течение 10 дней после облуче:
Эффективность «Альтана» оценивали по частоте возникновения, длительности течения и сро.
заживления лучевых реакций и повреждений в коже крыс, которые получали препарат, в сравнениг
облученным контролем. Кроме того, на 30-е сутки в сыворотке крови определяли показатели межфаз:
тензиометрии с помощью аппарата АОБА (Канада), используя метод висящей капли. Резулк
поверхностного натяжения предоставляли в виде тензиограмм (кривых зависимости ПН от времени 0 '
Оценивали параметры межфазной тензиометрии при больших временах жизни поверхности - ПН4 (1 —«с
УНК2 (угол наклона кривой тензиограмм), а также параметры реометрии - вязкоэластичность (Е) и в]
релаксации (Т).
Полученные результаты свидетельствуют о том, что одноразовое облучение бедра крыс у живо'
1-й группы вызывало острое лучевое повреждение кожи с развертыванием характерных клиничес
изменений. Первичная эритема развивалась через 24-48 часов после облучения у всех животных дан»
группы. Реакции сухой десквамации развивались, начиная с 6-х суток после облучения. У отдель:
животных в этот срок наблюдалось нарушение целостности кожи и участки оголенной поверх»
Развитие реакций влажной десквамации в сроки манифестации этого типа реакций приводило
формированию больших участков мокнущей поверхности кожи с образованием трещин и бурых корок
70 % животных возникали язвы, которые не заживали до конца срока наблюдения.
Исследование также показало, что запуск механизмов формирования и течение патологическо'
процесса при местных лучевых реакциях сопровождается изменениями клеточной мембраны, пораже:
которой отражается в показателях межфазной тензиометрии и реометрии. У животных с местным лучевым
облучением кожи отмечается уменьшение модуля вязкоэластичности (21,3±0,52 мН/м) в сравнении с
интактными животными (24,5±0,61 мН/м), что можно объяснить сдвигом равновесия в адсорбционном слое,
которое наступает в результате перестройки адсорбированных молекул на фоне патологического процесса.
Также были зафиксированы изменения времени релаксации (Т), характеризующего способность моносла*
восстанавливать первичное состояние, то есть отображать кинетику адсорбции из раствора и процессы
перестройки адсорбированных молекул. При этом Т в сыворотке крови значительно превышало егг
содержание в группе интактных животных (158,6±3,84 сек и 137,3±4,25 сек соответственно). Кроме тоге у
животных 1-й группы отмечалось повышение ПН4 (47,6±0,23 мН/м) и снижение УНК2(144,4± 12,81 м Н /м ':
ш) в сравнении с группой интактных животных, где эти показатели составляли 42,6±03 мН/м к
223,4±13,1 мН/м~'с~1/2.
Системное применение препарата "Альтан" снижает степень тяжести и сокращает время течек*
острых лучевых повреждений кожи в зоне облучения, способствует ускорению репаративных процессов. V
животных, получавших препарат, сокращался срок развития и снижалась частота появления сухссг
дерматита. В сравнении с животными 1-й группы в группах с применением альтана, в большинстве случал
признаки влажной десквамации выражены в меньшей степени. Под влиянием альтана восстановлен*
целостности эпителия и заживления пораженной поверхности кожи в зоне облучения наблюдалось раныш
чем у крыс контрольной группы. При определении показателей межфазной тензиометрии у облученный
животных, получавших курс терапии альтаном, наряду с улучшением клинической картины отмечалась
нормализация параметров, достигая показателей интактных животных: снижение времени релаксашр
(136,38±3,78 сек), повышение вязкоэластичности (23,3±0,78 мН/м) и УНК2 (203,8±13,72 мНЛг'с'" ~.
ПН4 составляет 45,2±0,43 мН/м.
Таким образом, лучевые реакции кожи сопровождаются изменениями показателей межфазнэ*
тензиометрии и реометрии крови, что можно использовать для интегральной оценки течения лучевые
реакций и эффективности терапии. Применение альтана в лечебно-профилактическом режиме оказывав:
корригирующее влияние на показатели межфазной тензиометрии и реометрии крови. Нормализация э т и
показателей сопоставляется с клиническими признаками местных лучевых повреждений: альта
способствовал снижению выраженности воспалительного процесса в поврежденных облучением тканях I
ускорению репаративных процессов в них.
ЛИ ТЕРА ТУРА
1. Казаков В.Н., Синяченко О.В., Игнатенко Г.А. и др. Межфазная тензиометрия биологические
жидкостей в терапии. - Донецк: Донеччина, 2003. - 584 с.
2. Барабой В.А. Растительные фенолы и здоровье человека. - М.: Наука, 1984. - 160 с.
3. Барабой В.А., Орел В.Э., Карнаух И.Н. Перекисное окисление и радиация. - К.: Наукова думка, 199
- 2 5 6 с.
4. Казаков В.Н., Синяченко О.В., Игнатенко Г.А., Бахтеева Т.Д., Лобас В.М. Физико-химически:
свойства биологических жидкостей в ревматологии. - Донецк: Донеччина, 2003. - 279 с.
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УДК 615(075)

