6 Pharma DR Ahmed Abdelrahman

GENERAL PHARMACOLOGY 2011/2012
Pharmacology:
It is the science which deals with drugs.
Drugs:
 These are chemical agents used for:
1) Treatment (cure) of diseases.
2) Prophylaxis (prevention) of diseases as rifampicin in prophylaxis against meningitis,
aspirin in prophylaxis against thrombo-embolism, and nitrates in prophylaxis
against angina pectoris.
3) Diagnosis of diseases as radioactive iodine (I132) in diagnosis of thyroid function.
4) Prevention of pregnancy (contraception).
 Drugs "modify" an existing cell function either by stimulation (activation) or inhibition

(depression) but they do not create a new function. However; gene therapy may be
beneficial in "creating" a function as ability to secrete insulin in type I diabetes mellitus.
 Names (Nomenclature) of drugs:

1) Chemical name
2) Non-proprietary = Generic name (may be referred to as scientific name).
3) Proprietary = Commercial name (may be referred to as trade name).
 Most drugs are purchased only according to a "prescription" and are known as
"Prescription-only medication = POM" whereas few drugs are purchased without a
prescription as antipyretics (aspirin and paracetamol), drugs for common cold, and
laxatives used in treatment of constipation. These drugs are known as "Over The
Counter" drugs (OTC).
Points to discuss about drugs (Scheme):

1) Source
2) Chemistry
3) Pharmacokinetics (and Routes of Administration)
4) Pharmacodynamics
5) Pharmacotherapeutics: Indications (Therapeutic uses) and dosage
6) Adverse effects
7) Contraindications
8) Drug Interactions
2 Dr.Ahmed Abdelrahman www.medadteam.org

I- Sources of Drugs:
1) Plant sources: e.g. Atropine is obtained from Atropa belladonna and other plants,
Morphine is obtained from Papaver somniferum, Ephedrine is obtained from Ephedra
plant, etc…
2) Animal sources: e.g. animal Insulin was prepared from pigs (known as porcine insulin)
and from cattle (known as bovine insulin), Heparin (unfractionated heparin = UFH) is
obtained from the lungs and intestines of cattle and pigs. These drugs are highly
antigenic and are replaced now by human insulin and low molecular weight heparins
(LMWHs); respectively.
3) Microorganisms: Antibiotics (as penicillin G) are prepared from microorganisms as fungi
and bacteria.
4) Mineral sources: e.g. iodine and magnesium sulphate, and also radioactive isotopes as
I131 (therapeutic) and I132 (diagnostic).
5) Synthetic drugs: most drugs are chemically synthesized, e.g. Aspirin, Propranolol,
Sulphonamides, Benzodiazepines, Paracetamol, etc…
6) Biotechnology (genetic engineering): some drugs are prepared using "recombinant
DNA technology" as Human insulin, Growth hormone, recombinant tissue Plasminogen
Activator (r- tPA = Alteplase).
The main disadvantage of these drugs is their high cost (expensive).
II- Chemistry:
 Some drugs as Aspirin (Acetyl Salicylic Acid) and Barbiturates- are weak acids, whereas
others- as Ephedrine and Amphetamine- are weak bases.
 Most drugs are organic compounds but few drugs are inorganic elements as Lithium
and Iron.
 Some drugs contain a specific chemical ring, e.g. Steroid hormones as Cortisone contain
a steroid ring, and catecholamines as Adrenaline contain a catechol ring.
III- Pharmacokinetics:
The term "pharmacokinetics" describes the movement of drugs inside the body, and is
usually referred to as "what the body does to the drug".
Pharmacokinetics includes:
1) Absorption
2) Distribution
3) Metabolism = Biotransformation
4) Excretion
(N.B.: Pharmacokinetics is sometimes referred to as "absorption and fate", and
metabolism and excretion are called together "elimination" or "clearance").

IV- Pharmacodynamics:
The term pharmacodynamics is referred to as "what the drug does to the body" and it
includes:
1) Mechanism of Action:
The most important mechanism of action is on specific "receptors", but some drugs
may act on enzymes, cell membrane, DNA, chemically, physically, etc. (see later).
2) Pharmacological Actions:
The actions of the drug may be:
1) Local actions (also known as topical actions) where the drug acts at the site of
application, e.g. skin ointments and eye drops.
2) Systemic actions: the drug reaches the systemic circulation and is distributed to
different systems as CNS, CVS, respiratory system, etc.
3) Reflex actions (also called remote actions): e.g. drugs that elevate arterial blood
pressure as Noradrenaline lead to "reflex bradycardia" through vagal stimulation.
V- Indications = Therapeutic uses:

The diseases for which the drug is prescribed to treat or prevent, e.g. Aspirin is indicated in
treatment of headache and fever, and to prevent thromboembolism.
N.B.: "Pharmacotherapeutics" includes therapeutic uses and dosage of drugs.
VI- Adverse effects:

This term describes the unwanted drug effects and is sometimes referred to as "side
effects" or "toxic effects" (see later).
VII- Contraindications:
The diseases in which the drug should be avoided, e.g. Aspirin is contraindicated in peptic
ulcer.
VIII- Drug Interactions:

1) Drug-Drug interactions: when 2 or more drugs are prescribed to the patient, these
interactions may be beneficial (favorable) or harmful (unfavorable).
2) Drug-Food interactions, e.g. MAO inhibitors (used in treatment of depression) interact
with food containing tyramine as cheese and yoghurt and lead to serious and may be
fatal elevation of arterial blood pressure.
IX- Routes of Administration (see later).

Pharmacokinetics
As previously mentioned; the term "pharmacokinetics" describes the movement of drugs
inside the body, and is usually referred to as
"What the body does to the drug". Pharmacokinetics includes:
1) Absorption
2) Distribution
3) Metabolism = Biotransformation
4) Excretion
1-Absorption:
 Definition: it is the passage (transfer) of the drug from the site of administration to the
systemic circulation.
 It is obvious that absorption from any site (GIT, lung, skeletal muscles, skin, and mucous
membranes) occurs by passage of the drug across the cell membrane (which is made of
phospholipid bi-layer and contains minute water-filled channels and ion channels).
 Passage of drugs across cell membranes "transmembrane movement of drugs":
occurs by one of the following methods:
a) Passive transfer:
1) Simple diffusion (the most important method for drug absorption).
2) Filtration (important for drug excretion by the kidney).
b) Special transfer (Specialized transport):
1) Active transport.
2) Facilitated diffusion.
N.B. Active transport and facilitated diffusion are known as "carrier-mediated
transport".
3) Pinocytosis (Endocytosis or Cell drinking): it is an active process (energy-
dependent) in which the drug is "engulfed" inside the cell, e.g. absorption of
vitamin B12/ intrinsic factor complex by the ileum.

Method Characteristics Factors and forces affecting

1-Simple 1) The drug passes through the lipid 1) Lipid solubility (lipid/water or
diffusion: bi-layer of the cell membrane. oil/ water partition
2) The drug moves from the higher to coefficient): the more the
the lower concentration = along lipophilicity of the drug, the
(with) concentration gradient. more the absorption.
3) No energy is needed. 2) Degree of ionization: the
4) No carrier is needed. more the unionized (non-
5) No saturation occurs. ionized) form of the drug, the
6) No competition with other drugs more its lipid solubility and
or endogenous substances. accordingly the more its
absorption.
3) Molecular size: the smaller
the molecular size, the better
the absorption.
4) Concentration gradient: the
higher the gradient, the
higher the rate of passage of
the drug.
5) Water solubility is a must.
2-Filtration: 1) The drug passes through the 1) Water solubility.
aqueous pores (channels) in the 2) Molecular weight: the pores
cell membrane. have minute size and allow
2) The drug moves from the higher to only the passage of drugs of
the lower osmotic pressure = low molecular weight (< 500).
along (with) osmotic pressure 3) The drug must be free
gradient. (unbound to plasma
3) No energy is needed. proteins).
4) No carrier is needed. 4) Blood flow.
5) No saturation occurs. 5) Hydrostatic and osmotic
6) No competition with other drugs gradient.
or endogenous substances.
(Glomerular filtration is essential for
renal excretion of most drugs).

3-Active 1) The drug passes through the lipid

transport: bi-layer.
2) The drug moves from the lower to
the higher concentration = against
concentration gradient.
3) Energy is needed.
4) Carrier is needed.
5) Saturation occurs.
6) Competition with other drugs or
endogenous substances may
occur.
(Active transport is also required for
the renal excretion of some drugs as
penicillin and is known as "active
tubular secretion").
4-Facilitated 1) The drug passes through the lipid The drug is lipid insoluble
diffusion: bi-layer. (cannot pass by simple diffusion)
2) The drug moves from the higher and too large (cannot pass by
to the lower concentration = filtration).
along (with) concentration Example: glucose absorption.
gradient.
3) No energy is needed.
4) Carrier is needed.
5) Saturation occurs.
6) Competition with other drugs or
endogenous substances may
occur.

Drug Ionization (Effect of pH on oral absorption and renal excretion):

How much of the drug is ionized (lipid insoluble-hydrophilic-polar) and how much is
unionized (nonionized-lipid soluble-lipophilic) is determined according to the following
rules:
1) Most drugs are either weak acids as aspirin (salicylates) and phenobarbitone
(barbiturates), or weak bases as ephedrine and amphetamine.
2) Drugs are present either in an acidic medium (as the stomach which is highly acidic, or
urine which is slightly acidic), or in an alkaline medium (as the intestine).
3) The presence of an acidic drug-as aspirin- in an acidic medium-as the stomach- makes
most of the drug unionized and lipid soluble, so it will be easily absorbed by simple
diffusion.
4) The presence of an acidic drug- as aspirin- in an alkaline medium as the small intestine -
makes most of the drug ionized and lipid insoluble, and accordingly it will be poorly
absorbed (ion trapping).
5) The presence of a basic drug in an acidic medium renders most of the drug ionized and
poorly absorbed (ion trapping); whereas the presence of a basic drug in an alkaline
medium allows most of the drug to be in the unionized form and almost complete
absorption occurs.
6) Ionization Constant = Dissociation Constant=pKa: it is the pH of the medium in which
50% of the drug is ionized and 50% is unionized.
It is clear that pKa is "constant" for every drug, e.g. pKa of aspirin = 3.5. This means
that at pH 3.5, 50% of aspirin is ionized and 50% is unionized.
7) Henderson-Hasselbalch Equation: this equation clarifies the relation between pKa, pH,
and degree of drug ionization. It states that:
Un ionized form
1) pKa = pH + log (For acidic drugs)
Ionized form
Ionized form
2) pKa = pH + log (For basic drugs)
Unionized form
8) The same rules are applied to renal excretion of drugs: alkalinization of urine by
NaHCO3 enhances (increases) renal excretion of acidic drugs as aspirin because aspirin
will be mostly ionized so it will be hydrophilic and excreted not reabsorbed (ion
trapping), but if urine is made more acidic by vitamin C (ascorbic acid) or NH4Cl, most of
aspirin will be unionized and lipid soluble so it will be "reabsorbed" by renal tubules.
On the other hand, basic drugs as amphetamine and ephedrine will be more excreted
by acidification of urine.

Factors affecting (modifying) drug absorption:

The factors that influence drug absorption can be classified into factors related to the drug
and factors related to the patient.
a) Factors related to the drug:

1) Lipid solubility and lipid-water partition coefficient: the more the lipid solubility (i.e.
the higher the lipid-water partition coefficient), the better the absorption.
2) Degree of ionization: the more the unionized form of the drug, the more the lipid
solubility and hence the better the absorption.
3) Valency: ferrous salts (Fe2+) are better absorbed than ferric salts (Fe3+).
4) Chemical nature: inorganic drugs are better absorbed than organic drugs (due to
smaller molecules).
5) Pharmaceutical formulation:
 Aqueous solutions are better absorbed than suspensions.
 Drugs that are rapidly disintegrated (dissolved) in the stomach –as paracetamol-
are better absorbed than slowly disintegrated drugs as digoxin.
Important notes:
1) Quaternary ammonium drugs as Neostigmine are ionized and so poorly absorbed orally.
2) Tertiary amine drugs as Physostigmine are unionized and lipid soluble, and accordingly
are well absorbed orally.
3) Aminoglycosides-as Streptomycin-have high pKa, so they are always ionized in any
medium in the body including the alkaline medium of the intestine, and accordingly are
almost not absorbed orally.
4) Some drugs are not absorbed orally although they are unionized, e.g. Sulfaguanidine.
b) Factors related to the patient:
1) Route of administration:
 Intravenous injection (I.V.): 100% of the drug reaches the systemic circulation
almost immediately.
 Intramuscular injection (I.M.): most of the drug is rapidly absorbed due to the
high vascularity of skeletal muscles.
 Subcutaneous injection (S.C.): absorption is less than after I.M. injection because
the S.C. tissue is much less vascular than the skeletal muscles.
 Inhalation: lipid soluble drugs as inhalation general anaesthesia are rapidly and
almost completely absorbed because the alveoli have a very wide surface area
and very rich blood supply.
 Sublingual: drugs given as sublingual pellets –as nitroglycerin in treatment of
acute anginal attacks-are better and more rapidly absorbed than orally
administered drugs because they reach the systemic circulation directly and
avoid passage through GIT and the liver.

 Oral absorption is usually variable due to the effect of GIT and the liver on the
drug before reaching the systemic circulation; this is known as
"1st pass effect" (see later).
(I.V. > Inhalation > I.M. > S.C. > Intact skin).
2) Surface area of the absorbing surface: the more the surface area exposed to the
drug, the better the absorption; e.g. small intestine (about 1000 times the surface
area of the stomach due to the presence of microvilli) and lung alveoli.
3) Vascularity (blood supply) of the absorbing surface: the richer the blood supply of
the absorbing surface, the better the absorption; e.g. the small intestine and the
lung alveoli.
4) State of health of the absorbing surface: oral absorption is greatly decreased in the
presence of diseases of GIT as malabsorption.
5) State of general circulation: in cases of shock; blood flow to the subcutaneous (S.C.)
tissues is markedly reduced due to diminished tissue perfusion and sympathetic
stimulation causing vasoconstriction of subcutaneous blood vessels. That is why
drugs as morphine should be given I.V. in case of shock.
6) Specific factors: oral vitamin B12 is absorbed only in the presence of intrinsic factor
synthesized by the gastric parietal cells.
Factors affecting (modifying) oral drug absorption:
a) Factors related to the drug: see before.
b) Factors related to the patient:
1) Surface area of the absorbing surface: see before.
2) Vascularity (blood supply) of the absorbing surface: see before.
3) State of health of the absorbing surface: see before.
4) Specific factors: see before.
5) Gut motility: drugs that stimulate gut motility and accelerate gastric emptying-
known as "prokinetic drugs" as (metoclopramide) will increase oral absorption of
rapidly disintegrated drugs as paracetamol but they will decrease absorption of
slowly disintegrated drugs as digoxin. Drugs that inhibit gut motility and slow gastric
emptying as (atropine) have opposite effects.
6) Gut pH: acidic drugs as aspirin are better absorbed in acidic medium as the stomach,
whereas basic drugs as ephedrine and amphetamine are better absorbed in alkaline
medium as the intestine (why?).
7) Gut contents (food and other drugs):
 As a general rule; drugs should be given on empty stomach (before meals or 2
hours after meals) to avoid:
a) Dilution of the drug by food.
b) Competition between amino acids (from digested dietary proteins) and some
drugs as L-DOPA on the same carrier (transporter).

 Exceptionally; irritant drugs-as aspirin and other NSAIDs, and iron preparations-
should be given after meals.
 Food containing Ca2+ (as milk and dairy products), and antacids containing Al3+
and Mg2+ decrease absorption of tetracyclines due to chelation.
 Tetracyclines and tannic acid (in tea and coffee) decrease absorption of iron.
 Cholestyramine and activated charcoal decrease absorption of most drugs
(activated charcoal adsorbs drugs).
 Tannic acid in tea and coffee decreases absorption of iron.
 Grape fruit inhibits P-glycoprotein-which is responsible for reversed transport of
drugs from gut mucosa into gut lumen-and so grape fruit increases drug
absorption.
 P-glycoprotein also causes efflux of anticancer drugs as Methotrexate out of the
cancer cells. It was found that Verapamil-a calcium channel blocker-inhibits P-
glycoprotein and so it increases uptake of methotrexate
8) First pass effect (first pass metabolism or pre-systemic metabolism): orally-
administered drugs may be partially or completely metabolized while passing in GIT
(gut first pass) or the liver (hepatic first pass) before reaching the systemic
circulation.
a) Gut first pass effect:
 Some penicillins are destroyed by gastric acidity and are known as "acid-
sensitive penicillins", e.g. benzyl penicillin (penicillin G).
 Polypeptide hormones as insulin are destroyed by the digestive enzymes.
 Some drugs are metabolized by the gut mucosa as chlorpromazine and α-
methyl dopa.
b) Hepatic first pass effect (much more important than gut first pass):
 Lipophilic drugs are metabolized by the liver (see later).
 Some of these drugs are largely metabolized by first pass hepatic effect, e.g.
propranolol. Other drugs are extensively metabolized, as nitroglycerin, or
almost completely metabolized as lidocaine and natural sex hormones.
Hydrophilic drugs as Atenolol and Nadolol are minimally metabolized by the
liver.
How to avoid first pass effect ?:

1) Increase the dose of orally- administered drugs as propranolol and nitroglycerin.
2) Change the route of administration: the drug may be given I.V. as benzyl penicillin and
lidocaine, S.C. as insulin, or sublingual (S.L.) as nitroglycerin.

Bioavailability:
 Definition: it is the fraction (proportion or percentage) of the chemically unchanged
drug reaching the systemic circulation following administration by any route.
 Bioavailability after I.V. injection = 100%.
 Bioavailability is very high following administration by inhalation (inhalation general
anaesthetics).
 Bioavailability after I.M. injection is higher than after S.C. injection.
 Bioavailability after S.L. administration is higher than after oral administration
 Oral bioavailability is variable because of first pass effect, and is calculated as
follows:
AUCoral
▬▬▬▬▬ x 100
AUCIV
AUC: Area Under plasma concentration-time Curve.
 The factors affecting bioavailability are the same factors affecting absorption of
drugs (see before).
 Bioequivalence: two drugs or two forms of the same drug show bioequivalence if
they have the same bioavailability and the same rate of absorption (they reach the
peak plasma concentration at the same time).
 Therapeutic equivalence: two drugs have the same efficacy and safety.

2- Distribution:
Once the drug is absorbed from any site, i.e. it reaches the systemic circulation; it may be
distributed to the body fluids and tissues as follows:
A) Compartment Model:
The body fluids = 42 L. representing 60% of the total body weight (TBW) of an average 70
Kg. person and include: plasma (4 L.), interstitial fluid (10 L.), and intracellular fluid (28 L.).
The plasma is referred to as "intravascular compartment", whereas the plasma and the
interstitial fluid together (14 L.) are referred to as "extracellular compartment".
28 Liters
10 Liters
4 Liters
PLASMA INTERSTITIAL INTRACELLULAR

Drugs are distributed according to one of the following patterns of distribution:
1) One Compartment Model:
Drugs that are extensively bound to plasma proteins and drugs that have a very high
molecular weight as high molecular weight heparin (HMWH) and dextran (plasma
expander) can not pass through the capillary endothelium and are distributed in plasma
only = intravascular compartment = 4 L.
2) Two Compartment Model:
Drugs that are hydrophilic and with low molecular weight can pass through the
capillary endothelium but can not pass the cell membranes being lipid insoluble and
ionized-as quaternary ammonium compounds (neostigmine)-and accordingly are
distributed in 2 compartments: plasma and interstitial fluid =extracellular compartment
= 14 L.
3) Multicompartment Model:
Drugs that are of low molecular weight, non-ionized, and lipophilic are distributed in all
compartments-both extracellular and intracellular-and accordingly are distributed in
42L.
4) Special Distribution=Tissue reservoir:
Some drugs are concentrated in certain tissues, e.g. tetracyclines are concentrated in
bone and teeth (Ca2+-containing)-iodine is concentrated in thyroid tissue-thiopentone
in fatty tissues-heavy metals as lead and arsenic in hair and skin-digitalis in cardiac
muscles-thiopentone in fat-Vitamin B12 and chloroquine in the liver.

B) Binding of Drugs to Plasma Proteins:

 After reaching the systemic circulation, any drug will be found in 2 forms; the free
(unbound) form and the bound form.
Free Form Bound Form

 Diffusible.  Non-diffusible (confined to plasma).
 Active.  Inactive.
 Liable to liver metabolism.  Not liable to liver metabolism.
 Liable to renal excretion (mostly by  Not liable to renal excretion.
glomerular filtration).  Acts as a "reservoir".
 Drugs are bound reversibly mainly to albumin and to a lesser extent to globulin and α-
acid glycoprotein.
 Some drugs as aspirin and sulphonamides have a highly affinity (are highly bound) to
plasma proteins and they displace other drugs with lower affinity as digoxin,
sulphonylureas (oral hypoglycemics), and warfarin (oral anticoagulant) if administered
together, which results in increase in the free "active" form of the latter drugs and this
may lead to severe adverse (toxic) effects:
 Aspirin and sulphonamides displace digoxin leading to digitalis toxicity.
 Aspirin and sulphonamides displace sulphonylureas (as Tolbutamide) leading to
hypoglycemia.
 Aspirin and sulphonamides displace warfarin leading to bleeding.
 Sulphonamides displace bilirubin from plasma proteins, which increases free bilirubin
causing hyperbilirubinemia and may be kernicterus in neonates.
 In conditions causing "hypoalbuminemia" as in old age, liver diseases, malnutrition or

starvation; the free form of drugs as phenytoin (antiepileptic) is higher than in normal
individuals and toxic effects may occur with therapeutic doses.
 The more the bound form of the drug, the longer its duration. This is shown with some
sulphonamides.

C) Passage across Barriers:

1) Passage across blood brain barrier (B.B.B.):
 Lipid soluble unionized drugs can penetrate B.B.B. and exert C.N.S. actions, whereas
hydrophilic ionized drugs cannot pass across B.B.B. and have almost no C.N.S.
actions in normal conditions.
 Penicillins cannot penetrate normal meninges but can pass across inflamed
meninges to C.S.F. in case of meningitis (due to increased permeability), and so are
useful in treatment of meningitis.
2) Passage across placental barrier to fetus:

 Most drugs can pass across the placental barrier from the maternal circulation to
the fetus.
 Lipid soluble unionized drugs pass more easily than hydrophilic ionized drugs.
 Some drugs –as aspirin, cortisone, ACE inhibitors, benzodiazepines, phenytoin,
etc…cause fetal malformations known as "teratogenicity" or "fetotoxicity" especially
if given in early pregnancy (1st trimester).
N.B. Thalidomide (which was used as axiolytic and hypnotic) caused amelia or
phocomelia on a large number of newborn infants which was known as "Thalidomide
disaster". Recently; drugs are classified into categories: A, B, C, D, and X according to
their possible teratogenic effect.
3) Passage through breast milk:
 Most drugs can pass through breast milk to the suckling babies; some of which may
cause serious adverse effects as morphine, fluroquinolones, radioactive iodine, etc...
 Basic drugs are ionized and "trapped" in breast milk because its pH is relatively more
acidic (= 7) compared to plasma pH (= 7.4).
 Lipophilic drugs are retained in breast milk because of its rich fat content.
D) Apparent volume of distribution (Vd):

 The apparent volume of distribution (Vd) is a rough measure of drug distribution; the
larger the Vd, the more the drug distribution.
 The apparent volume of distribution is calculated in liters (or in liters /Kg.) according to
the following equation:
Amount of drug
Vd = ▬▬▬▬▬▬▬▬▬▬▬▬
Concentration in plasma
A (in mg.)
Vd = ▬▬▬▬▬▬ (A →Amount or dose of the administered drug, C →Concentration of the drug in plasma)
C (in mg. /ml)

Significance of Vd:
1) The term "apparent" indicates that it is a hypothetical - not always a true value -as in
the case of digoxin which has a Vd of 500 liters which is much higher that the total fluid
volume (42 L. in an average 70 Kg. person).
2) High Vd indicates that the drug is distributed as a multicompartment model or has high
tissue concentration (highly bound to tissue proteins). Drugs with very high Vd have
slow rate of elimination and long T1/2.
3) Low Vd indicates that the drug is retained in plasma (intravascular, one compartment
model) mostly due to high binding to plasma proteins.
4) Knowing the Vd allows the estimation of the "loading dose" which is the initial dose
required to reach a specific drug concentration, and also allows measurement of the
total amount of the drug in the body: A = Vd X C
5) Drugs with low Vd as aspirin are highly bound to plasma proteins meaning that they a
have high plasma concentration, that is why hemodialysis is useful in treatment of
acute toxicity by these drugs.
It is clear that hemodialysis is not beneficial in treatment of acute toxicity by drugs with
high Vd because they have low plasma concentration being highly distributed or highly
concentrated in tissues.

3-Metabolism=Biotransformation:
 These are chemical reactions that occur mainly in the liver.
 The aim of biotransformation reactions is to "convert lipophilic (lipid soluble) drugs into
water-soluble (hydrophilic, ionized,or polar) metabolites to be easily excreted in urine.
 It is clear that water-soluble drugs do not undergo metabolism and are excreted
"unchanged" in urine.
 On the other hand; lipophilic drugs-after filtration through the renal glomeruli-will
undergo "reabsorption" by the renal tubular cells, making renal excretion of these
drugs very slow. So, they are metabolized to be converted into water soluble form to
promote their renal excretion.
Phases of Biotransformation Reactions:

a) Phase I Reactions:
 These are "Non-Synthetic" reactions.
 The drug undergoes either: oxidation, reduction, or hydrolysis.
 Phase I reactions will result in one of the following:
1) Conversion of an active drug into an "inactive" metabolite.This is the most
common result, e.g.:
Hydrolysis
Acetylcholine ▬▬▬▬▬▬▬► choline + acetic acid
2) Conversion of an active drug into an "active" metabolite, e.g.:
oxidation
Phenacetin (active) ▬▬▬▬▬► paracetamol = acetaminophen (active).
reduction
Chloral hydrate (active) ▬▬▬▬▬▬►trichloroethanol (active).
3) Conversion of an "inactive" drug into an "active" metabolite and in this case the
parent drug is known as a "prodrug", e.g. cortisone (inactive) is changed into
cortisol=hydrocortisone (active), and enalapril(inactive) is metabolized into
enalaprilate (active).
Oxidation
Imipramine ▬▬▬▬▬► desipramine.
4) Very rarely; a toxic metabolite is formed, e.g. methyl alcohol (methanol) is
metabolized by oxidation into formaldehyde which causes permanent blindness,
being retinotoxic. (‫ اﺻﺎﺑﺔ ﻋدة اﺷﺧﺎص ﺑﺎﻟﻌﻣﻰ ﻟﺗﻧﺎول اﻟﺧﻣور اﻟﻣﻐﺷوﺷﺔ‬: ‫)إﻗرأ ﻓﻰ ﺻﻔﺣﺔ اﻟﺣوادث‬
In addition, insecticides as Parathion and Malathion are oxidized into toxic
Para oxon and Mala-oxon; respectively.

b) Phase II Reactions:
 These are "Synthetic" or "Conjugation" reactions.
 The drug or a metabolite resulting from phase I reaction is "conjugated" with an
endogenous polar compound as glucuronic acid, sulphate, glycine, acetate, glutathione
or methyl group.
 Phase II reactions mostly result in drug inactivation, with some exceptions as morphine
(active) which is partially converted into morphine 6-glucuronide (active metabolite),
and minoxidil (inactive) is conjugated into minoxidil sulphate (active).
N.B. most drugs are metabolized by phase I reactions followed by phase II reactions,
undergo phase I reaction only, or phase II reactions only. Few drugs as isoniazid is
metabolized by conjugation (phase II) followed by hydrolysis (phase I), i.e. there is
"reversal of order of the phases".
Sites of biotransformation reactions:
1) The liver: it is the main site of drug metabolism.
2) The plasma: e.g. plasma cholinesterase (pseudo cholinesterase) is responsible for
metabolism of some drugs as Succinylcholine.
3) Other sites: the lung, the kidney, the skin, and GIT.
Types of Enzymes Responsible for Biotransformation Reactions:
Microsomal Enzymes Non-Microsomal Enzymes
1) Found in smooth endoplasmic reticulum of 1) Found in the cytoplasm and
liver cells, that is why they are referred to as mitochondria of liver cells, skin, GIT,
"Hepatic" microsomal enzymes (HME). lungs, and in plasma.
2) They catalyze the following biotransformation 2) They catalyze the following

reactions: biotransformation reactions:
 Oxidation (by cytochrome P 450 =CYP450  Oxidation.
enzymes).  Reduction.
 Reduction.  Hydrolysis.
 Hydrolysis.  Conjugation except with
 Conjugation with glucuronic acid only. glucuronic acid.
3) Their activity varies with age, sex of the 3) ☻Their activity varies with age and
patients, starvation, liver diseases, and by sex, but is not affected by drugs
drugs: their activity is increased or decreased
by drugs known as HME inducers and HME
inhibitors; respectively (see later).
4) Act on lipophilic drugs. 4) Act on lipophilic and hydrophilic
drugs metabolites.

Factors Affecting Hepatic Microsomal Enzyme activity:
1) The Effect of Drugs:

 Some drugs increase the activity of hepatic microsomal enzymes (HME) and are known
as HME inducers or activators, whereas other drugs reduce or inhibit the activity of
HME and are thus called HME inhibitors.
 Examples of HME inducers: phenytoin, phenobarbitone, rifampicin, nicotine (tobacco
smoking), testosterone (androgens), carbamazepine, griseofulvin, chronic alcohol
ingestion, coffee and tea.
 Examples of HME inhibitors:
1) Direct HME inhibitors: cimetidine, chloramphenicol, contraceptive pills (containing
estrogen and/or progesterone), ketoconazole, erythromycin, fluroquinolones,
allopurinol, grape fruit, omeprazole, sulphonamides, sodium valproate, MAO
Inhibitors, isoniazid, and acute alcoholism.
2) Indirect HME inhibitors, which are either:
a) Drugs causing hepatic toxicity as carbon tetrachloride.
b) Drugs reducing hepatic blood flow as Propranolol and Cimetidine.
Importance of HME induction:

1) HME inducers increase their own metabolism (auto-induction), which may lead to
tolerance and dependence, e.g. phenobarbitone, nicotine and chronic alcoholism.
2) HME inducers increase the metabolism of other drugs given at the same time leading to
decreased activity of the other drugs. This requires increasing the dose of the other
drugs.
3) Some HME inducers as phenytoin increase the metabolism of vitamins as folic acid,
vitamin K, and vitamin D; leading to megaloblastic anemia, hemorrhage, and
osteomalacia; respectively.
4) HME inducers as phenobarbitone are used in treatment of mild hyperbilirubinemia in
neonates as they induce conjugation of bilirubin.
Importance of HME inhibitors:

Administration of HME inhibitors with some drugs – as warfarin, digitalis, oral
hypoglycemics and theophylline- may lead to increased plasma levels of such drugs even
with therapeutic doses, which may lead to "toxicity". That is why we should reduce the
dose of warfarin, digitalis, oral hypoglycemics and theophylline if given with HME
inhibitors.

2) Age:
The activity of HME is lower in extremities of age; i.e. neonates (especially if premature)
and old age, so they should be treated with lower doses than adults.
3) Sex (Gender):
Male sex hormones (androgens) act as HME inducers whereas female sex hormones
(estrogen and progesterone) act as HME inhibitors. This is an important cause why females
receive lower doses than males (of the same age and weight).
4) Pathological conditions:
Liver diseases as cirrhosis markedly reduce the activity of HME and the dose of drugs
metabolized by these enzymes should be adjusted according to liver function tests.
Cancer and starvation have the same effect on HME activity.
5) Genetic factors (Pharmacogenetics):

There is marked variation (polymorphism) in the enzyme activity among the population
which influences drug action and toxicity.
In addition, genetic abnormalities may result in defective or abnormal enzymes; e.g.
genetic defect in pseudocholinesterase enzyme greatly reduces metabolism –and
increases the action- of succinylcholine (skeletal muscle relaxant) and may lead to
"apnea". This abnormal drug response due to genetic defect is known as "idiosyncrasy".

4- Excretion:
Drugs and their metabolites are excreted by the following routes:
1-Kidney (Renal excretion):
 The most important route of drug excretion is excretion in urine.
 The drug undergoes one –or more-of the following processes in the nephrons:
1) Glomerular Filtration (passive process): the free (unbound) form of the drug is
filtered, depending on the glomerular filtration rate.
2) Tubular Reabsorption (passive process): the unionized (lipophilic) form of the drug
undergoes tubular reabsorption.
3) Tubular Secretion (active process): some drugs- as well as endogenous substances
as uric acid-are actively transported into the lumen of the proximal convoluted
tubules (PCT) of nephrons.
 There are 2 active transport systems (carriers); one for secretion of organic acidic drugs
as penicillin, thiazides, loop diuretics (frusemide), and probenecid, and the other for
secretion of organic basic drugs as digoxin, quinidine, ephedrine and amphetamine.
 Penicillin and probenecid compete for the same carrier are secreted by the same
transport system (carrier); that is why probenecid increases the duration of action of
penicillin, as probenecid will decrease tubular secretion of penicillin leading to increase
in its plasma concentration.
 The pH of urine changes the rate of urinary excretion of drugs; i.e. alkalinization of
urine by NaHCO3 increases urinary excretion of acidic drugs as aspirin and
phenobarbitone, because most of the drug will be in the ionized hydrophilic form,
which is easily excreted and not reabsorbed (ion trapping).
On the other hand; acidification of urine by ammonium chloride (NH4Cl) or vitamin C
(ascorbic acid) promotes excretion of basic drugs as amphetamine and ephedrine.
These facts are clinically useful in treatment of acute drug toxicity by increasing their
excretion in urine through changing the pH of urine.

2-GIT:
Some drugs may be excreted by:
a) Bile:
 Some drugs are excreted in bile; either as free drugs (active), as ampicillin and
rifampicin, or conjugated drugs, as morphine and phenolphthalein (a chemical
laxative).
 Ampicillin and Rifampicin are effective in treatment of GIT infections and gall
bladder infections (cholecystitis) being excreted in an active form in bile.
 Some drugs excreted by bile (as phenolphthalein and rifampicin) may be reabsorbed
from GIT undergo, i.e. undergo "entero-hepatic recycle" which prolongs the
duration of action of such drugs.
 The unabsorbed drugs are excreted in feces.
b) Saliva: e.g. morphine, iodine (which may cause a metallic taste and inflammation of the
salivary glands), aspirin, and rifampicin.
c) Stomach: morphine is partially excreted in the stomach; that is why stomach wash is
performed in case of acute morphine poisoning despite the fact that morphine is
administered intravenously.
d) Large Intestine (Stools): drugs that are poorly absorbed orally as aminoglycosides (e.g.
streptomycin) and some tetracyclines are excreted in stools.
3-Respiratory System: inhaled general anaesthetics, whether gases as nitrous oxide, or

volatile liquids as halothane, are excreted by lungs.
4-Sweat: very few drugs are excreted in sweat as rifampicin and B12.
5-Breast milk: many drugs can be excreted in breast milk and can affect suckling infants,
e.g. laxatives (as phenolphthalein), antihistaminics (in common cold medications), oral
anticoagulants (as warfarin), antibiotics (as chloramphenicol, tetracyclines and
fluroquinolones), morphine, antithyroid drugs, etc.
It is well known that basic drugs as amphetamine and morphine are "trapped" and
excreted in breast milk (see before).
N.B.
1) Rifampicin is excreted in urine, sweat, saliva, and even in tears causing orange-
red discoloration of all the fluids.
2) Sweat glands and mammary glands are called "skin glands".

Give Reason (Explain):

1. Aspirin is partially absorbed from the stomach.
2. NaHCO3 is essential in treatment of acute salicylate toxicity.
3. Acidification of urine by NH4Cl or ascorbic acid is helpful in treatment of acute
amphetamine toxicity.
4. Salicylates are better absorbed from the upper part of the small intestine than from its
terminal part.
5. In case of shock; morphine should be given I.V. and not S.C.
6. Drugs are absorbed mainly from the small intestine not from the stomach.
7. The dose of orally- administered nitroglycerin is much higher than the S.L. dose.
8. It is not advisable to prescribe aspirin to patients treated with warfarin.
9. Sulphonamides are contraindicated in late pregnancy and neonates.
10.Hemodialysis is beneficial in acute salicylate toxicity.
11.The dose of drugs metabolized by HMEs is higher in smokers than in non-smokers.
12.The dose of warfarin should be reduced in patients treated with allopurinol.
13.The dose of theophylline should be increased in patients treated with phenobarbitone.
14.Hypoglycemic coma may occur if oral hypoglycemic drugs are given with cimetidine.
15.Severe hemorrhage may occur in patients treated with warfarin and consuming grape
fruit.
Enumerate:
1) Factors affecting drug absorption.
2) Factors affecting oral absorption.
3) Factors affecting bioavailability.
4) Factors affecting drug distribution.
5) Factors affecting hepatic microsomal enzyme activity.
Define:
1) Absorption
2) Pka
3) Bioavailability
4) Vd

Routes of Drug Administration:
There are 4 main routes of drug administration:

1) Enteral route: drugs are given through GIT. It is either:
a)Oral (P.O.) b) Sublingual (S.L.) c)Rectal (P.R.).
2) Parenteral route: includes injection and S.C. implantation.
3) Inhalation: either for local action (as treatment of bronchial asthma), or for systemic
action (as inhalation general anaesthesia).
4) Topical (local): on skin and mucous membranes as eye, nose, ear, and vagina.
Route The drug Advantages Disadvantages

should be
1-Enteral: 1) Stable. 1) Easy. Not suitable for:
a)Oral 2) Not irritant. 2) Convenient. 1) Emergencies (due to
3) Absorbable (if 3) Economic. delayed onset of action).
systemic action is 4) Safe. 2) Unconscious patients (for
needed). 5) Suitable for most fear of aspiration
drugs. pneumonia).
3) Irritant drugs.
4) Unabsorbable drugs as
aminoglycosides
(streptomycin).
5) Uncooperative patients (as
children, insane patients).
6) In presence of vomiting.
7) Drugs with almost complete
first pass effect (as
lidocaine).
8) Absorption is affected by
the presence of food and
other drugs
b)Sublingual 1-Stable. 1-Rapid onset of

(S.L.): e.g. 2-Soluble in saliva. action.
nitroglycerin 3-Palatable. 2-Avoids first pass
pellets in 4-Effective in small effect.
acute anginal doses. 3-Overdose effects
attacks. can be avoided by
swallowing or
spitting.

c)Rectal: In the form of Can be used if oral 1-Psychologically inconvenient

suppository and route is ineffective as for most patients.
enema. Enema is in: 2-may cause rectal
either:1-retention Unconscious- inflammation (proctitis).
enema (MgSO4, Vomiting-Irritant 3-variable absorption
glucose,steroids) drugs-Uncooperative especially when the rectum if
2-evacuant enema patients-Drugs with full of stools.
( in constipation). extensive first pass. 4-Not suitable in diarrhea.
2-Injection: All drugs should be

sterile and pyrogen-
free.
a)I.V.: 1)most drugs should 1)The most rapid 1)Allergic reactions as
(bolus or be slowly injected. route so useful in anaphylactic shock.
infusion) 2)Only aqueous emergencies. 2)Rapid injection of
solutions are allowed. 2)Achieves 100% aminophylline causes severe
bioavailability. hypotension and
3-)Useful for highly arrhythmias=velocity reaction.
irritant drugs. 3)Pyrogenic reaction may
4)Useful in occur.
unconscious 4)Thrombophlebitis.
patients. 5)Transmission of diseases as
5)Useful for drugs hepatitis B and C.
not absorbed orally. 6)Extravasation of the drug
6)Useful in vomiting. may cause necrosis (see
7)Large volumes can noradrenaline).
be given by I.V. 7)Avoid oily preparations and
infusion. suspensions to avoid
embolism.
b)I.M.: 1)Solutions. Rapid onset and high 1)Avoid highly irritant drugs (to
2)Suspensions. bioavailability. avoid inflammation).
3)Oily preparations. 2)Heparin should never be
4)Moderately irritant. given IM to avoid hematoma.
3)Pain, irritation.
4)Phenytoin and
benzodiazepines as Diazepam
strongly bind to muscle
proteins leading to irregular
absorption after IM injections.

c)S.C.: As IM. Use only non- Slower and lower Not suitable in:
irritant drugs. bioavailability than 1)Shock.
IM (less vascular). 2)irritant drugs.
3)large volumes.
3-Inhalation Gases-Volatile liquids- 1-Useful for systemic Irritation of bronchi by some

Aerosol (solution given actions as general drugs-irregular dosage.
by inhaler or anaesthesia and local
nebulizer)-finely actions as treatment
micronized powder of bronchial asthma.
(given by spinhaler). 2-Very rapid onset
and very high
bioavailability if
systemic action is
desired.
4-Topical:
A-Skin: 1-Ointments, creams, Absorption of some harmful
and powders are drugs as steroids (cortisol)
applied for local especially in children,
actions. organophosphorous
2-Transdermal compounds (in the form of
delivery system (TDS) insecticides), and nicotine (in
as transdermal workers collecting tobacco
patches which are leaves) may occur causing
applied for systemic systemic actions.
actions as
nitroglycerin. It
avoids 1st pass and
has long duration.
B-Mucous 1-Used for local Undesirable systemic actions

membranes: actions, e.g. eye may occur, e.g. timolol eye
1) Nose. drops in glaucoma. drops used in glaucoma may
2) Ear. 2-May be used for cause severe bronchospasm in
3) Eye. systemic actions as asthmatic patients.
4) Mouth. nasal vasopressin
(ADH) in treatment
of diabetes insipidus.
N.B.: Drugs given orally are liable to 1st pass metabolism, whereas drugs given S.L.,
injection, inhalation, and by TDS avoid 1st pass effect.
Skin absorption can be increased by:
1) Inunction (rubbing off oily drugs).
2) Iontophoresis (galvanic current for water soluble drugs).

Other Routes of Administration:

Other methods of injection:
1) Intra-dermal: sensitivity tests and vaccines.
2) Intra-arterial: thrombolytics (fibrinolytics), angiography and in cancer chemotherapy.
3) Intra-cardiac: adrenaline in cardiac arrest (cardiac resuscitation).
4) Intra-articular: cortisol in treatment of arthritis.
5) Intra-peritoneal: in peritoneal dialysis.
6) Intra-thecal: in spinal anaesthesia and in treatment of meningitis.
7) Intra-cameral: injection into aqueous humor.
8) Intra-osseous: injection through the shaft of long bones.
Subcutaneous implantation: e.g. contraceptives as norgestrel which is in the form of a

solid capsule (pellet) implanted under the skin, from which the hormone is released for a
long period (up to 5 years).
How to prolong the duration of action of drugs:

1) Delay absorption by:
a) Add vasoconstrictors as adrenaline to local anaesthesia.
b) Add oil to the drug (as vasopressin).
c) Add gelatin to heparin.
d) Use suspensions as protamine zinc insulin.
e) S.C. implants as contraceptives (norgestrel).
f) Use long-acting preparations as sustained release (SR) preparations, also known as
controlled release (CR) and timed-release (TR) preparations.
2) Use preparations that are highly bound to plasma proteins (long acting sulphonamides).
3) Decrease metabolism by HME inhibitors.
4) Delay renal excretion e.g. by adding probenecid to penicillin.
Fundamental Principles of Pharmacokinetics:

1) Steady State Concentration (Css):
 To achieve the desired effect of any drug an almost constant (steady) plasma
concentration should be reached and maintained, known as the "steady state
concentration" or "Css".
 The most accurate method to achieve Css is by IV infusion.
 For any routes the dose regimen is designed so that the rate of drug administration
equals the rate of drug elimination.
 For most drugs Css is reached after 4-5 half-life times (t1/2) of the drug (see later).

2) Plasma half-life =Elimination half-life (t1/2):

 It is the time needed by the body to reduce the plasma concentration of any drug by
50% (i.e. it is the time needed to eliminate 50% of the drug in plasma).
 It is constant for drugs following "first-order kinetics" but variable with few drugs
that follow "zero-order kinetics" (see later).
 Most drugs reach Css concentration after 4-5 t1/2.
 For most drugs, almost the entire drug (> 95%) is eliminated within 4-5 t1/2.
 For some drugs, the effect of the drug may be much longer than the plasma t1/2,
i.e. the biological t1/2 outlasts the plasma t1/2. Examples include the proton pump
inhibitors (PPIs as Omeprazole) which cause irreversible inhibition of H+/K+ ATPase
(proton pump), and Reserpine.
3) First order kinetics and Zero order kinetics:

Drug elimination follows one the following processes:
First order kinetics Zero order kinetics
(Linear kinetics) (Non-linear kinetics-Saturation kinetics)
1) A constant proportion (percent, fraction) 1) A constant amount (number of moles) of the
of the drug is eliminated /unit time. drug is eliminated /unit time.
2) The rate of elimination is proportional to 2) The rate of elimination is not proportional to
the drug plasma concentration. the drug plasma concentration.
3) Css (plateau) is reached after 4-5 t1/2. 3) Css is not necessarily reached after 4-5 t1/2.
4) Plasma t1/2 is constant whatever the 4) Variable plasma t1/2, it increases as the
plasma drug concentration (dose). plasma concentration (dose) increases.
5) No saturation of metabolizing enzymes or 5) Saturation of metabolizing enzymes or
carriers needed for renal excretion. carriers needed for renal excretion occurs.
6) Linear drug disappearance curves (log. 6) Non-linear drug disappearance curves (log.
Concentration-time curves). Concentration-time curves).
7) AUC is proportional to the drug plasma 7) AUC is not proportional to the drug plasma
concentration. concentration.
8) Less liable to cumulation and toxicity. 8) Cumulation occurs if the rate of drug intake
exceeds the rate of elimination and may lead
to toxicity.
9) Examples: most drugs (including small 9) Examples: large doses of aspirin, phenytoin,
doses of aspirin, phenytoin, and alcohol). and alcohol.

Pharmacodynamics
Pharmacodynamics is usually referred to as "what the drug does to the body".

It includes:
A) Mechanism of action. B) Pharmacological actions.
A) Mechanism of action of drugs:
Mechanism of Action Examples
1-Physical:
a) Adsorption: 1) Kaolin adsorbs toxins in case of diarrhea.
2) Activated charcoal adsorbs other drugs in
treatment of acute toxicity.
b) Osmosis: 1) Osmotic diuretics as mannitol.

2) Osmotic saline purgatives as magnesium sulphate
(MgSO4).
c) Demulcent: The drug forms a soothing layer that covers and

forms a protective layer on mucous membranes, e.g.
Liquorice in pharnygitis and dry cough.
d) Astringent: The drug precipitates superficial proteins to form a

protective layer, e.g. tannic acid in treatment of
gingivitis.
2-Chemical:
a) Neutralization (Chemical 1) Antacids as NaHCO3 are used to neutralize HCl in
Antagonism) cases of hyperacidity.
2) Protamine sulphate is used to neutralize heparin
(protamine sulphate is the specific heparin
antidote).
b) Chelation: 1) Desferrioxamine to chelate Fe3+ iron.

Combination of organic 2) Dimercaprol (BAL) to chelate heavy metals as
compound with a heavy metal mercury, lead, and antimony.
to form non-toxic easily 3) Sodium edentate to chelate Ca2+ in cases of
excreted complex. hypercalcemia.
4) D-Penicillamine to chelate Copper in treatment of
Wilson's disease and Copper toxicity.

3-Inhibition of cell division Cancer chemotherapy as Methotrexate and Nitrogen

(cytotoxic action): mustard.
4-Interference with normal Sulphonamides inhibit bacterial folic acid synthesis
metabolic pathway: by competition with PABA.
5- Interference with selective 1) Na+ channel blockers as lidocaine (lead to
passage of ions through ion membrane stabilization, used as local
channels: anaesthetics and antiarrhythmics).
2) Ca2+ channel blockers as verapamil which block
voltage gated Ca2+ channels, L-type (used as anti-
anginals, antiarrhythmics and antihypertensives).
6-Action on Enzymes (mostly by 1) Aspirin irreversibly inhibits cyclooxygenase (COX)
enzyme inhibition; which is either enzymes.
"reversible" or "irreversible") 2) Organophosphprous compounds irreversibly
inhibit cholinesterase enzyme.
3) Neostigmine and physostigmine inhibit reversibly
cholinesterase
4) Allopurinol inhibits reversibly xanthine oxidase
enzyme.
7-Action on Receptors: Acetylcholine (agonist) and atropine (antagonist) act
(The most important mechanism on muscarinic receptors.
of drug action). Adrenaline (agonist) and propranolol (antagonist) act
on β-receptors.
RECEPTORS:
 Receptors are specific chemo-sensitive, chemo-selective protein macromolecules
present on the cell membrane (e.g. α- and β-adrenergic receptors, and muscarinic and
nicotinic receptors), inside the cytoplasm (e.g. receptors for steroid hormones and
vitamin D), and inside the nucleus (e.g. receptors for thyroid hormones).
 Any chemical substance that has the ability to bind to a receptor is called a "ligand".
 Ligands may be: drugs, hormones, or chemical transmitters (neurotransmitters).
 The ability of the ligand to bind to the receptor is called "affinity".
 Affinity may be due to the fact that the shapes of the ligand and the receptor are
complementary (Key and Lock theory), which allows the drug to "fit" onto the receptor.

 Drugs acting on receptors are classified into:

1) AGONISTS:
 Agonists are drugs that activate (stimulate) the receptors.
 They are characterized by having:
1) Affinity.
2) Efficacy (intrinsic activity): agonists have the ability to change the activity of the cell;
either by stimulation or inhibition (e.g. adrenaline acts as an agonist on β-receptors
in the heart causing stimulation of cardiac properties as heart rate, and acts on β-
receptors in the smooth muscles of the intestine causing inhibition or relaxation).
3) Rapid rate of association and dissociation:
Association
Ka
D+R▬▬▬▬►DR complex▬▬▬►drug response
◄▬▬▬▬
Dissociation
Kd
(D: drug- R: receptor –Ka: rate of association- Kd: rate of dissociation).
 Examples of agonists: Acetylcholine-Adrenaline-Noradrenaline.

 The response (effect or action) of the agonist depends on:
1) The number of receptors occupied by the agonist: the more the number the more
the response. This is known as "occupation theory ".
2) The rate of association / dissociation of the agonist with / from the receptors: the
more rapid the rate, the more the response of the agonist. This is known as "rate
theory of Paton".
N.B.: a number of receptors remains unoccupied even with maximum response of

an agonist and are called "spare receptors".
Receptors regulation: Under normal conditions; the number of receptors is fixed. This may
vary in the following conditions:
1) Long use of an agonist leads to decrease in the number (and sensitivity) of
receptors, this is known as "down-regulation".
2) Long use of an antagonist or deficiency of an endogenous agonist as
neurotransmitters leads to increase in the number (and sensitivity) of receptors.
This is known as "up-regulation".

Dose-Response Curves of Agonists:
Graded Dose- Response Curves:

 The dose or log. dose of a drug is plotted versus response. If the dose if plotted versus
response; the curve is hyperbolic in shape, but if the log. dose is plotted versus
response, the shape of the curve becomes sigmoid.
 Efficacy = Emax: it is the maximum response obtained by the drug. Drugs with high
efficacy are known as "high ceiling" e.g. loop diuretics.
 Potency = ED50: it is defined as the dose that achieves 50% of the maximal response
(the lower the ED50 the more potent the drug).
Graded Dose-Response Curves
2-ANTAGONISTS = BLOCKERS:

Antagonists are drugs that block the receptors thus preventing the action of the agonist,
and are characterized by the following:
1) Affinity.
2) No efficacy (zero efficacy): no change in the activity of the cell in the absence of an
agonist, but they prevent the action of the agonist.
3) Slow rate of association and dissociation.
Types of Pharmacological antagonists:

1) Competitive Antagonists: there is competition between the agonist and antagonist on
the same receptor, and excess agonist can displace the antagonist. Examples: Atropine-
Propranolol-Prazosin-Curare. Competitive antagonists cause "parallel shift to the right
with same efficacy" of the log dose/ response curve of the agonist.
2) Non-competitive Antagonists: the antagonist cannot be displaced by excess agonist.
They cause "non-parallel shift to the right with reduced efficacy" of the agonist
log dose/ response curve.
Non-competitive antagonists are further subdivided into:
a) Reversible Antagonists: the effect of the antagonist is of short duration because it is
rapidly metabolized, e.g. succinylcholine (non-competitive neuro-muscular blocker).
b) Irreversible Antagonists: the effect of the antagonist is prolonged because it binds to
the receptor by a "covalent bond", and its effect is terminated by synthesis of new
receptors, e.g. phenoxybenzamine (irreversible α-blocker).
Non-Parallel shift to the right. parallel shift to the right.

Lower efficacy (Emax). same efficacy (Emax is not reduced).
Agonist after Agonist after
Non-Competitive Antagonist competitive Antagonist
Graded Dose-Response Curves following different types of Antagonists

3-PARTIAL AGONISTS (Dualists):

Few drugs act as partial agonists having the following characters:
1) Affinity.
2) Moderate efficacy (less than the agonist and higher than the antagonist).
3) Slow or moderate rate of association and dissociation (slower than the agonist).
Partial agonists are used clinically as antagonists. Examples: some
β-blockers as oxprenolol, pindolol, and acebutolol-Nicotine in large dose-Succinylcholine.
Types of Receptors and Signal-Transduction Mechanisms:
Receptors have 2 main functions; to bind ligands and to initiate a "response" or effect in
the cells by signal transduction.
There are (4) types of receptors according to the signal transduction mechanism
responsible for inducing the response of agonists:
1) Ion-channel linked receptors= Ligand-gated ion channels
They are located in the cell membrane on the gates of ion channels. Activation of this type
of receptors by specific agonists leads to change in the shape of the receptor
(conformational change) followed by opening of the gates of specific ion channels.
Examples include:
1) Nicotinic receptors (N): They are formed of 5 subunits: 2 α, 1 β, 1 γ, and 1 δ.
Activation of this receptor by acetylcholine (which binds to both α subunits) induces
opening of Na+-channels → Na+ influx and depolarization.
2) GABA receptors: There are 2 types of GABA receptors in CNS: GABAA receptors
which open Cl- channels leading to Cl- influx and hyperpolarization, and GABAB
receptors which open K+-channels also leading to K+ efflux and hyperpolarization
and may also block Ca2+-channels.
2) G-protein-linked receptors:
They are serpentine in shape, made up of 7 polypeptide loops that span the cell
membrane (7 α helical segments).
Type of G- Receptors Signal transduction
Protein
Gs 1) All β-receptors. Activation of adenyl cyclase and
2) H2-receptors. increase in c-AMP.
3) D1-receptors.
Gi 1) α2-receptors. Inhibit adenyl cyclase and
2) M2-receptors. decrease c-AMP, and may open
3) 5-HT1-receptors. K+-channels.
4) D2-receptors.
Gq 1) α1-receptors. Activation of phospholipase C
2) M1 and M3 (except on blood vessels). and increased DAG, IP3, and
3) H1-receptors (except on blood vessels). Ca2+.
4) 5HT2 receptors.

3) Tyrosine kinase-linked receptors:

Examples include: growth hormone and insulin receptors.
Insulin receptors are made up of 4 subunits (domains): 2 α subunits on the cell membrane
and 2 β subunits transfixing the cell membrane (see endocrine pharmacology).
4) DNA- linked intracellular receptors (Gene active receptors):

Steroid hormones and vitamin D receptors are found in the cytoplasm whereas thyroid
hormones receptors are present in the nucleus.
They regulate gene transcription, translation of m-RNA, and protein synthesis, that is why
the have slow onset of action (see endocrine pharmacology).
B-Pharmacological Actions:
The actions of the drug may be:
1) Local actions (also known as topical actions) where the drug acts at the site of
application, e.g. skin ointments and eye drops.
2) Systemic actions: the drug reaches the systemic circulation and is distributed to
different systems as CNS, CVS, respiratory system, etc.
3) Reflex actions (also called remote actions): e.g. drugs that elevate arterial blood
pressure as Noradrenaline lead to "reflex bradycardia" through vagal stimulation.

Dosage of Drugs (Posology):

 Therapeutic Dose: It is the dose required to achieve therapeutic effect in an adult
male of average weight (70 Kg.).
 Loading Dose: It is the dose administered at the beginning of therapy in acute
conditions as acute heart failure to reach the steady state plasma concentration (Css)
rapidly. It is usually a large dose and it may lead to toxicity if applied to drugs with
low therapeutic index as digoxin.
Loading dose (LD) = Vd X Css
 Maintenance Dose: It is dose given regularly to maintain Css and is equivalent to the
amount of drug eliminated.
Maintenance dose = clearance of the drug (Cl) X Css X Dose interval (Tm)
Maintenance dose (MD) = Cl X Css X Tm
N.B.:
1) The smaller the dose interval (Tm), the smaller the maintenance dose.
2) In case of IV infusion there is no dose interval and the maintenance dose = Infusion rate
= Cl X Css
3) Clearance (Cl): it is the volume of the body fluids cleared from the drug in a unit time,
measured in ml/ minute (the volume of body fluids from which the drug is removed by
metabolism and /or excretion in a unit time).
Clearance = constant of elimination X Vd
Cl = Kel X Vd
Cl = 0.693 X Vd
T½
 Minimal effective dose: the lowest dose required to produce a therapeutic effect.
 Maximal Tolerated Dose: It the maximum dose that can be safely administered without
inducing toxic effects.
 Median Effective Dose (ED50): It is the dose that induces a specific therapeutic effect in
50% of experimental animals.
 Median Toxic Dose (TD50): It is the dose that induces a particular toxic effect in 50% of
experimental animals.
 Median Lethal Dose (LD50): It is the dose that induces death in 50% of experimental
animals.
 Therapeutic Index: = LD50/ED50 .It is a measure of drug safety; the higher the index the
safer the drug.

Factors Modifying the Dose and Action of Drugs:

1) Age:
 Infants (younger than 2 years) and children require smaller doses than adults due to:
1) Underdevelopment of hepatic microsomal enzymes.
2) Lower level of plasma proteins and low binding capacity.
3) Reduced renal excretory function.
4) Immature B.B.B.
N.B. some drugs as digitalis are rapidly metabolized in children than in adults and
accordingly they need higher doses (children are more tolerant to digitalis than adults).
 Infant's dose is calculated according to Clark's Formula:
Infant dose = Adult dose X weight in pounds or weight in Kg
150 70
 Child dose is calculated according to Young' Formula:
Child dose =Adult dose X Age in years
Age in years +12
 Child dose can also be calculated according to Dilling's Formula:
Child dose = Adult dose X Age in years
20
 The dose can be also calculated by the percentage method:
Age Percent of Adult

Dose
1 month: 10%.
1 year: 25%.
3 years: 33%.
7 years: 50%.
12 years: 75%.
 Elderly between 60 and 70 years require 2/3 of the adult dose and those over 70 years
require 1/2 of the adult dose due to:
1) Weakness of hepatic microsomal enzymes.
2) Reduced renal excretory functions.
2) Body Weight:
 The more the body weights the higher the dose except in cases of edema or fat which
are not taken into consideration.
 In obese patients due to excessive body fat increase the dose of lipophilic drugs and
reduce that of hydrophilic drugs.

3) Body Surface Area:

This is a more accurate parameter for calculation of doses than age and body weight and it
can be obtained from specific charts.
Infant's dose = Adult dose X infant's surface area_
1.73(Adult body surface area = 1.73 m2).
4) Sex (Gender):
 Females usually require smaller doses than males of the same age because:
1) Female sex hormones are hepatic microsomal enzyme inhibitors whereas male sex
hormones act as inducers.
2) Females contain higher body fat.
 Special situations in females:
1) During menstruation avoid drugs that may cause bleeding as aspirin and castor oil.
2) During pregnancy avoid teratogenic drugs (as aspirin, cortisone, ACE inhibitors,
cyclizine, meclizine) and uterine stimulants (oxytocic drugs as ergotamine, PG
analogs as misoprostol).
3) During lactation avoid harmful drugs excreted in breast milk as chloramphenicol,
antithyroid drugs, morphine, and oral anticoagulants.
5) Route and Time of Administration:

 Oral dose is higher than parenteral and S.L. doses to compensate for first pass effect
(GIT and hepatic).
 S.C. dose is higher than I.M. due to less vascularity of subcutaneous tissue compared to
skeletal muscles.
 The route of administration affects the action of some drugs as magnesium sulphate:
 It acts as a cholagogue (in small dose) and purgative (in large dose) if given orally.
 It acts as a dehydrating agent (as in acute glaucoma) if given rectally as retention
enema.
 It acts as an anticonvulsant and skeletal muscle relaxant if given by I.V. infusion.
 Most drugs are better given orally before meals because the presence of food may
reduce absorption, but irritant drugs as NSAIDs are better given after meals.

6) Tolerance:
 Definition: failure to obtain the usual response by the usual dose.
 Types:
a) Congenital which is either:
1) Racial: Negros are tolerant to the mydriatic action of ephedrine.
2) Species: rabbits are tolerant to the systemic actions of atropine due to the
presence of atropine esterase (atropinase) in their plasma.
3) Individual: this is due to genetic variations.
b) Acquired: long use of drugs as morphine, barbiturates, nicotine, ethyl alcohol, and
amphetamine leads to acquired tolerance which is usually reversible, and may occur
to some –not all- actions of the drug (see morphine).
 Causes of acquired tolerance:
a) Pharmacokinetic causes: HME inducers as nicotine and barbiturates increase their
own metabolism.
b) Pharmacodynamic causes: long use of drugs leads to "down-regulation" of receptors
or depletion of endogenous transmitters. Animal insulin induces antibody formation
 Special types of acquired tolerance:
Tachyphylaxis: acute acquired tolerance (see effect of ephedrine on ABP).
Cross tolerance: occurs between drugs having similar effects as morhine, barbiturates,
or ethyl alcohol with general anaesthesia (all are CNS depressants).
7) Dependence:
It is either:
a) Psychic dependence = Habituation: sudden cessation of the drug does not cause
withdrawal symptoms but may cause emotional distress for a short time, e.g.
methylxanthine beverages as tea and coffee.
b) Psychic and Physical dependence = Addiction:
Sudden cessation of the drug leads to severe –and may be fatal- withdrawal symptoms
"Abstinence syndrome" which are the reverse of the drug actions, e.g. opiates
(morphine, heroin, and codeine), ethyl alcohol, barbiturates, and nicotine.
8) Supersensitivity =Intolerance:
It is an exaggerated normal drug response. It is due to upregulation of receptors, due to
inhibition of metabolizing enzymes, or due to diseases as thyrotoxicosis (see adrenaline). It
requires reduction of the dose.

9) Hypersensitivity = Allergy:
 It is an abnormal unpredictable drug response due to antigen-antibody reaction (the
drug or a metabolite acts as an antigen or binds to a hapten).
 It does not occur on the first exposure to the drug which sensitizes the patient but
occurs on subsequent exposures, and is not dose-dependent.
 Manifestations: skin rash, urticaria, photosensitivity (skin rash on exposure to sun-
light), asthma, angioneurotic edema, anaphylactic shock, bone marrow depression
(blood dyscrasias) by chloramphenicol, sulphonamides, dipyrone and thioamide
antithyroids-cholestatic hepatitis and jaundice by chlorpropamide, testosterone,
chlorpromazine, and alpha methyldopa.
 Cross allergy occurs between drugs having the same chemical structure as
sulphonamides and thiazide diuretics, or between drugs having the same mechanism of
action as aspirin and other NSAIDs in asthmatics.
10) Idiosyncracy:
It is an abnormal unpredictable drug response due to genetic defects.
Drugs Idiosyncratic reaction

Succinylcholine 1-Succinylcholine apnea in patients with
pseudocholinesterase deficiency.
2-Malignant hyperthermia.
Halothane Malignant hyperthermia.
Aspirin, Primaquine, Phenacetin, Hemolytic anemia in patients with

Sulphonamides deficiency of G-6-PD.
Isoniazid- Hydralazine Peripheral neuritis in slow acetylators.
Hydralazine SLE- like syndrome in slow acetylators.
Corticosteroids Elevate IOP and induce glaucoma
11) Pathological state:

The action of the drug occurs only in the presence of pathological conditions, e.g. aspirin
lowers high body temperature to normal but does not lower normal body temperature
(aspirin is an antipyretic not hypothermic).

12) Emotional state:

To distinguish between the real pharmacodynamic effect of a drug from the psychological
effect; a "Placebo" is used (dummy medication made of an inert substance as starch or
sugar).
13) Cumulation:
It occurs when the rate of drug administration exceeds the rate of elimination (by
metabolism and excretion), e.g. cardiac glycosides especially digitoxin, and guanethidine. It
is more liable with drugs following zero order kinetics (see later).
14) Drug-Drug Interactions (Drug Combinations):

When 2 or more drugs are administered together interactions may occur, which are either
beneficial (e.g. thiazide diuretics are combined with K+-sparing diuretics), or harmful (e.g.
loop diuretics and aminoglycosides are ototoxic drugs).
I-Pharmacoceutical interactions:
They occur before drug administration as during drug formulation (Calcium salts cause
chelation of tetracyclines in capsules) - mixing of drugs with IV fluids (Calcium salts with
NaHCO3)- mixing of drugs in the same syringe (Protamine zinc insulin with soluble insulin).
II-Pharmacokinetic interactions:
1) Absorption: antimuscarinic drugs as atropine and propantheline increase absorption of
digitalis- antacids decreases absorption of tetracyclines, digitalis and ACE inhibitors-
cholestyramine decreases absorption of any other drug if given concomitantly.
2) Distribution: a drug may displace other drugs from their plasma protein binding sites
leading to toxicity, e.g. NSAIDs as aspirin and loop diuretics as frusemide displace
warfarin causing bleeding, quinidine displaces digoxin leading to digitalis toxicity.
3) Metabolism: HME inducers (as nicotine, phenytoin, barbiturates, rifampicin, and
androgens) increase elimination of drugs metabolized by these enzymes; whereas HME
inhibitors (as cimetidine, female sex hormones, chloramphenicol, erythromycin, and
grape fruit) reduce clearance and may cause toxicity.
4) Excretion: quinidine and verapamil decrease renal excretion of digoxin, and probenecid
decreases active secretion of penicillin (prolongs the action of penicillin) and thiazides
and loop diuretics (antagonizes their diuretic action).
III-Pharmacodynamic Interactions: may lead to:
1) Addition = Summation: the result of 2 active drugs given together equals the algebraic
sum of their individual actions (1 + 1 = 2).
2) Potentiation: the result of an active drug with an almost inactive drug is more than the
action of the active drug alone (1 + 0 › 1), e.g. caffeine and barbiturates potentiate the
analgesic effect of aspirin.
3) Synergism: the result of adding 2 active drugs is more than the algebraic sum (1 + 1 › 2),
e.g. rifampicin + isoniazid in T.B. and penicillin + aminoglycosides in serious infections.

4) Antagonism: which may be:

a) Pharmacological: agonist + antagonist; it may be competitive (as acetylcholine +
atropine, adrenaline + propranolol, noradrenaline + prazosin) or non-competitive
(noradrenaline + phenoxybenzamine).
b) Physiological: 2 different compounds act on 2 different receptors causing 2 opposing
actions as adrenaline and histamine.
c) Chemical: chemical antacids neutralize excess HCl, and protamine sulphate
neutralizes excess heparin.
5) Reversal of action: Adrenaline reversal after alpha1-blockers.
N.B.: "Drug-Food interaction": tyramine found in yoghourt and cheese leads to
hypertensive crisis in depressed patients treated by MAO inhibitors (cheese
reaction).
15) Biological variations.
Adverse Effects and Toxicity of Drugs

a) Unpredictable adverse effects:
1) Allergy. 2) Idiosyncracy.
b) Predictable adverse effects:
1. Side effect: unavoidable action of the drug not related to the dose, e.g. atropine causes
dry mouth.
2. Secondary effect: e.g. prolonged use of broad-spectrum antibiotics especially if
incompletely absorbed orally causes superinfection and vitamin B and K deficiency.
3. Overdose: e.g. hypoglycemia due to overdose of insulin.
4. Hepatotoxicity: e.g. by halothane.
5. Nephrotoxicity: e.g. by aminoglycosides.
6. Neurotoxicity = Nerve damage: e.g. ototoxicity by aminoglycosides and loop diuretics.
7. Teratogenicity.
8. Bone marrow suppression (blood dyscrasias).
9. Tolerance, dependence, and addiction.
10.Intolerance (supersensitivity).
11.Iatrogenicity: drug-induced (physician-induced) disease; e.g. aspirin causes peptic ulcer;
alpha methyldopa and reserpine cause parkinsonism.
12.Carcinogenicity: by tobacco smoking.
13.Drug interactions.

Adverse drug effects are classified into:
Type A (Predictable undesirable side effects):

Include: side effects – overdose toxicity – Supersensitivity – Secondary effects –
Cytotoxicity (hepato-, nephro-, and neuro-toxicity) – Drug interactions.
Type B (Unpredictable side effects):
Include: Hypersensitivity and idiosyncracy.
Type C (Chronic effects):
Include: Tolearnce and dependence – Iatrogenicity.
Type D (Delayed effects):
Include: Teratogenicity – Mutagenicity – Carcinogenicity.
Type E (End of use effects):
Include: rebound effect after sudden withdrawal of clonidine and beta blockers – acute
Addisonian crisis after sudden withdrawal of corticosteroids – withdrawal symptoms
(abstinence syndrome) in addicts to morphine, heroin, alcohol, barbiturates, tobacco…
Type F (Failure of therapy):
1) Primary Failure: the drug did not prove the desired therapeutic effect from the start of
treatment.
2) Secondary Failure: failure to get the desired effect after a failure to get the desired
effect after a period of adequate response.
Example: oral insulin secretagogues as Sulfonylureas in treatment of non-insulin
dependent D.M.

ANS
Autonomic Nervous System

(A.N.S.)
Index
Title Page
1. Introduction 2
2. Cholinergic agonists 18
(Parasympathomimetics)
3. Cholinergic antagonists 36
(Parasympatholytics)
4. Adrenergic agonists 48
(Sympathomimetics)
5. Adrenergic antagonists 76
(Sympatholytics)
6. Pheochromocytoma 97

ANS
Introduction to A.N.S.
 The nervous system is divided into "central" and "peripheral" nervous system. The
peripheral nervous system is divided physiologically into afferent (sensory) and efferent
(motor-effector) nervous system.
 The motor nervous system can be further divided into "somatic" nervous system,
"autonomic" nervous system, and "enteric" nervous system (known as the brain of the
gut).
 The main differences between the somatic and autonomic nervous systems are:
Somatic Nervous System Autonomic Nervous System

 Controls voluntary skeletal muscles.  Controls involuntary organs.
 Somatic nerves have no ganglia.  Autonomic nerves relay in ganglia.
 Somatic nerves originate from the  Most autonomic nerves originate from
anterior horn cells of the spinal cord. the lateral horn cells of the spinal cord.
The involuntary effector organs controlled by A.N.S. are:
a) Heart: Cardiac properties include:

1) Automaticity (the ability of pacemaker cells to initiate an impulse) and rhythmicity.
2) Conductivity (the impulse is conducted in atria, AV node and bundle, and finally
ventricles).
3) Excitability.
4) Contractility.
The cardiac properties also determine the cardiac output (C.O.P.) and myocardial
oxygen requirements.
b) Smooth muscle fibers:

1) Blood vessels: especially the arterioles, which determine the total peripheral
resistance (T.P.R.) and arterial blood pressure (A.B.P.).
2) Bronchi.
3) GIT: both in the wall and sphincter.
4) Urinary bladder: both in the wall (detrusor muscle) and sphincter.
5) The uterus.
6) The male sex organs.
7) The intra-ocular muscles: dilator pupillae muscle (DPM), constrictor pupillae muscle
(CPM), and ciliary muscle.
8) Erector pili muscles.

ANS
c) Exocrine glands:
Including salivary, lacrimal, bronchial, gastric (secreting HCl), intestinal, and sweat
glands.
A.N.S is divided-both physiologically and anatomically- into two main divisions; the
sympathetic nervous system and the parasympathetic nervous system.
Character Sympathetic Nervous System Parasympathetic nervous System
(Stress: fear-fight-flight-exercise) (Rest and digest)
1) Origin From all thoracic and upper 3 lumbar From nuclei of 3rd,7th,9th and 10th
segments of spinal cord Cranial nerves and from 2nd, 3rd,
(Thoraco-lumbar outflow) and 4th sacral segments of spinal
cord (Cranio-sacral outflow)
2) Ganglia Paravertebral Terminal (very near or embedded in

the effector organ)
3) Preganglionic Short Long

Nerves
4) Postganglionic Long Short

Nerves:
5) Actions
a) C.V.S.
i. Heart
1) Automaticity Increases (accelerates heart rate= Decreases(slows heart rate=
Tachycardia= +ve chronotropic) (β1). Bradycardia= -ve chronotropic) (M2)
2) Conductivity Increases (+ve dromotropic) all Increases atrial conduction,

over the heart (β1) decreases AV conduction (M2) and
has no effect on ventricular
conduction
3) Excitability Increases (β1) Decreases atrial excitability (M2),

but no effect on ventricular
excitability
4) Contractility Increases (+ve inotropic) (β1) Decreases atrial contractility (M2)

but has no effect on ventricular
contractility

ANS
5) Cardiac output Increases Decreases
6) Myocardial O2 Increase. Decreases

Requirements
ii. Blood vessels Vasoconstriction: skin and No effect (most blood vessels are
(B.V.) mucous membrane B.V. (α1). non-innervated by parasympathetic
Vasodilation: skeletal muscle and nerves But contain muscarinic
coronary B.V (β2) receptors (M3)
iii. Blood Pressure Elevates B.P (hypertension) Decreases B.P. (hypotension)

(B.P.)
II-Smooth Muscle
Fibers:
Bronchi Bronchodilatation (β2) Bronchoconstriction (M3)
GIT Relaxation of the wall (β and α) and Contraction of the wall and
contraction of the sphincter (α1) relaxation of the sphincter, and
induces defecation (M)
Urinary bladder Relaxation of the wall (detrusor Contraction of the wall and
muscle) (β2) and contraction of the relaxation
Sphincter (α1) leading to retention of of the sphincter, and induces
Urine Micturition (M)
Male sex organs Ejaculation (α1) Erection (M)
Eye Active mydriasis by contracting 1-Miosis by contracting constrictor

dilator pupillae muscle (α1) pupillae muscle. 2-Accommodation
to near vision by contracting the
ciliary muscle.3-Widening of the
canal of Schlemm with subsequent
increase in drainage of aqueous
humor and decrease of intraocular
pressure (M)
No effect
III-Exocrine glands
Sweat glands Induces sweating from all types Profuse watery secretion
of sweat glands: eccrine glands
=thermotegulatory glands
present all over the body (M) and
apocrine = non-thermoregulatory
Other glands glands in palm and sole (α1)
Salivary glands Scanty viscid secretion

ANS
Important Notes:
a) Most of the involuntary organs receive "dual (double) innervation".

b) The predominant tone in these organs is usually parasympathetic; except in stress
conditions (fear, fight, exercise) when the sympathetic tone becomes
predominant.
c) Few organs have single innervation; either sympathetic only:
d) Ventricles of the heart, most blood vessels, dilator pupillae muscle, sweat glands,
adrenal medulla (which is considered as a "modified sympathetic ganglion), and
erector pili muscles, or parasympathetic only: Constrictor pupillae muscle.
e) Sympathetic nervous system acts as one unit and its activity is reinforced by the
hormones adrenaline and noradrenaline released from the adrenal medulla.
f) The activity of parasympathetic system is "discrete", i.e. localized to a particular
organ.
g) In most involuntary organs receiving dual innervation, sympathetic and
parasympathetic actions are antagonistic except the action on atrial conduction
(both systems increase atrial conduction) and the action on salivary glands (both
increase salivation). Their action on male sex organs is complementary to each
other.
h) Both systems are controlled by higher centers in the hypothalamus and cerebral
cortex.
i) The activity of A.N.S. is based on the presence of specific "neurotransmitters"
acting on specific "receptors".
1) Neurotransmitters (Chemical transmitters) in A.N.S.:
 There are 2 main neurotransmitters in A.N.S. which are: Acetylcholine and

Noradrenaline (Norepinephrine).
 Acetylcholine is synthesized, stored and released from specific neurons (fibers)
known as Cholinergic neurons; whereas noradrenaline is synthesized, stored, and
released from specific Adrenergic neurons.
a) Cholinergic neurons:
 All preganglionic neurons; both sympathetic and parasympathetic.
 All postganglionic parasympathetic neurons.
 The nerve to adrenal medulla (sympathetic).
 Exceptional postganglionic sympathetic neurons, e.g. to eccrine sweat
glands and skeletal muscle blood vessels.
 All somatic neurons (they are voluntary not autonomic fibers).
 Some areas in CNS as the basal ganglia and spinal cord.

ANS
b) Adrenergic neurons:
Include all postganglionic sympathetic neurons except those supplying sweat
glands and skeletal muscle blood vessels (which are cholinergic).
2) Steps involved in neurohumoral (neurochemical) transmission:

a) The nerve action potential (NAP) causes accumulation of vesicles (granules) at
nerve ending.
b) Influx of Ca2+ inside the nerve terminal occurs. Ca2+ interacts with specific
Vesicle Associated Membrane Proteins (VAMPs) causing release of the
neurotransmitters from the vesicles (exocytosis).
c) The neurotransmitter acts on specific postsynaptic receptors.
d) The interaction of the neurotransmitter with the receptors initiates a response in
the form of either:
e) Excitatory post-synaptic potential (EPSP) due to Na+ influx, or
f) Inhibitory post-synaptic potential (IPSP) due to K+ efflux.
g) The action of the neurotransmitter is terminated by enzymatic hydrolysis and/or
reuptake (see below).
Synthesis, Storage, Release, and Fate of Acetylcholine:.
A-Synthesis: 1) Active uptake of choline. Inhibited by hemicholinium.
2) Choline + acetyl CoA in presence of choline Inhibited by triethylcholine.

acetyl transferase (CAT) = choline acetylase
→Acetylcholine.
B-Storage: Acetylcholine is stored with protein in vesicles Inhibited by vesamicol.
(granules) of cholinergic neurons.
C-Release: See before: steps involved in neurochemical Inhibited by: local
transmission. anaesthetics as procaine-
botulinum toxin-low Ca2+-
excess Mg2+-Aminoglycosides
as streptomycin.
D-Fate:  NO uptake. Inhibited by
 Very rapid hydrolysis (metabolism) by true anticholinesterases (either
and pseudo-cholinesterases into choline reversible as physostigmine
(undergoes uptake to share in acetylcholine and neostigmine or
synthesis) and acetic acid. irreversible as
organophosphorous
compounds).

ANS
Synthesis, Storage, Release, and Fate of Noradrenaline:
A-Synthesis: 1) Phenylalanine is hydroxylated by 1) Inhibited by metyrosine

hydroxylase into tyrosine. (α-methyltyrosine).
2) Tyrosine is hydroxylated by tyrosine 2) Inhibited by α-
hydroxylase into Dopa. methyldopa and
carbidopa (peripherally
3) Dopa is decarboxylated by dopa only, not in CNS).
decarboxylase into dopamine. 3) Inhibited by reserpine.
4) Dopamine is uptaken into vesicles and is

hydroxylated by dopamine β hydroxylase
(oxidase) into noradrenaline.
B-Storage: Noradrenaline is stored in vesicles with Inhibited by reserpine.
chromogranin, ATP, RNA, and dopamine
β-hydroxylase (the only vesicular enzyme)
C-Release: See before: steps involved in neurochemical Inhibited by guanethidine.
transmission.
D-Fate: 1) The most important fate (80%)is by Inhibited by cocaine-tricyclic
"uptake" which is classified into: antidepressants-
a) Neuronal uptake (reuptake) =Uptake I: guanethidine-
noradrenaline undegoes uptake into the chlorpromazine-
adrenergic neurons and is liable to phenoxybenzamine.
enzymatic degradation by MAO.
b) Vesicular (granular) uptake=Uptake III: Inhibited by reserpine.

A part of noradrenaline undegoes
uptake into the vesicles and is protected
from degradation.
c) Extra-neuronal (tissue) uptake= Uptake Inhibited by

II: a part of noradrenaline undergoes phenoxybenzamine.
uptake by tissues and is metabolized by
COMT and MAO.
2) Metabolic (enzymatic) degradation (15%): Inhibited by MAO inhibitors

Noradrenaline is metabolized by MAO and COMT inhibitors (see CNS
(present in mitochondria of adrenergic pharmacology).
neurons, in CNS, and in liver) and COMT
(present in cytoplasm of tissues and liver).
The end product is vanilmandelic acid (VMA)
which is excreted in urine.
3) Excretion in urine unchanged (5%).

ANS
Important notes:
1. Adrenaline is synthesized from noradrenaline by phenyl-ethanolamine-N-methyl
transferase (PENMT) in CNS and adrenal medulla only, not in the adrenergic neurons
due to lack of the enzyme.
2. The fate of adrenaline is the same as noradrenaline, and accordingly VMA is the
metabolic end product of both.
3. Normal level of VMA in urine ranges between 2 and 6 mg. / 24 hours urine. Higher
levels (above 50 mg.) indicate the presence of a tumor in the adrenal medulla
known as "pheochromocytoma".
Receptors in A.N.S.
The receptors in A.N.S. are classified-according to the neurotransmitter that stimulates

them-into "Cholinergic" receptors (cholinoceptors) and "Adrenergic" receptors
(adrenoceptors).
1. Cholinergic receptors (stimulated by acetylcholine) are classified into Muscarinic (M)
and Nicotinic (N) receptors.
2. Muscarinic receptors are further subdivided into M1, M2, M3, M4, and M5,
whereas nicotinic receptors are subdivided into Nn (Ng) and Nm.
3. Adrenergic receptors (stimulated by noradrenaline) are classified into Alpha (α) and
Beta (β) receptors.
4. α-receptors are subdivided into α1 and α2, whereas β-receptors are subdivided into
β1, β2, and β3.

ANS
7) Eye → stimulation of aqueous humor formation.

8) Liver→ glycogenolysis →↑ blood sugar.
9) Skeletal muscles → glycogenolysis →↑blood lactate, tremors, ↑uptake of
K+ leading to hypokalemia.
10) Pancreas
11) B3-receptors are found in:
a) Adipose tissues
b) N.B.: presynaptic β-receptors stimulate release of noradrenaline from
adrenergic neurons.
4) Agonists:
a) Non-selective agonists: Adrenaline- isoprenaline
b) Selective β1 agonists: Dobutamine-prenalterol.
c) Selective β2 agonists: Salbutamol (albuterol)- terbutaline- ritodrine.
d) Selective β3 agonists: Octopamine.
5) Antagonists:
a) Non-selective antagonists: Propranolol- nadolol- timolol.
b) Selective β1 antagonists: Atenolol- metoprolol- esmolol.
c) Selective β2 antagonists: Butoxamine.
Receptors Sites Signal transduction Agonists Antagonists
M1 1-Gastric parietal cells Gq- Acetylcholine Atropine.
↑HCl linked Pirenzepine.
2-Autonomic ganglia. PLC→↑DAG and IP3 Telenzepine.
3-C.N.S. →↑Ca2+ Dicyclomine.
M2 1-Heart: Gi-linked Acetylcholine Atropine.