Фармакологія : підручник/Бобирьов В. М., Дев’яткіна Т. О.,

П ідручник для студентів вищ их м едичних навчальних закладів IV рівня

P h arm acology : a textbook / Viktor M. Bobyrov, Tetyana O. Devy­

I In і, мішці. Ini -.iiiili'iils id Inflict medical e d u c a tio n a l e s ta b lis h m e n ts o f t h e 4“' level

Chapter 28. ACIDS, A LK A LIS, SALTS. EN ZY M ES AND

IDDM - insulin-dependent diabetes mellitus

MAIN CONCEPTS OF PHARMACOLOGY

ROUTS OF DRUGS ADMINISTRATION

Tablet. 1. Routs o f drugs adm inistration

Enteral routs Parenteral routs Topical application

1. Sublingual (under the tongue) 1. Injections 1. On the surface of skin

Fig. 1.2. The comparison of drug concentration in blood in different

Fig.1.3. Schematic representation of drug absorption, distribution, and elimination.

Factors influencing absorption are:

Bioavailability is the fraction o f administered drug that reaches the systemic

DRUGS TRANSPORT IN THE ORGANISM

by blood cells (e.g. antibiotics-macrolides)

Active or, Inactive

Fig. 1.6. Stages of drugs biotransformation. a

Stage I reactions are non-synthetic and include oxidation, reduction, hydrolysis.

MAIN PATHWAYS OF DRUGS EXCRETION

Hydrophilic drug ( ® ) Lipophilic drug

Renal Renal excretion

Fig. 1.8. Drugs elimination in the kidney.

TESTS FOR SELF-CONTROL

№2. In the blood plasma drugs are transported:

№4. Drugs administered by injections:

№5. Phenobarbifal is the inducer of microsomal oxidation in the liver. Warfarin is

TYPES OF DRUGS DOSES

TYPES OF DRUGS ACTION

Fig. 2.1. Schematic representation of drug-receptor relationship.

Receptors are located:

Receptors fu n ctio n s are achieved by:

Drugs interaction with receptors (fig. 2.3):

Table 2.1. Two types of drugs interaction

COMBINED ACTION OF DRUGS

Table 2.2. M ain kinds of drugs com bined action

a cancerogenous and mutagenous action as the ability to provoke the

Hist amino and other mediators

Urticaria, asthma, shock

Fig. 2.4. Allergic reaction (by H. Lttllmann, 2000).

Age of the fetus

EFFECTS OF REPEATED DOSES OF DRUGS

D rug dependence is irresistible aspiration to take the drug for euphoria or

TESTS FOR SELF-CONTROL

№ 2. The notions connected with a combined action o f medications are:

№ 3. Types o f drugs’ action are represented by:

№ 4. The true information concerning the receptor mechanism o f action is:

DRUGS INHIBITING AFFERENT INNERVATION

DRUGS FOR LOCAL ANESTHESIA

Fig. 3.1. The influence of pH on properties of local anesthetics.

Distinctive features of local anesthetics of different groups

Table 3,1. D istinguishes between the esters and the am ides

Local anesthetic Propagated

Purpose o f adrenaline addition to local anesthetics

allergic complications including anaphylaxis, collapse, hypotension, seizures (in

Fig. 3.3. Medicinal plants containing astringent substances:

TESTS FOR SELF-CONTROL

№ 2. Tannin realizes its anti-inflammatory action due to:

№ 3. Local anesthetics have the following common properties:

№4. The starch mucus realizes its action due to:

№ 5. Lidocaine was administered to the patient with ventricular tachyarrhythmia

DRUGS STIMULATING AFFERENT INNERVATION

P h arm acology : a textbook / Viktor M. Bobyrov, Tetyana O. Devy

№ 5. A patient with chronic constipation was prescribed with a synthetic laxa