↓heart rate of Gallamine.
(bradycardia) adenylcyclase→↓c-
AMP
And opening of
2Presynaptic:↓release K+channels.
of acetylcholine and
noradrenaline
3-C.N.S.
M3 1-Smooth muscle Gq-linked** Acetylcholine Atropine.

fibres. 2- HHSD*.
Exocrine Glands.
3-C.N.S.
M4 C.N.S. Acetylcholine Atropine.
M5 C.N.S. Acetylcholine Atropine.

ANS
HHSD: Hexa-Hydro-Sila-Difenidol.
M3 receptors in blood vessels are "non-innervated" and stimulate synthesis of nitric oxide
(NO)-which was known as endothelium-derived relaxing factor (EDRF)-causing
vasodilatation.
Receptors Sites Signal Agonists Antagonists

transduction
Nn(Ng) 1-All autonomic ganglia, Ligand-gated Acetylcholine. Ganglion blockers:

both sympathetic and ion channel: A-competitive:
parasympathetic. open Na+ Trimetaphan.
2-Adrenal medulla. channels. B-Non-competitive
3-C.N.S. (Depolarizing):
nicotine large dose.
Nm Skeletal muscle (neuro- As Nn. Acetylcholine Neuro-muscular
muscular junction=NMJ) blockers:
A-Competitive:
Curare.
B-Depolarizing:
Succinylcholine.
Receptor Sites Signal Agonists Antagonist

transduction
α1 Smooth muscle Gq-linked a) Noradrenaline.- Phentolamine.
fibres Adrenaline. Phenoxybenzamine
. PLC→↑DAG andb) Selective agonists: -Selecive antagonists
IP3→ e.g. phenylephrine. as prazosin.
2+
↑Ca
α2 1-CNS. Gi- -Noradrenaline. -Phentolamine.

2-Kidney. linked -Adrenaline. -Phenoxybenzamine
3-Pancreas. n of -Selective agonists: -Selective antagonist:
4-Platelets. adenylcyclase→ clonidine, yohimbine.
5-Adipose tissues. ↓c-AMP guanfacin,
6-Presynaptic. and opening of guanabenz,α-
K+channels. methyl
dopa.

ANS
β1 1-Heart. All β-receptors -Adrenaline. -Propranolol.

2-Kidney. are coupled -Isoprenaline. -Atenolol.
3-C.N.S. to Gs -Selective agonists -Labetalol.
4-Adipose tissue. of adenyl as Dobutamine.
cyclase→↑c-
AMP.
β2 1-Smooth muscle Adrenaline. -Propranolol.
fibers Isoprenaline. -Selective blocker:
2-Liver. Selective agonists Butoxamine.
3-Pancreas. as
4-Skeletal muscles. Salbutamol and
Terbutaline.
β3 Adipose tissues.
Pre-synaptic receptors (autoreceptors):
Action Sites Receptor

↓ Acetylcholine release from cholinergic Cholinergic neurons. 1-Presynaptic muscarinic
neurons. (mostly M2).
Adrenergic and 2-Presynaptic alpha (α2).

↓ Noradrenaline release fromadrenergic Cholinergic
neurons, neurons.
and ↓acetylcholine release from cholinergic 3-Presynaptic beta.
neurons. Adrenergic neurons.
↑ Noradrenaline release from adrenergic

neurons.

ANS
Involuntary Organ Receptors and Actions

 Heart 1-M2: ↓heart rate -
2-β1:
 Blood vessels 1-α1: V.C. (skin and mucous membrane).

2-β2: V.D. (coronaries and skeletal muscles).
3-M3: V.D. (skeletal muscle blood vessels innervated by
sympathetic "cholinergic" neurons).
 Bronchi 1-β2: bronchodilatation.

2-M3: bronchoconstriction.
 Eye 1-α1: active mydriasis (DPM).

2-α2:
3-β2 (and β1):
4-M3: miosis (CPM) – accommodation to near vision
(ciliary muscle) - ↓IOP –
5-Nm: twitches of eye lids.
 G.I.T. 1-α1: contract sphincter and relax wall.

2-α2: relax wall.
3-β2: relax wall.
4-β1: relax wall.
5-M3: contract wall and relax sphincter.
 Urinary bladder 1-α1: contract sphincter.

2-β2: relax wall (detrusor).
3-M3: contract wall and relax sphincter.
 Male sex organs 1-M3: erection.

2-α1: ejaculation.
 Uterus 1-α1: contraction.

2-β2: relaxation.
3-M3: contraction.
 Sweat glands: M 3:
Eccrine (thermoregulatory) α 1:
Apocrine (non-thermoregulatory)

ANS
DRUGS IN A.N.S.
Drugs acting on autonomic receptors are generally classified into the following groups:
1) Parasympathomimetics:
These are cholinergic agonists which cause actions similar to parasympathetic activity by
stimulation of muscarinic receptors. Some of them can also stimulate nicotinic receptors.
2) Parasympatholytics:
These are cholinergic antagonists which block muscarinic receptors. They are also known
as antimuscarinic drugs.
3) Sympathomimetics:
These are adrenergic agonists which cause actions similar to sympathetic activity by
stimulation of adrenergic receptors.
4) Sympatholytics (Sympathetic Depressants):

These are drugs that decrease sympathetic activity. Some of them act as adrenergic
receptor antagonists
5) Drugs Acting on Autonomic Ganglia:

They include ganglion stimulants and ganglion blockers.

ANS
A-Parasympathomimetics
(Cholinomimetics=Cholinergic agonists=Muscarinic agonists)
Definition: these are drugs that stimulate muscarinic receptors (± nicotinic receptors).
1) Classification:
Parasympathomimetisc are classified according to their chemical structure as well as
according to their mechanism of action.
2) A-Chemical classification:
Parasympathomimetics are classified chemically into:
a) Choline esters:
 Acetylcholine (natural).
 Methacholine. –Carbachol – Bethanechol (all are synthetic).
b) Cholinomimetic Alkaloids: include the following:
 Pilocarpine.
 Muscarine (not used as a drug).
(Cholinomimetic alkaloids are obtained from plants).
c) Anticholinesterases which are further subdivided into:

 Reversible anticholinesterases: physostigmine- neostigmine-neostigmine
substitutes as edrophonium.
 Irreversible anticholinesterases: which are chemically organic phosphoric acid
derivatives known as "organophosphorous compounds".
3) B-Classification according to the mechanism of action:

a) Direct acting drugs:
 Act as agonists on Muscarinic±Nicotinic receptors.
 They include choline esters and cholinomimetic alkaloids.
b) Indirect acting drugs:

 They do not stimulate cholinergic receptors by themselves but they inhibit
hydrolysis of endogenous acetylcholine by inhibiting cholinesterases; then the
accumulated acetylcholine stimulates Muscarinic+Nicotinic receptors.
 They include anticholinesterases –also known as "cholinesterase inhibitors"-
both reversible and irreversible.

ANS
Common muscarinic actions of parasympathomimetics:
1) C.V.S.:
a) Bradycardia, 2).
b) Vasodilatation and ↓TPR (M3).
c) ↓ABP (M2 and M3).
2) Smooth muscle fibers:

a) Miosis, contraction of ciliary muscle, ↓IOP (M3).
b) Bronchospasm (M3).
c) Contraction of wall and relaxation of sphincter of G.I.T. (M3).
d) Contraction of wall and relaxation of sphincter of urinary bladder (M3).
3) Exocrine glands:
↑ Watery secretion from lacrimal, bronchial, salivary, sweat from eccrine glands (M3)
Choline Esters:
1-Acetylcholine:
a) Source:
 Natural: present as a neurotransmitter in the cholinergic neurons (see page 4) and
in CNS.
 Synthetic.
b) Chemistry:
 Choline ester.
 Quaternary ammonium compound ( N ).
 The molecule of acetylcholine is composed of two heads: "cationic" head and
"esteratic" head.
c) Pharmacokinetics:
 Absorption: not absorbed orally, (must be given by I.V. injection when used
experimentally).
 Distribution: poorly penetrates B.B.B – distributed extracellularly.
 Fate: very rapid hydrolysis by both "true" and "pseudo" cholinesterases, so it has
a very short duration of action (transient effect).

ANS
Pseudo cholinesterase True cholinesterase

1-Present in liver and plasma. 1-Present in: cholinergic sites, CNS, RBCs.
2-Non-specific: hydrolyses acetylcholine, 2-Specific: hydrolyses only acetylcholine
succinylcholine, ester local anaesthetics as procaine. and methacholine.
3-Resynthesis occurs within 3 weeks. 3-Resynthesis occurs within 3 months.
d) Pharmacodynamics:
 Mechanism of action: direct agonist on all cholinergic receptors; both muscarinic
and nicotinic.
 Pharmacological actions:
The pharmacological actions of acetylcholine are divided into muscarinic
actions and nicotinic actions.

ANS
e) Muscarinic Actions:
1. Actions on CVS:
 Heart (M2 receptors):↓heart rate (Bradycardia) - -
- no effect on the ventricles in humans.
 Blood vessels (M3 receptors): most blood vessels do not have
parasympathetic innervation but contain M3 receptors (non-innervated M
receptors), but blood vessels of skeletal muscles contain M3-receptors
innervated by sympatheic "cholinergic" neurons. Exogenous acetylcholine and
other M3 agonists cause vasodilatation (by releasing N.O. from the
endothelium of the blood vessels).
 Arterial Blood Pressure (A.B.P):
Acetylcholine causes "hypotension" by:
1) Stimulation of M2 receptors → bradycardia and ↓C.O.P.
2) Stimulation of M3 receptors
N.B.: the hypotensive action of acetylcholine can be "reversed" (see later)
2. Actions on Smooth Muscle Fibres (M3):
1) Blood vessels: see before.
2) Bronchi: bronchoconstriction.
3) GIT: increases tone and motility (peristalsis) of the wall and relaxes the
sphincter.
4) Urinary bladder: contracts the muscles of the wall (detrusor muscle)
and relaxes the sphincter.
5) Uterus: contraction (of no clinical importance).
6) Male sex organs: erection.
7) Eye:
 Miosis: by contraction of constrictor pupillae muscle (CPM).
 Accomodation to near vision: by contraction of the ciliary muscle.
 ↑drainage of aqueous humor (by widening of spaces of Fontana in the
angle of filtration following miosis, and opening of canal of Schlemm
following contraction of the ciliary muscle) with consequent ↓ of IOP.
3. Action on exocrine glands (M3 receptors mainly):
Acetylcholine increases secretion from all exocrine glands as:
salivation (profuse watery saliva), lacrimation, bronchial secretion, sweat (from
eccrine thermoregulatory sweat glands) and HCl from gastric parietal cells (M1).

ANS
f) Nicotinic Actions:
Acetylcholine acts as a chemical transmitter on Nicotinic receptors found in
autonomic ganglia -both sympathetic and parasympathetic- and in the adrenal
medulla (Nn=Ngreceptors), and nicotinic receptors found in the neuro-muscular
junctions (NMJ) of skeletal muscles (Nm receptors).
Stimulation of these receptors leads to:
1. Transmission of nerve action potential (NAP) from pre-ganglionic to post-ganglionic

nerves and release of the chemical transmitter from post-ganglionic nerves
(acetylcholine is released from cholinergic nerves and noradrenaline from adrenergic
nerves).
2. Release of adrenaline and noradrenaline from the adrenal medulla into the blood
stream.
3. Excitation-contraction coupling of skeletal muscles.
●The nicotinic actions of exogenous acetylcholine are "masked" by its muscarinic actions
but can be demonstrated by an experiment performed on the blood pressure of an
anaesthetized cat or dog as follows:
Steps and Explanation:
1. Small dose of acetylcholine is given I.V. and causes rapid but transient hypotension due
to stimulation of M3 and M2 receptors leading to ↓TPR and
2. Atropine is injected I.V. to block all types of M receptors.
3. Small dose of acetylcholine is injected again to test the blocking action of atropine.
4. Large dose of acetylcholine is given I.V. causing stimulation of Nn receptors in
sympathetic ganglia thus releasing noradrenaline from adrenergic nerves and more
importantly stimulation of Nnreceptors in the adrenal medulla releasing adrenaline
(mainly) and noradrenaline into the blood stream leading to elevation of A.B.P.
This is known as "Acetylcholine Reversal" on A.B.P. which occurs with large doses of
acetylcholine after full atropinization.

ANS
N.B.
1. All parasympathomimetics having both muscarinic and nicotinic actions will produce
"reversal" of A.B.P.; including: Acetylcholine-Carbachol- and all Anticholinesterases.
2. All parasympathomimetics having muscarinic actions with no-or insignificant-nicotinic
actions will not cause reversal of A.B.P.; including: Methacholine-Bethanechol-and
Pilocarpine.
3. Nicotinic action of parasympathomimetics can be demonstrated by local application into
the eye leading to "twitches" of the eye lids due to stimulation of Nm receptors in the
skeletal muscles of the eye lids.
Pharmacotherapeutics=Therapeutics Uses (Indications):
Acetylcholine has no therapeutic uses because it has the following disadvantages:
1. Not effective orally.

2. Non-specific actions due to stimulation of all types of M receptors.
3. Very short duration of action due to very rapid degradation of by both true and pseudo
cholinesterases.
Synthetic Choline Esters

 They include: Methacholine – Carbachol – Bethanechol.
 They are "quaternary ammonium compounds".
 They are used clinically because they have the following advantages over acetylcholine:
1. Can be given orally due to better absorption.
2. More selective actions than acetylcholine.
3. Longer duration of action.
2-Methacholine:
a) Source: synthetic.
b) Chemistry: it is methyl acetylcholine (acetyl-β-methyl-choline) – choline ester -

quaternary ammonium.
 Absorption: incomplete oral absorption.
 Distribution: poor passage across B.B.B.
 Fate: hydrolyzed by true cholinesterase only.

ANS
 Mechanism of action: direct agonist on muscarinic receptors with almost no
nicotinic actions.
Muscarinic actions of methacholine are more selective on CVS leading to:
Bradycardia - – vasodilatation and hypotension.
Stimulation of M receptors in smooth muscles of the bronchi causes bronchospasm.
e) Therapeutic uses:
Methacholine is used nowadays in diagnosis of bronchial asthma (provocative test), it was
used in:
1. Peripheral vascular diseases as Raynaud's disease.
2. Paroxysmal atrial tachycardia (P.A.T.)
3. Diagnosis of paroxysmal type of pheochromocytoma.
3-Charbachol:
b) Chemistry: it is carbaminoyl (carbamoyl) choline – choline ester- quaternary

ammonium.
 Absorption: well absorbed orally.
 Distribution: can penetrate B.B.B.
 Fate: not hydrolyzed by cholinesterases. Excreted mostly in urine
d) Pharmacodynamics
 Mechanism of action: direct agonist on both muscarinic and nicotinic receptors.
1) Muscarinic actions of carbachol are more selective on smooth muscle fibers of GIT
(increases tone and motility),--urinary bladder (contracts the wall and relaxes
the sphincter leading to evacuation of the bladder), and the eye (miosis,
contraction of the ciliary muscle and ↓IOP).
2) Nicotinic actions: twitches of eye lids (on local application), and reversal of
hypotension into hypertension after atropine.

ANS
1. Glaucoma (eye drops).
2. Post-operative non-obstructive paralytic ileus and gastric atony =dilatation of the
stomach (orally or S.C.).
3. Post-operative and post-partum non-obstructive urine retention (orally or S.C.).
4-Bethanechol:
b) Chemistry: it is methyl carbachol.
 Absorption: well absorbed orally.
 Distribution: penetrates B.B.B.
 Fate: as carbachol.
 Mechanism of action: direct agonist on muscarinic receptors without nicotinic
actions.
 Pharmacological actions: muscarinic actions as carbachol.
1. Post-operative non-obstructive paralytic ileus and gastric atony =dilatation of the
stomach (orally or S.C.).
2. Post-operative and post-partum non-obstructive urine retention (orally or S.C.).

ANS
Adverse effects and contraindications of choline esters:
Adverse effects Contraindications

1-Bradycardia. 1-Bradycardia.
2-Slow AV conduction. 2-AV block (heart block).
3-Hypotension. 3-Hypotension.
4-Bronchospasm + 4-Bronchial asthma.
5-Stimulation of HCl secretion. 5-Peptic ulcer.
6-Choline esters that pass B.B.B. 6-Ischemic heart disease (angina pectoris) as
worsen parkinsonism. hypotension decreases coronary blood flow.
7-Thyrotoxicosis (increased atrial conduction →

atrial fibrillation.
8-IV and IM injection→severe bradycardia and

hypotension (treated by atropine).
9-Carbachol and bethanechol are contraindicated

in parkinsonism.

ANS
Acetylcholine Methacholine Carbachol Bethanechol
Source: Natural. Synthetic. Synthetic. Synthetic.
Absorption Not absorbed. Poorly absorbed. Well absorbed. Well absorbed.
Fate: Hydrolyzed by true Hydrolyzed by true Not hydrolyzed Not hydrolyzed

and pseudo enzyme only. by true or by true or
cholinesterase. pseudo. pseudo.
Duration: Very short. Longer than Long duration. Long duration.

acetylcholine.
M-Actions: Non-selective. Selective on CVS. Selective on eye, Selective on GIT

GIT, and urinary and urinary
bladder. bladder.
N-Actions: Present. Almost no action. Present. Almost no action.
Important Notes:
1. The presence of methyl group in methacholine and bethanechol causes very weak or
even loss of nicotinic action of these drugs.
2. Local instillation of carbachol causes twitches of the eye lids, whereas instillation of
bethanechol does not (Why?).
3. The hypotensive action of acetylcholine and carbachol is reversed after atropine, but
the hypotensive action of methacholine and bethanechol is abolished (absent) after
atropine.

ANS
Cholinomimetic Alkaloids:
1-Pilocarpine:
a) Source: plant origin (Pilocarpus jaborandi).
b) Chemistry:
 Alkaloid.
 Tertiary amine.
 Absorption: well absorbed orally (given also as eye drops and hair lotion).
 Distribution: passes through B.B.B.
 Fate: not metabolized by cholinesterases, partially metabolized by other enzymes
and partially excreted unchanged in urine.
 Mechanism of action: direct agonist on M receptors with no nicotinic action (no
reversal of B.P and no eye lid twitches).
 Pharmacological actions: muscarinic actions as acetylcholine, but are marked on the
smooth muscle fibres (eye, GIT, and urinary bladder), and on exocrine glands
(sweat and salivary glands).
1. Eye: miosis- contraction of the ciliary muscle- ↓IOP.
2. GIT: contraction of the wall and relaxation of sphincter.
3. Urinary bladder: contraction of the detrusor muscle of the wall and relaxation of
the sphincter leading to evacuation of the bladder.
4. Sweat glands: increases sweat secretion from eccrine (thermoregulatory sweat
glands); this action is known as "diaphoresis".
5. Salivary glands: increases salivation, an action known as "sialagogue" action.
1. Treatment of glaucoma.
2. To counteract mydriatics (used for fundus examination).
3. To cut recent fibrin adhesions between iris and lens in case of eye infections as iritis,
used alternatively with mydriatics.
4. Pilocarpine was used as diaphoretic in fever, sialagogue in dry mouth (caused by
atropine or ganglion blockers), and to promote hair growth in treatment of hair fall
(by dilatation of blood vessels of hair follicles)

ANS
2-Muscarine:
toxic alkaloid obtained from mushroom (alkaloid of toxic mushroom), not used clinically
nowadays (obsolete).
Anticholinesterases (Cholinesterase inhibitors):
 They are "indirect" cholinergic agonists that inhibit cholinesterases

endogenous acetylcholine
They are classified into:
a) Reversible anticholinesterases:
physostigmine- neostigmine-neostigmine substitutes.
 They form a loose bond with cholinesterases, thus preventing hydrolysis of

acetylcholine.
 They have short duration of action, and the enzymes rapidly regain activity to
hydrolyze acetylcholine.
 They include:
Carbamatesas physostigmine and neostigmine, which bind to both sites (anionic
and esteratic) leading to formation of "carbamylated enzyme". They are
hydrolyzed by cholinesterases (substrates for the enzymes).
Simple alcohols (quaternary ammonium alcohols) as edrophonium, which bind
only to the anionic site by electrostatic force, and are not hydrolyzed by
cholinesterases (not substrates for the enzymes).
b) Irreversible anticholinesterases:
 Chemically known as organo-phosphorous compounds.
 They bind only to the esteratic site, forming at first a loose bond, but later on they
form a firm irreversible bond leading to "phosphorylation" and aging of
enzymes, so they have long duration of action.The ability to hydrolyze
acetylcholine is regained by re-synthesis of new enzymes.

ANS
2nd Classification:
Anticholinesterases are classified according to the site of binding (combination) with
cholinesterases into:
1. Rapidly reversible anticholinesterases:

Simple alcohol as edrophonium.
2. Reversible anticholinesterases:
Carbamates as physostigmine, neostigmine, pyridostigmine.
3. Irreversible anticholinesterases:
Organophosphorous compounds.
1. Reversible Anticholinesterases:
 They compete with acetylcholine for the active sites (anionic and / or esteratic
sites) of cholinesterases forming a loose bond thus preventing hydrolysis of
acetylcholine.
 They have short duration of action, and the enzymes regain activity to hydrolyze
acetylcholine.
 They include:
a) Carbamates: -Physostigmine -Neostigmine –Pyridostigmine.
They bind to both sites of cholinesterases and are hydrolyzed by the enzyme
(they are substrate for the enzyme).
b) Quaternary ammonium alcohol: Edrophonium
It binds to the anionic site of the enzyme for about 5 minutes- but it is not
hydrolyzed by the enzyme- then it is excreted unchanged in urine, so it has a
very short duration of action.

ANS
1-Physostigmine 2-Neostigmine
1. Source  Natural: plant origin.  Synthetic.
2. Chemistry:  Carbamate-Tertiary amine.  Carbamate-quaternary ammonium.
3. Pharmacokinetics  Well absorbed orally.  Poorly absorbed orally.

Absorption:  Penetrates B.B.B.  Poorly passes B.B.B.
Distribution:  Hydrolyzed by (substrate of) cholinesterase.  As physostigmine.
Fate:
4. Mechanism of Binds reversibly to both anionic and esteratic As physostigmine.

action: sites of cholinesterases preventing hydrolysis of
endogenous acetylcholine.
5. Pharmacological  Muscarinic actions (by accumulated  Muscarinic actions (by accumulated

actions: endogenous acetylcholine). acetylcholine).
 Nicotinic actions (by accumulated  Nicotinic actions (by accumulated
endogenous acetylcholine). acetylcholine).
 CNS action: stimulation, which may lead to  Direct skeletal muscle stimulation.
convulsions.  No CNS actions.
6. Therapeutic uses: 1. Diagnosis and treatment of

1. Local uses in the eye:
 Glaucoma. Myasthenia gravis (atropine should
 To counteract mydriatics be given before neostigmine).
 Alternatively with mydriatics to cut 2. Treatment of poisoning by curare
recent adhesions in iritis. and other competitive neuro-
2. Treatment of acute atropine poisoning muscular blockers (atropine should
especially if CNS manifestations are present be given before neostigmine).
(however physostigmine may be dangerous 3. Treatment of peripheral symptoms
as it causes CNS stimulation itself). of acute atropine poisoning.
3. Treatment of Alzheimer's disease 4. Non-obstructive post-operative
(dementia). urine retention.
5. Non-obstructive post-operative
paralytic ileus.
6. PAT.
7. Glaucoma.

ANS
7. Adverse effects: Bradycardia-hypotension -bronchospasm and As physostigmine but no CNS

- -CNS manifestations
stimulation (convulsions).
8. Contraindications: Bradycardia-hypotension-bronchial asthma- As physostigmine (except parkinsonism).

peptic ulcer-hyperthyroidism-parkinsonism.
9. Acute toxicity: Manifestations: Manifestations: as physostigmine except

 Muscarinic: bradycardia-hypotension, CNS –Treatment: stomach wash and
bronchospasm, miosis. atropine.
 Nicotinic: twitches of skeletal muscles.
 CNS: convulsions, coma, death to
depression of R.C
Treatment:
 Stomach wash.
 Artificial respiration.
 Specific antidote= atropine.
 Anticonvulsants.
3. Ambenonium and 4. Pyridostigmine.

They are long acting neostigmine substitutes with weak GIT action and are used in
treatment of myasthenia gravis.
5. Demecarium: neostigmine substitute used in treatment of glaucoma.
6. Benzpyrinium: neostigmine substitute used in post-operative urine retention and
paralytic ileus.
7. Anticholinesterases in treatment of Alzheimer's disease:
Alzheimer's disease is a neuro-degenerative disease of cholinergic neurons in CNS
causing deficiency of acetylcholine and excessive activity of glutamate and aspartate
(acting on NMDA receptors). It is manifested by deterioration of memory, recognition,
and speech.
The aim of treatment is to increase the level of acetylcholine in CNS by
anticholinesterases, or to block NMDA receptors by mamantine.
Reversible anticholinesterases used in treatment of Alzheimer's disease act more
selectively on CNS and include:
a) Tacrine: not commonly used as it causes hepatotoxicity, nausea and vomiting.
b) Donepezil, Rivastigmine and Galantamine are safer than tacrine.

ANS
8. Edrophonium:
a) Source: Synthetic.
b) Chemistry: Quaternary ammonium alcohol.
 Absorption: not absorbed orally, given by I.V.injection.
 Distribution: poor penetration into CNS.
 Fate: not hydrolyzed by cholinesterases (not substrate for the enzyme).Excreted
unchanged in urine.
 Mechanism of action: rapidly reversible anticholinesterase by binding loosely to
the anionic site of the enzyme thus preventing hydrolysis of acetylcholine.
 Pharmacological actions: nicotinic and muscarinic actions of acetylcholine
(marked action on Nm receptors).
1. Diagnosis of myasthenia gravis (not suitable for treatment as it must be given
I.V. and has a very short duration of action).
2. Differentiation between cholinergig crisis and myasthenic crisis that may occur in
myasthenia gravis.
3. Treatment of myasthenic crisis.
4. Treatment of toxicity of curare and other competitive NM blockers.
5. Treatment of PAT. (N.B.: in treatment of curare poisoning and PAT,
edrophonium should be repeatedly injected).
Myasthenia Gravis
1. Definition:
an auto-immune disease in which auto antibodies are synthesized against Nm receptors
at NMJ of skeletal muscles, leading to skeletal muscle weakness and easy fatiguability
especially with repeated muscle activity.
2. Diagnosis:
edrophonium (I.V.) or Neostigmine (S.C. or I.M.), but must be preceeded by atropine to
block muscarinic actions of accumulated acetylcholine.
3. Treatment:
a) Anticholinesterases: neostigmine or neostigmine substitutes as pyridostigmine and
ambenonium (oral).
b) Atropine (oral) to avoid the undesired muscarinic actions.
c) Adjuvant drugs as ephedrine (facilitates NM transmission and dilates blood vessels
of skeletal muscles), and caffeine (stimulates skeletal muscles) may be added.

ANS
d) Immunosuppressive drugs as glucocorticoids (cortisol) and azathioprine may be

needed.
e) Surgical treatment: thymectomy may be performed.
f) Plasmaphoresis in severe cases.
Differentiation between Myasthenic crisis and Cholinergic crisis:

Myasthenic crisis Cholinergic crisis
Cause : The dose of neostigmine (or a substitute) The dose of neostigmine (or a substitute) is
is less than required (under-treatment). more than required leading to sustained
depolarization (over-treatment).
Diagnosis by I.V. Leads to improvement of muscle Leads to worsening of muscle weakness, but for
Edrophonium: weakness. 5 minutes only.
Correction: Increase the dose of neostigmine (or its Reduce the dose of neostigmine (or its
substitute). substitute).
B- Irreversible Anticholinesterases (Organophosphorous Compounds)

 They bind to the esteratic site of cholinesterases thus preventing hydrolysis of
acetylcholine.
 The bond between these compounds and the enzyme starts as a "loose" bond but it
becomes "covalent" and "irreversible" after a time period –which varies from one
compound to another-causing aging of the enzyme.
 The ability to hydrolyze acetylcholine after aging of the enzyme requires re-synthesis
(re-generation) of new cholinesterases which takes 2-3 weeks for pseudo-
cholinesterase and 2-3 months for true cholinesterase.
 They include:
 Drugs: Echothiophate (for treatment of glaucoma) - Metrifonate (anti-bilharzial
drug).
 Insecticides: Parathion – Malathion.
 War gases: (also known as nerve gases): Sarin-Tabun-Soman-Isofluorophate
(=DFP: Di-isopropyl-Fluro-Phosphate) which was used in treatment of glaucoma.

ANS
Acute Organophosphorous Toxicity:

Causes:
1) Accidental exposure to insecticides (especially in farmers and children).
2) Suicidal ingestion of insecticides.
3) Exposure to war gases.
 It should be noted that organophosphorous compounds are extremely lipid
soluble-except echothiophate-and are therefore absorbed orally, by inhalation,
and from intact skin, and can easily pass B.B.B.
Manifestations:
Accumulated acetylcholine cause muscarinic actions, nicotinic actions at the NMJ, and CNS
actions:
1) Muscarinic Actions:
 Bradycardia- hypotension- bronchospasm and increased bronchial secretion-
nausea, vomiting, colics and diarrhea- excessive salivation- miosis
(useful diagnostic sign).
2) Nicotinic Actions:
 At first there are skeletal muscle twitches but later on there is skeletal muscle
paralysis due to sustained depolarization of Nm receptors, leading to "peripheral
respiratory failure".
3) CNS Actions:
Manifestations :start by CNS stimulation: anxiety, restlessness, insomnia, and
convulsions, then CNS depression occurs: coma and depression of the respiratory centre
(R.C.) leading to central respiratory failure, and depression of the vasomotor centre
(VMC). The cause of death is central and peripheral respiratory failure and circulatory
failure.
Treatment:
1) Stomach wash (gastric lavage) by NaHCO3 (in case of oral ingestion), skin wash by
NaHCO3 and removal of contaminated clothes (in case of skin contamination).
2) Care of respiration by suction of bronchial secretion, oxygen, and artificial respiration if
available.
3) Antidote: Atropine is "LIFE-SAVING". It is given I.M. or I.V. (1-2 mg. every 5-10 minutes)
until signs of atropinization appear: tachycardia, mydriasis, and dry mouth.
4) Cholinesterase reactivators (Oximes):
 Include: Pralidoxime (PAM) and Diacetylmonoxime (DAM).

 They bind to the free anionic site of the enzyme and attract phosphorous atom of
OPC to "set free" the enzyme if given early –within 12 hours- before aging, but they
are ineffective if given late after enzyme aging.

ANS
 They are given by I.V. infusion (1g. in 100 mL. saline).

 DAM has the advantage of crossing B.B.B.
5) Symptomatic treatment, e.g. anticonvulsant as diazepam I.V. to control convulsions.
6) Fresh blood transfusion: fresh blood contains cholinesterases.
Prevention:
1) Avoid inhalation and skin contamination by wearing protective clothes and masks.
2) Proper washing of sprayed vegetables and fruits.
3) Keep insecticides out of the reach of children.
Cholinergic Receptor Antagonists

(Anticholinergic Drugs- Cholinoceptor Blockers)
These drugs block cholinergic receptors, and are classified into:
1) Muscarinic Receptor Antagonists:
 These drugs block muscarinic receptors and are also referred to as "anti-muscarinic
drugs" and were known as "parasympatholytics".
2) Nicotinic Receptor Antagonists:

 These drugs block nicotinic receptors and are also referred to as "anti-nicotinic
drugs". They are further subdivided into:
a) Ganglion Blockers:
 These drugs block Nn (Ng) receptors in autonomic ganglia and adrenal
medulla.They are subdivided according to their mechanism of action into:
 1-Competitive ganglion blockers: e.g. trimetaphan, mecamylamine,
chlorisondamine.
 2-Depolarizing (non-competitive) ganglion blockers: e.g. nicotine large dose.
b) Neuromuscular Blockers:
 These drugs block Nm receptors in neuromuscular junction of skeletal muscles
leading to skeletal muscle relaxation.
 They are subdivided according to their mechanism of action into:
i. Competitive neuro-muscular blockers: e.g. curare, gallamine,
pancuronium, vecuronium, atracurium.
ii. Depolarizing (non-competitive) neuro-muscular blockers: succinylcholine.

ANS
Muscarinic Receptor Antagonists
 Definition: they are "competitive antagonists (blockers) that compete with acetylcholine
for muscarinic receptors".
Classification: they are classified according to their source and according to their
selectivity on muscarinic receptors.
 Classification according to the source:
1) Natural Belladonna Alkaloids:

 Source: they are obtained from the following plants: Atropa belladonna, Hyoscyamus
niger, and Datura stramonium.
 Chemistry: they are tertiary amine esters of tropic acid.
 They include Atropine and L- Hyoscine (Scopolamine).
2) Synthetic Atropine and Hyoscine Substitutes (Derivatives):
 Homatropine, Pirenzepine, Ipratropium, Benztropine, Emepronium and others (see
later).
 Classification according to selectivity :

1) Non-selective Muscarinic Antagonists:
a) They block all types of muscarinic receptors. They include atropine and hyoscine.
2) Selective Muscarinic Antagonists:

a) Selective M1 antagonists: Pirenzepine- Telenzepine- Dicyclomine (used in treatment
of peptic ulcer).
b) Selective M2 antagonists: Gallamine (it is originally a competitive neuromuscular
blocker).
c) Selective M3 antagonists: Tolterodine (used in treatment of urinary incontinence),
and HHSD (an experimental drug = Hexa Hydro Sila Difenidol).

ANS
Natural Belladonna Alkaloids

1-ATROPINE
a) Source: natural from plant origin (Datura, Belladonna).

b) Chemistry: alkaloid- tertiary amine- ester of tropic acid and tropine base.
1) Absorption: completely absorbed orally and may be given by I.M. and I.V. injection,
and topically as eye drops. It is not absorbed from intact skin.
2) Distribution: penetrates B.B.B., and is distributed to all tissues.
3) Fate: partly metabolized by the liver (about 40%) and partly excreted in urine
unchanged (about 60%).
N.B.:
1) Renal excretion of atropine can be enhanced by acidification of urine (why?).
2) Rabbits have atropine esterase (atropinase) in their plasma; that is why they are
tolerant to atropine. This type of congenital tolerance is known as "species tolerance".
3) Humans show "acquired tolerance" to atropine.
Mechanism of action: atropine is a non-selective competitive muscarinic antagonist.
e) Pharmacological actions:
1) Local actions:
a) On skin: mild local anaesthetic (analgesic) action.
b) On the eye:
 Passive mydriasis due to block of M3 receptors in constrictor pupillae muscle
(CPM).
 Loss of light reflex due to block of M3 receptors in CPM.
 Loss of accommodation to near vision due to block of M3 receptors in the ciliary
muscle causing its paralysis which is known as "cycloplegia".
 ↓ drainage of aqueous humor caused by narrowing of spaces of Fontana and
narrowing of canal of Schlemm leading to ↑ IOP.
 ue to block of M3 receptors in lacrimal glands causing
dryness of the eye (xerophthalmia).
 No effect on conjunctival blood vessels.

ANS
2) Systemic Actions:
a) CVS:
1. Heart:
 Atropine blocks cardiac M2 receptors leading to:
 Tachycardia.

 ↓ Atrial conduction (of little clinical significance).
 Important Notes:
1) Atropine may cause initial transient bradycardia followed by tachycardia if
given by IV injection, which is explained by:
a) Central action: atropine stimulates vagal cardio-inhibitory centre (CIC).
b) Block of presynaptic M2 receptors (before blocking post-synaptic M2
receptors) leading to stimulation of acetylcholine release which acts on
post-synaptic M2 receptors causing initial bradycardia. Tachycardia occurs
when atropine blocks post-synaptic M2 receptors.
2) Atropine-induced tachycardia is more marked in young individuals; especially
athletes, because they have high vagal tone.
2. Blood vessels:
 Therapeutic doses of atropine have no effect on most blood vessels because
there is no parasympathetic innervation.
 Large and toxic doses of atropine cause vasodilatation especially in children,
causing" atropine flush" of the face and neck. This may be due to histamine
release, or a compensatory reaction to allow heat loss by radiation (because
atropine may decrease heat loss by evaporation as it decreases sweating).
3. Blood pressure:
 Therapeutic doses of atropine have almost no effect on blood pressure (no
effect on the tone of most blood vessels and accordingly no effect on T.P.R.
and A.B.P.).
 Atropine "reverses" the hypotensive effect of large doses of acetylcholine,
carbachol, and anticholinesterases as neostigmine, but "abolishes" the
hypotensive effect of methacholine and bethanechol (why?).
b) Smooth Muscle Fibres:

1. Blood vessels: see before.
2. Eye: see before.
3. Bronchi: bronchodilatation.
4. GIT: relaxation of the wall ( decreases tone and motility=antispasmodic action)
and contraction of the sphincter, leading to constipation.

ANS
5. Urinary bladder: relaxation of the muscle wall (detrusor) and contraction of the
sphincter, leading to urine retention. Also causes relaxation of ureteric smooth
muscles.
c) Exocrine glands:
 Atropine decreases all secretions (except milk, urine, and bile).
1. Lacrimal glands: atropine decreases lacrimation causing dryness of the eye
(xerophthalmia).
2. Salivary glands: atropine decreases salivary secretion leading to dry mouth
(xerostomia).
3. Bronchial glands: atropine decreases watery secretion leading to thick viscid
secretion. It also impairs the muco-ciliary action of bronchial mucosa.
4. Gastric glands: atropine decreases gastric secretion (both volume of secretion
and HCl content).
5. Sweat glands: atropine decreases sweat secretion from eccrine
(thermoregulatory ) sweat glands. Toxic doses of atropine cause a rise of body
temperature known as "atropine fever".
d) CNS Actions:
 Atropine causes both CNS stimulant actions and depressant actions. However, it is
considered a CNS stimulant drug because the stimulant actions are more
predominant.
1. Stimulant actions:
 Stimulation of R.C.
 Stimulation of cardio-inhibitory centre (C.I.C.) which partly explains the
initial transient bradycardia that may be observed.
 Large doses stimulate the cerebral cortex leading to restlessness, anxiety,
hallucination and confusion. Toxic doses may cause convulsions followed by
coma and death due to depression of R.C.
2. Depressant actions:
 Antiemetic action by blocking M receptors in the medullary vomiting
centre.
 Antiparkinsonian action by blocking M receptors in the basal ganglia.

ANS
Therapeutic uses (Indications):

 Atropine has a wide range of therapeutic uses but it has been replaced in some of
them by hyoscine or by synthetic substitutes.
Therapeutic use Disadvantages of Atropine

Atropine Substitute
1) CVS: 1-Treatment of bradycardia (due to β-
blockers, digitalis, verapamil, and in carotid sinus
syndrome=vagotonia=vasovagal attack).
2) CVS: 2- Treatment of AV block (due to β-

blockers, digitalis, verapamil, and myocardial
infarction).
3) Antidote of muscarinic agonists in treatment of

acute organophosphorous toxicity (atropine is
lifesaving), acute physostigmine toxicicy, and if
synthetic choline esters are given I.V. or I.M.
4) Atropine is given before neostigmine in diagnosis

of myasthenia gravis and in treatment of acute
curare toxicity to avoid the unwanted muscarinic
actions.
5) Eye uses: Atropine is not Synthetic

 To prevent adhesions (synechia) between iris preferred in fundus mydriatic
and lens in iritis and iridocyclitis. examination because: atropine
 Fundus examination. Long duration of action substitutes are
 Measurement of errors of refraction in (7-10 days) preferred as:
uncooperative patients as children. Not easily antagonized Homatropine-
by miotics. Tropicamide-
Marked cycloplegia. Cyclopentolate.
6) GIT: Antispasmodic in treatment of colics as Atropine is absorbed Antisecretory-

intestinal, renal, and biliary colics (may be from GIT - passes Antispasmodic
added to morphine) and in diarrhea (may be B.B.B. –non selective atropine
combined to morphine-like drugs as antimuscarinic; leading substitutes as:
diphenoxylate in travelers' diarrhea). to many adverse propantheline-
effects (see later). atropine methyl
nitrate-hyoscine
butyl bromide
which act locally
on GIT.

ANS
7) GIT: Treatment of peptic ulcer. Atropine is absorbed Selective M1

from GIT, is a non- antagonists as:
selective Pirenzepine-
antimuscarinic, and Telenzepine-
passes B.B.B. leading Dicyclomine.
to many adverse
effects.
8) Respiration: Prophylactic treatment in bronchial 1. Atropine is Ipratropium-

asthma. absorbed from GIT, Tiotropium-
is a non-selective Oxtropium.
antimuscarinic, and
passes B.B.B.
causing several
adverse effects.
2. Atropine decreases
watery content of
bronchial secretion
forming thick viscid
sputum (mucous
plug).
3. Atropine decreases
muco-ciliary action.
9) CNS:
 Treatment of Parkinsonism. Atropine is a non- Antiparkinsonian
selective atropine
antimuscarinic causing substitute as:
many adverse effects. Beztropine-
Benzhexol.
Atropine may cause Hyoscine

10)Treatment and prophylaxis of nausea and marked tachycardia. (scopolamine) is
vomiting (Antiemetic). the drug of
11)Exocrine Glands: choice.
 Hyperhiderosis (excessive sweating).
12)Urinary System: Atropine is a non- Emepronium-

 Nocturnal enuresis, urinary incontinence selective Oxybutynin-
(urgency) and post-operative bladder spasm. antimuscarinic causing Tolterodine
several adverse effects. (selective M3
antagonist in
post-operative
bladder spasm).

ANS
13)Pre-anaesthetic medication to:

 Prevent excess vagal stimulation by some 1. Tachycardia. Hyoscine.
general anaesthetics which causes 2. Post-operative
bradycardia and increase in salivary and urine retention.
bronchial secretion which may cause 3. Post- operative
aspiration pneumonia. constipation due to
 Stimulate R.C. to counteract the inhibitory intestinal
effect of other drugs given during general hypomotility.
anaesthesia as morphine.
 Avoid vomiting that may cause aspiration
pneumonia.
Adverse Effects and Acute Atropine Toxicity:

1) Tachycardia, palpitation, and anginal pains in anginal patients.
2) Dry mouth (xerostomia).
3) Constipation.
4) Urine retention which may be acute in old male patients with benign prostatic
hyperplasia (BPH).
5) Blurring of vision, loss of accommodation to near vision (due to cycloplegia), dryness
of the eye (xerophthalmia), and increased IOP which may precipitate acute
glaucoma especially in old patients.
6) Flushing and elevation of body temperature (hyperthermia) due to reduced sweating
especially in children.
7) CNS stimulation: agitation and delirium.
8) Acute atropine toxicity (Datura toxicity):
 Manifestations: tachycardia-dry mouth-constipation-urine retention-passive
mydriasis (useful diagnostic sign)-atropine flush-atropine fever (red hot dry skin)-
CNS stimulation: agitation, delirium, convulsions, coma and depression of R.C.
causing death.
 Treatment:
 Stomach wash by tannic acid.
 Care for respiration: oxygen and artificial respiration in case of R.C. depression.
 Specific antidote: neostigmine (corrects peripheral manifestations of atropine
toxicity) or physostigmine (if atropine causes peripheral and CNS symptoms,
but remember that physostigmine is dangerous as it may cause CNS
stimulation).
 Symptomatic treatment: diazepam to control convulsions, cold fomentations
(ice bags or alcohol) to control hyperthermia.
 Acidification of urine by vitamin C or NH4Cl to promote urinary excretion
(atropine is a weakly basic drug).

ANS
Contrinadications:
1) Glaucoma (especially narrow angle glaucoma) and old patients with elevated IOP.
2) Old male patients with benign (senile) prostatic hypertrophy.
3) Tachyarrhythmias.
4) Angina pectoris.
5) Constipation.
6) Fever.
2)HYOSCINE (SCOPOLAMINE)
a) Source: natural from plant origin (see before).

b) Chemistry: alkaloid - tertiary amine - ester of tropic acid and scopine base.
 Absorption: well absorbed orally, given also parenterally and as a transdermal patch
(absorbed from the skin).
 Distribution: penetrates B.B.B. and is distributed to all tissues.
 Fate: partly metabolized by the liver and partly excreted unchanged in urine.
 Mechanism of action: non-selective competitive muscarinic antagonist.
 Pharmacological actions: similar to atropine with the following differences:
1) Shorter duration of action.
2) Stronger antimuscarinic action on the eye and exocrine glands.
3) Weaker antimuscarinic action on the heart (less-or no tachycardia) and GIT.
4) CNS depressant more than stimulant:
a) Depressant actions: -sedation, drowsiness, amnesia, and hypnosis. - inhibits
the basal ganglia (antiparkinsonian) and the vomiting centre (potent
antiemetic).
b) Stimulant actions: it may cause excitation, delirium, and hallucination if given
in large doses. It potently stimulates R.C.
5) No local analgesic (anodyne) action.

ANS
Indications:
1) Pre-anaesthetic medication: preferred to atropine because:
a) Less tachycardia, especially in cardiac and thyrotoxic patients.
b) Potent antisecretory.
c) Potent antiemetic.
d) Potent R.C. stimulation.
e) Causes sedation, amnesia to recent events, and hypnosis.
2) Antiemetic: hyoscine is the drug of choice in prophylaxis of motion sickness, given as a
transdermal patch.
3) Meniere's disease and labyrinthitis (to stop vertigo).
4) Treatment of Parkinsonim.
5) Antispasmodic in treatment of colics and in diarrhea.
Adverse Effects:
1) Dry mouth.
2) Blurred vision, cycloplegia, xerophthalmia, and elevation of IOP.
3) Constipation.
4) Urine retention.
5) Sedation, drowsiness, hypnosis, and excitation, hallucination, and delirium if used in
large doses.
Contraindications:
1) Glaucoma and in old patients with high IOP.
2) Benign prostatic hypertrophy.
Character Atropine Hyoscine

Chemistry: Ester of tropic acid and Ester of tropic acid and
"tropine" base. "scopine" base.
Absorption from the Not absorbed. Absorbed (transdermal

skin: patch in prophylaxis of
motion sickness).
Duration: Long duration. Short duration.
Actions:
1. Local anasethetic: Present. Absent.
2. Heart: Marked tachycardia. Less or no tachycardia.
3. Eye: Less potent actions. More potent actions.

ANS
4. GIT: More potent actions. Less potent actions.
5. Urinary bladder: More potent actions. Less potent actions.
6. Exocrine glands: Less potent actions. More potent actions.
7. CNS: Stimulant actions Depressant actions mainly

mainly-less stimulation (sedation, amnesia,
of R.C.-less potent hypnosis)
antiemetic. -more stimulation of R.C. -
more potent antiemetic.
Synthetic Atropine Substitutes
There are 5 main groups of synthetic atropine substitutes (derivatives):
1) Mydriatic atropine substitutes.
2) Antisecretory antispasmodic atropine substitutes.
3) Antiparkinsonian atropine substitutes.
4) Atropine substitutes to reduce urinary bladder activity.
5) Atropine substitute in bronchial asthma (antiasthmatic atropine substitutes).
1) Mydriatic Atropine Substitutes:
 They include: Homatropine- Tropicamide- Cyclopentolate.
They have the following advantages over atropine:
1) Shorter duration of action.
2) Antagonized completely by miotics (physostigmine and pilocarpine).
3) Less cycloplegia.
 Therapeutic uses: Fundus examination.
 Adverse effects: Blurred vision- xerophthalmia- cycloplegia- ↑IOP.
 Contraindications: glaucoma and old patients with high IOP.
Atropine Homatropine Tropicamide Cyclopentolate
Duration 7-10 days 1 day 6 hours 6 hours

Concen. 0.5-1% 2-5% 0.5-1% 0.5-2%
Passive +++ ++ ++ ++
mydriasis
Cycloplegia +++ ++ ++ ++
Antagonism Not complete Complete Complete Complete
Therapeutic Iritis, irido-cyclitis Fundus Fundus Fundus examination
uses and corneal ulcer examination examination
Contraind. Glaucoma Glaucoma Glaucoma Glaucoma

ANS
2) Antisecretory Antispasmodic Atropine Substitutes:

 They include: Propantheline- Oxyphenonium- Atropine methyl nitrate- Hyoscine
butyl bromide (Buscopan)
 They are quaternary ammonium compounds given orally with minimal absorption,
with little systemic actions especially on CNS.
 They are used in treatment of intestinal and renal colics and peptic ulcer. Atropine
methyl nitrate is used to relax the pylorus in hypertrophic pyloric obstruction.
 They are contraindicated in glaucoma and prostatic hypertrophy.
3) Antiparkinsonian Atropine Substitutes:

 They include: Benztropine- Trihexphenidyl =Benzhexol.
 They are tertiary amines and can easily pass B.B.B.
 They improve tremors more than rigidity.
 Adverse effects and contraindications: as atropine.
4) Atropine Substitutes to decrease urinary bladder activity:

They include:
1) Emepronium: in treatment of urinary incontinence and nocturnal enureseis.
2) Oxybutynin: in treatment of urinary incontinence and to relieve bladder spasm
following urological operations.
3) Tolterodine: selective M3 antagonist used in treatment of urinary incontinence.
5) Atropine Substitutes in Bronchial Asthma:

 They include: Ipratropium- Tiotropium- Oxytropium.
 They have the following advantages over atropine:
 They are given by inhalation.
 They are quaternary ammonium compounds with minimal systemic actions
especially on CNS.
 They do not cause dryness of bronchial secretion.
 They do not decrease muco-ciliary activity.
 They are used in prophylaxis of bronchial asthma, may be given with selective β2
agonists in acute attacks, and are used in treatment of chronic obstructive
pulmonary diseases (COPD).
Very important note:

Atropine, hyoscine, atropine substitutes and all drugs having atropine-like action-as
sedating antihistaminics, some antiarrhythmic drugs (as disopyramide), tricyclic
antidepressants, some antipsychotics (as phenothiazines)- are contraindicated in glaucoma
and prostatic hypertrophy.

ANS
SYMPATHOMIMETICS
(Adrenergic Agonists)
 Definition:
These are drugs that stimulate adrenergic receptors leading to actions similar to
sympathetic stimulation.
 Classification:
Sympathomimetics are classified according to the chemical structure and according to
the mechanism of action.
a) Chemical Classification:
Sympathomimetics are classifiefd chemically into "Catecholamines" and "Non-
catecholamines".
Catecholamines Non-catecholamines
Chemistry: Contain a catechol ring. No catechol ring.

Pharmacokinetics
Absorption: Not absorbed orally. Well absorbed orally.
Distribution: Poorly penetrate B.B.B. Easily penetrate B.B.B.

(minimal CNS actions). (marked CNS actions).
Fate: 1) Metabolized by MAO and 1) Not metabolized by MAO or

COMT COMT
2) Uptake 2) No uptake
3) Minimal excretion 3) Mainly eliminated
unchanged in urine. unchanged in urine.
Onset of Action: Rapid onset (given by injection, Slow onset (usually given
S.L., inhalation). orally).
Duration of Action: Short duration (due to rapid Long duration (due to slow
metabolism and uptake). excretion in urine).
Examples: Adrenaline- Noradrenaline- Ephedrine- Amphetamine-
Dopamine- Isoprenaline- Salbutamol- Terbutaline-
Isoetharine- Dobutamine. Phenylephrine- Methoxamine.
N.B. adrenaline, noradrenaline,
and dopamine are "Natural"
but isoprenaline, isoetharine,
and dobutamine are
"Synthetic".

ANS
b) Classification According to Mechanism of Action:

1) Direct Sympathomimetics:They are direct agonists on adrenergic receptors. Examples
include: all catecholamines (see table), salbutamol, phenylephrine…
2) Indirect Sympathomimetics:They do not stimulate adrenergic receptors directly but act

by one of the following mechanisms:
a) Inhibition of neuronal reuptake of noradrenaline leading to accumulation of
endogenous noradrenaline which then stimulates α- and β- adrenergic receptors.
Example: cocaine.
b) Stimulation of release of noradrenaline from adrenergic neurons, the released
noradrenaline then stimulates α- and β- receptors. Examples: amphetamine,
methamphetamine, and tyramine.
3) Dual (Mixed) acting Sympathomimetics: They act both directly by stimulation of

adrenergic receptors and indirectly by stimulation of noradrenaline release from
adrenergic neurons. Examples: ephedrine and mephentramine.
Important Notes:
1) Direct sympathomimetics show "supersensitivity"- i.e. exaggerated normal response to
drugs- when administered after denervation sympathectomy, following drugs as
reserpine, guanethidine (adrenergic neuron blockers=sympatholytics that deplete
adrenergic neurons from noradrenaline), cocaine (inhibits neuronal uptake), MAO
inhibitors (inhibit metabolic degradation), ganglion blockers (inhibit NAP in adrenergic
neurons), or due to some pathological conditions as acute hemorrhagic pancreatitis,
thyrotoxicosis, diabetic ketoacidosis, and glaucoma. This may be due to "up-regulation"
of post-synaptic adrenergic receptors.
2) Indirect sympathomimetics show "tachyphylaxis"(acute acquired tolerance), i.e. the

response to a fixed dose of the drug decreases on repeated administration in a short
period of time due to depletion of noradrenaline stores from adrenergic neurons. It is
clear that sympathectomy abolishes the action of indirect sympathomimetics.
3) Dual-acting sympathomimetics show both supersensitivity and tachyphylaxis.

ANS
CATECHOLAMINES
1) ADRENALINE (Epinephrine)
 Source:
1) Natural: adrenaline is synthesized in the brain and in the adrenal medulla
(constitutes about 80% of its secretion) from noradrenaline by the enzyme PENMT
(phenyl ethanolamine-N-methyl transferase).
Tyrosine →Dopa →Dopamine →Noradrenaline →Adrenaline
N.B.: Adrenaline is not synthesized in the adrenergic neurons due to absence of PENMT.
2) Synthetic.
 Chemistry:
1) Adrenaline is a catecholamine.
2) L-isomer is more active than D-isomer (20 times more active).
3) As all catecholamines; adrenaline is chemically unstable and is oxidized on exposure
to air and light into toxic hallucinogenic "adrenochrome" which is pink in colour. That
is why adrenaline should be kept in dark ampoules, and a reducing agent as vitamin C
or sodium bisulphite is added.
N.B.: Adrenaline is more stable (not oxidized) in the blood due to the presence of reducing
agents as vitamin C and glutathione.
 Pharmacokinetics:
1) Absorption:
 Adrenaline as all catecholamines is not absorbed orally (low lipid solubility-causes
vasoconstriction (V.C.) of GIT mucosa which decreases absorption-metabolized in GIT
and liver). Adrenaline is given by the following routes of administration:
a) S.C. injection: delayed onset as adrenaline causes V.C. of subcutaneous blood
vessels (α1 action).
b) I.M. injection: rapid onset because adrenaline causes V.D. of skeletal muscle
blood vessels (β2 action). However, it may cause severe hypertension and
arrhythmias.
c) Intracardiac: cardiac resuscitation in case of cardiac arrest.
d) Local (topical) application:
 Inhalation (by inhaler or nebulizer) in acute attacks of bronchial asthma.
 Eye drops in open angle glaucoma.
 Nasal pack in treatment of epistaxis.
N.B.: I.V. injection of adrenaline is extremely dangerous and may be fatal as it may lead to
ventricular fibrillation (V.F.), sudden severe hypertension, and apnea (reflex inhibition of
R.C. through stimulation of baroreceptors).

ANS
2) Disribution: poor passage across B.B.B
3) Fate:
a) Enzymatic degradation (80%) by COMT and MAO into vanillyl mandelic acid
(VMA) which is excreted in urine.
Adrenaline (epinephrine) ▬▬▬►metanephrine ▬▬▬►VMA

COMT MAO
Noradrenaline (norepinephrine) ▬▬►normetanephrine ▬▬►VMA
b) Uptake (18%): mainly neuronal uptake, granular (vesicular) uptake and extra-
neuronal (tissue) uptake.
c) A very small amount (2%) is excreted unchanged in urine.
N.B.:
 Adrenaline may be present in the adrenergic neurons due to neuronal uptake and not
due to synthesis inside the neurons.
 VMA is the end metabolite of adrenaline and noradrenaline, and its level in urine
increases in tumors of the adrenal medulla known as "pheochromocytoma".
 Pharmacodynamics:
 Mechanism of action: direct agonist stimulating ALL adrenergic receptors (β1, β2, β3 and
α1, α2).
 Pharmacological actions:
a) Local Actions:
1) On skin and mucous membranes: V.C. of blood vessels due to α1-stimulation leading
to the following:
a. Decongestion.
b. Hemostasis (stops bleeding as in cases of epistaxis).
c. Delays absorption of drugs given by subcutaneous injection (S.C.) as local
anaesthetics leading to prolongation of action and reducing their systemic
adverse effects as convulsions.
2) On the Eye:
a. Decongestion of conjunctiva (α1).
Decreases IOP mainly by decreasing formation of aqueous humor (α).
No mydriasis in normal individuals because adrenaline does not pass easily inside the
eye as it causes V.C., and is destroyed by the alkaline medium and enzymes of the
tears.

ANS
Adrenaline causes active mydriasis if given systemically and when applied locally in
patients with supersensitivity (sees before).
3) On Bronchi:
Adrenaline causes bronchodilatation due to β2-stimulation and decongestion of
bronchial mucosa due to α1-stimulation.
b) Systemic Actions:
1. CVS:
 Heart: adrenaline stimulates cardiac β1-receptors leading to:
1. Increases automaticity=Tachycardia (positive chronotropic action).
2. Increases conductivity all over the heart (positive dromotropic action).
3. Increases contractility (positive inotropic action).
4. Increases excitability.
5. Increases cardiac output (COP) due to increase in contractility and heart rate.
6. Increases myocardial oxygen needs due to increased cardiac work; this may
cause anginal pain in patients with angina pectoris.
 Blood vessels:
1. V.C. of skin and mucous membrane blood vessels through α1-stimulation.
2. V.D. of skeletal muscle and coronary blood vessels through β2-stimulation.
 Arterial Blood Pressure (A.B.P.):"ADRENALINE ELEVATES ABP"
Systolic BP =COP X TPR , but Diastolic BP is controlled by TPR only.
Adrenaline has the following actions on ABP:
1. Increases systolic blood pressure (β1-stimulation → ↑ COP).
2. Variable effect on diastolic blood pressure: small doses of adrenaline stimulate
β2-receptors in blood vessels → V.D. → ↓TPR. Large doses of adrenaline
stimulate α1-receptors in blood vessels → V.C. → ↑ TPR.
3. Elevates mean ABP.
4. Increases pulse pressure.
5. Injection of adrenaline in anaesthesized cat after α1-blockers as phentolamine
causes hypotension because adrenaline will cause unopposed stimulation of
β2-receptors leading to V.D. This is known as "Adrenaline Reversal".
6. Injection of adrenaline in anaesthesized cat after non-selective β-blockers
blocking β2-receptors will cause unopposed stimulation of α1-receptors leading
to V.C. and more elevation of ABP.
2. Respiration:
a) Bronchodilatation (β2-stimulation).
b) Decongestion of bronchial mucosa (α1-stimulation).

ANS
c) Adrenaline weakly stimulates R.C., but I.V. injection of adrenaline causes reflex
inhibition of R.C. (through the chemoreceptors and baroreceptors). This is
known as "Adrenaline Apnea".
3. Eye:
a) Active mydriasis by stimulation of α1-receptors in dilator pupillae.
b) Decongetion (see local actions).
c) Decreases IOP (see local actions).
4. GIT:
a) Relaxation of the wall leading to decrease in tone and motility (β-and α-
stimulation).
b) Contraction of the sphincter (α1-stimulation).
5. Urinary Bladder:
 Relaxation of the detrusor muscle (β2-effect) and contraction of the sphincter
(α1-effect) causing retention of urine.
6. Uterus:
 Adrenaline has a variable effect on the uterus but it causes relaxation in late
pregnancy and during labor (β2-stimulation).
7. Sweating:
 Adrenaline increases sweat secretion from apocrine (non-thermoregulatory
sweat glands) by stimulation of α1-receptors.
8. Salivary glands: thick viscid saliva which may be due to V.C. of blood vessels to
salivary glands.
9. Metabolic Actions:
a) Calorigenic action: adrenaline increases BMR and oxygen consumption.
b) Lipolysis and increasing free fatty acids in blood through simulation of β1 and
β3-receptors.
c) Liver glycogenolysis leading to hyperglycemia, and skeletal muscle
glycogenolysis leading to increased blood lactic acid (β2-stimulation).
Hyperglycemia may be also due to decreased insulin release (α2-effect).
d) Increased potassium uptake which may cause hypokalemia (β2) following initial
hyperkalemia due to increased release of K+ from the liver (α1).

ANS
10.Anti-allergic Action:
 Adrenaline is considered the "Physiological antagonist of histamine" on blood
vessels, A.B.P., and bronchi.
Histamine Adrenaline
1) Stimulates H1 and H2 receptors on blood 1) Stimulates α1 receptors on blood
vessels→ V.D. and severe hypotension (shock). vessels
2) Stimulates H1 receptors on bronchi→ 2) Stimulation of β2 receptors on

bronchospasm. bronchi
Physiological antagonism: 2 different drugs acting on 2 different sites (e.g. receptors)

causing 2 opposing actions.
Blood Coagulation:
Adrenaline stimulates factor V.
11.Skeletal Muscles:
a) Facilitation of neuro-muscular transmission and anti-fatigue action (α1).
b) Tremors (β2).
c) Glycogenolysis (β1).
d) Increased potassium uptake which may cause hypokalemia (β2) following initial
hyperkalemia due to increased release of K+ from the liver (α1).
e) V.D. of skeletal muscle blood vessels (β2).
f) Increased K+ uptake leading to hypokalemia.
12.CNS:
 Weak CNS actions (mainly β1): stimulation of R.C., anxiety and headache.
 Therapeutic Uses:
1) Adrenaline is life saving in anaphylactic shock and angioedema, it is usually given S.C. (it
is the physiological antagonist of histamine).
2) Adrenaline is used in cardiac resuscitation in case of cardiac arrest and is given by

intracardiac injection.
3) Adrenaline is added to local anaesthetics (L.A.)-except cocaine- to increase the duration

of action, to reduce systemic action of L.A., and to stop bleeding. Never add adrenaline
to L.A. in fingers, toes, and in circumscision to avoid gangrene.

ANS
4) Acute attacks of bronchial asthma, adrenaline is given by inhalation or by S.C. injection

(Selective β2-agonists are better).
5) To stop bleeding as in cases of epistaxis except in hypertensive patients

(adrenaline is given locally as nasal pack).
6) Decongestant in eye and nose (given locally).
7) Hypoglycemic coma due to overdose of insulin or oral hypoglycemic drugs

(glucose IV is better).
8) Contraction ring of the uterus (selective β2-agonists as ritodrine are better).
9) Open angle glaucoma (Dipivefrin is a prodrug converted into adrenaline and is

preferred to adrenaline as it is more lipophilic and causes less irritation).
10) Diagnostic tests:

Loewe's test: local adrenaline causes active mydriasis in patients with acute hemorrhagic
pancreatitis due to supersensitivity.
Thorn test: to test the integrity of the hypothalamic-pituitary (hypophyseal) adrenocortical

axis. Adrenaline stimulates the hypothalamus to release corticotrophin releasing hormone
(CRH) and
release from the adrenal cortex →eosinopenia.
N.B.: eosinopenia may be due to direct effect of adrenaline on bone marrow.

ANS
Summary of the therapeutic uses of adrenaline:

Therapeutic uses Route of Disadvantages Alternative
adminstration drug
1) Anaphylactic shock S.C. injection
(adrenaline is life-saving),
angioedema, urticaria
(α1+β2).
2) Cardiac resuscitation in Intracardiac.

cardiac arrest (β1).
3) Acute attacks of bronchial Inhalation- β1stimulation→tachycar Short acting

asthma S.C.injection. dia-palpitations-anginal selective β2
(β2 + α1). pains. agonists
α1stimulation→↑A.B.P. (SABA) as
salbutamol.
4) Open angle glaucoma (α). Eye drops. Irritation, lacrimation, Dipivefrin.

pigmentation.
5) Treatment of S.C.injection. β1stimulation→tachycar Glucose I.V.

hypoglycemic coma due dia-palpitations-anginal
to insulin overdose (β2 + pains.
α2). α1stimulation→↑A.B.P.
6) Contraction ring of the S.C.injection. β1stimulation→tachycar Selective β2

uterus: β2. dia-palpitations-anginal agonists as
pains. ritodrine.
7) Decongestant (α1). Nasal and eye α1stimulation→↑A.B.P.
drops.
8) Hemostatic as in epistaxis Nasal pack.

(α1).
9) With L.A.(α1). Infiltration.

ANS
Adverse effect Contraindication

1) Tachycardia, palpitations, and arrhythmia 1) Tachyarrhythmia.
(treated by β blockers as propranolol). These
adverse effects are particularly more 2) Pulmonary embolism.
dangerous in thyrotoxicosis, pulmonary
embolism, and when adrenaline is given with 3) Thyrotoxicosis.
digitalis or with halothane (an inhalation
general anaesthetic which sensitizes the heart 4) With halothane.
to catecholamines) as serious ventricular
arrhythmias may occur as ventricular 5) With digitalis.
fibrillation (V.F.).
2) Increased cardiac work and precipitation of 6) Angina pectoris (ischemic heart

anginal attacks. disease=coronary heart disease).
7) Hypertension.
3) Elevation of A.B.P. and may cause cerebral 8) Severe hypertension if
hemorrhage in hypertensive patients. adrenaline is given with non-
selective β blockers as
4) Gangrene if added to L.A. in fingers and toes, propranolol.
and during circumscision (treated by α1
blockers). 9) Gangrene if added to L.A. in
fingers and toes, and during
5) Weak CNS stimulation: anxiety, headache, and circumscision
tremors.
6) Lacrimation, irritation, and pigmentation of

the eye when applied locally for long time. 10) With MAO inhibitors, ganglion
blockers, cocaine, guanethidine,
7) Supersensitivity occurs with MAO inhibitors, and reserpine.
ganglion blockers, cocaine, guanethidine, and
reserpine. 11) Hemorrhagic shock (severe V.C.
of renal blood vessels occurs
and may lead to acute renal
failure and death).

ANS
Drug Interactions:
1) With L.A. around fingers and toes, and in circumscision →gangrene.
2) With cocaine→ severe V.C. and gangrene because cocaine inhibits neuronal uptake of
adrenaline.
3) With halothane →cardiac arrhythmias.
4) With digitalis →ventricular arrhythmias.
5) With non-selective β-blockers→severe hypertension due to unopposed α1-stimulation.
6) With MAO inhibitors, ganglion blockers, guanethidine, and reserpine.
(use smaller doses of adrenaline).
2) NORADRENALINE (Norepinephrine)
Source:
1) Natural: noradrenaline is present in the human body in:
Adrenergic neurons, adrenal medulla (about 20% of normal secretion) and CNS.
2) Synthetic.
Chemistry:
1) Catecholamine.
2) L-isomer is more active than D-isomer.
3) Unstable on exposure to air and light.
Pharmacokinetics:
1) Not absorbed orally (as adrenaline), given only by I.V. infusion (drip). Noradrenaline
should never be given I.M. or S.C. to avoid gangrene due to severe V.C.
2) Poor passage across B.B.B.
3) Fate: as adrenaline (metabolized by COMT and MAO into VMA which is excreted in
urine- Uptake- a small percent is excreted unchanged in urine).
Pharmacodynamics:
Mechanism of action: direct agonist simulating mainly α1-receptors, weak action on β1-
receptors, and almost no action on β2-receptors.

ANS
Pharmacological actions:
1) CVS:
a) Heart:
 Noradrenaline has a weak stimulating action on cardiac β1-receptors leading to
minimal increase in excitability, conductivity, and contractility. As regards the
effect of noradrenaline on heart rate:
 Noradrenaline has a weak direct stimulant action on β1-receptors tending to
cause "direct tachycardia".
 Noradrenaline has a very strong stimulant action on α1-receptors → V.C. → ↑
T.P.R.
C.I.C.→ "reflex bradycardia".
 Reflex bradycardia overcomes direct tachycardia so the net result of
noradrenaline is elevation of A.B.P. and reflex bradycardia.
 Reflex bradycardia is absent in cases of vagotomy and by the following drugs:
atropine, ganglion blockers, and α1-blockers.
b) Blood vessels: V.C. of all blood vessels (α1).
c) A.B.P.:
 Increases both systolic and diastolic B.P. due V.C. which elevates T.P.R.
with almost no change in pulse pressure.
 The hypertensive action of noradrenaline is abolished-not reversed- by α1-
blockers because it has no action on β2-receptors.
2) Eye: as adrenaline (local actions: decongestion and
decongestion, 1 receptors
α in DPM).
3) Bronchi: NO BRONCHODILATATION because it does not stimulate β2-receptors.
4) GIT: contraction of the sphincter and relaxation of the wall.
5) Urinary bladder: contraction of the sphincter.
Therapeutic uses:
1) To elevate A.B.P. in cases of severe hypotension caused by spinal anaesthesia,
overdose of ganglion blockers (not commonly used) or following sympathectomy
(not commonly performed).
2) To prolong the action of L.A.-except cocaine- and contraindicated in fingers, toes,
and circumscision.

ANS
Advese effects:
1) Severe elevation of A.B.P. is the most serious adverse effect, this may lead to
cerebral hemorrhage.
2) Bradycardia (reflex).
3) Necrosis, gangrene, and sloughing if extravasation occurs (leakage of the drug
outside the veins during I.V. infusion), if given with cocaine, or with other L.A. in
operations in the fingers, toes, and circumscision.
4) Minimal CNS manifestations as headache, tremors, anxiety, and insomnia.
5) Supersensitivity with MAO inhibitors, adrenergic neuron blockers, ganglion blockers.
Contraindications:
1) Hypertension.
2) Bradycardia.
3) With drugs causing supersensitivity.
4) With cocaine and with L.A. around fingers, toes, and in circumscision to avoid
gangrene.
Precautions during IV infusion:

1) Monitor B.P. and heart rate.
2) Avoid extravasation.
3) Never stop infusion suddenly to avoid sudden hypotension.
3) DOPAMINE
Source:
1) Natural: dopamine is present in certain areas of the brain, e.g. the basal ganglia, and
is present in the adrenergic neurons and adrenal medulla as the immediate precursor
of noradrenaline.
2) Synthetic.
Chemistry:
1) Catecholamine.
3) Unstable .
Pharmacokinetics:
1) Absorption: not absorbed orally, given by I.V. drip.
2) Distribution: poor passage across B.B.B.
3) Fate: metabolized by COMT and MAO (mainly) into homovanilic acid (HVA) which is
excreted in urine.

ANS
Pharmacodynamics:
Mechanism of action: direct stimulation of specific dopaminergic (D1) receptors, β1-
receptors, and α1-receptors according to the rate of infusion.
Pharmacological actions: depend on the rate of infusion as follows:

1) Slow rate of infusion (2.5-5 µg/kg/minute): dopamine stimulates D1-receptors in
blood vessels leading to V.D. especially renal, mesenteric, and coronary blood
vessels, which increases blood flow to the vital organs as the kidney.
2) Moderate rate of infusion (5-10 µg/kg/minute): dopamine stimulates cardiac β1-
receptors leading to increase in COP.
3) Rapid rate of infusion (> 10 µg/kg/minute): dopamine stimulates α1-receptors leading
to V.C., increase in TPR and ABP.
(Renal V.C. leads to acute renal failure and death).
Therapeutic uses:
1) Shock (hypovolemic, cardiogenic, and endotoxic): dopamine is given at a slow-
moderate rate to increase tissue perfusion and blood flow to vital organs as the
kidney, and to increase COP and accordingly urine output and ABP –especially
systolic - increase.
Blood volume should be corrected, e.g. by blood transfusion, before administration
of dopamine "fill up then open up".
2) Heart failure: especially acute and resistant heart failure, dopamine is given in a
moderate infusion rate.
Adverse effects:
1) Tachycardia, palpitation, arrhythmias (ventricular), and anginal pains due to direct
and reflex β1-stimulation (treated by β1- blockers).
2) Hypertension if given with MAO inhibitors or in rapid infusion rate due to α1-
stimulation (treated by α1- blockers).
3) Nausea and vomiting (due to stimulation of D2-receptors in C.T.Z.)
4) Weak CNS actions as headache and anxiety.
Important notes:
1) Dopamine is not effective in treatment of Parkinsonism as it cannot pass B.B.B., but
its precursor L-dopa can pass easily and is converted into dopamine by dopa
decarboxylase in CNS.
2) Dopamine receptor subtypes are D1, D2, D3, D4, and D5 (see CNS).

ANS
3) To antagonize the pharmacological actions of dopamine we have to block the

following receptors:
a) D1- receptors: by dopaminergic antagonists as "haloperidol".
b) β1- receptors by: β1-blockers as" propranolol".
c) α1- blockers by: α1-blockers as "phentolamine".
4) The dose of dopamine should be reduced in patients treated with MAO inhibitors to
avoid elevation of ABP (explain).
5) Precautions during infusion: monitor heart rate by ECG -monitor ABP and urine
volume -replace fluids before dopamine -avoid extravasation-stop infusion gradually
Fenoldopam:
 Synthetic.
 Catecholamine.
 Given by I.V. infusion (rapidly metabolized by conjugation).
 Selective D1-agonist → V.D. → ↓ T.P.R. → ↓ A.B.P.
 Used in emergency hypertension.●Adverse effects are due to V.D.: headache, flushing,
tachycardia (mostly reflex).
Ibopamine: as dopamine but is effective orally
Dopexamine:
1) Synthetic analog of dopamine.
2) Given by I.V. drip.
3) Stimulates D1, D2, and β-receptors.
4) Used in shock and heart failure (acute and resistant).
4) DOBUTAMINE
Source: synthetic.
Chemistry:
Catecholamine- L-isomer is more active than D-isomer –Unstable.
Pharmacokinetics:
1) Not absorbed orally; given by I.V. infusion.
2) Poorly penetrates B.B.B.
3) Fate: metabolized by COMT mainly.

ANS
Pharmacodynamics:
Mechanism of action: direct selective β1 agonist.
Pharmacological actions: positive inotropic action more than chronotropic leading to
elevation of COP.
N.B. in contrast to dopamine; dobutamine does not stimulate dopaminergic receptors and
has no effect on α1-receptors (so has no effect on TPR).
Therapeutic uses:
1) Acute and resistant heart failure.
2) Cardiogenic shock (due to myocardial infarction).
3) Treatment of cardiac decompensation after cardiac surgery
Adverse effects: tachycardia, palpitation, anginal pains-much less than dopamine- and
headache
Prenalterol: as dobutamine but being a non-cateholamine it is given orally as well as
parenterally.
5) ISOPRENALINE (Isoproterenol)
Source: Synthetic.
Chemistry:
1) Catecholamine.
3) Unstable.
Pharmacokinetics:
1) Absorption: not absorbed orally, given by sublingual administration (S.L.), by inhalation,
and by I.V. infusion.
 S.L. administration has the following advantages: rapid onset of action –avoids hepatic
metabolism (first pass effect) –adverse effects can be avoided by swallowing or spitting
the pellet.
2) Poorly passes B.B.B.
3) Fate: uptake (mainly tissue uptake) and metabolism by COMT and MAO.
Pharmacodynamics:
Mechanism of action: direct agonist on all β-receptors with no effect on α-receptors.
1) CVS:
a) Heart: stimulation of cardiac β1-receptors increases all cardiac properties leading
to increase in heart rate, excitability, conductivity, contractility, COP, and
myocardial oxygen needs.

ANS
b) Blood vessels: V.D. especially of coronary and skeletal muscle blood vessels
→↓T.P.R.
c) A.B.P.:
It decreases diastolic B.P. due to V.D. and decreased T.P.R.
Isoprenaline causes Hypotension.
It slightly elevates systolic B.P. by elevating COP due to β1-receptors.
It increases pulse pressure.
Its hypotensive action is abolished by non-selective β-blockers as propranolol,
and is augmented by α1-blockers.
2) Bronchi: bronchodilatation (β2-action).
3) GIT: relaxation of the wall (β2-action).
4) Urinary bladder: relaxation of the wall (β2-action).
5) Metabolic actions:
a) Glycogenolysis in liver and skeletal muscles (β2-action) leading to increased blood
glucose and lactate; respectively.
b) Lipolysis and increased free fatty acids (β1 and β3 action).
6) Skeletal muscles:
a)Tremors.
b)Increased potassium uptake and hypokalemia.
c)V.D. of blood vessels.
d)Glycogenolysis and increased blood lactate.
7) CNS: weak actions as headache and anxiety.
Therapeutic uses:
1) Acute attacks of bronchial asthma, isoprenaline is given by inhalation but selective β2
agonists have replaced isoprenaline.
2) Acute A.V. block, isoprenaline is given S.L. or I.V. infusion.
Adverse effects:
1) Marked tachycardia (both direct and reflex), palpitation, and anginal pains.
2) Hypotension.
3) Headache, flushing, and tremors.
Contraindications:
2) Angina pectoris.
3) Hypotension.

ANS
Summary of Catecholamines:
Adrenaline Noradrenaline Dopamine Dobutamine Isoprenaline
Source: Natural. Natural. Natural. Synthetic. Synthetic.
Chemist  Catechol. as adrenaline. as as adrenaline. as adrenaline.

ry  L-isomer is more adrenaline.
active.
 Unstable.
Kinetics:  Not absorbed. as adrenaline. as as adrenaline. as adrenaline.
 Poor passage adrenaline.
across BBB.
 Metabolism by
MAO and
COMT-uptake.
Route(s) 1. S.C. I.V. infusion (drip). I.V. infusion I.V. infusion 1-S.L.
: 2. Inhalation. (drip). (drip). 2-Inhalation.
3. Eye drops. 3- I.V. infusion
4. Nasal pack. (drip).
5. Intracardiac.
Agonist All α and β. Mainly α1 weak β1 1, α1.βD1, selective β1 β1,2,3 –no α
on: no β2.
no D or α.
Action ↑H.R. -↑A.B.P. ↓H.R. (reflex)- ↑H.R. Minimal effect H.R.↑↑both

on H.R. (↑systolic-variable ↑A.B.P. (↑both (slow- (more ino- than directly and
and effect on diastolic- systolic and moderate chrono- and no reflexly-
↑pulse pressure-
A.B.P.: diastolic-no effect rate)- effect on blood ↓A.B.P.
reversed after α-
blockers). on pulse pressure- ↑A.B.P vessels). (↓diastolic-
abolished after α- (rapid rate). variable effect
blockers). on systolic-
↑pulse
pressure).
Uses: 1-Anaphylactic To elevate A.B.P. in 1. Shock. 1. Cardiogenic 1-AV block.
shock. severe hypotension. 2. Heart shock (due 2-Asthma.
2-Cardiac failure. to
resuscitation.
myocardial
3-With L.A.
4-Decongestant infarction).
5-Hemostatic. 2. Heart failure.
6-Asthma.
7-Glaucoma.
8-Contraction ring
of uterus.

ANS
NON-CATECHOLAMINES
Common Characteristics:
1) They do not contain a "catechol" ring (nucleus).
2) They are well absorbed orally.
3) They can easily pass B.B.B. and exert marked CNS actions,
4) They are not metabolized by COMT and MAO (except tyramine) and are mainly excreted
unchanged in urine.
5) They have a relatively slow onset of action after oral administration, and long duration
of action compared to catecholamines.
N.B.: They may act directly on adrenergic receptors (as phenylephrine and salbutamol),
indirectly by stimulating noradrenaline release (as amphetamine and tyramine), or by dual
mechanism (as ephedrine). Remember that all catecholamines act as direct agonists on
adrenergic receptors.
EPHEDRINE
Source:
1) Natural: from plant origin (ephedra plant).
2) Synthetic.
Chemistry:
1) Non-catecholamine.
2) Alkaloid.
Pharmacokinetics:
1) Absorption: completely absorbed orally from lower part of small intestine (why?), can
be given by S.C. and I.M. injection and locally as eye drops and nasal drops.
2) Distribution: easily penetrates B.B.B.
3) Fate: not metabolized by COMT or MAO (may inhibit MAO), part is slowly metabolized
in liver and most is excreted unchanged in urine. Acidification of urine by vitamin C or
ammonium chloride increases its excretion.
Pharmacodynamics:
1) Mechanism of action: Dual mechanism of action:
a) Directly stimulates α and β- receptors (similar to adrenaline).
b) Indirectly by stimulation of noradrenaline release from adrenergic neurons leading to
stimulation of α and β1-receptors.
N.B.: Ephedrine markedly stimulates α-receptors by both direct and indirect mechanisms.

ANS
2) Pharmacological actions:
a) Local actions:
 On skin and mucous membranes: decongestion and hemostasis (α1-stimulation).It
may cause "rebound congestion" as it causes irritation.
 Eye: decongestion- ↓ IOP – active mydriasis except in negros with heavily
pigmented iris. This is known as "racial tolerance".
b) Systemic Actions:
Similar to adrenaline with the following differences:
 Slower onset of action (ephedrine is usually given orally).
 Longer duration of action (ephedrine is excreted unchanged in urine).
 Potent α effect (directly and indirectly).
 Marked CNS stimulation.
c) CVS:
 Heart: β1-stimulation causes increase in heart rate, conductivity, excitability,
contractility, COP, and myocardial oxygen consumption.
 Blood vessels: V.C. of skin and mucous membrane blood vessels by α1-
stimulation, and V.D. of skeletal muscles and coronary blood vessels due to
stimulation of β2-receptors.
 A.B.P.:
 Ephedrine elevates A.B.P.
 If ephedrine is injected I.V. it acts mainly indirectly, i.e. by releasing
noradrenaline from adrenergic nerves which in turn elevates both systolic and
diastolic B.P. and its hypertensive action is "abolished" not reversed by α-
blockers.
 "Tachyphylaxis" occurs on repeated injection.
d) Bronchi: bronchodilatation and decongestion.
e) GIT: relaxation of the wall and contraction of the sphincter.
f) Urinary bladder: relaxation of the wall and marked contraction of the sphincter
leading to urine retention.
g) CNS:
 Stimulation of cerebral cortex and reticular activating system leading to
wakefulness, alertness, and insomnia.
 Simulation of the vital medullary centres (R.C. and V.M.C. =analeptic).
h) NMJ: facilitation of neuro-muscular transmission.
i) Antiallergic action:
(NO metabolic actions & NO stimulation of hypothalamus).
Adverse effects:
As adrenaline (hypertension, tachycardia, arrhythmia, anginal pains) + urine retention
especially in prostatic hypertrophy + CNS simulation (insomnia) + tolerance (but no
addiction).

ANS
Therapeutic uses:
1) To prevent and treat severe hypotension during spinal anaesthesia, or due to overdose
of ganglion blockers and adrenergic neuron blockers.
2) Treatment of AV block.
3) Prophylaxis of bronchial asthma (long acting selective β2-agonists are better).
4) Mydriatic in fundus examination.
5) Nasal decongestant (local and orally, but local ephedrine causes rebound congestion as
it is irritant. Pseudoephedrine is better).
6) Treatment of narcolepsy (sudden and recurrent sleep attacks, amphetamine is better as
it is a more powerful CNS stimulant).
7) Adjuvant to neostigmine in myasthenia gravis.
8) Treatment of nocturnal enuresis.
Contraindications:
As adrenaline (hypertension, thyrotoxicosis, arrhythmia, angina) + prostatic hypertrophy in
old males.
Adrenaline Ephedrine
1) Source Natural in human body- synthetic. a) Natural from plant origin
b) synthetic.
2) Chemistry Catecholamine. Non-catecholamine
3) Pharmacokinetics a) Not absorbed orally. a) Well absorbed orally.
b) Poorly passes B.B.B. b) Penetrates easily B.B.B.
c) Undergoes uptake and c) Not metabolized by COMT
metabolism by COMT and or MAO.
MAO.
4) Mechanism of action Direct. Dual (direct and indirect)
5) Action on ABP a) Elevates systolic a) Elevates both systolic and
b) variable effect on diastolic diastolic
c) reversed by α1-blockers. b) abolished by α1-blockers.
6) Locally on eye a) Decongetion a) Decongestion

b) ↓IOP b) ↓IOP
c) No mydriasis except in c) Mydriasis except in
supersensitivity. negroes
7) CNS actions Weak. Marked
8) Skeletal muscles Weak action. Marked action (adjuvant in
myasthenia gravis
9) Effect of denervation Exaggerated action due to Decreases action
sympathectomy supersensitivity.
10) Tachyphylaxis No tachyphylaxis Tachyphylaxis occurs

ANS
AMPHETAMINE
Source: Synthetic.
Chemistry:
1) Non-catecholamine.
2) Basic drug.
3) L-isomer is more potent as sympathomimetic but D-isomer is more potent as CNS
stimulant.
Pharmacokinetics:
1) Well absorbed orally.
2) Easily penetrates B.B.B.
3) Partly metabolized by the liver and partly excreted unchanged in urine. Urinary
excretion can be enhanced by acidification of urine by NH4Cl or vitamin C.
Pharmacodynamics:
1) Mechanism of action: Indirect sympathomimetic by stimulation of noradrenaline
release from adrenergic neurons.
a) Sympathomimetic actions: the released noradrenaline stimulates α1-receptors
leading to V.C.→↑ ABP (both systolic and diastolic) → reflex bradycardia.
Stimulation of α1- receptors in dilator pupillae muscle causes active mydriasis.
b) CNS actions: amphetamine is a very potent CNS stimulant leading to:
 Euphoria, wakefulness, alertness, and antifatigue (increases mental and physical
activity), insomnia. These actions are followed by fatigue and dysphoria.
 Stimulation of R.C. and V.M.C. (analeptic action).
 Anorexigenic action.
 Stimulation of mono- and polysynaptic spinal cord reflexes.
 Potentiates the analgesic action of morphine.
 Tolerance and physical dependence (addiction) occur on prolonged use.
N.B.: Amphetamine causes sedation in children.
Therapeutic uses:
(Amphetamine is not commonly used nowadays)
1) Narcolepsy.
2) Attention Deficit Hyperkinetic Disorders in children (ADHD).
3) Treatment of obesity.
4) Nocturnal enuresis.

ANS
5) Psychic depression and to elevate mood in Parkinsonism and chronic alcoholics.

6) Treatment of acute toxicity of drugs that inhibit R.C. as morphine and barbiturates
(amphetamine has analeptic action).
Adverse effects:
1) Hypertension.
2) Reflex bradycardia.
3) Insomnia.
4) Anorexia and weight loss.
5) Tolerance and addiction (=chronic toxicity).
6) Acute toxicity
Manifestations:
hypertension- bradycardia- active mydriasis- insomnia- delirium and hallucinations
(psychotic manifestations) - convulsions, followed by coma and death due to depression of
R.C. (central respiratory failure).
Treatment:
1- Stomach wash if it was orally administered.
2- Artificial respiration in case of respiratory failure.
3- No specific antidote.
4- Symptomatic treatment: α1-blockers to treat hypertension- chlorpromazine
(antipsychotic) to treat psychotic manifestation- anticonvulsant as diazepam.
5- Increase the rate of urinary excretion by acidification of urine by ascorbic acid or
ammonium chloride.
Contraindications:
1) Hypertension.
2) Bradycardia.
3) Psychic disorders as schizophrenia.
Drug interactions:
With MAO inhibitors → hypertensive crisis (treated by α1-blockers,
Or a combination of α1- and β1- blockers but never use non-selective β-blockers alone
(why?).
Amphetamine derivatives:
1) D-amphetamine: very potent CNS stimulant with weak sympathomimetic actions.
2) Methamphetamine: as D-amphetamine.
3) Phenmetrazine, Diphenmetrazine, Diethylpropion, Fenfluramine, and Mazindol:
anorexigenic drugs used in treatment of obesity.
4) Methylphenidate and Modafinil: used in treatment of ADHD.

ANS
Question:
How to differentiate between acute atropine toxicity and acute amphetamine toxicity?
TYRAMINE
Source:
Naturally present in many foods as yoghourt, cheese, broad beans, salted fish and others.
Chemistry: non-catecholamine.
Pharmacokinetics:
1) Well absorbed orally.
2) Passes B.B.B.
3) Metabolized by MAO (in contrast to other non-catecholamines).
Pharmacodynamics:
1) Mechanism of action: indirect sympathomimetic by releasing noradrenaline from
adrenergic nerves.
a) in normal individuals tyramine has no pharmacological actions because it is
metabolized by MAO in liver
b) in patients suffering from psychic depression who are treated by MAO inhibitors,
tyramine will not be metabolized and releases noradrenaline which will accumulate
because MAO is inhibited. This causes severe acute hypertension known as
"hypertensive crisis" which may be fatal due to cerebral hemorrhage.
Important Notes:
1) The interaction between tyramine and MAO inhibitors is known as "CHEESE REACTION".
2) Hypertensive crisis is treated by α1-blockers, or a combination of α1- and β1- blockers
but never use non-selective β-blockers alone (why?).
3) The cheese reaction is a very famous example of "Drug-Food interaction".
Question:
Which patient can commit suicide by eating yoghourt and cheese?

ANS
α-AGONISTS
1) Adrenaline: stimulates α and β receptors
2) Noradrenaline:
stimulates mainly α1-receptors with weak action on β1-receptors and no action on β2-
receptors.
3) Selective α1-agonists:
a) Include:
 Phenylephrine
 Methoxamine
 Midodrine.
b) Actions:
 V.C. leading to: decongestion- hemostasis- prolongation of action of L.A.-
elevation of ABP (both systolic and diastolic)- and reflex bradycardia
 Active mydriasis.
c) Therapeutic uses:
 Phenylephrine and methoxamine are used in:
 Decongestion (applied locally to eye and nose or orally).
 Hemostatic in epistaxis (never in hypertensive patients).
 To prolong the action of L.A., to reduce their systemic effect, and to decrease
bleeding (never in fingers, toes, and circumscision).
 To elevate ABP in cases of severe hypotension (given by I.V.injection).
 Treatment of P.A.T. but avoid elevation of systolic B.P. above 160 mmHg.
 Fundus examination.
 Midodrine is a prodrug converted into active metabolite, given orally in treatment
of chronic postural (orthostatic) hypotension.
4) Nasal Decongestants:
They are α1-agonists given orally or locally (as nasal drops or nasal spray).
a) Local Nasal Decongestants:
 They include:
 Naphazoline
 Tetrahydrazoline
 Oxymetazoline
 Xylometazoline.
 Used in treatment of allergic rhinitis, sinusitis, and common cold.
 They do not cause rebound congestion but may cause drowsiness in children, and
long-term use may cause atrophy of olfactory mucosa and loss of smell sensation
(anosmia).

ANS
b) Systemic(Oral) Decongestants:
They include:
 Pseudoephedrine which is added to cold remedies
 Phenylpropanolamine which was withdrawn due to high incidence of
cerebrovascular (hemorrhagic) strokes.
N.B.: phenylephrine and ephedrine are used as a nasal decongestant orally and
locally, but local ephedrine is not preferred because it is irritant and causes "rebound
congestion".
β-AGONISTS
1) Non-Selective β-Agonists:
a) Adrenaline.
b) Isoprenaline.
c) Orciprenaline:
 non-catecholamine
 not metabolized by COMT or MAO
 given orally or by inhalation in bronchial asthma.
d) Isoxsuprine:
used in
 peripheral vascular diseases (PVD)
 contraction ring of the uterus.
2) Selective β1-Agonists:
a) Dobutamine.
b) Prenalterol:
 non-catecholamine which increases contractility without marked increase in heart
rate (more ino- than chrono-).
 Given orally or IV in treatment of heart failure
 tolerance to its action may occur.
3) Selecive β2-Agonists:
a) Include:
 Isoetharine: catecholamine metabolized by COMT.
 Salbutamol, Terbutaline
 non-catecholamines
 Short Acting selective β2Agonists = SABA
 used in treatment of acute attacks of bronchial asthma
 Salmeterol,Formoterol, Bambuterol
 non-catecholamines
 Long Acting selective β2Agonists = LABA
 used for prophylaxis of bronchial asthma.

ANS
 Ritodrine:
 non-catecholamine
 used as uterine relaxant (tocolytic) in:
 Contraction ring of the uterus
 premature labor
 threatened abortion
 dysmenorrhea.
b) Mechanism of action:
stimulation of β2-receptors → Gs stimulation ion of adenyl cyclase → ↑c-
AMP.
c) Pharmacological actions:
 V.D. especially of skeletal muscle blood vessels leading to decrease in ABP.
 Bronchodilatation, mast cell stabilization (inhibition of degranulation) and
inhibition of release of allergotoxins as leukotrienes, and reduction of bronchial
secretion.
 Uterine relaxation.
 Tachycardia (usually reflex following hypotension, but may be direct if given
repeatedly in large doses because "selectivity is not absolute").
 Tremors.
d) Therapeutic uses:
 Bronchial asthma: given orally, parenterally, and more commonly by inhalation
(salbutamol and terbutaline in acute attacks, salmeterol and formoterol in
prophylaxis).
 Contraction ring of the uterus, premature labor, threatened abortion, and
dysmenorrhea (ritodrine is commonly used).
e) Adverse effects:
 Tachycardia.
 Hypotension, headache, and flushing.
 Tremors.
 Nervousness and irritability.
 Tolerance due to down-regulation of receptors (can be avoided by co-
administration of cortisone).
 Hypokalemia.

ANS
Classification of Non-catecholamines
1) CNS Stimulants:
a) Amphetamine (D-isomer is more potent).
b) Methamphetamine.
c) Ephedrine.
2) Anorexigenics:
a) Phenmetrazine.
b) Fenfluramine and dexfenfluramine.
c) Mazindol.
3) Vasopressors:
a) Phenylephrine.
b) Methoxamine.
c) Midodrine.
N.B.:(Noradrenaline is a vasopressor 'catecholamine').
4) Nasal decongestants:
a) Naphazoline.
b) Xylometazoline.
c) Oxymetazoline.
d) Tetrahydrazoline.
e) Pseudoephedrine (oral).
5) Vasodilators and uterine stimulants:
a) Ritodrine.
b) Isoxsuprine.
6) Bronchodilators:
a) A-SABA: Salbutamol (Albuterol)-Terbutaline.
b) B-LABA: Salmeterol-Formoterol-Bambuterol.

ANS
Sympathetic Depressants
These are drugs that decrease sympathetic activity. They were formerly known as
"Sympatholytics".
They are classified into the following groups according to the mechanism of action:
1) Central α2-Agonists:
a) They stimulate α2-receptors centrally (
and C.A.C., accordingly decrease sympathetic outflow) and peripherally by
stimulation of presynaptic α2-receptors (↓ release of noradrenaline from adrenergic
neurons).
b) They include: Clonidine- α-methyldopa- Guanfacin- Guanabenz.
c) They induce renal V.D. and are therefore beneficial in hypertension with renal
insufficiency (impairment).
N.B.: Imidazoline receptor (I1) agonists as Rilmenidine and Moxonidine reduce V.M.C.
activity (as α2-agonists) leading to V.D. and decrease in A.B.P. and are available for
treatment of hypertension. They cause less sedation than central α2-agonists.
2) Ganglion Blockers:
a) They block Nn-receptors in autonomic ganglia (both sympathetic and
parasympathetic) and adrenal medulla.
b) They were used in treatment of hypertension but are not used nowadays because of
many adverse effects, except Trimetaphan which is used in emergency hypertension.
3) Adrenergic Neuron Depressants:

They act on the adrenergic neurons inhibiting one of the following steps:
a) Inhibition of noradrenaline synthesis: α-methyldopa (inhibits dopa decarboxylase)
and α-methyltyrosine (inhibits tyrosine hydroxylase).
b) Inhibition of noradrenaline storage: Reserpine.
c) Inhibition of noradrenaline release: Guanethidine and Bretylium.
4) Adrenoceptor Antagonists (Blockers):

a) α-blockers: as Phentolamine, Phenoxybenzamine,and Prazosin.
b) β-blockers: as Propranolol, Atenolol, Metoprolol, and Timolol.
c) β- and α-blockers: as Labetalol and Carvedilol.

ANS
1) Central α2-Agonists
a) Clonidine:
 Source: Synthetic.
- Well absorbed orally. Clonidine can be given as a transdermal patch.
- Passes B.B.B.
- Partly metabolized and partly excreted unchanged in urine.
- Mechanism of action: direct agonist on α2-receptors centrally and peripherally
(presynaptic).
- Pharmacological actions:
1) Stimulation of central α2-receptors
outflow from CNS → V.D. (and decrease in TPR) and
bradycardia (and decreased C.O.P.) and accordingly decrease ABP.
2) Stimulation of presynaptic α2-receptors → ↓release of noradrenaline from
adrenergic neurons→ V.D. and decrease in TPR, ↓ Heart rate and COP
(bradycardia is due to reduced sympathetic tone and predominance of
vagal tone).
3) Stimulation of α2 receptors in kidney→↓Renin release.
Both central and peripheral actions decrease A.B.P.
4) blocks postsynaptic α1 receptors on blood vessels → V.D.
5) Anti-serotonin action.
 Therapeutic uses:
1) Treatment of hypertension, including hypertension with renal impairment
(clonidine increases renal blood flow) and high renin hypertesion.
2) Prophylaxis of migraine headache.
3) Control of withdrawal symptoms in morphine and nicotine addicts.
4) Analgesic (given intrathecal).
 Adverse effects:
1) Rebound hypertension if clonidine is stopped suddenly. This is due to
upregulation of α1-receptors with chronic use of clonidine, it may be
accompanied by tachycardia (due to upregulation of β1-receptors). Rebound
hypertension can be treated by re-administration of clonidine (to reduce
noradrenaline release) or by α1-blockers ± β-blockers but never use non-
selective β-blockers without α1-blockers to avoid more hypertension by
unopposed α1-stimulation.

ANS
2) Sedation and drowsiness due to decreased sympathetic activity.

3) Dry mouth (may be due decreased acetylcholine release from cholinergic
neurons to salivary glands).
4) Bradycardia (see before).
 Drug interaction:
Tricyclic antidepressants (TCAs) inhibit neuronal reuptake of noradrenaline (cocaine-like
action) and antagonize the effect of clonidine.
N.B. Apraclonidine and brimonidine are α2 agonists used in treatment of glaucoma (as eye
drops), whereas tizanidine is a central α2 agonist used as central skeletal muscle relaxant.
b) Guanfacin and c) Guanabenz: similar to clonidine but have the advantages of

longer duration of action and less adverse effects.
d) α- Methyldopa:
1) Source: Synthetic.
2) Chemistry: derivative of DOPA (precursor of dopamine).
3) Pharmacokinetics:
i. Given orally but in undergoes extensive "gut first pass metabolism", so it has
low oral bioavailability (25%).
ii. Passes B.B.B.
iii. Excretion: inactive metabolites are excreted in urine.
4) Pharmacodynamics:
i. 1-α-methyldopa is converted into α-methyldopamine by dopa decarboxylase
then into α-methylnoradrenaline by dopamine β-hydroxylase.
ii. α-methyl noradrenaline acts as α2-agonist centrally and peripherally (on
presynaptic α2-receptors) leading to reduction in sympathetic outflow from
CNS and reduction in noradrenaline release from adrenergic neurons→ V.D.,
↓ TPR, ↓ heart rate and COP. It also ↓ renin release.
iii. This will decrease ABP.
iv. 2-α-methyldopa competitively inhibits dopa decarboxylase (identical to L-
aromatic amino acid decarboxylase) reducing synthesis of noradrenaline in
adrenergic neurons, and also reduction of synthesis of noradrenaline,
adrenaline, dopamine, and serotonin in CNS.
v. That is why the level of VMA (metabolic end product of noradrenaline and
adrenaline) and 5-HIAA (metabolic end product of serotonin) in urine are
reduced.

ANS
5) Therapeutic uses:
Treatment of hypertension especially with renal impairment (it increases renal
blood flow) and in hypertension during pregnancy (drug of choice).
6) Adverse effects:
i. Sedation, nightmares, and psychic depression (due to deficiency of
monoamines in CNS).
ii. Parkinsonism (iatrogenic Parkinsonism due to decreased dopamine in basal
ganglia).
iii. Hyperprolactinemia (due to reduction of dopamine which is "prolactin
inhibitory factor") causing galactorrhea-amenorrhea in females and
gynecomastia, loss of libido, and impotence in males.
iv. Hypersensitivity: fever, hepatitis (and may cause hepatotoxicity),
auto-immune hemolytic anemia (positive Coomb' test), and bone marrow
depression.
v. Dry mouth.
vi. Mild salt and water retention on prolonged use, so diuretics may be added to
α-methyldopa.
vii. Minimal bradycardia and diarrhea (due to parasympathetic predominance),
and mild nasal congestion and postural hypotension (due to reduced
sympathetic tone to veins →↓venous return→↓ COP and ABP).
7) Contraindications:
i. Allergy to the drug.
ii. Liver disease.
iii. Parkinsonism.
iv. Psychic depression.
2) Ganglion Blockers
a) Definition: They are drugs that block Nn (Ng) receptors in autonomic ganglia –both
sympathetic and parasympathetic-and in adrenal medulla.
b) Classification: They are classified into:
 Depolarizing (non-competitive) ganglion blockers, e.g. nicotine large dose. They
are not used clinically.
 Competitive (non-depolarizing) ganglion blockers, e.g. chlorisondamine,
mecamylamine, hexamethonium (C6), and trimetaphan.
 They were used in treatment of hypertension, but are not used anymore –except
trimetaphan-because of their adverse effects.

ANS
1) Emergency hypertension.
2) 2- Controlled hypotension: to decrease ABP during plastic surgery and
neurosurgery to ↓ bleeding.
3) Adrenergic Neuron Depressants (Blockers)

They include:
a) alpha-methyldopa (inhibits synthesis of noradrenaline in adrenergic neurons, but it is
considered mainly as a central α2-agonist), and alpha- methyltyrosine ( inhibits
synthesis of noradrenaline and adrenaline in adrenal medulla, so used in treatment
of pheochromocytoma).
b) Reserpine: inhibits storage of noradrenaline inside vesicles.
c) Guanethidine and Bretylium: inhibit release of noradrenaline from adrenergic
neurons. (Bretylium is also a class III antiarrhythmic drug).
Guanethidine Reserpine
1-Source: ●Natural (plant origin).
2-Absorption: ●Poorly absorbed orally. ●Well absorbed orally.
Given also as eye drops. Given also IV and IM.
3-Passage across BBB: ●Cannot pass BBB. ●Passes BBB.
4-Fate: ●Slowly excreted in urine- ●Excreted in urine-less
Cumulative. cumulative.
5-Mechanism of action: ●Inhibits neuronal uptake of ●Inhibits granular uptake of
noradrenaline noradrenaline and inhibits
noradrenaline from adrenergic its storage of
neurons of noradrenaline from
noradrenaline release from adrenergic nerves. It also
neurons (sometimes called depletes monoamines
pharmacological (noradrenaline, dopamine,
sympathectomy). No action on and serotonin) in CNS.
CNS or adrenal medulla.
6-Pharmacological actions: 1-V.D. → ↓TPR and ↓ABP. ●As guanethidine + CNS
2-Parasymathetic predominance actions due to depletion of
→bradycardia and ↓COP, monoamines leading to:
psychic depression-
↑salivary secretion, miosis and Parkinsonism- -
↓IOP.

ANS
7-Therapeutic uses 1- Hypertension (in chronic ●Hypertension (usually

cases, a diuretic is usually emergency). It was used in
added). 2-Glaucoma. treatment of psychosis.
8-Adverse effects: 1-postural and exertional ●As guanethidine + CNS
hypotension. adverse effect: sedation-
2-nasal congestion (stuffiness). psychic depression-
3-parotid swelling and pain. iatrogenic Parkinsonism-
4-failure of ejaculation. hyperprolactinemia
5-colics, diarrhea. (galactorrhea -amenorrhea
6-bradycardia. in females, gynecomastia,
7-Na+ and water retention impotence, and loss of
(↓COP and ABP→ ↓RBF). libido in males).
9-Contraindication 1-Pheochromocytoma (it 1-Psychic depression.

inhibits neuronal uptake and 2-Parkinsonism.
causes supersensitivity of α1- 3-Peptic ulcer.
receptors causing more 4-Hypotension.
elevation of ABP). 5-Bradycardia.
2-Hypotension.
3-Bradycardia.
4) Adrenoceptors Antagonists
1) α-Adrenoceptor Antagonists
(α-Blockers)
 Classification:
α-Blockers are classified according to their selectivity into:
1) Non-selective α-blockers:
 They block both α1- and α2-receptors.
 They include: Imidazoline α-blockers:Phentolamine-Tolazoline,
β-haloalkylamines: Phenoxybenzamine, and some ergot alkaloids as
Ergotamine (they act as partial agonists).
2) Selective α1-blockers:
Prazosin-Terazosin-Doxazosin-Trimazosin-Tamsulosin-Indoramin.
3) Selective α2-blockers:
Yohimbine: aphrodisiac (increases male sexual desire and performance).

ANS
N.B.: Many drugs have α-blocking action as labetalol and carvedilol (β-blockers),
chlorpromazine (phenothiazine antipsychotic), and tricyclic antidepressants (TCAs) but are
not categorized as α-blockers.
 Common Characteristics:
1) They are "competitive antagonists"; i.e. they compete with α-agonists as
adrenaline and noradrenaline on α-receptors, except Phenoxybenzamine which is
a non-competitive irreversible antagonist.
2) They "reverse" the hypertensive action of adrenaline and "abolish" the
hypertensive action of noradrenaline and ephedrine, except Yohimbine which is a
selective α2-antagonist.
3) They cause V.D. and are used in treatment of peripheral vascular diseases (P.V.D.)
as Raynaud's disease, except Ergotamine (causes V.C. as it is a partial agonist), and
Yohimbine (no effect on α1 receptors).
4) They
hypertension-except selective α1-blockers- because they cause tachycardia and ↑
COP by the following mechanisms:
a) Reflexly due to fall in ABP.
b) Block of pre-synaptic α2-receptors → ↑ release of noradrenaline from
adrenergic neurons innervating the heart β 1-receptors.
c) Selective α1-blockers as prazosin are useful in treatment of primary
hypertension because they do not block pre-synaptic α2-receptors, and they
produce minimal reflex tachycardia because they inhibit cardiac
phosphodiesterase (PDE) -AMP (induces
tachycardia) and c-GMP (induces bradycardia).
5) They relax the smooth muscles of the sphincter of the urinary bladder and the
prostate, and are useful in old male patients suffering from BPH to facilitate
micturition (Tamsulosin is the drug of choice).
 Common Therapeutic Uses:
1) Treatment of P.V.D.
2) Treatment of B.P.H. (Tamsulosin is the drug of choice and it is a selective α1A-
antagonist).
3) Treatment of hypertension secondary to pheochromocytoma (pre- and intra-
operatively and if the tumor is surgically inoperable) usually in combination with
β-blockers.
4) Treatment of rebound hypertension due to sudden withdrawal of clonidine,
hypertensive crisis in "cheese reaction", and if extravasation occurs during IV
infusion of noradrenaline or rapid rate of infusion of dopamine.

ANS
 Specific Therapeutic Uses:

1) Primary hypertension: selective α1-blockers as Prazosin.
2) Congestive heart failure: selective α1-blockers as Prazosin, they decrease both
venous return (preload) by venodilatation and TPR (afterload) by arteriodilatation
leading to increased COP in these patients.
3) Erectile dysfunction in males: Phentolamine is injected intracavernous with
papaverine (Inhibitors of PDE type 5 as sildenafil =viagra™ are now the most
commonly used drugs to treat erectile dysfunction, as they increase c-GMP→V.D.
and initiation and maintenance of erection).
4) Shock: phenoxybenzamine is used after correction of hypovolemia as it causes
V.D. and decreases release of ADH (vasopressin).
 Common Adverse Effects:

1) Postural hypotension due to arterio- and venodilatation (avoid in old patients).
2) Tachycardia (due to reflex action following arteriodilatation, and block of pre-
synaptic α2-receptors), except selective α1-blockers.
3) Nasal congestion (stuffiness).
4) Failure of ejaculation in males.
2) Imidazoline α-Blockers:
They include phentolamine and tolazoline.
Phentolamine:
b) Chemistry: chemically related to histamine.
c) Mechanism of action: competitive non-selective α-blocker.
d) Pharmacological actions:
 Blocks α1-receptors in blood vessels → V.D. of arteries and veins → ↓ABP (postural
hypotension), reflex tachycardia, nasal congestion.
 Blocks α1-receptors in urinary bladder
 Blocks α1-receptors in male sex organs
 Blocks pre-synaptic α2-receptors on adrenergic nerves→ ↑noradrenaline release →
β1-stimulation →tachycardia and ↑COP.
 Tachycardia and increased COP antagonizes the vasodilator action and accordingly it
is not useful in treatment of hypertension.
 Stimulation of histamine receptors (H1 and H2) due to chemical similarity leading to
V.D., bronchospasm, and increase in gastric acid.
 Stimulation of M-receptors leading to bronchospasm, increased gastric acid, and
increased GIT motility.
 Blocks 5-HT receptors (anti-serotonin action).

ANS
 P.V.D. as Raynaud's disease.
 B.P.H. (Tamsulosin is better).
 Pheochromocytoma (phenoxybenzamine is better).
 Treatment of rebound hypertension following sudden clonidine withdrawal,
hypertensive crisis due to cheese reaction, and severe V.C. after leakage of
noradrenaline infusion (extravasation).
N.B. Phentolamine was used in diagnosis of pheochromocytoma (causes more

hypotension in this case than in other causes of hypertension). This test was known as
"Regitine test"
f) Adverse effects:
 Postural hypotension.
 Tachycardia, arrhythmia, and anginal pains
 Nasal congestion.
 Failure of ejaculation.
 Bronchospasm.
 Hyperacidity, colics, and diarrhea.
g) Contraindications:
 Hypotension.
 Tachycardia, arrhythmia, and angina.
 Bronchial asthma.
 Peptic ulcer.
Tolazoline:
As phentolamine with less potent α-blocking action.
(Remember that tetrahydrazoline, xylometazoline, oxymetazoline, and naphazoline are α1-
agonists used as nasal decongestants, whereas tolazoline is α-blocker).
3) β-Haloalkylamines:
Phenoxybenzamine and Dibenamine:
a) Phenoxybenzamine is a prodrug.
Non-competitive irreversible, non-selective α-blocker. It has a slow onset (till converted
into active metabolite), and a long duration (till synthesis of new receptors).
c) Pharmacological actions:
 Blocks α1-receptors (as phentolamine).
 Blocks α2-receptors (as phentolamine).

ANS
Blocks H1-receptors = antihistaminic

Blocks 5-HT receptors. (anti-serotonin).
Blocks M-receptors = antimuscarinic = atropine-like action.
Inhibits neuronal uptake (uptake I) and extraneuronal uptake (uptake II) of
noradrenaline.
 7-Antishock: by V.D. and ↓release of ADH (vasopressin) from hypothalamus (don't
forget to fill up before open up).
d) Therapeutic uses: as phentolamine + shock (hypovolemic and endotoxic).
e) Adverse effects: common adverse effects (postural hypotension – tachycardia – nasal
congestion – failure of ejaculation) + sedation and drowsiness + atropine-like adverse
effects.
f) Contraindications:
 Hypotension.
 Tachycardia, arrhythmia, and angina.
 Glaucoma.
4) Selective α1-Blockers:
Prazosin:
a) Mechanism of action:
1. Competitive selective α1-blocker.
2. Inhibits phosphodiesterase enzyme (PDE) → ↑both c-AMP (which causes V.D. and
tachycardia) and c-GMP (which causes V.D. and bradycardia).
b) Pharmacological actions:
 V.D. of both arteries ( oad) by α1
block and increase c-AMP and c-GMP, and ↓ A.B.P.
 No (or minimal) tachycardia because:
1) No α2-blocking action and no increase in noradrenaline release.
2) Inhibition of PDE leading to increase in both c-AMP (↑ heart rate) and
3) c-GMP (↓heart rate).
 Relaxation of urinary bladder sphincter.
1. Treatment of essential (primary) hypertension (a diuretic may be added on
prolonged use).
2. Treatment of congestive heart failure (CHF) as it reduces both preload due to
venodilatation and afterload due to arteriodilatation. This increases COP in these
patients.
3. P.V.D. as Raynaud's disease.
4. Secondary hypertension due to pheochromocytoma.

ANS
5. BPH (Tamsulosin is more selective).

6. Rebound hypertension after sudden clonidine cessation, hypertensive crisis in
depressed patients treated by MAO inhibitors (cheese reaction), and severe V.C. if
extravasation of noradrenaline occurs.
d) Adverse effects:
1. "First dose phenomenon": severe postural hypotension after the first dose due to
potent venodilatation. It can be prevented by starting treatment with a small dose
given at bed time, then the dose is gradually increased.
2. Nasal congestion.
3. Failure of ejaculation.
4. Na+ and water retention due to decreased RBF, corrected by adding a diuretic.
5. Headache and dizziness (due to cerebral V.D.).
Question: How to correct hypotension induced by α-blockers as phentolamine?
2) β-Adrenoceptor Antagonists
(β-Blockers)
 Common Characteristics:
1) They are competitive antagonists that compete with β-agonists as adrenaline and
isoprenaline on β-receptors.
2) They block β1-receptors except Butoxamine which is an experimental drug acting as a
selective β2-blocker.
 Classification:
a) Classification according to selectivity:
1. Non-selective β-blockers= First generation β-blockers:
 They block both β1- and β2-receptors.
 Examples: Propranolol, Pindolol, Oxprenolol, Nadolol, Sotalol, and Timolol.
2. Cardioselective β-blockers= Selective β1-blockers= Second generation β-blockers:
 They block β1-receptors (but if given in large doses or for long periods, they can
block β2-receptors because "selectivity is not absolute").
 Examples: Atenolol, Metoprolol, Acebutolol, Bisoprolol, and Esmolol.
3. β-Blockers with additional action= Vasodilator β-blockers= Third generation β-
blockers:
 Labetalol and Carvedilol: they block β1, β2, and α1-receptors. Carvedilol has also an
antioxidant action.
 Celiprolol: blocks β1-receptor and is an agonist (or partial agonist) on β2-receptors.

ANS
 Nebivolol: blocks β1-receptor selectively and acts as a β2-agonist, and releases

nitric oxide (NO) causing vasodilatation. It is known as "nitrogenic β-blocker".
 Medroxalol.
 Bucindolol.
4. Selective β2-blocker: Butoxamine which has no clinical uses and used only
experimentally.
b) Classification according to degree of lipid solubility:

Most β-blockers are lipophilic drugs, and a few β-blockers are hydrophilic drugs as
Nadolol, Atenolol, Sotalol.
The differences between lipophilic and hydrophilic β-blockers are shown in the
following table:
Lipophilic β-Blockers Hydrophilic β-Blockers
1-Absorption: Well absorbed orally. Incomplete (poor-delayed) oral
absorption.
2-Distribution: Passes easily B.B.B.→marked CNS Poorly penetrates B.B.B.→weak

actions. CNS actions.
3-Plasma protein Highly bound to plasma proteins Less bound to plasma proteins
binding: and less liable to drug
interactions.
4-Fate: Mainly rapidly metabolized by Mainly excreted slowly

hepatic microsomal enzymes unchanged in urine → less liable
(HME) to drug interactions, but we
HME inducers and inhibitors. should adjust the dose
Metabolism is slow in cases of according to renal function.
decreased hepatic blood flow,
liver diseases, and if given with
HME inhibitors.
5-Duration and Short, requires frequent daily Long, given as single daily dose
t1/2: doses →poor compliance. →good compliance.
6-Examples: Propranolol-Oxprenolol-Pindolol- Nadolol-Atenolol-Sotalol.

Timolol-Metoprolol.

ANS
c) Classification according to "Membrane Stabilizing Activity"(MSA):

1) Some β-blockers have the ability to block Na+ channels leading to an additional
antiarrhythmic action known as "quinidine-like action", and local anaesthetic
action. Examples: Propranolol-Metoprolol.
2) Other β-blockers do not block Na+ channels and have no MSA. Examples: Nadolol-
Atenolol.
d) Classification according to "Intrinsic Sympathomimetic Activity"(ISA):

1) Most β-blockers are "pure antagonists", i.e. they block β-receptors without initial
stimulation. Examples: Propranolol- Atenolol- Metoprolol- Nadolol.
2) Few β-blockers have partial agonistic activity (P.A.A.), i.e. they stimulate β-
receptors before blocking them, and are said to have intrinsic sympathomimetic
activity (I.S.A.). Examples: Pindolol- Oxprenolol- Acebutolol.
1) PROPRANOLOL
 It is the" prototype" of all β-blockers.
 Source: Synthetic (all β-blockers are synthetic).
 Chemistry: Related to isoprenaline.
Propranolol is a lipophilic β-blocker:
a) Well absorbed orally, may be given parenterally.
b) Higly bound to plasma proteins.
c) Passes easily through B.B.B. and has marked CNS actions.
d) Has extensive 1st pass hepatic metabolism (it has low oral bioavailability, that is
why oral dose is much higher than the parenteral dose).

ANS
 Competitive non-selective β-antagonist. Propranolol is a pure antagonist and has
no ISA.
 Propranolol also blocks Na+ channels = MSA = L.A. action and antiarrhythmic
action (quinidine-like action).
1) CVS:
 Heart: blocking of β1-receptors leads to:
 action (↓heart rate and may cause
bradycardia). The effect of β-blockers on heart rate is more marked during
exercise than during rest.

heart including AV conduction).
 ↓excitability.
 ↓ myocardial contractility= negative inotropic action.
 ↓COP.
 ↓myocardial O2 requirements.
 The anti-arrhythmic action of propranolol is due to: β1-blocking action
(decreases excitability, automaticity, and conductivity) + membrane
stabilizing activity (MSA) due to Na+-channel block (quinidine-like).
 Blood vessels: blocking of β2-receptors in blood vessels leads to initial V.C.
especially in skeletal muscles, coronary, and hepatic blood vessels.
 ABP:
 At the start of treatment of hypertensive patients with propranolol; ABP is
not reduced although propranolol
especially in skeletal muscle blood vessels by blocking β2-receptors.
 After continous treatment with propranolol (at least for 4 weeks); ABP is
reduced due to the following mechanisms:
1) ↓COP.
2) ↓renin release by blocking β1-receptors in juxta-glomerular apparatus
in kidney.
3) ↓noradrenaline release from adrenergic neurons by blocking pre-
synaptic β-receptors.
4) 1-receptors
β
(propranolol is "lipophilic").
5) Re-setting of baroreceptors.
6) Stimulation of synthesis of vasodilator prostaglandins, as prostacyclin
(PGI2) and PGE2.

ANS
N.B.: Propranolol and all non-selective β-blockers "abolish" the hypotensive action of
isoprenaline and "augment" the hypertensive (pressor) action of adrenaline (they have no
effect on the hypertensive action of noradrenaline).
2) Bronchi:
 Propranolol and all non-selective β-blockers induce bronchospasm by blocking
β2-receptors in bronchial smooth muscles. This is very dangerous in asthmatic
patients as it may precipitate attacks of asthma.
 Cardio-selective β-blockers are less dangerous but remember that "selectivity
is not absolute".
3) Metabolic actions:
 ↓lipolysis by blocking β 1and β3-receptors and reduces free fatty acids.
 ↓glycogenolysis by blocking β 2-receptors in liver and skeletal muscles. This
may be dangerous in case of insulin-induced hypoglycemia.
 Long-term (chronic) use of propranolol may induce atherosclerotic changes as
it increases VLDL and LDL and decreases HDL (this is less marked with β-
blockers having ISA, and with cardio-selective β-blockers).
 ↓uptake of K+ by skeletal muscles, and may lead to "hyperkalemia", by
blocking β2-receptors in skeletal muscles.
Important Notes:
1) Hypoglycemia=stress → ↑sympathetic activity β 1-
stimulation), Glycogenolysis and increased blood glucose (β2-stimulation), and increased
sweating (M3-stimulation in thermoregulatory sweat glands).
2) Propranolol will mask the symptoms of hypoglycemia except sweating (why?). This may
lead to "silent hypoglycemia" and coma in diabetic patients receiving overdoses of
insulin or oral hypoglycemic drugs.
4) Eye:
 β -receptors (β2 mainly) in ciliary
body, and accordingly decrease IOP.
 No change in the size of the pupil and no action on the ciliary muscle.
 Local application of timolol may lead to systemic actions as bradycardia and
bronchospasm (how?).
5) CNS actions:
 Reduces anxiety by blocking β1-receptors in CNS.
 Reduces tremors mainly by blocking β2-receptors in skeletal muscles and
mainly by CNS action (propranolol is lipophilic).

ANS
6) Liver:
 V.C. of portal blood vessels decreases portal pressure in cases of portal
hypertension due to liver cirrhosis.
 Reduction of hepatic blood flow reduces HME activity leading to "non-specific"
or "indirect" HME inhibition which may decrease hepatic metabolism of drugs.
 Thearpeutic Uses of β-Blockers:
a) CVS:
1) Prophylaxis of angina pectoris (ischemic heart disease), useful in stable angina
and in unstable angina as it decreases cardiac work and myocardial oxygen
requirements, but it is contraindicated in variant=Prinzmetal angina=vasospastic
angina which is due to sudden coronary V.C. (due to supersensitive α1-receptors
in coronary blood vessels) as it leads to more V.C. due to "unopposed α1 effect.
2) Treatment of essential hypertension (propranolol decreases ABP after prolonged
use).
3) Treatment of supra-ventricular tachycardia (as PAT) and ventricular arrhythmias
(due to general anaesthesia, digitalis, β1agonists as adrenaline and isoprenaline,
acute myocardial infarction, thyrotoxicosis, and cardiac surgery).
(Β-blockers are "Class II" antiarrhythmic drugs).
4) After acute myocardial infarction (AMI) to decrease size of infarction, treat
arrhythmias, decrease cardiac work and myocardial oxygen requirements, and
increase survival (decrease mortality rate).
5) Acute dissecting aortic aneurism (with sodium nitroprusside).
6) Obstructive hypertrophic cardiomyopathy= chronic hypertrophic subaortic
stenosis (it may increase COP in this case by reducing cardiac muscle spasm).
7) Some β-blockers as metoprolol, carvedilol, and bisoprolol are given in small doses
(then the dose is gradually increased) in some cases of congestive heart failure
(class II-III heart failure but not in class IV). However; β-blockers are
contraindicated in "compensated" heart failure when COP is dependent on
sympathetic drive on the heart (see CVS pharmacology) and should never be
given suddenly or in large doses.
An additional benefit is by ↓ renin release and ↓ABP.
b) Liver:
 To reduce portal pressure in portal hypertension due to bilharzial or alcoholic
cirrhosis.
c) Eye:
 Teatment of glaucoma: Timolol, Betaxolol, Levobunolol, and Carteolol are used.
(Timolol may induce bronchospasm in asthmatic patients although it is given as
eye drops, how?).

ANS
d) Endocrine:
1) To control CVS symptoms (tachycardia, angina, and arrhythmia) and CNS
symptoms (anxiety, tremors and insomnia) of thyrotoxicosis.
Propranolol is the drug of choice because:
 Has no ISA.
 Passes B.B.B.
 Decreases conversion of T4 (active) into T3 (more active), i.e. it inhibits
peripheral de-iodination.
 Can be given orally (in chronic cases) and I.V. (in thyrotoxic crisis).
2) Treatment of pheochromoctoma but should be combined with α1-blockers, non-
selective β-blockers should never be used alone (why?).
e) CNS:
1) Prophylaxis of migraine headache.
2) Treatment of "situational anxiety".
f) Skeletal Muscles:
 To control tremors (as essential tremors in old age and tremors due to
Parkinsonism).

ANS
Adverse Effects Contraindications

1) Bradycardia (treated by atropine). 1) Bradycardia.
2) Decreases AV conduction and may cause AV block 2) AV block.

(treated by atropine).
3) Hypotension (no postural hypotension, WHY?). 3) Hypotension.
4) Bronchospasm especially in asthmatics. 4) Bronchial asthma.
5) Cold extremities, claudication, and fatigue (due to 5) Peripheral vascular diseases

V.C.). (PVD) as Raynaud's disease.
6) V.C. of coronary blood vessels especially in variant 6) Prinzmetal (variant or

angina. vasospastic) angina.
7) Unopposed α-effect if propranolol is used alone in 7) Never use non-selective β-

pheochromocytoma, rebound hypertension due to blockers ALONE in these
sudden clonidine withdrawal, and cheese reaction→ conditions (combine with α-
more hypertension. blockers, or use drugs blocking
both α-and β-receptors as
8) Decrease myocardial contractility and may labetalol).
precipitate heart failure.
8) Severe heart failure or if the
case is compensated by
9) Aggravate insulin-induced hypoglycemia and mask sympathetic stimulation.
the symptoms=silent hypoglycemia (except 9) Use non-selective β-blockers
sweating). "cautiously"in diabetics treated
by insulin or oral hypoglycemics.
10) Sexual dysfunction in males (decrease sexual desire
due to central effect). 10)Severe depression.
11) Increse in LDL and decrease in HDL causing 11) Never Stop β-Blockers Suddenly
atherosclerosis (non-selective β blockers mainly). (Abruptly).
12) Hyperkalemia especially in renal impairment.
13) CNS manifestations: sedation, sleep disturbances,

depression (lipophilic β blockers).
14) "Rebound" angina, arrhythmia, and even infarction

if suddenly stopped after chronic use, due to up-
regulation (and supersensitivity) of β1-receptors.

ANS
β-and α-Blockers:
1) Labetalol:
 Blocks β- and α1-receptors in a ratio of 3:1.
 Less potent than propranolol as β-blocker, and less potent than phentolamine as α1-
blocker.
 Decreases ABP by decreasing both COP and TPR.
 It causes V.D. and hypotension without reflex tachycardia (why?).
 Used in:
1. Essential hypertension, including emergency hypertension.
2. Pheochromocytoma (it is used alone).
2) Carvedilol:
 As labetalol: β and α1 blocker + Antioxidant.
Pheochromocytoma
a) Definition:
A tumor of the adrenal medulla secreting huge amounts of catecholamines; mainly
noradrenaline (90%) and to a less extent adrenaline (10%). This is in contrast to the
normal hormonal secretion from the gland.
b) Manifestations:
1) Hypertension (2ry hypertension) due to α1-stimulation is the main manifestation.
2) Tachycardia, arrhythmia, and anginal pains due to β1-stimulation.
c) Types:
1) Sustained type: in which the tumor secretes excessive catecholamines continuously.
2) Paroxysmal type: in which the tumor secretes excessive catecholamines in a
paroxysmal pattern.
d) Diagnosis:
1) Estimation of VMA in 24-hours urine. Normally VMA in 24-hours urine is 2: 6.5 mg.
2) Abdominal ultrasonography and C.T. scan.
3) Pharmacological tests: Sustained type was diagnosed by IV administration of
phentolamine which causes marked hypotension (25-35 mmHg in 5 minutes) in
pheochromocytoma than in patients suffering from hypertension due to other
causes (Regitine test).
Paroxysmal type was diagnosed by "provocative tests" by methacholine TEA, or
histamine which induce release of catecholamines from the tumor (may cause acute
hypertension and cerebral hemorrhage).

ANS
e) Treatment:
 Treatment is mainly surgical (excision of the tumor).
 Medical treatment: pre-operatively and intra-operatively to control ABP before and
during surgery, and in inoperable tumors. Drugs used are:
1) α1-blockers, e.g. phenoxybenzamine, phentolamine, and prazosin.
(phenoxybenzamine is preferred because it is a non-competitive irreversible
blocker and is the most potent α1-blocker).
2) β-blockers may be added to α-blockers to control cardiac symptoms.
3) drugs blocking both β and α receptors may be used as labetalol and carvedilol.
4) α-methyl tyrosine: inhibits synthesis of noradrenaline and adrenaline.
f) Drugs contraindicated in pheochromocytoma:
1) Non-selective β-blockers alone (without α1-blockers, WHY?).
2) Drugs blocking neuronal uptake (uptake I) of noradrenaline as guanethidine.
3) Sympathomimetics.

Pharmacology of The Eye 2011/2012
Pharmacology of The Eye

(Ocular Pharmacology)
Autonomic Innervation of the Eye:

1. Sympathetic innervation:
 To dilator pupillae muscle = DPM: causes active mydriasis.
 To conjunctival blood vessels: causes V.C. and decongestion.
 Theses actions are due to stimulation of α1-receptors.
2. Parasympathetic innervation
 (through occulomotor nerve = 3rd cranial nerve):
 To constrictor pupillae muscle = CPM: causes miosis.
 To ciliary muscle: causes accommodation to near vision.
 Widening of the spaces of Fontana due to miosis, widening of the canal of Schlemm
due to contraction of the ciliary muscle, and increased drainage of aqueous humor
and decreased IOP.
 To lacrimal glands: increases lacrimation.
 These actions are due to stimulation of muscarinic receptors (M3).
Autonomic Receptors in the Eye:

1. α1-receptor: stimulation of this receptor leads to:
a) Active mydriasis due to contraction of DPM.
b) V.C. and decongestion of conjunctival blood vessels.
c) and ↓IOP.
2. α2-receptor in the ciliary body: stimulation leads to ↓ c-AMP and ↓aqueous humor
synthesis, and ↓IOP.
3. β-receptor in the ciliary body: stimulation leads to ↑c-AMP and ↑ aqueous humor
synthesis.
4. M-receptor: stimulation of this receptor leads to:
a) Miosis due to contraction of CPM.
b) Accomodation to near vision due to contraction of the ciliary muscle.
c) ↑ drainage of aqueous humor and ↓ IOP.
d) V.D. and congestion of conjunctival blood vessels (M3-receptors on blood vessels are
non-innervated).
e) Lacrimation.
5. Nm-receptors in skeletal muscles of the eye lids, stimulation leads to twitches.
1 Dr.Ahmed Abdel Rahman www.medadteam.org

Reflexes:
1. Light reflex: is abolished by local application of anti-muscarinic drugs
(parasympatholytics) as atropine, hyoscine, and synthetic atropine substitutes, and by
systemic administration of ganglion blockers.
2. Sensory reflex (corneal and conjunctival reflexes): is abolished by local surface
anaesthetics as cocaine (causes active mydriasis) and tetracaine (no mydriasis).
Drugs Acting on the Eye

1) Drugs Affecting the Size of the Pupil:
a) Miotics:
1. Muscarinic Agonists (Parasympathomimetics):
 Actions:
Miosis-Accomodation to near vision-↑drainage of aqueous humor- ↓IOP-
Lacrimation- V.D. of conjunctival blood vessels (congestion).
 Examples:
Choline esters: Carbachol- Bethanechol.
Cholinomimetic alkaloids: Pilocarpine.
Reversible anticholinesterases: Physostigmine-Neostigmune- Demecarium.
Irreversible anticholinesterases: Echothiophate-Isofluorophate=DFP (long acting-
better avoid chronic use as it may cause cataract).
N.B.:
Carbachol and all anticholinesterases cause "twitches" of the eye lids because they
stimulate Nm-receptors in the skeletal muscles of the eye lids, whereas Pilocarpine, and
Bethanechol do not cause twitches as they do not have nicotinic actions.
a) Treatment of glaucoma.
b) To counteract mydriatics.
c) To cut recent adhesions between iris and lens in cases of iritis, they are used
"alternatively" with mydriatics.
2. Guanethidine:
 Actions:
Decreases release of noradrenaline from adrenergic (sympathetic) nerves leading
to parasympathetic predominance causing miosis and decrease IOP.
Treatment of glaucoma.

3. Morphine:
 Action: morphine causes miosis when given systemically by stimulation of specific
opiate receptors in 3rd nerve nucleus (Edinger-Westphal nucleus), this is
sometimes known as "central miosis".
N.B.
 Acute morphine toxicity causes severe miosis known as "Pin Point Pupil=PPP".
 Miotic action of morphine is antagonized by: local atropine and systemic naloxone
(opiate receptor antagonist).
b) Mydriatics:
1. Active Mydriatics: they stimulate α1-receptors in DPM, either directly or indirectly (see
later).
 Actions:
a) Active mydriasis.
b) Light reflex is present (intact-preserved), and no cycloplegia.
c) V.C. and decongestion of conjunctival blood vessels.
 They include:
a) Direct α1-Agonists (direct sympathomimetics): Phenylephrine.
b) Indirect (indirect sympathomimetics): Amphetamine stimulates noradrenaline
release from adrenergic nerves.
c) Dual action: Ephedrine (remember that ephedrine does not cause mydriasis in
negros=racial tolerance).
a) Fundus examination.
b) Decongestion.
c) Alternatively with miotics to cut recent adhesions in iritis.
N.B.:
1. Adrenaline applied locally in the eye does not cause mydriasis except in cases of
supersensitivity (see adrenaline).
2. Active mydriatics do not cause cycloplegia.
Cocaine:
 Indirect α1-agonist by inhibition of neuronal reuptake of noradrenaline (uptake I), and
MAO inhibition α 1-stimulation.
 Local surface anaesthetic.
 loss of sensory reflex.

2. Passive Mydriatics:
a) Anti-Muscarinic Drugs (Parasympatholytics):
 Actions:
1. Passive mydriasis by blocking M-receptors in CPM.
2. Light reflex is absent (abolished).
3. Cycloplegia (paralysis of the ciliary muscle) by blocking M-receptors.
4. Xerophthalmia (dryness of the eye due to block of M-receptors in lacrimal
glands).
5.
6. No effect on conjunctival blood vessels.
 Examples:
1. Atropine and hyoscine (natural belladonna alkaloids).
2. Homatropine, tropicamide, eucatropine, and cyclopentolate (synthetic atropine
substitutes).
1. Fundus examination (except atropine).
2. Atropine is used in irits, iridocyclitis, and corneal ulcer and measurement of the
errors of refraction in children.
 Contraindication:
Glaucoma.
b) Ganglion Blockers:
They cause passive mydriasis when given systemically.
In Experimental Pharmacology Exam:

An unknown drug is applied locally (topically) into a rabbit's eye, it may produce:
1. Miosis + Twitches of eye lids = Muscarinic AND Nicotinic agonist (Carbachol,
Physostigmine, Demecarium, Ecothiophate, and DFP).
2. Miosis – Twitches of eye lids = Muscarinic agonist WITHOUT nicotinic action
(Bethanechol and Pilocarpine).
3. Mydriasis + light reflex + sensory reflex = α1-agonist (Phenylephrine, Amphetamine,
and Ephedrine).
4. Mydriasis + light reflex – sensory reflex = Cocaine.
5. Mydriasis – light reflex + sensory reflex = Anti-muscarinic drug (Atropine, Hyoscine,
Homatropine, Tropicamide, and Cyclopentolate).

GLAUCOMA
 Glaucoma is elevation of IOP (normally IOP is between 15-25 mmHg.).

 It is considered as "imbalance between rate of formation of aqueous humor by the ciliary
epithelium and the rate of drainage".
 Drainage of aqueous humor occurs by 2 routes: 1-Conventional route through the
trabecular network into the canal of Schlemm, it drains about 90%. 2-Uveo-scleral
pathway through the ciliary body into the suprachoroidal space, it drains about 10%.
Types and Treatment:

a) Wide (Open) Angle Glaucoma:
 It is due to imbalance between formation and drainage of aqueous humor. It is
usually chronic and is treated medically by:
1. Muscarinic agonists (parasympathomimetics) acting as "miotics" which increase
drainage of aqueous humor: carbachol-bethanechol-pilocarpine-physostigmine-
neostigmine-demecarium
N.B.:
1. Ecothiophate and DFP are long acting but are not preferred as they may produce
irritation and congestion, and may induce cataract.
2. Physostigmine use is limited due to allergic reactions.
3. Parasympathomimetics applied locally in the eye may lead to systemic adverse effects as
bradycardia and bronchospasm.
2. Sympathomimetics (α1-Agonists): they decrease formation of aqueous humor by
V.C.: adrenaline (causes irritation and pigmentation of conjunctiva)-dipivefrin
(prodrug converted into adrenaline inside the eye, more lipophilic and less irritant
than adrenaline). They also cause active mydriasis.
N.B.: mydriatics should be avoided in narrow angle glaucoma.
3. Sympathetic Depressants:
 β-Blockers: block β-receptors in ciliary body→↓c-AMP
aqueous humor: timolol-betaxolol-levobunolol-carteolol. They do not change
the size of the pupil.
(Remember that timolol can precipitate asthmatic attacks in susceptible
patients, HOW?).
 α2-Agonists: stimulate α2-receptors in the ciliary body → ↓c-AMP→
: apraclonidine-brimonidine. No change in the
size of the pupil.
 Guanethidine: inhibits noradrenaline release
predominance→miosis and increased drainage of aqueous humor.

4. Carbonic Anhydrase Inhibitors:

 They decrease formation of aqueous humor.
 They do not change the size of the pupil.
 They may be given topically as dorzolamide and brinzolamide, or systemically as
acetazolamide and dichlorophenamide.
5. PGF2α-analogues: they increase drainage of aqueous humor through the
uveoscleral outflow, they may cause irritation and pigmentation of the iris.
Examples: latanoprost, travoprost, and bimatoprost. No change in pupil size
occurs.
b) Narrow (Closed) Angle Glaucoma:

 It is due to occlusion of the angle of filtration by the root of the iris. It may be acute
and is usually treated surgically by iridectomy. Drugs are used to lower IOP before
surgery and in acute conditions and include:
1. Short acting miotics: pilocarpine (drug of choice), physostigmine, carbachol. Avoid
long acting miotics (organophosphorous compounds as echothiophate) as they
cause congestion and severe miosis.
2. Dehydrating agents (osmotic agents): mannitol (I.V.infusion), magnesium
sulphate (rectal enema) ,isosrbide (orally) in acute congestive glaucoma.
3. Carbonic Anhydrase Inhibitors: given locally as dorzolamide or orally as
acetazolamide.
4. Alpha 2 agonists as Brimonidine.
N.B.:
1. Avoid mydriatics in closed angle glaucoma. .
2. Recently Beta blockers are used with pilocarpine.
Drugs Contraindicated in Glaucoma:

1) Antimuscarinic drugs: atropine, hyoscine, and synthetic substitutes homatropine,
tropicamide, and cyclopentolate.
2) Ganglion blockers: e.g trimetaphan.
3) Drugs with atropine-like action: 1st-generation antihistaminics-some antiarrhythmic
drugs as disopyramide-Tricyclic antidepressants-Phenothiazine antipsychotics.
4) Glucocorticoids: such as cortisol, may also cause cataract.
5) Vasodilators: as nitrates and fenoldopam.
6) Succinylcholine: depolarizing neuro-muscular blocker.

Miscellaneous Drugs Affecting The Eye

a) Toxic Drugs on the Eye:
1. Glucocorticoids: may cause glaucoma and cataract. Immunosuppressive action may
cause 2ry infection.
2. Digitalis: causes disturbance of green and yellow vision (chromatopsia).
3. Ethambutol: anti-T.B., causes optic neuritis.
4. Chloroquine: anti-malarial and anti-inflammatory, causes retinopathy.
5. Chlorpromazine: phenothiazine antipsychotic, causes corneal and lens deposits.
6. Indomethacin: NSAID, may cause corneal deposits.
7. Methyl alcohol (Methanol): metabolized into formaldehyde which is retinotoxic
causing blindness (see general pharmacology).
b) Diagnostic Drugs used in the Eye:

1. Fluorescin dye: used in diagnosis of corneal ulcers.
2. Hydroxyamphetamine:
 Amphetamine derivative which stimulates release of noradrenaline from
sympathetic post-ganglionic adrenergic neurons. In contrast to amphetamine it
has weak CNS actions.
 It is used to differentiate between pre-ganglionic and post-ganglionic injury in
"Horner's syndrome" (injury of the sympathetic supply of the face causing ptosis,
miosis, and anhydrosis). Hydroxyamphetamine causes mydriasis in pre-ganglionic
lesions but cannot induce mydriasis if there is post-ganglionic lesion.
c) Anti-allergic Drugs in the Eye:

1. Antihistaminics (H1-Blockers): antazoline.
2. Glucocorticoids: cortisol, predisolone, dexamethasone.
3. Mast-cell Stabilizers: disodium cromoglycate.
d) Anti-inflammatory Drugs in the Eye:

1. NSAIDs: diclofenac.
2. Steroidal Anti-inflammatory drugs=Glucocorticoids.
e) Local Anaesthetics in the Eye:

1. Surface anaesthetics: tetracaine(no mydriasis)and cocaine ( causes active mydriasis
and V.C.), used in minor procedures as foreign body extraction.
2. Infiltration anaesthetics: lidocaine and procaine, used in eye surgery as cataract.

f) Treatment of Eye Infections:

1. Antibacterial drugs: chloramphenicol, tobramycin, penicillin, tetracycline,
sulphonamides, and norfloxacin.
2. Antiviral drugs: acyclovir in treatment of Herpes simplex virus.
3. Antifungal drugs: amphotericin B, and azoles as ketoconazole.
4. Antiseptic drugs: boric acid lotion and zinc sulphate in conjunctivitis.
g) Conjunctival Irritants:
1. Chloroacetophenone=Tear gas: causes lacrimation.
2. Ethyl morphine: causes irritation of conjunctiva leading to V.D. and stimulates healing
of corneal ulcers.

Autacoids 2011/2012
AUTACOIDS
Autacoids are biologically active substances of heterogenous chemical structures, which
may be involved in some pathological conditions, and are known as "Locally- acting
hormones".
Classification:
Autacoids are classified chemically into:
a) Amino Acid derivatives:
1. Histamine (derived from histidine).
2. Serotonin = 5-Hydroxytryptamine = 5-HT (derived from tryptophan).
b) Vasoactive Peptides:
1. Angiotensin.
2. Kinins: bradykinin and kallidin.
3. Substance P.
4. Endothelin.
5. Vasoactive Intestinal Peptide (VIP).
6. Atrial Natriuretic Peptide (ANP).
c) Eicosanoids (Fatty acid derivatives):
1. Prostaglandins.
2. Leukotrienes.
d) Others:
Cytokines as interferons
1- HISTAMINE
Synthesis:
histidine
L-Histidine ▬▬▬▬▬▬► Histamine
decarboxylase
Storage:
Histamine is stored in mast cells (with heparin), in basophils, and other cells. Histamine is
abundant in epidermis of skin, lungs, and GIT.
Release:
1-Antigen-antibody reactions (allergy or immunological reactions).
2-Physical and chemical injury.
3-Proteolytic enzymes.
4-Insect bites and snake venom.

Autacoids 2011/2012
5-Drugs: some basic drugs as morphine, trimetaphan, curare, succinylcholine, and atropine
(large and toxic doses) may induce histamine release, and are known as "histamine
liberators"..
Pharmacodynamics:
Mechanism of action:
Histamine stimulates specific G-protein coupled receptors:
Receptor Signal transduction Sites Actions

H1 Gq 1. Smooth muscle fibers 1. Spasmogenic effect.
PLC→ ↑DAG and as bronchi, GIT, uterus. 2. Vasodilatation and
IP3→↑ Ca2+. 2. Endothelium of Blood increase capillary
vessels. permeability by
increasing synthesis of
nitric oxide.
3. Skin and sensory nerve 3. Itching, urticaria, triple
endings. response, pain.
4. CNS (post-synaptic). 4. Alertness.
H2 Gs→ activation of 1. Parietal cells of the 1. Stimulate secretion of
A.C.→ ↑c-AMP. stomach. HCl and pepsin.
2. Heart. 2. Increase cardiac
properties (+ve inotropic,
+ve chronotropic).
3. Blood vessels. 3. Vasodilatation.
4. CNS (post-synaptic). 4. Alertness.
H3 Gi CNS (pre-synaptic). ↓ Release of
A.C.→↓ c-AMP. neurotransmitters.
H4 Gi Inflammatory cells as CD4 Modulation of cytokines.
A.C.→↓ c-AMP. T lymphocytes-
Neeutrophils-Esinophils.
1-Stomach: histamine stimulates HCl and pepsin secretion from the parietal cells by acting
on H2-receptors (histamine is the most powerful secretagogue),
2-Smooth muscle fibres: histamine is spasmogenic on the bronchi, GIT and uterus by acting
on H1-receptors.
3-Skin:
 Itching (pain occurs if histamine is deeply injected).
 Triple response: localized redness (due to capillary V.D.) – spreading redness=flare due
to arteriolar V.D. - localized edema (wheal) due to increased capillary permeability.
 These actions are mediated by H1 receptors.

Autacoids 2011/2012
4-CVS:
 Heart: myocardial stimulation, both directly by H2-receptor stimulation, and reflexly
following V.D. and hypotension.
 Blood vessels: V.D. by stimulation of H1- and H2 –receptors (mainly H1).
 ABP: Hypotension due to V.D. and increased capillary permeability, and anaphylactic
shock may occur in severe allergy.
5-Stimulation of catecholamines release from adrenal medulla: both directly and reflexly
following hypotension.
6-CNS: Arousal (H1-mainly).
Indications:
Histamine has no therapeutic uses nowadays.
Histamine Antagonists:
1. Pharmacological Antagonists:
a) H1-Antagonists = Antihistaminics = Antiallergic drugs.
b) H2-Antagonists: Cimetidine-Famotidine-Ranitidine-Nizatidine.
Used in treatment of peptic ulcer (see GIT pharmacology).
2. Physiological Antagonist:
"Adrenaline is the physiological antagonist of histamine" (2 different agents acting on 2
different receptors causing 2 opposing actions).
3. Inhibitors of Histamine release:

a) Glucocorticoids: inhibit antibody formation and antigen-antibody reaction, and
accordingly inhibit histamine release.
b) Mast Cell Stabilizers = Degranulation inhibitors as disodium cromoglycate=cromolyn,
and nedocromil (see pharmacology of Respiratory system).
4. Desensitization.

Autacoids 2011/2012
H1-Antagonists (Antihistaminics-Antiallergics)
 All antihistaminics are competitive antagonists with histamine on H1-receptors.

 All antihistaminics are "Antiallergic drugs" used in treatment of allergic conditions such
as: skin rash- urticaria- angioneurotic edema-anaphylactic shock (remember: adrenaline
is life-saving in anaphylactic shock).
Pharmacokinetics:
1. They can be given orally, parenterally, and topically as skin ointment-eye drops-nasal
drops-and ear drops.
2. "First generation" antihistaminics can pass easily B.B.B. whereas "Second generation"
drugs poorly penetrate B.B.B.
3. Pass placental barrier and may be teratogenic in experimental animals (Cyclizine-
Meclizine).
4. Metabolized by the liver and excreted in urine, and are partly excreted in breast milk.
N.B.:
1. Antihistaminics are not essential in treatment of bronchial asthma because the role of
histamine is insignificant.
2. Treatment of anaphylactic shock: Adrenaline (Life saving) + Corticosteroid +
Antihistaminic.
Classification:
First Generation=Sedating Antihistaminics. Second Generation= Non-
sedating Antihistaminics
●Pass B.B.B. and cause sedation and drowsiness, ●Poor passage through B.B.B. and do
but toxic doses cause hallucination, excitation and not have CNS actions, i.e. No sedation
convulsions. They have anti-emetic (by blocking H1 and no antiemetic action.
and M receptors in the medullary vomiting centre)
and anti-parkinsonian (by blocking M receptors in
basal ganglia) actions.
-6 hours) due to rapid -24 hours) due to
metabolism by hepatic microsomal enzymes. slower metabolism by hepatic
microsomal enzymes (mainly CYP
3A4).
Actions: Actions:
1. Antihistaminic action: antagonize the actions of 1. Antihistaminic action: antagonize
histamine on H1-receptors in blood vessels, the action of histamine on H1-
bronchi, GIT, and skin. receptors in blood vessels, bronchi,
and skin.

Autacoids 2011/2012
2. Atropine-like actions leading to: 2. No atropine-like action

a) Antiemetic action including in motion accordingly:
sickness. a) No antiemetic action.
b) Antiparkinsonian action. b) No antiparkinsonian action.
c) Urine retention (contraindicated in BPH). c) Not contraindicated in BPH.
d) ↑IOP (contraindicated in glaucoma). d) Not contraindicated in
glaucoma.
3. Some have Na+-channel blocking action 3. No Na+-channel blocking action.

(Membrane stabilizing action) leading to
Local anaesthetic action and Antiarrhythmic
action (Quinidine-like action); e.g: Antazoline.
4. Some have Antiserotonin action leading to 4. No antiserotonin action.

stimulation of appetite; e.g.Cyproheptadine.
5. α-blocking action. 5. No α-blocking action.
 Examples:  Examples:
 Diphenhydramine, Dimenhydrinate,  Astemizole.
Promethazine  Cetrizine.
 (antiemetics and antiparkinsonian).  Loratadine.
 Meclizine and Cyclizine (antiemetics but  Terfenadine (was withdrawn as
contraindicated in pregnancy, being it may cause fatal arrhythmias).
"teratogenic").  Fexofenadine (is the active
 Chlorpheniramine maleate (in common cold metabolite of terfenadine but is
medications)-Antazoline (antiarrhythmic). safe, sometimes it is referred to
 Clemastine and Chemizole. as "Third Generation"
 Cyproheptadine (also antiserotonin) - antihistaminic).
Mepyramine (in experimental
pharmacology)- Ketotifen (also
antiserotonin and a mast cell stabilizer) –
Hydroxyzine – Carbinoxamine.

Autacoids 2011/2012
First Generation=Sedating Antihistaminics Second Generation=Non-sedating

Antihistaminics
 Therapeutic uses:  Therapeutic uses:
1. Treatment of allergic conditions (allergic Treatment of allergic conditions
rhinitis, rash, urticaria, angioneurotic (rash, urticaria, angioneurotic
edeme, and anaphylactic shock). edema, and anaphylactic shock).
2. Antiemetics in motion sickness, vertigo
and Meniere's disease.
3. Parkinsonism (Diphenhydramine).
4. Arrhythmias (Antazoline).
5. Anxiety and insomnia (situational).
 Adverse effects:  Adverse effects:

1. Sedation and drowsiness. Cardiac arrhythmias especially in
2. Excitement, hallucinations, convulsions, overdose or if given with HME
and may be coma in acute toxicity. inhibitors as erythromycin and
Excitation is more common in children. ketoconazole.
3. Teratogenicity (Cyclizine and Meclizine).
4. Allergic reactions.
5. Atropine-like adverse effects as dry
mouth, constipation, urine retention,
tachycardia, and elevation of IOP.
 Contraindications:
1-Car drivers. 2-Pregnancy. 3-Glaucoma. 4-BPH.

Autacoids 2011/2012
2- EICOSANOIDS
They include:
1. Prostaglandinds (prostanoids).
2. Leukotrienes.
They are not stored in the body but are synthesized and rapidly metabolized, they have very
short duration
Cell Membrane Phospholipids
Phospholipase A2 Phospholipase C
(inhibited by cortisol)
DAG
DAG lipase
Arachidonic Acid
Cyclooxygenases (COX) 5-lipooxygenase (LOX)
(inhibited by NSAIDs) (inhibited by Zileuton)
Prostaglandins G2 and H2 5-HPETE and HETE
Prostaglandin Prostacyclin Thromboxane A2

synthetase synthetase synthetase Leukotrienes
(A4, B4,C4,D4,E4,F4)
PGs E,F PGI2 TXA2
(prostacyclin) (Thromboxane A2)
DAG: Diacyl glycerol. 5-HPETE: 5-Hydroperoxyeicosatetraenoic acid. HETE:

Hydroxyeicosatetraenoic acid.

Autacoids 2011/2012
PGs act on specific G-protein coupled receptors, known as EP-FP-DP-IP-and TP which are
stimulated by PGE2-PGF2α-PGD2-PGI2-and TXA2, respectively.
Actions of PGs:
1. CNS:
a) Pain (algesic action): PGs stimulate pain transmission in the thalamus and sensitize
pain receptors to serotonin and kinins.
b) Fever (pyrctic action): PGs elevate the set point of hypothalamic heat regulating
centre (HRC):
Pyrogens
↑ production of PGE2 H.R.C.
2. Inflammation:
PGs are very potent inflammatory mediators.
3. Eye:
PGF2α increases drainage of aqueous humor through the uveoscleral pathway
and accordingly decreases IOP. It does not change the size of the pupil.
4. Female reproductive system:

a) Uterus: PGs –especially PGF2α and PGE2 stimulate uterine contractions
(oxytocic action) leading to induction of abortion and pregnancy and controlling
post- partum hemorrhage.
b) PGs play an important role in fertilization and ovulation.
5. Male reproductive system:

a) PGE1 enhances erection.
b) PGE and F may have a role in male fertility.
6. GIT:
a) Stomach: PGE and PGI are Cytoprotective by: reducing HCl secretion – increasing
mucus secretion – increasing bicarbonate in duodenum – increasing blood flow to
promote healing of damaged mucosa.
b) Small intestine:
PGs increase motility leading to colics and diarrhea.

Autacoids 2011/2012
7. Bronchi:
Some PGs are bronchodilators as PGE and I, but others as PGF2α and TXA2 cause
bronchospasm.
8. CVS actions:
a) Some PGs, as PGE and PGI, are vasodilators but TXA2 and PGF2α cause V.C.
b) PGE2 maintains the patency of Ductus Arteriosus during fetal life.
c) Recently it is assumed that PGE2 induces angiogenesis which may be the cause of
cancer colon.
d) Platelets: PGI2 inhibits platelet aggregation and TXA2 stimulates platelet aggregation.
9. IX-Kidney:
PGs increase renal blood flow by V.D. of renal blood vessels. PGI2 increases renin
release.
N.B.:
PGI2 is synthesized from the intact endothelium of blood vessels causing V.D. and
inhibition of platelet aggregation, whereas TXA2 is synthesized from platelets in cases of
injury of blood vessels and is "hemoststic" by causing V.C. and stimulation of platelet
aggregation.
Actions of Leukotrienes:
LTs act on specific G-protein coupled receptors known as "cysteinyl leukotriene
receptors", and induce inflammatory reaction in bronchi leading to bronchial asthma in
susceptible persons (especially LTC4 and D4). LTB4 may have a role in Rheumatoid Arthritis.
N.B.:Leukotrienes have no therapeutic uses.

Autacoids 2011/2012
Therapeutic uses of PG analogs:
Therapeutic use Drugs used

a) Gynecological and obstetrical uses: Dinoprostone
1. Induction of abortion in the second (PGE2 analog, given as vaginal
trimester. suppository).
2. Induction of labor.
3. To control post-partum hemorrhage. Carboprost
(PGF2α analog, given IM or intra-
amniotic which may cause
b) Treatment of erectile dysfunction. anaphylactic shock or CV collapse.
Alprostadil
c) GIT use: (PGE1 analog, given as urethral
suppository of intracavernous
Prophylaxis and treatment of peptic ulcer,
injection).
especially iatrogenic ulcer caused by NSAIDs
and Steroids.
Misoprostol
(PGE1 analog, given orally-may cause
d) CVS uses: colics and diarrhea, and bone pains-
1. To maintain the patency of ductus causes abortion in pregnant
arteriosus before surgical correction of females).
congenital heart diseases in neonates.
2. Treatment of pulmonary hypertension. Alprostadil.
3. Inhibition of platelet aggregation, e.g. during
hemodialysis. Epoprostenol
4. Treatment of peripheral vascular diseases (PGI2 analog, given by IV infusion).
(PVD).
Latanoprost
e) Ophthalmic use: (PGF2α analog, given as eye drops)
Treatment of open angle glaucoma.

Autacoids 2011/2012
Inhibitors of Eicosanoid Synthesis
1. Glucocorticoids(Cortisol): inhibit PLA2 by stimulation of synthesis of a protein known as

"Lipocortin" and accordingly inhibit synthesis of eicosanoids ( arachidonic acid, PGs,
and LTs).
2. NSAIDs: (e.g. aspirin, indomethacin, ibuprofen).They inhibit cyclooxygenases (non-

selective COX inhibitors) and accordingly inhibit PGs synthesis. They have analgesic,
antipyretic, and anti-inflammatory actions but may cause peptic ulcer and renal
ischemia especially with prolonged use of large doses.
3. Dazoxiben and Aspirin(Infantile dose): selectively inhibit TXA2 synthase an accordingly

inhibit platelet aggregation.
4. Leukotrienes inhibitors: are used in prophylaxis of bronchial asthma and include:

a) 5-LOX inhibitors: Zileuton inhibits synthesis of leukotrienes.
b) LT-Receptor Antagonists: Montelukast and Zafirlukast .
Important Notes:
1. There are 3 types of cyclooxygenase enzyme:
a) COX1: is"constitutive" and is involved in synthesis of PGs that cause cytoprotection of
the stomach and renal V.D.
b) COX2: is "inducible"stimulating synthesis of PGs involved in pain, fever, and
inflammation. Celecoxib and Rofecoxib are selective COX2 inhibitors
c) COX3: in CNS (formation of PGs causing pain and fever). Paracetamol
(Acetaminophen) and Dipyrone are selective COX3 inhibitors .
2. NSAIDs and Glucocoricoids cause peptic ulcer (iatrogenic ulcer) due to inhibition of
synthesis of cytoprotective PGs. It can be prevented and treated by PG analogs as
Misoprostol (but it is contraindicated in pregnancy as it can lead to abortion).
3. NSAIDs –but not glucocorticoids-may induce attacks of bronchial asthma in asthmatics

because they shift arachidonic acid into synthesis of LTs.

Autacoids 2011/2012
ERGOT ALKALOIDS
Source:
Ergot alkaloids are derived from ergot fungus which grows parasitically on rye grains.
Chemistry:
 Derivatives of lysergic acid.
 L-isomers are more active.
 Classified into:
1. Amino Acid Alkaloids: Ergotamine – Ergotoxine-Ergosine.
2. Amine Alkaloids: Ergometrine (ergonovine).
1-Ergotamine:
Pharmacokinetics:
 Poorly absorbed orally, absorption is enhanced by adding caffeine (Cafergot).
 Ergotamine can also be given S.L., inhalation, I.M., I.V., and rectal.
 Passes B.B.B.
 Partly metabolized by the liver and partly excreted in urine.
Pharmacodynamics:
 Mechanism of action:
Partial agonist at α1-receptors and 5-HT receptors.
1. V.C. of blood vessels e.g. cerebral, coronary, and peripheral blood vessels.
2. Oxytocic action (stimulates contraction of the uterus).
3. CNS actions:
4. Stimulation of C.T.Z. leading to nausea and vomiting.
5. Stimulation of C.I.C. leading to bradycardia.
6. Inhibition of V.M.C. and R.C. especially in acute toxicity (Ergotism).
Therapeutic uses:
Acute attacks of migraine headache as it causes cerebral V.C.
Adverse effects: Contraindications:
1-Tingling, numbness and gangrene of 1- P.V.D.
fingers. 2- Angina pectoris.
2- Anginal pains. 3- Hypertension.
3- Elevation of ABP. 4- Pregnancy.
4- Abortion. 5- Bradycardia.
5- Nausea and vomiting. 6-Liver and kidney diseases.
6- Bradycardia.

Autacoids 2011/2012
(Ergotism) :
It is acute ergot toxicity due to toxic doses of ergotamine or due to eating contaminated
rye grains; it is manifested by nausea, vomiting, bradycardia, hypertension, tingling and
numbness, abortion in pregnant females, and CNS manifestations as hallucinations,
convulsions, coma and death due to depression of R.C. and V.M.C.).
Dihydroergotamine
Is similar to ergotamine causing cerebral V.C. and is used in treatment of acute attacks of
migraine.
2- Ergotoxine:
More antagonistic action on α1-receptors than ergotamine, and inhibits V.M.C. leading to
V.D.
Dihydroergotoxine
Has more antagonistic action on α1-receptors and weaker agonistic action than ergotoxine
leading to V.D.
Uses:
1. P.V.D.
2. Cerebral ischemia (cerebro-vascular insufficiency).
3-Ergometrine (Ergonovine):
Pharmacokinetics:
Completely absorbed orally and has short duration of action.
Pharmacodynamics:
1. Weak α1-agonist → weak V.C. but NO α-blocking action.
2. Partial agonist on 5-HT receptors.
3. No CNS actions.
4. Powerful oxytocic action.
Therapeutic uses:
1. Prevention and treatment of post-partum hemorrhage.
2. Involution of the uterus after labor.
3. Diagnosis of Prinzmetal angina (=variant=vasospastic angina): ergometrine is given by
4. I.V.infusion during angiography and it induces coronary V.C. in Prinzmetal angina.
Methylergometrine(Methergin) :
more potent oxytocic than ergometrine, used in prevention and treatment of post-partum
hemorrhage and to help involution of the uterus after labor.

Autacoids 2011/2012
Migraine Headache
Definition:
Paroxysmal severe unilateral pulsating headache usually accompanied by nausea and
vomiting and preceded by "aura" characterized by visual disturbances.
Pathophysiology:
5-HT causes V.C. of cerebral (cranial) blood vessels→ Aura.
Accumulation of metabolites and release of inflammatory mediators→ V.D. and edema
of the wall of cranial blood vessels
Treatment of acute attacks:

1. Analgesics as NSAIDs (as aspirin) and paracetamol may be tried in mild cases.
Antiemetics as metoclopramide and domperidone are useful if the attack is
accompanied with vomiting
2. Ergotamine is given orally, inhalation, S.L., I.M., I.V., or rectally.
Caffeine may be added to ergotamine to increase oral absorption and potentiat
its action (caffeine causes cerebral V.C.). Antiemetics (as metoclopramide) may be also
added.
N.B.: the dose of ergotamine should never exceed 6 mg. per attack and 10 mg. per week.
Never give ergotamine within 24 hours after administration of triptans to avoid severe
systemic V.C.
3. Dihydroergotamine.
4. Triptans: Sumatriptan, Rizatriptan, Zolmitriptan
5. HT1D-agonist causing cranial V.C.
Contraindications: ischemic heart diseases (angina)- Hypertension- PVD.
Prophylactic treatment:
1. Propranolol (the most commonly used drug).
2. Anti-serotonin drugs: Methysergide (long use causes fibrosis of the serous membranes
as retroperitoneal fibrosis which may lead to renal failure) – Cyproheptadine (in
resistant cases, it is also H1-antagonist) – Pizotifen and Ketotifen (as cyproheptadine).
3. Clonidine (in small doses).
4. Calcium channel blockers: Flunarizine- Verapamil.
5. Tri-Cyclic Antidepressants (TCAs) as Amitriptyline.
Drugs that should be avoided:

Some drugs increase frequency of migraine attacks as Oral contraceptives (estrogen).

Pharmacology of The Respiratory system 2011/2012
Pharmacology of Respiratory System

BRONCHIAL ASTHMA
Definition: Chronic inflammatory disease of the airways due to hyper-responsiveness of
bronchi to various stimuli.
Clinical picture: Recurrent paroxysmal attacks of dyspnea (shortness of breath), cough,

wheezes, and chest tightness.
In between the attacks the patient is free of symptoms.
Pathogenesis of bronchial asthma:

1) On the first exposure to a specific antigen in genetically predisposed persons, synthesis
of IgE occurs.
2) On re-exposure, antigen-antibody reaction occurs leading to rupture of the mast cell
membrane (degranulation) and allergotoxins-mainly P.A.F. and cysteinyl leukotrienes
(LTC4 and LTD4)-are released.
3) P.A.F. and cysteinyl LTs act on specific receptors causing: bronchospasm, inflammation
(edema and cellular infiltration) of bronchial mucosa, and secretion of thick viscid plugs
of mucus.
Factors Precipitating Asthma=Triggering stimuli:

1) Exposure to the allergens which are environmental as pollen grains, smoke, dust, mites,
pollutants and fur of animals, occupational as industrial fumes, or viral respiratory
infection.
2) Exposure to cold air, humid air, or sulfur dioxide.
3) Exercise (exercise-induced asthma).
4) Emotional stress.
5) Drugs: NSAIDs -Non-selective β-blockers-Morphine-Muscarinic agonists-ACE inhibitors-
histamine releasers as Curare and Trimetaphan.
Lines of treatment of bronchial asthma:

1) Avoid the precipitating factors (see before).
2) Desensitization (hyposensitization).
3) Drug therapy.
1 Dr.Ahmed Abdel Rahman

www.medadteam.org
Drug Therapy in Bronchial Asthma:

a) Bronchodilators (Short-term asthma relievers):
1) Sympathomimetic β2-Agonists.
2) Methylxanthines.
3) Antimuscarinic drugs (Anticholinergic drugs-Muscarinic antagonists).
b) Anti-inflammatory drugs (Long-term asthma controllers):

1) Glucocorticoids (Corticosteroids).
2) Leukotriene antagonists=Leukotriene inhibitors=Leukotriene
modifiers=Antileukotrienes: LT receptor antagonists (Montelukast and Zafirlukast)
and LT synthesis inhibitors (Zileuton) which inhibits 5-lipooxygenase enzyme.
3) Degranulation inhibitors = Mast cell stabilizers.
N.B.:
a) Anti-inflammatory drugs are not bronchodilators and are not used in acute attacks of
bronchial asthma, but used for prophylaxis.
b) NSAIDs –except Paracetamol-are contraindicated in bronchial asthma (why?).
A) Bronchodilators
1) β2-Agonists:
They are non-catecholamines: absorbed orally-pass BBB and not metabolized by
COMT or MAO.
stimulation of β2-receptors -
AMP ll stabilization and inhibition of release of
bronchoconstrictor mediatorsfrom mast cells + reduction of mucus secretion +
increase muco-ciliary clearance + decrease microvascular leakage (capillary
permeability)
 Classification:
a) Selective β2-Agonists: They are the most important drugs in treatment of
bronchial asthma, they include:
1) Short-acting β2-agonists=Asthma relievers:
2) Salbutamol and Terbutaline – given by inhalation in acute attacks – duration
3-4 hours.
3) Long-acting β2-agonists=Asthma controllers:
Salmeterol, Formoterol given by inhalation, and Bambuterol given orally-duration
12 hours.

www.medadteam.org
 Role in bronchial asthma:

1) The drugs of choice in acute attacks: SABA are given by inhalation.
2) LABA are given for long-term prophylaxis with inhaled steroids.
3) Salbutamol is given by inhalation (nebulizer) or IV in severe acute asthma
(status asthmaticus).
1) Tremors of the skeletal muscles.
2) Tachycardia (mostly reflex due to V.D. and hypotension, but may be due to
direct stimulation of cardiac β1 receptors especially with repeated doses
because selectivity is not absolute).
3) Tolerance (due to down-regulation of β2-receptors, corrected by
corticosteroids).
4) Nervousness Tension.
5) Hypokalemia.
6) Hypotension-Headache-Flushing.
7) LABA increase the risk of asthma-related death if used alone in patients
with ischemic heart disease or arrhythmia, that is why they should be
combined with inhaled corticosteroids (ICS).
b) B-Non-Selective β-Agonists:
They are not commonly used because of cardiac adverse effects as tachycardia,
palpitation,arrhhythmia and anginal pains due to β1-stimulation. Examples:
 Adrenaline (inhalation and S.C.).
 Isoprenaline (inhalation and S.L.).

www.medadteam.org
2) Methylxanthines:
Theophylline and Aminophylline (theophylline ethylene diamine).
1) Theophylline is given orally as "sustained release" preparations (SR) to achieve
constant plasma levels for about 12 hours with less frequent administration
and less fluctuation in plasma levels. Aminophylline is given as rectal
suppository or IV administration.
2) Pass BBB.
3) Metabolized by HME.
1) Inhibit phosphdiesterase type 4 → ↑ intracellular c-AMP
+ mast cell stabilization and inhibition of release of bronchoconstrictor
mediatorsfrom mast cells + reduction of mucus secretion + increase muco-
ciliary clearance + decrease microvascular leakage (capillary permeability) .
2) Block of adenosine receptors
release..
3) Improve diaphragmatic contractions.
4) Inhibition of PDE-4 in inflammatory cells reduces the release of cytokines and
reduces cell migration.
 The Role of Methylxanthines in Bronchial asthma:

1) Aminophylline may be given very slowly IV (250-500 mg.) in acute attacks
(asthma reliever) if there is no response to inhaled selective β2- agonists. This
may be dangerous especially if aminophylline is rapidly injection as it may lead
to arrhythmia and severe hypotension (velocity reaction).
2) Theophylline is given as sustained release tablets or capsules in prophylaxis of
bronchial asthma (asthma controller).
Aminophylline may be also given as rectal suppositories (500 mg.).
3) Aminophylline is given by IV infusion in life-threatening asthma (status
asthmaticus =severe acute asthma).

www.medadteam.org
1) Theophylline and Aminophylline have low therapeutic index and the plasma
level should be measured to avoid toxicity.
2) Therapeutic plasma concentration of theophylline: 5-20 mg / L (5-20 μg / mL)
and the toxic level > 20 mg / L.
Adverse effects include:
a) CNS manifestations: nervousnss, insomnia, headache, and seizures
(convulsions).
b) CVS manifestations: tachycardia, palpitations, arrhythmias, anginal pains, and
hypotension.
c) GIT manifestations: anorexia, nausea, vomiting, ulceration, and proctitis (rectal
suppository).
d) Thrombophlebitis (IV injection).
 Symptoms of toxicity may start at plasma level of 15 mg/L.
 Seizures and arrhythmia occur at plasma levels above 40 mg/L.
 Drug interactions:
1) The clearance of theophylline is reduced by:
a) HME inhibitors as: Erythromycin (Macrolide antibiotics)-Fluroquinolones-
Chloramphenicol-Cimetidine-Contraceptive pills.
b) Hepatic cirrhosis.
c) Heart failure (causes liver congestion).
d) In these conditions the dose of theophylline should be reduced to avoid
toxicity.
2) The clearance theophylline is increased by:
a) HME inducers as: Phenobarbitone- Phenytoin-Rifampicin – Cigarette smoking
(nicotine).
b) The dose of theophylline should be increased in these conditions to achieve
therapeutic levels.

www.medadteam.org
3) Anti-Muscarinic Drugs:
Atropine was previously used in prophylaxis of bronchial asthma but is now replaced
by synthetic substitutes.
Examples: Ipratropium -Oxtropium –Tiotropium.
They are competitive antagonists that block muscarinic receptors in bronchi by
competition with acetylcholine released as a result of vagal stimulation.Role of
Antimuscarinic Drugs in Bronchial asthma:
1) They are given by inhalation in prophylaxis of bronchial asthma (the response
varies according to degree of vagal stimulation on bronchi).
2) They are used as alternatives to LABA patients who are intolerant to LABA as in
cases of arrhythmia or ischemic heart diseases.
3) They may be added to LABA to achieve synergism.
4) They are the drugs of choice in asthmatic attacks precipitated by non-selective
beta antagonists as propranolol.
5) Chronic obstructive pulmonary disease (COPD).
 Advantages of Synthetic substitutes:
Disadvantages of Atropine Advantages of Ipratropium

1-Tertiary amine-given orally-Passes 1-Quaternary ammonium-given by
BBB. inhalation.
2-Systemic anticholinergic actions: dry 2-Minimal systemic anticholinergic actions.

mouth –constipation-urine retention-
tachycardia-blurred vision and elevation
of IOP.
3-CNS actions. 3-No CNS (cannot penetrate BBB).
4-Causes dryness of bronchial secretion 4-Little effect on bronchial secretion.

leading to thick viscid sputum.
5-Decreases muco-ciliary clearance. 5-No effect on muco-ciliary clearance.

www.medadteam.org
4)Anti-inflammatory Drugs
a) Corticosteroids (Glucocorticoids):
1) Anti-inflammatory action by inhibition of phospholipase A2 leading to
inhibition of synthesis of arachidonic acid, leukotrienes and
prostaglandins.
2) Anti-inflammatory action by inhibition of synthesis of cytokines as
interleukins (IL1,2,3,4) and tumor necrosis factor (TNF).
3) Potentiate the effects of β2-agonists (by upregulation of receptors) thus
prevent tolerance.
4) Inhibit IgE antibody synthesis and antigen-antibody reaction.
5) Corticosteroids are not bronchodilators and are not used in acute
attacks.
 The Role of Corticosteroids in Bronchial asthma:

1) Inhaled corticosteroids (ICS) as Beclomethasone, Fluticasone,
Triamcinolon, Budesonide, are used in prophylaxis of bronchial asthma.
This is the preferred route to avoid the serious adverse effects of
systemic steroids (immunosuppression-osteoporosis-edema-
hypertension-ulcer…).
2) Systemic steroids as Hydrocortisone sodium succinate or
methylprednisolone IV is the drug of choice in status asthmaticus (200
mg. / 4-6 hours for 24 hours).
This is followed by oral prednisolone for 7-10 days then gradually
withdrawn to avoid acute adrenocortical insufficiency.
3) Systemic steroids as predisolone orally are used only in severe
persistent asthma not responding to other anti-asthmatic drugs (see
later).
 Adverse effects of Inhaled steroids:

1) Oro-pharyngeal candidiasis (moniliasis): prevented by mouth wash after
corticosteroid inhalation, and treated by oral Nystatin.
2) Dysphonia (voice abnormality, e.g. weakness and hoarseness).
3) Systemic adverse effects may occur on prolonged use, e.g. growth
retardation in children and osteoporosis in females

www.medadteam.org
b) Mast Cell stabilizers = Degranulation Inhibitors:

Cromolyn (Disodium cromoglycate) and Nedocromil.
1) Inhibition of the release of allergic mediators from mast cells and other
inflammatory mediators by stabilizing the cell membrane by altering the
permeability of chloride channels.
2) They are not bronchodilators and are not used in acute attacks.
 Role of Mast Cell stabilizers in Bronchial asthma:

1) Used only for prophylaxis and given by inhalation, either in the form of
solution (inhaler) or in the form of powder (by spinhaler).
2) They are used before exposure to allergen (environmental asthma),
before exposure to industrial fumes (occupational asthma), and before
exercise (exercise-induced asthma).
3) They decrease: bronchial hyper-responsiveness, the need
bronchodilators, and the severity of symptoms.
4) They may be used with ICS.
 Other uses:
1) Allergic rhinitis (given as nasal drops or nasal spray).
2) Allergic conjunctivitis (given as eye drops).
Bronchospasm, cough, chest tightness, throat irritation, dry mouth, and
anaphylaxis (rare).
c) Leukotriene Modifiers:
1) Inhibition of 5-Lipooxygenase and inhibition of leukotrienes synthesis by
Zileuton (not commonly used as it may cause hepatotoxicity).
2) Competitive antagonists of cysteinyl leukotriene receptors (LTD4 mainly):
by Montelukast and Zafirlukast.
 Role in Bronchial asthma:
1) They are given for prophylaxis against bronchial asthma.
2) They have the following advantages: 1-Montelukast is safely used in
children (as young as 6 months) 2-easy administration as they are given
orally.

www.medadteam.org
5)New Drugs in Treatment of Bronchial Asthma:

a) Omalizumab: anti-IgE monoclonal antibody
 Synthesized by recombinant DNA technology.
 Mechanism of action: binds to IgE thus prevents binding of IgE to its receptors
on mast cells, and inhibits degranulation and release of allergic mediators.
 It is given SC in severe persistent asthma not controlled by other drugs as ICS
and LABA (see later).
b) Calcium channel blockers.
c) Potassium channel openers as cromokalim.
d) Prostaglandin E2.
e) Nitric oxide donors.
6)Drugs Contraindicated in Bronchial Asthma:

a) NSAIDs (except paracetamol=acetaminophen).
b) Non-selective β-Blockers (Propranolol-Nadolol-Timolol-Sotalol-Oxprenolol-
Pindolol).
c) ACE inhibitors as Captopril.
d) Morphine (depresses R.C., cough centre, and releases histamine).
e) Muscarinic agonists = Parasympathomimetics (Carbachol-Bethanechol-
Pilocarpine-Physostigmine-Neostigmine).
f) Other drugs: Histamine liberators as morphine-curare-trimetaphan-Histamine like
drugs as phentolamine and tolazoline-Barbiturates (due to depression of R.C.).
Management of a Case of Bronchial Asthma

Acute Attacks:
Drug Used: Short acting selective β2-agonist (asthma relievers) as salbutamol or
Terbutaline.
Route of administration: Inhalation.
Dose: 1-2 puffs (100-200 μg.).
Mechanism of action: see before.
Adverse effects: see before.
If no response to selective β2-agonists:
Drug Used: Aminophylline.
Route of administration: Slowly IV injection.
Dose: 250-500 mg.
Mechanism of action,Adverse effects, Therapeutic and toxic plasma concentrations,
Drug interactions: see before.

www.medadteam.org
Acute severe asthma = Life-threatening asthma

(Status asthmaticus):
It is characterized by severe dyspnea, cough, wheezes, cyanosis, sweating,
tachycardia, and exhaustion. Management should include:
1) Hospitalization
2) Oxygen therapy (40-60%).
3) Hydocrtisone 200 mg. IV / 4-6 hours or Methylprednisolone IV for 24 hours
followed by oral predisolone (30-60 mg.) for 2 weeks.
4) IV fluids as glucose 5% to correct dehydration and for nutrition.
5) Salbutamol or terbutaline inhalation by nebulizer.
6) Aminophylline IV infusion (250 mg. IV infusion over 20 minutes).
7) Antibiotics (to treat associated chest infection e.g. Azithromycin).
8) Anxiolytics (benzodiazepines -as diazepam-are safe as they do not depress R.C.).
Treatment of Chronic asthma=Prophylactic Treatment:

1) Avoid exposure to the antigen, stress, exercise, and drugs that induce asthma (see
before).
2) Desensitization (Hyposensitization).
3) Drugs used for prophylactic treatment are chosen according to the type of
bronchial asthma:
Type of Asthma Treatment
1-Mild intermittent asthma: No treatment is needed.

2-Mild persistent asthma: Low dose inhaled corticosteroid (ICS) is the
preferred treatment,
Or Leukotriene modifiers orally,
Or SR theophylline orally.
3-Moderate persistent asthma: Medium dose ICS,
OrLow dose ICS + Leukotriene modifier orally, Or
Low dose ICS + SR theophylline orally,
Or Low dose ICS + LABA.
4-Severe persistent asthma: Medium or high dose ICS + LABA ± Leukotriene
modifier orally ± SR theophylline orally.
5-If no improvement of severe Add Omalizumab SC and lowest dose oral
persistent asthma: glucocorticoid as prednisone.
N.B.:
In all types of asthma acute attacks are treated by SABA as needed.

www.medadteam.org
COUGH THERAPY
Cough is a symptom not a disease.
Causes:
1) Local causes: upper and lower respiratory diseases as bronchial asthma.
2) Other causes: diseases as gastro-esophageal reflux disease =GERD (reflux esophagitis)
and drugs as ACE inhibitors (why?).
 There are 2 types of cough known as "dry, non-productive, or useless cough" which is
treated by "Anti-tussive drugs", and "productive or useful cough" which is treated by
"Expectorants" and "Mucolytics".
1)Anti-Tussive Drugs:
They are act by inhibition of the cough reflex, and are divided according to their
mechanism of action into:
a) Central anti-tussives: which inhibit cough center in the medulla.
b) Peripheral anti-tussives: which act by inhibition of irritation of sensory nerve
endings in the respiratory mucosa.
a) Central Anti-tussives:
1) Non-narcotic non addictive drugs: Dextromethorphan, Narcotine, Oxeladin
and Benzonatate (acts also peripherally as local anaesthetic, chemically related
to tetracaine).
Benzonatate and oxeladine are synthetic non-opiates.
2) Narcotic less addictive drugs : as codeine and pholcodine (not commonly
used).
3) Narcotic highly addictive drugs: as morphine, heroin, and methadone (are not
used nowadays as anti-tussives).
b) Peripheral Anti-tussives:
1-Demulcents as lozenges and pastilles used in pharyngitis and laryngitis.
2-Steam inhalation with tincture benzoin co. and menthol which stimulates the
secretion of mucus, used in tracheo-bronchitis.
3-Benzonatate: see before.
4-Guafenesin: used to relieve cough associated with common cold and acute
bronchitis.

www.medadteam.org
2)Expectorants:
Expectorants are drugs that liquefy sputum (decrease viscosity of sputum) and make
it easier for the patient to cough sputum, they are divided into:
a) Sedative expectorants which sedate (soothe) the respiratory mucosa by
stimulating mucus secretion and increase water content (fluidity) of sputum thus
decreasing the frequency of cough, but sputum becomes more "productive". They
include:
1) Saline Expectorants: as sodium or potassium iodide. Iodide irritates and
stimulates secretion of exocrine glands including bronchial glands. They are
used in chronic bronchitis.
Adverse effects:
a) Allergy.
b) Iodism: nausea, vomiting, metallic (bitter) taste, sialdenitis, salivation,
conjunctivitis, lacrimation, rhinitis.
c) Interfere with thyroid functions.
Contraindications:
a) Acute bronchitis (irritation causes more inflammation)
b) T.B. as iodide may dissolve fibrous tissue and cause spread of infection.
c) Allergy to iodine.
d) Pregnancy: iodine may interfere with fetal thyroid function.
2) Alkaline Expectorants: as sodium or potassium acetate, benzoate, or citrate
which are converted into bicarbonate which is secreted in exocrine glands
including bronchial glands thus increases bronchial watery secretion and
dissolves mucus (see uses of NaHCO3 in peptic ulcer).
3) Nauseant Expectorants: Tincture ipecacuanha, Tincture senega, Ammonium
chloride and ammonium carbonate are given in sub-emetic doses to induce
nausea
peripheral emetics in GIT pharmacology).
b) Stimulant Expectorants:
 They "stimulate" healing and repair of chronically inflamed respiratory mucosa
(vulnerary action), and accordingly increase the number of glands and the
amount of secreted fluid.
 They have "deodorant" action.
 They have mild antiseptic action.
 They are used in suppurative lung diseases as bronchiectasis and lung abscess.
 Examples: Creosote, Guaiacol, Terpene hydrate (terpene hydrate contains
about 42% alcohol which may result in congenital anomalies if used during
pregnancy).

www.medadteam.org
3)Mucolytics:
They "break down" and liquefy viscid sputum and facilitate the action of
expectorants.
1) Bromhexine (Bisolvon®) and Ambroxol:
Depolymerize mucopolysaccharide of the ground substance of mucus, given
orally, rectally, or by injection.
2) Acetylcysteine and S-Carboxymethylcysteine:

a) Contain free SH group which break disulfide bonds in mucus.
b) They are given orally, by inhalation, or by injection.
c) Acetylcysteine has antioxidant action.
d) Indications:
 Mucolytic in acute and chronic pulmonary diseases as T.B., pneumonia, and
cystic fibrosis.
 To liquefy bronchial secretion before diagnostic bronchial studies as
bronchoscopy.
 Acetylcysteine is used in acute paracetamol (acetaminophen) toxicity to
detoxify NABQI by donation of free SH groups (see CNS pharmacology). It is
considered as "acetaminophen antidote".
3) Dornase alfa:
a) Given by inhalation in cystic fibrosis.
b) Synthesized by recombinant DNA technology from ovarian cells of Chinese
hamsters.
4) Erdosteine: used as mucolytic in acute bronchitis.

www.medadteam.org
Diuretics 2011/2012
DIURETICS
Definition:
drugs that increase urine volume.
Classification:
a) Pre-renal (Extra-renal) diuretics:
They increase urine output without acting on the nephrons, examples include:
1. Methylxanthines (theobromine, theophylline, caffeine), dopamine, dobutamine, and
cardiac glycosides (digitalis) increase renal blood flow and glomerular filtration rate
(GFR) by increasing COP and/or causing renal vasodilatation.
(Methylxanthines have also renal action- Cardiac glycosides have diuretic action in
patients with heart failure only).
2. Water and ethyl alcohol inhibit A.D.H.
3. Plasma expanders as dextran.
b) Renal diuretics: they act on the nephrons and may be classified into:
1. Thiazide diuretics: they are moderate efficacy- they inhibit Na+ transport in proximal
segment of distal convoluted tubules (DCT).
2. Loop diuretics: they are high efficacy diuretics- they inhibit Na+ transport in the loop of
Henle.
3. K+-sparing (retaining=conserving) diuretics: they are low efficacy diuretics- they are
either aldosterone antagonists as spironolactone, or non-aldosterone antagonists as
amiloride and triamterene.
4. Carbonic anhydrase inhibitor(CAIs): they inhibit Na+/H+ exchange in proximal
convoluted tubules (PCT) mainly. They are low efficacy and are self-limiting because
they cause acidosis (see later).
5. Acidifying diuretics: as NH4Cl, they are also self-limiting diuretics due to acidosis.
6. Osmotic diuretics: as Mannitol.
N.B.:
Thiazide diuretics, loop diuretics, K+-sparing diuretics, and CAIs are known as "Natriuretics"
or "Saluretics" because they increase urinary excretion of Na+ with its iso-osmotic water.

Diuretics 2011/2012
Thiazide Diuretics
Source: Synthetic.
Chemistry: Related to sulphonamides.
Pharmacokinetics:
1. Well absorbed orally.
2. Pass placental barrier and may cause teratogenicity.
3. Excreted in PCT to (act from the inner side of the nephron) by active secretion thus
reducing secretion of uric acid leading to hyperuricemia. Probenicid reduces active
transport of thiazides and reduces their diuretic action.
Pharmacodynamics:
1. Diuretic action: characterized by:

a) Onset: delayed onset (thiazides are given only orally so they are not useful in
emergencies).
b) Duration: some thiazides are short acting as hydrochlorothiazide and others are long
acting as metolazone.
c) Efficacy: moderate efficacy.
d) Site of action: act on the proximal segment of DCT inhibiting Na+, Cl- and water
reabsorption which will be excreted in urine. The sulphonamide structure inhibits
carbonic anhydrase enzyme which causes very mild additional diuretic action.
e) Part of Na+ reaching DCT is reabsorbed in exchange for K+ (mainly) and H+ (to a less
extent).
f) Urine will also contain excess Mg2+ and lesser amounts of Ca2+.
g) In conclusion, thiazides will produce the following changes in urine and in blood:
URINE BLOOD
1. Excess Na+ (natriuresis). 1. Hyponatremia.
2. Excess water (diuresis). 2. Hypovolemia (moderate).
3. Excess Cl- (chloruresis). 3. Hypochloremia.
4. Excess K+ (kaluresis). 4. HYPOKALEMIA.
5. Excess H+ (acidic urine). 5. Alkalosis.
6. Excess Mg2+. 6. Hypomagnesemia.
7. Less Ca2+. 7. Hypercalcemia.
8. Less uric acid. 8. Hyperuricemia.

Diuretics 2011/2012
2. Thiazides reduce Renal Blood Flow (RBF):

a) They are contraindicated in patients with renal impairment.
b) Reduction RBF leads to reduction of Glomerular Filtration Rate (GFR) and accordingly
thiazide act as Anti-diuretics only in patients with nephrogenic Diabetes Insipidus
(which may be induced by some drugs as Lithium, Methoxyflurane, and
Demeclocycline).
3. Antihypertensive action:
a) Arteriolar V.D.: this is the most important mechanism and can be explained by:
 Depletion of Na+ from the wall of arterioles thus reducing the vasoconstrictor
(pressor) response to noradrenaline and angiotensin.
 Increasing synthesis of vasodilator PGs (that is why NSAIDs may partially
antagonize the antihypertensive action of thiazides).
 Opening of K+ channels leading to hyperpolarization and V.D.
 Block of Ca2+ channels in arterioles causing V.D.
b) Diuretic action: this is of little importance in the antihypertensive action of thiazides.
4. Hyperuricemia: Thiazides reduce active tubular secretion of uric acid in PCT.
5. Hyperlipidemia: Thiazides increase LDL-cholesterol and triglycerides.
6. Hyperglycemia: Thiazides open K+ channels in B-cells of islets of Langerhans →

Hyperpolarization
Therapeutic uses:
1. Treatment of edema which is either: Cardiac (in mild and moderate congestive heart
failure), Renal, or Hepatic edema.
2. Treatment of mild and moderate hyperternsion: thiazides are preferred to loop diuretics
because they are arteriodilators Except in cases of emergency hypertension and in
patients with renal impairment where loop diuretics are preferred (loop diuretics can be
given I.V. and they increase renal blood flow).
3. Treatment of nephrogenic diabetes insipidus.
4. Treatment of idiopathic hypercalciurea and recurrent calcium stones.
5. Treatment of pre-menstrual tension syndrome.

Diuretics 2011/2012
Adverse Effects Contraindications (precautions)
1. Hypokalemia (causes fatigue, headache, 1. With Digitalis (hypokalemia

and cardiac arrhythmias). induces digitalis toxicity).
2. Hyponatremia (causes muscle cramps).
3. Hypovolemia.
4. Hypomagnesemia (may also precipitate

digitalis toxicity).
5. Hypochloremic alkalosis.
6. Hypotension. 2. Hypotension.
7. Hypersensitivity (purpura, dermatitis, 3. Allergy to thiazides and

photosensitivity, necrotizing vasculitis or sulphonamides.
bone marrow depression) and cross allergy
with sulphonamides.
8. Hyperlipidemia.
9. Hyperglycemia. 4. Diabetes mellitus.
10.Hyperuricemia and may precipitate acute 5. Gout.

gouty attacks.
11.Decrease renal blood flow. 6. Renal insufficiency
12.Teratogenicity. 7. Pregnancy.
13.May lead to hepatic coma in hepatic 8. Hepatic insufficiency.

insufficiency.
14.Gut upsets. 9. With steroids (as cortisol): see

later.

Diuretics 2011/2012
How to Avoid Hypokalemia?:
1. Addition of a K+-sparing diuretic (amiloride-triamterene-spironolactone) or ACE

inhibitors.
2. Dietary potassium (in fruits and vegetables).
3. K+ supplements: K+ tablets (cause GIT irritation) or syrup (less irritant).
4. Intermittent use of diuretics.
Drug interactions:
1. With digitalis: Hypokalemia is the most important precipitating factor of digitalis toxicity.
2. With steroids: steroids cause Na+ and water retention thus antagonize the diuretic effect
of thiazides but more seriously they cause hypokalemia.
3. With sulphonamides: cross allergy.
4.
With K+-sparing diuretics: synergism and correction of serum K+.
5. With ACE inhibitors and AT1 antagonists: synergism and correction of serum K+.
6. With insulin and oral hypoglycemic drugs: thiazides antagonize the action of these drugs.
7. With uricosuric drugs (drugs that increase uric acid excretion in urine): thiazides
antagonize the action of these drugs.
8. With Probenicid: probenicid decreases active transport of thiazides and antagonizes their
diuretic action.
9. With NSAIDs: NSAIDs antagonize the antihypertensive action of thiazides because they
cause Na+ and water retention and inhibit the synthesis of vasodilator PGs.
Preparations:
1. Short acting thiazides:
Chlorthiazide and Hydrochlorothiazide (given/6-12 hours).
2. Long acting thiazides:
Chlorthalidone, Metolazone, and Polythiazide (given once daily).
3. Thiazide analogues: they are similar to thiazides in action but not in chemical structure.
Examples include:
a) Indapamide: weak diuretic but it causes arteriodilatation as thiazides (most probably
due to calcium channel block. Used in treatment of hypertension in sub-diuretic dose,
and is excreted in bile (long acting given once daily).
b) Diazoxide: it is a vasodilator drug (opens K+ channels) related to thiazides but is Not a
diuretic. It is given I.V. in emergency hypertension.
c) Metolazone.

Diuretics 2011/2012
Loop Diuretics (High efficacy = High Ceiling Diuretics)

1. Source: synthetic.
2. Chemistry:
some are related to sulphonamides as frusemide (they inhibit carbonic anhydrase which
contributes very mildly to their diuretic action but may cause allergic reactions and cross
allergy with sulphonamides) but others are not sulphonamide derivatives as ethacrynic
acid.
3. Pharmacokinetics:
 Well absorbed orally, and can be given by I.V. and I.M. injection (useful in
emergencies).
 Highly bound to plasma proteins and can displace other drugs as warfarin leading to
toxicity (bleeding in case of warfarin).
 Pass placental barrier and may cause teratogenicity (fetotoxicity).
 Loop diuretics are actively secreted in PCT and-as thiazides- act from the inner side of
the nephron. They interfere with active tubular secretion of uric acid leading to
hyperuricemia, and probenicid reduces their diuretic effect.
 Partly metabolized by the liver.
4. Pharmacodynamics:
1. Diuretic action: characterized by:
a) Onset: rapid onset.
b) Duration: short duration.
c) Efficacy: high efficacy (the most potent available diuretics).
d) Site of action: loop diuretics inhibit reabsorption of Na+, K+, and 2Cl- (co-transport)
from the thick segment of the ascending limb of loop of Henle leading to excess
excretion of these electrolytes in urine with iso-osmotic water. In addition; loop
diuretics decrease osmolarity of the medulla of the kidney and consequently
decrease water reabsorption from the collecting tubules causing potent diuresis.
e) Part of excess Na+ reaching DCT is reabsorbed in exchange for K+ (mainly) and H+
(to a less extent).
f) Urine will also contain excess Mg2+ and excess Ca2+.
In conclusion loop diuretics will produce the following changes in urine and in blood

Diuretics 2011/2012
Urine Blood
1. Excess Na+ (natriuresis). 1. Hyponatremia.
2. Excess water (diuresis). 2. Hypovolemia (marked).
3. Excess Cl- (chloruresis). 3. Hypochloremia.
4. Excess K+ (kaluresis). 4. HYPOKALEMIA.
5. Excess H+ (acidic urine). 5. Alkalosis.
6. Excess Mg2+. 6. Hypomagnesemia.
7. Excess Ca2+ (calciurea). 7. Hypocalcemia.
8. Less uric acid. 8. Hyperuricemia.
2. Loop diuretics increase renal blood flow: they are the diuretics of choice in renal
insufficiency. This is because loop diuretics increase synthesis of vasodilator PGs (PGE
and PGI) in the kidney, this action is antagonized by NSAIDs. (Remember that
thiazides reduce RBF and GFR).
3. Antihypertensive action: this is due to their diuretic action and NOT due to
arteriodilatation.
(In contrast to thiazides; loop diuretics cause venodilatation but not arteriodilatation).
4. Hyperlipidemia: as thiazides; loop diuretics increase LDL-cholesterol and triglycerides.
5. Hyperglycemia: loop diuretics decrease insulin release from the pancreas less
markedly than thiazides.
5. Therapeutic uses:
a) Edema: loop diuretics are used in severe, acute, and refractory edema (combined
with K+-sparing diuretics) which may be cardiac (due to congestive heart failure),
renal, or hepatic edema.
b) Loop diuretics are given I.V. in acute left ventricular failure (LVF) as they cause
diuresis and venodilatation which decreases pre-load). Also used in cerebral edema.
c) Hypertension: loop diuretics are preferred to thiazides in the following conditions:
 Hypertension in patients with renal insufficiency.
 Emergency hypertension.
 Resistant hypertension.
 Severe hypertension, especially with other antihypertensive drugs that may cause
Na+ and water retention as arteriodilators.
d) Acute renal failure.
e) Hypercalcemia.

Diuretics 2011/2012

1. Hypokalemia. 1. With Digitalis: hypokalemia
precipitates digitalis toxicity.
2. Hypovolemia and dehydration.
3. Hyponatremia.
4. Hypomagnesemia.
5. Hypotension. 2. Hypotension.
6. Hypochloremic alkalosis.
7. Hypocalcemia.
8. Hypersensitivity (and cross 3. Allergy to loop diuretics and

allergy with sulphonamides with sulphonamides.
some loop diuretics).
9. Hyperglycemia. 4. Diabetes mellitus.
10.Hyperuricemia. 5. Gout.
11.Hyperlipidemia.
12.Teratogenicity. 6. Pregnancy.
13.Ototoxicity: damage of the 8th 7. With other ototoxic drugs as

cranial nerve which may cause aminoglycosides.
deafness, especially if given
concomitantly with other
ototoxic drugs as
aminoglycosides (streptomycin)
or in renal impairment.
8. Liver insufficiency: may precipitate

hepatic coma.
14.Gut upset. 9. With steroids as Cortisol.

Diuretics 2011/2012
6. Drug interactions:
1. With Digitalis: Hypokalemia and hypomagnesemia induce digitalis toxicity.

(How to avoid hypokalemia?).
2. With steroids: see thiazide diuretics.
3. With sulphonamides: see thiazide diuretics.
4. With K+-sparing diuretics and ACE inhibitors (or AT1-antagonists): see thiazide
diuretics.
5. With NSAIDs: NSAIDs antagonize partially the diuretic action of loop diuretics because
they reduce vasodilator PGs which increase RBF, and they cause Na+ and water
retention.
6. With insulin and oral hypoglycemic drugs: see thiazide diuretics.
7. With probenicid: see thiazide diuretics.
8. With uricosuric drugs: see thiazide diuretics.
9. With Ototoxic drugs as Aminoglycosides: severe ototoxicity.
10.Reduce renal clearance of lithium (anti-manic and mood stabilizing agent) leading to
acute lithium toxicity (see CNS pharmacology).
Preparations:
1. Sulphonamide derivatives: Frusemide (Lasix®)- Bumetanide- Torsemide.
2. Non-sulphonamide derivatives: Ethacrynic acid.
Very Important Note:

K+-Losing (depleting) diuretics are commonly used in treatment of heart failure with digitalis
but never allow hypokalemia in these patients because it is the most important factor
precipitating digitalis toxicity.

Diuretics 2011/2012
Thiazide Diuretics Loop Diuretics

1-Chemistry: Sulphonamide derivatives. Sulphonamide derivatives
and non-sulphonamides.
2-Route: Oral only. Oral and parenteral.
3-Onset and Slow onset, may be short acting, Rapid onset and short
duration: or long acting. duration.
4-Efficacy: Moderate efficacy. High efficacy.
5-Site of action: Proximal segment of DCT. Thick segment of ascending

limb of loop of Henle.
6-Diuretic action: Must be actively secreted into Must be actively secreted

PCT, inhibit Na+ , Cl-, and water into PCT, inhibit Na+, K+,
reabsorption from proximal and 2Cl- reabsorption from
segment of DCT leading to: Loop of Henle leading
Natriuresis- diuresis-chloruresis- to:Natriuresis-diuresis-
kaluresis-acidic urine-excess chloruresis-kaluresis-acidic
Mg2+- urine-excess Mg2+-excess
less Ca2+-less uric acid. Ca2+ -less uric acid.
7-RBF and GFR: Decrease RBF and GFR: Increase RBF

 Contraindicated in renal (by increasing PG synthesis)
impairment. and GFR. They are the
 Useful in nephrogenic diuretics of choice in renal
diabetes insipidus. impairment.
8-Antihypertensive  Mainly by arteriodilatation.  Only by diuresis and no

action:  Less importantly by diuresis. arteriodilatation.
9-Therapeutic uses: 1. Mild and moderate edema 1. Severe, refractory, and

(Cardiac edema due to heart acute edema (acute
failure-Renal-Hepatic). LVF).
2. Mild and moderate 2. Emergency, severe, and
hypertension. resistant hyperternsion.
3. Nephrogenic diabetes 3. Acute renal failure.
insipidus. 4. Hypercalcemia.
4. Idiopathic hypercalciurea.
5. Pre-menstrual tension.

Diuretics 2011/2012
10-Adverse effects: Hypokalemia-Hypovolemia- Hypokalemia-Hypovolemia

Hyponatremia-Hypotension- and Dehydration-
Hypomagnesemia- Hyponatremia-
Hypersensitivity-Hyperglycemia- Hypotension-
Hyperlipidemia-Hyperuricemia- Hypomagnesemia-
Teratogenic-Decrease RBF- Hypersensitivity-
Hypercalcemia- Hyperlipidemia-
Hepatic coma in liver Hyperglycemia-
insufficiency. Hyperuricemia-
Teratogenic-Hypocalcemia-
Hepatic coma in liver
insufficiency-Ototoxicity.
11Contraindications Digitalis toxicity-Hypotension- Digitalis toxicity-

(Precautions): Allergy-Diabetes mellitus-Gout- Hypotension-Allergy-
Pregnancy-Renal impairment- Diabetes mellitus-Gout-
Liver insufficiency-With steroids. Pregnancy-Liver
insufficiency-With steroids-
With other ototoxic drugs.
12-Preparations: Short acting: Sulphonamides:

Chlorothiazide- Frusemide-Bumetanide-
Hydrochlorothiazide- Torsemide.
Long acting: Non-sulphonamides:
Chlorthalidone-Metolazone. Ethacrynic acid.
N.B: thiazides and loop diuretics are "K+ depleting diuretics".

Drugs causing Hypokalemia:
1. Thiazide diuretics (chlorothiazide-hydrochlorothiazide).
2. Loop diuretics (frusemide-bumetanide-ethacrynic acid).
3. Steroids: cortisol (glucocorticoid)-aldosterone (mineralocorticoid).
4. Adrenaline (by stimulation of renin release and β2-stimulation in skeletal muscles
increasing potassium uptake).

Diuretics 2011/2012
Drugs causing Hyperkalemia:

1. K+-sparing diuretics: spironolactone (aldosterone antagonist)-amiloride and triamtertene
(non-aldosterone antagonists).
2. ACE inhibitors (captopril) and AT1-receptor antagonists (losartan).
3. β-blockers as propranolol (by inhibition of renin release and blocking β2-receptors).
4. Succinylcholine (depolarizing NMB) especially in renal impairment, burns, and severe
tissue damage.
5. Heparin (inhibits aldosterone synthesis).
Potassium Sparing Diuretics
Common Characteristics:
1. Route of administration: they are given orally only.
2. Onset of action: delayed, not useful in emergencies.
3. Efficacy: they have low efficacy (weak diuretic action).
4. Site of action: distal segment of DCT and cortical collecting tubules.
5. Diuretic action: inhibit Na+/K+ exchange mainly and inhibit Na+/H+ exchange to a lesser
extent. This causes excretion of Na+, Cl-, and water in urine and retention of K+
(hyperkalemia) and H+ (metabolic acidosis).
6. They are contraindicated in renal impairment to avoid severe hyperkalemia.
7. Unlike thiazides and loop diuretics: they do not cause hyperglycemia, hyperlipidemia, or
hyperuricemia (they have mild uricosuric action) and are not related to sulphonamides
(no cross allergy and no carbonic anhydrase inhibition).
8. Classification: they are classified according to their mechanism of action into 2 groups:
a) Aldosterone antagonists: e.g. Spironolactone- Canrenone (active metabolite of
spironolactone) –Eplerenone.
They are competitive antagonists with aldosterone for specific intraceullar
(cytoplasmic) mineralocorticoid receptors in cells of DCT and collecting tubules.
b) Non-Aldosterone antagonists: e.g. Amiloride and Triamterene: they inhibit Na+ influx
by blocking Na+-channels in the luminal membrane of DCT and collecting tubular cells.

Diuretics 2011/2012
1) Aldosterone Antagonists:
a) Spironolactone (Aldactone):
1. Source: Synthetic.
2. Chemistry: Steroid.
 Absorbed orally.
 Converted in the liver into canrenone (active metabolite).
 Delayed onset and long duration.
 Passes B.B.B.
Competitive antagonists with aldosterone for mineralocorticoid receptors in DCT and
cortical collecting tubules leading to inhibition of Na+/K+ exchange (mainly) and
inhibition of Na+/H+ exchange.
5. Pharmacological actions:
a) Low efficacy diuretic action by increasing Na+,Cl-, and water excretion in urine.
b) Retention of K+ in blood leading to "Hyperkalemia".
c) Retention of H+ in blood leading to "Metabolic acidosis" and decrease H+ excretion
in urine causing slight alkalinization of urine.
d) No hyperuricemia, hyperglycemia, or hyperlipidemia (unlike thiazides and loop
diuretics).
a) Being weak diuretics they are usually combined with thiazide diuretics or loop
diuretics in treatment of edema and hypertension; to achieve synergism and
maintain normal blood potassium.
b) Treatment of refractory edema and resistant hypertension due to
Hyperaldosteronism which is either primary (Conn's syndrome) or more commonly
secondary to liver cirrhosis, nephrotic syndrome, and congestive heart failure.
They are given alone or combined with thiazide or loop diuretics.
c) Alternative to thiazides and loop diuretics whenever they are contraindicated in
allergy to sulphonamides, D.M., and gout.

Diuretics 2011/2012
7. Adverse effects:
a) Hyperkalemia especially in: renal impairment-drugs that inhibit renin release as β-
blockers, NSAIDs (inhibit PGI2 which stimulates renin release)-ACE inhibitors and
AT antagonists.
b) Metabolic acidosis.
c) Hypersensitivity reactions as skin rash.
d) Gut upset: gastritis, diarrhea, gastric bleeding.
e) CNS disturbances: headache, drowsiness, confusion, and lethargy.
f) Feminization (Gynecomastia) and impotence in males, and irregular menstruation
and masculanization in females (deepening of voice and hirsutism) due to steroid
structure.
8. Drug interactions:
a) With thiazide and loop diuretics: synergism in diuretic action and maintain normal
blood K+.
b) With ACE inhibitors, AT antagonists, β-blockers, and NSAIDS: severe hyperkalemia.
c) With Carbenoxolone( aldosterone-like drug derived from liquorice and acts as a
mucosal protective agent in treatment of peptic ulcer): spironolactone antagonizes
the action of liquorice on the stomach.
b) Eplerenone:
Similar to spironolactone but is non-steroid and accordingly no gynecomastia or
menstrual disturbances occur.
2) Non-Aldosterone Antagonists:
1. Source: Synthetic.
 Absorbed orally.
 Amiloride is excreted unchanged in urine. Triamterene is mainly metabolized in
the liver (shorter duration of action).
Mechanism of action: inhibit Na+ influx by blocking Na+ channels in DCT and cortical
collecting tubules (they do not compete with aldosterone) thus reducing Na+/K+
exchange and to a lesser extent Na+/H+ exchange.

Diuretics 2011/2012
4. Actions:
As Spironolactone:
Weak diuretic action- Hyperkalemia- Metabolic acidosis.
a) Amiloride and Triamterene are added to thiazides or loop diuretics in treatment of
edema (cardiac edema due to heart failure-renal edema - hepatic edema) to achieve
synergism and more importantly to correct hypokalemia induced by thiazides and
loop diuretics.
b) Amiloride can be used in lithium-induced nephrogenic diabetes insipidus.
6. Adverse effects:
a) Hyperkalemia especially in renal impairments and other drugs (see
Spironolactone).
b) Metabolic acidosis.
c) Hypersensitivity reactions: photosensitivity.
d) Gut upset.
e) Triamterene causes renal stones and may precipitate acute renal failure if given
with indomethacin (NSAID).
Carbonic Anhydrase Inhibitors

Therapeutic doses:
1. Glaucoma: in open angle glaucoma local CA inhibitors as dorzolamide and brinzolamide
are used, in narrow angle glaucoma acetazolamide is also given systemically.
2. Treatment of metabolic alkalosis.
3. Absence seizures (petit-mal epilepsy).
4. To alkalinize the urine, as in treatment of acute toxicity of acidic drugs as salicylates and
barbiturates.
5. Rarely used as diuretics (low efficacy and self-limiting).
Osmotic Diuretics:
 They are pharmacologically inert substances.
 They are freely filtered by the glomeruli but are not –or incompletely-reabsorbed, so
they are excreted in urine with iso-osmotic water and diuresis occurs. They increase
urinary Na+, Cl-, K+, Mg2+, HCO3- and Ca2+.

Diuretics 2011/2012
 Examples:
a) Mannitol:
 Polysaccharide given by I.V.infusion.
 Uses:
1. Acute elevation of intra-cranial pressure (ICP).
2. Acute elevation of IOP (acute narrow angle glaucoma=acute congestive glaucoma).
3. Prevent Acute renal failure.
Nausea and vomiting-Allergy-Transient expansion of extracellular fluid volume and
may aggravate acute heart failure.
Acute L.V.F. (acute pulmonary edema=cardiac asthma).
b) Glucose I.V.
c) Glycerin and isosorbide: given orally in acute narrow angle glaucoma.
Methylxanthines:
 Examples:
Caffeine,Theobromine, Theophylline, and Aminophylline.
 Diuretic action:
1. Pre-renal action by increasing COP and V.D. of renal blood vessels.
2. Renal action: inhibit Na+ reabsorption from PCT.
 Uses:
Aminophylline is given very slowly I.V. in acute L.V.F.
Cardiac glycosides:
Cardiac glycosides (digitalis) have diuretic action only in patients with congestive heart
failure by pre-renal action as they increase COP in these patients (see CVS pharmacology).
Dopamine:
Diuretic action occurs with moderate rate of infusion (stimulates D1-receptors causing renal
V.D. and increase renal blood flow) and with moderate rate of infusion (stimulate β1-
receptors causing increased COP).

Diuretics 2011/2012
Anti-Diuretics
1. ADH and drugs that increase release of ADH as morphine, nicotine, barbiturates, and
yohimbine.
2. Thiazide diuretics are anti-diuretics only in nephrogenic diabetes insipidus.
3. Amiloride is anti-diuretic in lithium-induced diabetes insipidus.
4. Chlorpropamide (anti-diabetic) is ADH like and is used in pituitary diabetes insipidus.
5. Vasoconstrictors as adrenaline and serotonin decrease renal blood flow and act as anti-
diuretics.
ADH Antagonists
1. Lithium carbonate: Antimanic and mood stabilizer. It induces nephrogenic diabetes
insipidus which is treated by amiloride.
2. Methoxyflurane: Inhalation halogenated general anaesthetic which may induce
nephrogenic diabetes insipidus.
3. Demeclocycline: Tetracycline antibiotic that may cause nephrogenic diabetes insipidus,
and is used to treat excess ADH secretion (Syndrome of Inappropriate ADH=SIADH).
Remember That:
 Diuretics causing Hypokalemia: Thiazides – Loop diuretics – CA inhibitors.
 Diuretics causing Hyperkalemia: Aldosterone antagonists (Spironolactone) and Non-

aldosterone antagonists (Amiloride and Triamterene).
 Diuretics causing Hypochloremic alkalosis: Thiazides and Loop diuretics.
 Diuretics causing Hyperchloremic Acidosis: CA inhibitors (Acetazolamide) and Acidifying

diuretics (NH4Cl).
 Self-Limiting diuretics: CA inhibitors and NH4Cl (due to acidosis).

Cardiovascular system 2011/2012
Angina Pectoris
Definition:
Severe central (retrosternsl) chest pain due to transient myocardial ischemia caused by
imbalance between myocardial oxygen supply (through the coronaries) and myocardial
oxygen demand (determined by the cardiac work).
N.B.: Angina is a "symptom" of a disease known as Ischemic Heart Disease (IHD), Coronary
Heart Disease (CHD) or Coronary Artery Disease (CAD).
Types and Causes:

1. Stable angina:
Also known as exertional angina-effort angina-classic or typical angina.
It is due to "atherosclerosis" of the coronaries which causes loss of elasticity, narrowing,
and roughness of the intima leading to platelet aggregation (the condition proceeds to
unstable angina) and thrombus formation (this condition is known as acute myocardial
infarction).
Pain is precipitated by exertion and relieved by rest.
2. Variant angina:
It is also known as Prinzmetal's angina-vasospastic angina.
It is not due to atherosclerosis but may be due to "supersensitivity" of α1-receptors in
the coronaries leading to reversible coronary spasm. Pain is not precipitated by exertion
and may occur at rest or during sleep.
3. Unstable angina:
It usually occurs in cases of stable angina complicated by platelet aggregation, spasm of
the coronaries, or rupture of atheromatous plaque into the lumen of the coronaries. It is
an emergency in which pain increases even with rest and anti-anginal drug therapy, and
may progress to acute myocardial infarction, that is why it is known as "pre-infarction or
crescendo angina" (angina at rest).
Risk Factors (Predisposing Factors):

1- Age. 2- Sex. 3- Family history. 4- Obesity. 5- Smoking.
6- Diabetes mellitus. 7- Sedentary life (lack of physical exercise).
8- Stress. 9- Hyperlipidemia (high LDL/HDL ratio).
10- Hypertension.
Precipitating Factors:
1- Exertion (physical and mental). 2- Heavy meals. 3- Cold weather.

Diagnosis:
1. History.
2. ECG: performed at rest and during exercise (Exercise Tolerance Test =ETT).
3. Angiography (Percutaneous Transluminal Coronary Angiography).
4. Ergometrine is used to diagnose variant angina.
Management:
1. Correction of Risk factors (if possible).
2. Avoidance of precipitating factors.
3. Treatment:
a) Surgical Treatment:
1. Percutaneous Transluminal Coronary Angioplasty. A stent may be implanted.
2. Coronary Artery Bypass Graft (CABG).
b) Drug Therapy:
The aim of drug therapy is to restore the balance between myocardial oxygen supply
(by V.D. of "normal" coronaries) and myocardial oxygen demand (by reducing cardiac
work).
 The following mechanisms may be used to reduce cardiac work:

1. Blocking cardiac β1-receptors to decrease cardiac properties.
2. Venodilatation to reduce pre-load (venous return).
3. Arteriodilatation to reduce after-load (TPR).
4. Inhibition of Ca2+ influx into cardiac cells to decrease cardiac properties, and into
arterioles to induce V.D.
 In stable and unstable angina; antiplatelet drugs must be given to inhibit platelet
aggregation.
 Accordingly; the anti-anginal drugs include:

1. β-Blockers.
2. Organic Nitrates.
3. Ca2+-Channel Blockers=CCBs (Ca2+-Entry Blockers = Ca2+ Influx Inhibitors = Ca2+ -
Antagonists).
4. Antiplatelet drugs (as aspirin in pediatric doses =75-150 mg.).
5. Nicorandil: K+-channel opener leading to hyperpolarization of smooth muscles of
blood vessels, and nitrate-like action. Both actions lead to V.D.

1)β-Blockers:
 All β-blockers –both selective and non-selective- are useful in prophylaxis of stable
angina because they decrease heart rate, contractility, and ABP leading to decreased
cardiac work and myocardial oxygen demands.
 Non-selective β-blockers are contraindicated in variant angina because they lead to
"unopposed α1-action" causing more vasospasm.
 Cardio-selective β-blockers are used with great caution and are better avoided in
variant angina because selectivity is not absolute.
 In unstable angina: β-blockers without ISA are used (in addition to I.V. nitroglycerin,
nifedipine(CCB), heparin and antiplatelet drugs as aspirin).
 Adverse effects and contraindications: see ANS,
But remember that they should never be stopped suddenly.
N.B.:
1. The dose of β-blockers is adjusted according to the heart rate, which should not exceed
50-60 beats/minute at rest, and 100-120 beats/minute during exercise.
2. β-blockers decrease heart rate -diastolic
volume (EDV) and ejection time → increased cardiac work and oxygen consumption
which partially antagonizes their beneficial effect in angina. This can be corrected by co-
administration of nitrates (nitrates increase heart rate reflexly and shorten diastole).
2)Nitrates and Nitrites:

 Source: synthetic.
 Chemistry:
a) Organic Nitrates:
1. Nitroglycerin (Glyceryl Tri-Nitrate =GTN).
2. Isosorbide Dinitrate.
3. Isosorbide Mononitrate.
(N.B.: Inorganic nitrates are inactive).
b) Nitrites:
Amyl nitrite. Nitrites are not commonly used as they may cause methemoglobinemia
(oxidation of ferrous iron of hemoglobin into ferric iron which causes anemic hypoxia
which is extremely dangerous in anginal patients).
a) Absorption:Well absorbed orally and can be given as S.L. tablets (pellets), as a buccal
(oral) spray, transdermal patch (disc), skin ointment and I.V. infusion.
b) Distribution: Pass B.B.B.

c) Metabolism:
Isosorbide dinitrate is converted into isosorbide mononitrate (active metabolite, has
100% bioavailability).
They are extensively metabolized by conjugation with glucuronic acid in the liver. 1st
pass metabolism can be avoided by giving them S.L., as buccal spray, through the
skin, I.V., and by increasing the oral dose.
d) Excretion: The conjugated metabolite is excreted in urine.
Classification:
1. Long acting nitrates: isosorbide mononitrate (oral), isosorbide dinitrate (oral), and
glyceryl trinitrate (sustained release oral capsules-skin ointment-transdermal patches).
For long-term prophylaxis against angina.
2. Short acting nitrates: glyceryl trinitrate and isosorbide dinitrate (S.L. and oral spray).
Used for treatment of acute attacks and for immediate prophylaxis.
Drug Routes of Indications

Administration
1. Nitroglycerin (glyceryl 1. Oral (sustained release 1. Long-term prophylaxis

trinitrate = GTN). capsules). of angina.
2. Transdermal patch 2. Long-term prophylaxis

(disc). of angina.
3. Skin ointment. 3. Long-term prophylaxis

of angina.
4. S.L. tablets (pellets) or 4. Acute angina and
buccal (oral) spray. immediate prophylaxis.
5. I.V.infusion. 5. Unstable angina and

acute myocardial
infarction.
3. Isosorbide Dinitrate 1. Oral (sustained release 1. Long-term prophylaxis
tablets). of angina.
2. S.L. pellets. 2. Acute attacks of angina

and immediate
prophylaxis.
4. Isosorbide Mononitrate Oral. Long-term prophylaxis.
5. Amyl Nitrite. Inhalation (volatile liquid in Acute attacks of angina.
fragile glass ampoules)

1. The molecule is "de-nitrated" in the tissues, i.e. a nitrite ion is released by
glutathione -S-transferase which requires sulfhydryl group.
2. Nitrite molecule is converted into "Nitric Oxide" (N.O.) which stimulates guanylyl
cyclase and increases synthesis of c-GMP which in turn leads to smooth muscle
relaxation particularly blood vessel and mainly veins(by dephosphorylation of
myosin light chain kinase).
i. CVS:
1. Nitrates and nitrites are mainly venodilators more than arteriodilators.
2. Venodilatation decreases venous return (pre-load) which decreases end-diastolic
volume (EDV). This leads to reduction of COP and consequently cardiac work and
myocardial oxygen demands are decreased. Reduction of COP decreases systolic
BP.
3. Venodilatation causes postural hypotension.
4. Arteriodilatation decreases TPR (after-load) which leads to reduction of
cardiac work and myocardial oxygen demands. Reduction of TPR decreases both
systolic and diastolic BP. (they decrease systolic BP more than diastolic, why?).
5. Reduction of ABP causes reflex sympathetic stimulation causing increased heart
rate (reflex tachycardia) and myocardial contractility, which increases cardiac
work and myocardial oxygen demands. Tachycardia also shortens diastole and
decreases coronary perfusion (filling of the coronaries occurs during diastole).
To correct these unwanted effects of nitrates they are combined with β-blockers
(or verapamil).
6. V.D. of normal epicardial coronary vessels leads to opening of collaterals and re-
distribution of blood into the ischemic areas.
(Remember that atherosclerotic vessels can not be dilated).
7. V.D. of cutaneous blood vessels causes flushing.
8. V.D. of meningeal blood vessels causes "throbbing" (pulsating) headache.
Indicates the beneficial actions of nitrates in angina.
ii. Platelets: Nitrates inhibit platelet aggregation by stimulating synthesis of c-GMP in
platelet.
iii. Other smooth muscle fibres: nitrates cause smooth muscle relaxation of bronchi,
GIT, uterus, and ureters.
iv. Methemoglobinemia: nitrites -and to a much less extent nitrates- oxidize ferrous
iron of hemoglobin into ferric iron. This is especially dangerous in IHD as it causes
more hypoxia.
However; methemoglobinemia is useful in treatment of cyanide poisoning (see
Pharmacology of Respiration).

1. Angina pectoris: nitrates are useful in all types of angina (stable, variant, and
unstable) and all conditions of angina (acute attacks, immediate prophylaxis, and
long-term prophylaxis).
The aim of therapy with nitrates in stable and unstable angina is to reduce cardiac
work and myocardial oxygen demands and not to dilate the coronaries, whereas the
aim of the aim of therapy in variant angina is to dilate the coronaries. They are given
S.L. or by buccal spray in acute attacks and immediate prophylaxis, and are given
orally, as skin ointment, and as transdermal patch for long-term prophylaxis.
Nitroglycerin is given by IV infusion in unstable angina.
2. Heart failure: they reduce pre-load mainly and after-load to a lesser extent.
Nitroglycerin is given by IV infusion in acute heart failure. Reduction of pre-load in
patients with heart failure improves myocardial contractility and increases COP (but
in patients without heart failure COP is reduced due to reduction of venous return
and EDV).
3. Emergency hypertension: nitroglycerin IV infusion is used.
4. Acute myocardial infarction: nitroglycerin IV infusion decreases cardiac work, dilates
the coronaries, and decreases pulmonary congestion. It may also reduce the size of
infarction.
5. Nitrites as amyl nitrite (inhalation) and sodium nitrite (IV) are used in cyanide
poisoning because they cause methemoglobinemia.
6. Treatment of acute bronchial asthma and intestinal, biliary, or renal colics (not
commonly used).
1. Reflex tachycardia (due to hypotension. It is avoided by adding β-blockers or
verapamil to nitrates).
2. Postural hypotension and dizziness, and may cause syncopal attacks (nitrate
syncope). This can be prevented by asking the patient to take S.L. pills when sitting -
not in the standing position- and to get rid of the pill after relief of pain, either by
swallowing or spitting.
3. Throbbing (pulsating) headache.
4. Flushing.
5. Methemoglobinemia and cyanosis especially with nitrites.
6. Allergic reactions as skin rash.
7. GIT disturbances.
8. Nitrate Tolerance: it is due to depletion of tissue SH group required for de-nitration
of nitrates. It is prevented by allowance of "nitrate-free" intervals of 8-10 hours or by
alternative use with other anti-anginal drugs as CCBs and β-blockers.
9. Nitrate dependence.
10.Carcinogenicity due to formation of nitrosamines.

N.B.:
1. In factory workers exposed to nitrates it has been noticed that headache and dizziness
occur rapidly after 1-2 days of exposure but rapidly disappear due to the development
of nitrate tolerance. However the symptoms recur at the beginning of the week (after
the week-end) and then disappear again and so on.
2. Nitrate dependence has been observed after prolonged exposure to nitrates if the
workers spend 1-2 days away from nitrates and is manifested as "variant angina".
 Drug Interactions:
1. Nitrates + β-blockers (propranolol) = beneficial combination.
2. Nitrates + Verapamil = beneficial combination.
3. Nitrates + Nifedipine = unfavorable combination.
4. Nitrates + Sildenafil (Viagra®)) = very dangerous combination because sildenafil
causes V.D., hypotension, and reflex tachycardia through inhibition of
phosphodiesterase 5 leading to increased intracellular c-GMP. They are given at least
6-hours apart.
(All are pharmacodynamic interactions)

3)Calcium Channel Blockers (CCBs):

 Chemistry: they are classified chemically into:

1. Phenylalkylamines as Verapamil.
2. Benzothiazepines as Diltiazem.
3. Dihydropyridines as Nifedipine, Amlodipine, Nimodipine, Nicardipine, Nitrendipine,
and Isradipine.
1. Absorption: well absorbed orally, and can be given parenterally.
2. Distribution: highly bound to plasma proteins (especially verapamil) and displace
other drugs from plasma proteins as digitalis, and pass B.B.B.
3. Fate: metabolized by the liver especially verapamil which is extensively metabolized
and its oral bioavailability (OBA) is about 25%, whereas nifedipine has OBA of about
50-70%. Metabolites are excreted in urine.
CCBs block voltage-gated Ca2+ channels and inhibit Ca2+ influx into cardiac and
smooth muscles especially arterioles. They act from the inner side of the cell
membrane.
It should be noted that CCBs have no effect on skeletal muscles because they do not
depend on Ca2+ influx to induce muscle contraction but depend on release of the
stored Ca2+ from the sarcoplasmic reticulum.
1. CVS:
a) Heart: verapamil and diltiazem have marked effect on the heart more than on
arterioles leading to: bradycardia (-ve chronotropic) – decreased AV conduction (-
ve dromotropic) – decreased contractility (-ve inotropic) – decreased excitability –
reduction in COP – reduction in myocardial oxygen needs.
(The actions of verapamil on the heart are similar to β-blockers).
b) Blood Vessels:
Dihydropyridines as nifedipine relax smooth muscles of arterioles mainly, leading to
V.D. of normal coronaries and other arterioles. Nifedipine causes reduction of TPR
and ABP, with consequent reflex sympathetic stimulation of the heart leading to
reflex tachycardia and increased myocardial contractility. Headache, dizziness, and
flushing also occur following V.D.

c) ABP: all CCBs cause hypotension (not related to posture, why?). The hypotensive
action of verapamil is mainly due to reduction in COP, but nifedipine causes
hypotension mainly due to V.D. and reduction of TPR.
2. Smooth muscle fibres: CCBs relax smooth muscles of the uterus, bronchi, GIT, and
ureters.
1. Angina pectoris: Prophylaxis of all types of angina. Verapamil is usually used in stable
angina as it reduces cardiac work and myocardial oxygen requirements. Nifedipine is
usually used in variant and unstable angina, due to its potent vasodilator effect.
2. Hypertension: all CCBs are useful in treatment of hypertension. Nicardipine I.V. is
useful in emergency hypertrension.
3. Arrhythmias: verapamil and diltiazem are used in supraventricular arrhythmia and
are classified as class IV antiarrhythmic drugs.
(Dihydropyridines as nifedipine are contraindicated in tachyarrhythmias as they lead
to reflex cardiac stimulation).
4. Hypertrophic obstructive cardiomyopathy (verapamil).
5. PVDs as Raynaud's disease (nifedipine).
6. Prophylaxis of migraine headache (flunarizine and verapamil).
7. Tocolytics in premature labor.
8. Nimodipine is used to prevent cerebral vasospasm after subarachnoid hemorrhage.
(N.B. Nifedipine is given S.L. in acute anginal attacks and in emergency hypertension).
a) Common Adverse effects:
1. Hypotension.
2. Constipation (more with verapamil).
3. Headache, flushing, and ankle edema (due to V.D., so they are more marked with
dihydropyridines as nifedipine).
b) Specific adverse effects of verapamil:
1. Bradycardia.
2. Reduction of AV conduction.
3. Decreases myocardial contractility.
c) Specific adverse effects of nifedipine:
1. Reflex tachycardia.
2. "Coronary Steal Phenomenon": nifedipine dilates normal coronaries and not
atherosclerotic vessels so the normal myocardium "steals" the blood from the
ischemic myocardium.

1. Hypotension.
2. Verapamil is contraindicated in: Bradycardia- AV block – Congestive heart failure.
3. Nifedipine is contraindicated in tachyarrhythmias.
a) Pharmacokinetic interactions:
1. CCBs especially verapamil displace digitalis from plasma proteins.
2. CCBs especially verapamil decrease renal excretion of digitalis (digoxin).
b) Pharmacodynamic interaction:
1. Verapamil + β-blockers = severe bradycardia, AV block, and diminished
contractility and may cause cardiac arrest.
2. Verapamil + Nitrates = beneficial combination (verapamil prevents reflex
tachycardia caused by nitrates).
3. Nifedipine + β-blockers = beneficial combination (β-blockers prevent reflex
tachycardia inducedc by nifedipine).
4. Nifedipine + Nitrates = severe hypotension and reflex tachycardia.
5. Verapamil + Nifedipine ???
 Other CCBs:
Bepridil: as verapamil.
Amiodarone: K+-channel blocker + CCB + α-blocker + β-blocker.
Used as antiarrhythmic (class III) and antianginal but is highly toxic.
4)Antiplatelet Drugs:
They inhibit platelet aggregation and are used in stable and unstable angina. They
include:
1. Aspirin (pediatric dose=75-150 mg. /day) and Dazoxiben. They inhibit TXA2 synthesis.
2. Dipyridamole: inhibits phosphodiesterase → ↑ c-AMP in platelets, blood vessels, and
heart platelet aggregation, V.D., and myocardial stimulation (also
reflexly due to hypotension). It is used in stable angina and in thrombo-embolic
diseases.
3. Ticlopidine and Clopidogrel: inhibit ADP-dependent platelet aggregation.
4. Sulphinpyrazone: inhibits COX.
5. PGI2 analogues as Epoprostenol.

Hypertension
1) Definition:
Elevation of ABP ≥ 140/90 mmHg, measured at least on 3 different occasions.
2) Types and Causes (Etiology):

a) Primary hypertension: = Idiopathic = Essential hypertension: occurs in over 90% of
patients. In these patients there is no cause for hypertension.
b) Secondary hypertension:
hypertension is caused by:
 Diseases: renal impairment- renal artery stenosis- Cushing syndrome-
Pheochromocytoma- Conn's disease.
 Drugs: sympathomimetics as adrenaline, noradrenaline, ephedrine, phenylephrine-
Cortisol- Contraceptive pills. (Remember "cheese reaction" and "rebound
hypertension" due to sudden clonidine withdrawal).
3) Management:
a) Treatment of the cause in secondary hypertension.
b) Dietary salt restriction.
c) Avoidance of stress (anxiolytics may be needed).
d) Regular physical exercise.
e) Drug therapy by antihypertensive drugs.
f) Treatment of complications.
4) Antihypertensive Drugs:
a) ABP is controlled by:
 COP which is dependent on myocardial contractility, heart rate, venous return and
blood volume.
 TPR which is dependent on the tone of peripheral arterioles.
 COP and TPR are controlled by the sympathetic nervous system and the renin-
angiotensin system (RAS).
 The influx of Ca2+ into the cardiac and smooth muscles of arterioles cells-through
voltage gated Ca2+ channels- increases COP TPR; respectively.

b) Accordingly; antihypertensive drugs include:

 ACE inhibitors (as Captopril) and Angiotensin receptor antagonists (as Losartan).
 Sympathetic Depressants:
a) Central α2-agonists (as Clonidine and alpha- methyldopa).
b) Competitive ganglion blockers (they are obsolete except Trimetaphan).
c) Adrenergic neuron depressants: Guanethidine-Reserpine(rarely used).
d) Adrenoceptor antagonists: β-blockers (as Propranolol)– selective α1-blockers
(as Prazosin) - drugs that block β and α-receptors(as Labetalol).
 Calcium channel blockers (as Verapamil and Nifedipine).
 Diuretics: Thiazide diuretics (as Hydrochlorothiazide)- Loop diuretics (as
Frusemide) – K+-sparing diuretics (Spironolactone- Amiloride- Triamterene).
 Vasodilators:
 Arteriodilators:
1) Common action: they cause V.D. of arterioles →↓TPR→↓ABP.
2) Common Adverse effects: hypotension causes reflex sympathetic stimulation
leading to:
a) Increased myocardial contractility and heart rate (reflex tachycardia).
b) Increased renin-angiotensin system which stimulates aldosterone synthesis
and release causing Na+ and water retention.
c) That is why they should be combined with β-blockers and loop diuretics.
d) Headache and flushing.
e) Examples include: Hydralazine – Minoxidil- Diazoxide.
 Venodilators as Nitrates (see Angina Pectoris).
 Mixed (Balanced or Combined) Dilators: they dilate both arteries and veins, as
sodium nitroprusside.
N.B.: ACE inhibitors and selective α1-blockers are also mixed dilators.

c) GENERAL RULES:
 Arteriodilators cause throbbing headache, flushing, reflex tachycardia, and salt and
water retention.
 Arteriodilators are useful in treatment of hypertension and heart failure as they
decrease TPR = After-load.
 Venodilators cause postural hypotension and may be syncope which is particularly
dangerous in old patients.
 Venodilators are less effective in treatment of hypertension than arteriodilators,
and are also used in treatment of angina and heart failure.
 Drugs that are given orally are used in chronic patients (Thiazides, β-blockers,
CCBs, ACE inhibitors, Minoxidil), drugs that are given parenterally only (IV, IV
infusion, IM) are used in emergency hypertension only (Na+ nitroprusside,
Diazoxide, Trimetaphan, Fenoldopam). Drugs that can be given both orally and
parenterally are useful in both chronic and emergency conditions (loop diuretics as
Frusemide, Enalaprilat, Hydralazine).
Arteriodilators:
1)Hydralazine:
b) Pharmacokinetics:
 Absorbed orally and may be given parenterally.
 Metabolized in the liver by acetylation(conjugation with acetate) which is
genetically determined; i.e. people are either fast acetylators or slow acetylators.
Slow acetylators are liable to idiosyncracy in the form of peripheral neuritis
(prevented and treated by pyridoxine = B6) and reversible iatrogenic systemic
lupus erythematosus (SLE).
 Metabolites are excreted in urine.
c) Pharmacodynamics:
 Mechanism of action: Direct arteriodilatation (?), may act by NO release.
1) V.D. of arterioles → ↓ TPR (after-load) →↓ABP.
2) Reflex sympathetic stimulation → reflex tachycardia (add β -blocker or
verapamil), and icreased renin-angiotensin-aldosterone activity →Na+ and water
retention (add loop diuretic as frusemide).

 Hypertension: severe chronic hypertension (add β-blocker and loop diuretics) and
emergency.
 Heart failure.
e) Adverse effects:
 Common adverse effects:
1) Reflex tachycardia.
2) Anginal pains.
3) Salt and water retention.
4) Headache and flushing.
 Specific adverse effects (especially in slow acetylators):
1) Peripheral neuritis.
2) Systemic-lupus erythematosus.
2) Angina pectoris.
2)Minoxidil:
 Given orally only (given as hair lotion in treatment of alopecia).
 Minoxidil is a prodrug converted by the liver into active minoxidil sulphate.
Minoxidil is a K+-channel opener → efflux of K+ and hyperpolarization of smooth
muscle of arterioles → V.D. of arterioles.
1) V.D. of arterioles →↓TPR (after-load) →↓ABP.
2) Reflex sympathetic stimulation → reflex tachycardia (add β-blocker or
verapamil) and increased renin-angiotensin-aldosterone activity → Na+ and
water retention (add loop diuretics as frusemide).
1) Hypertension: chronic hypertension resistant to hydralazine (add β-blockers and
loop diuretics).
2) Treatment of alopecia or baldness.

e) Adverse effects:
2) Anginal pains.
3) Salt and water retention.
 Specific adverse effect:
1) Hypertrichosis (specific adverse effect).
2) Angina pectoris.
3)Diazoxide:
b) Chemistry: related to thiazides.
 Absorbed orally and also given parenterally (IV injection and infusion).
 Highly bound to plasma proteins.
 Partly metabolized by the liver and partly excreted unchanged in urine (by active
transport as thiazides and interferes with uric acid secretion leading to
hyperuricemia).
As minoxidil; diazoxide is a K+-channel opener leading to hyperpolarization and
V.D. of arterioles.
1) V.D. of arterioles →↓ TPR (after-load) →↓ ABP.
2) Reflex sympathetic stimulation → reflex tachycardia (add β -blockers or
verapamil) and increased renin-angiotensin-aldosterone activity → Na+ and
water retention (add loop diuretics as frusemide).
3) Inhibition of insulin release from pancreas due to opening of K+-channels in B-
cells of pancreas (as thiazides).
4) Hyperuricemia.

 Emergency hyperternsion (given IV).
 Treatment of insulinoma (given orally).
f) Adverse effects:
2) Anginal pains.
3) Salt and water retention (in contrast to thiazides).
 Specific adverse effects:
Hyperglycemia-Hyperuricemia-Hypokalemia – Hypersensitivity reactions (as
thiazides) – uterine relaxation.
 Tachyarrhythmias.
 Angina pectoris.
4)Fenoldopam:
a) Selective D1-agonist → V.D. of arterioles.
b) Given by IV infusion.
c) Used in emergency hypertension.
d) Adverse effects: Reflex tachycardia- Headache – Flushing – Elevation of IOP.

Mixed Vasodilators
1)Sodium Nitroprusside:
 Given by IV infusion (should never be given orally as it is metabolized into
cyanide).
 Metabolized in RBCs into cyanide (toxic metabolite) which is rapidly metabolized
by rhodanase enzyme in the liver into thiocyanate (toxic metabolite) which is
excreted in urine.
Releases nitric oxide (NO) → activation of guanylyl cyclase→
↑c-GMP→ V.D. of both arterioles and veins and inhibition of platelet aggregation.
2) Arteriodilatation → ↓ TPR (after-load) and ABP.
3) Venodilatation → ↓ Pre-load.
4) Reflex sympathetic stimulation → Tachycardia.
5) Inhibits platelet aggregation.
N.B.: Nitroprusside in normal individuals causes slight reduction of COP due to
decrease in venous return, but in patients with heart failure it increases COP due to
reduction in after-load and ABP).
1) Emergency hypertension.
2) Acute heart failure.
3) Controlled hypotension during plastic and neurosurgery (Trimetaphan and
Halothane may be also used).
4) Acute dissecting aortic aneurysm (combined with β-blockers).

e) Adverse effects:
 Severe hypotension, reflex tachycardia and arrhythmia, and angina pains are
observed with overdose.
 Accumulation of cyanide occurs in hepatic insufficiency and may cause death (It is
prevented and treated by thiosulphate or hydroxocobalamin).
 Accumulation of thiocyanate occurs in renal impairment and leads to
disorientation, weakness, psychosis, and convulsions. It may cause hypothyroidism
due to inhibition of iodide uptake by the thyroid.
 It is treated by hemodialysis.
 Nitroprusside can worsen hypoxia in patients with COPD
 Rebound hypertension if stopped suddenly.
f) Precautions during IV infusion of Nitroprusside:
 Should be freshly prepared.

 Should be covered with foil-paper to avoid metabolism by sun-light into cyanide.
 Dose should be adjusted in liver and/or renal impairment to avoid accumulation of
cyanide and/or thiocyanate (thiosulphate or hydroxocobalamin may be added with
large doses).
 Monitor ABP and heart rate.
 Never stop infusion suddenly to avoid rebound hypertension.
6) Nesiritide:
a) Recombinant human Brain Natriuretic Peptide (BNP).

b) Given by IV infusion.
c) Used in acute decompensated heart failure.

Heart Failure
1) Definition:
It is the Inability of the heart to maintain an adequate COP sufficient to meet tissue oxygen
requirements. Heart failure is regarded to as "imbalance between COP and tissue oxygen
requirements".
2) Types of Heart Failure:

a) According to COP:
 Low COP failure: either due to systolic dysfunction or due to diastolic dysfunction.
 High COP failure: due to hyperthyroidism, severe anemia, pregnancy, or severe
vitamin deficiency. Treatment of this type of heart failure is by treatment of the
cause.
b) According to Onset:
 Chronic heart failure.
 Acute heart failure.
c) According to Side affected:

 Right -sided heart failure: leads to systemic congestion.
 Left-sided heart failure: leads to pulmonary congestion.
 Combined heart failure: leads to both systemic and pulmonary congestion.
3) Compensatory Mechanisms in Heart Failure:

They try to increase COP but will eventually fail and heart failure becomes "manifest" or
"decompensated".The compensatory mechanisms include:
a) Increase in cardiac size by hypertrophy and dilatation.
b) Reflex sympathetic stimulation: low COP → low ABP (except in hypertensive heart
failure) →1- Tachycardia. 2-V.C. of both arteries and veins (↑after-load and pre-load).
3-Increased renin-angiotensin activity → increased aldosterone synthesis and release
→ sodium and water retention→ edema and increased blood volume.

Aim of Treatment in Heart Failure Drugs Used

1. Increase myocardial contractility to 1. Positive inotropic drugs
increase COP. (myocardial stimulants).
2. V.D. of both veins and arteries to reduce 2. Vasodilators: Venodilators-
pre-load and after-load. Arteriodilators-Mixed dilators.
3. Decrease blood volume and edema. 3. Diuretics.
4)Positive Inotropic Drugs (Myocardial Stimulants)

a) To increase myocardial contractility it is essential to increase free Ca2+ inside cardiac
cells.
b) Mechanisms to increase free Ca2+ include:
 Increasing intracellular c-AMP by:
1) Stimulation of β1-receptors by Dopamine, Dobutamine,
and Prenalterol → activation of adenylyl cyclase →↑ synthesis of c-AMP.
2) Inhibition of phosphodiesterases (PDE) by Methylxanthines (as Aminophylline)
and Bipyridines (as Amrinone and Milrinone).
 Increasing intracellular Na+ by inhibition of Na+/K+ ATPase by Cardiac

Glycosides (Digitalis preparations).
5)Cardiac Glycosides (Digitalis Preparations):
a) Source: Plant origin (Digitalis purpurea, Digitalis lanata, Strophanthus).
b) Chemistry: each molecule is composed of:
1- Non-sugar part (aglycone) formed of a steroid nucleus; it is responsible for the

pharmacodynamic properties.
2- Sugar part (glycone) which is responsible for the degree of lipid solubility and
accordingly the pharmacokinetic properties.
(Both parts of the molecule are bound by an ether link).

The pharmacokinetic properties vary according to the type of digitalis as follows:
Pharmacokinetic Digitoxin Digoxin Ouabain

parameter:
1-Lipid Solubility: High. Moderate. Not lipid soluble,
polar,water soluble.
2-Oral Absorption: Almost complete. Moderate. Not absorbed.
3- Oral
bioavailability: 90 % 75% Zero
4- Route of
administration: Orally only. Orally and IV. IV only.
5-Plasma protein Highly bound. Moderate. Almost unbound.

binding:
6-Passage across Marked. Less. Cannot pass.

BBB:
7-Fate: Mainly metabolized Mainly excreted Excreted unchanged

by HME (avoided in unchanged in urine in urine (avoided in
liver diseases). (avoided in renal renal diseases).
diseases).
8-Elimination t1/2: 7 days (168 hours). About 1.5 day (40 About 1 day (21
hours). hours).
9-Cumulation Most cumulative. Moderate. Least cumulative.

(especially in
cardiac and
skeletal muscles):

Cardiac glycosides partially inhibit membrane-bound Na+/K+ ATPase (Na+ pump)
in cardiac cells → increase in intraceullar Na+ → increase in intracellular Ca2+ by:
1) ↓ Ca2+/Na+ exchange.
2) ↑Release of Ca2+ from sarcoplasmic reticulum.
3) Opening of voltage-gated Ca2+ channels.
4) Elevation of free Ca2+ increases myocardial contractility.
e) Very important note:

Cardiac glycosides and potassium (and to a less extent magnesium) compete for
Na+/K+ ATPase; that is why hypokalemia is the most important predisposing factor
for digitalis toxicity.
(K+ and Mg2+ activate but digitalis and Ca2+ inhibit the enzyme).
f) Pharmacological actions:
 Positive Inotropic action especially in left ventricular systolic dysfunction.
 Increased COP in patients with congestive heart failure, but it has no effect or may
even decrease COP in normal individuals due to bradycardia and decreased cardiac
size.
 Increased mechanical efficiency of the heart as digitalis increases contractility
(work done) without marked increase in oxygen consumption (energy consumed).
 Reduction of cardiac size to normal, and reduction of EDV, ESV, and venous
pressure.
 Heart rate:
1) Digitalis decreases SAN automaticity; it has negative chronotropic action
leading to decrease in heart rate. Remember that before digitalis there is
compensatory tachycardia.
2) Reduction in heart rate is due to:
a) Vagal action: digitalis stimulates vagal C.I.C. both directly and reflexly
through stimulation of baroreceptors, and sensitizes SAN to acetylcholine.
This vagal action is the mechanism of bradycardia in the beginning of
treatment by digitalis (early digitalization).
b) Direct action (extra-vagal action): digitalis decreases SAN automaticity
directly and decreases sensitivity of SAN to catecholamines (anti-
adrenergic action). This action occurs after full digitalization.
Very important note: the earliest objective manifestation of digitalis toxicity is
"BRADYCARDIA ‹ 60 beats / minute.
Give reason: Atropine can cause tachycardia if given in early digitalization but
cannot produce tachycardia in fully digitalized patients?

 Refractory Period (R.P.):
Vagal Action Direct Action Net effect

1. Atrial R.P. Shortens. Prolongs. Shortening.
2. AV R.P. Prolongs. Prolongs. Prolongation.
3. Ventricular R.P. No effect. Shortens. Shortening.
 Conductivity:
Vagal Action Direct Action Net Effect

1. Atrial Conductivity. Accelerates. Slows. Accelerates.
2. AV Conductivity. Slows. Slows. Slows.
3. Ventricular No effect. Accelerates. Accelerates.

Conductivity.
 Automaticity:
1) SAN: digitalis decreases SAN automaticity leading to ↓ heart rate (negative
chronotropic).
2) AV system: digitalis decreases AV conduction (negative dromotropic). This
may lead to AV block, but it is beneficial in supra-ventricular arrhythmias as it
protects the ventricles.
3) Purkinje fibres: in therapeutic levels, digitalis has no effect but in digitalis
toxicity there is increased automaticity leading to ectopic pace-makers and
ventricular arrhythmias.
Very important note:
Digitalis is useful in treatment of supra-ventricular arrhythmias but is contraindicated
in ventricular arrhythmias.
 Excitability:
1) In therapeutic levels digitalis increases excitability due to increased intra-
cellular Na+ which causes partial depolarization.
2) In cases of digitalis toxicity; excitability may be reduced due to inactivation of
fast Na+-channels.
 ABP:
1) Digitalis "normalizes" ABP if it was low as it increases COP. However; it may
increase ABP in case of toxicity by V.C. (direct action and by stimulation of
VMC).
2) Digitalis can be used in patients suffering from hypertensive heart failure.

 Diuretic Action:
Digitalis has a diuretic action only in cases of congestive heart failure as it
increases COP → ↑renal blood flow (RBF) →↑ GFR. In addition; improvement of
COP reduces sympathetic activity →↓ renin-angiotensin-aldosterone system.
 Blood Volume:
Diuretic action of digitalis in heart failure decreases blood volume.
 Coronary vessels:
1) Therapeutic levels of digitalis have no effect on coronary circulation and it can
be used in patients with angina and heart failure.
2) In digitalis toxicity coronary vasospasm may occur.
 E.C.G.
1) Prolongation of P-R interval: due to delay in AV conduction.
2) Short QRS and Q-T segment due to strong short systole and rapid
repolarization.
3) Depressed S-T segment (especially in case of toxicity).
4) Flat or inverted T-wave.
5) Bradycardia.
6) Ventricular arrhythmias (extrasystole-Pulsus Bigeminus or Trigeminus-
Ventricular tachycardia- Ventricular Fibrillation=V.F.).
g) Therapeutic uses:
 Congestive heart failure, especially left ventricular systolic dysfunction. Digitoxin
and digoxin can be used in chronic cases whereas digoxin and ouabain can be used
in acute heart failure (acute L.V.F.).
 Atrial Fibrillation (A.F.): digitalis is useful in A.F. with or without heart failure. It
has the following advantages:

Before Digitalis After Digitalis
1-Atrial rate: 400 or more-irregular. 1-Worsens atrial arrhythmia (due to

↑atrial conductivity).
2-Ventricular rate: about 150-
irregular. 2-Slows ventricular rate to normal
by ↓AV conduction (protects the
ventricle).
3-Pulse deficit present.
3-Eliminates pulse deficit.
4-Diminished ventricular
efficiency. 4-Restores mechanical efficiency of
the ventricles.
 Atrial Flutter: digitalis protects the ventricles by reducing AV conduction but it

may convert atrial flutter into A.F.
After stopping digitalis one of the following may occur:
1) Normal sinus rhythm is restored and the patient is cured.
2) A.F. persists.
3) The condition reverses into atrial flutter.
4) If A.F. persists or atrial flutter recurs; Quinidine is given to restore normal sinus
rhythm. It should be noted that quinidine should never be given before digitalis
because quinidine may increase AV conduction due to atropine-like action
leading to ventricular arrhythmia which may be fatal. In addition; quinidine
should never be given with digitalis to avoid serious drug interactions (see
later).
 Paroxysmal Atrial Tachycardia (PAT) and Nodal Tachycardia: digitalis decreases

SAN automaticity and AV conductivity.
 N.B. PAT is also treated by β-blockers, verapamil, and M2-agonists as
edrophonium and neostigmine.
h) Adverse effects (Toxicity):

 CVS: Bradycardia – Partial AV block – Ventricular arrhythmias (extrasystole-
pulsus bigeminus or trigeminus - ventricular tachycardia – V.F.).
 GIT: anorexia, nausea, vomiting, colics, and diarrhea. Nausea is mainly due to
central stimulation of CTZ and less probably due to local GIT irritation.
 CNS: headache, drowsiness, confusion, hallucinations, and convulsions (rare but
indicates serious toxicity).
 Eye: blurring of visison, disturbance of green and yellow vision (chromatopsia),
amblyopia, or diplopia.

 Gynecomastia: may be due to steroid structure (remember spironolactone).
i) Contraindications:
 Bradycardia (including carotid sinus hyperactivity).
 Partial AV block.
 Ventricular arrhythmias.
 Hypertrophic obstructive cardiomyopathy (treated by β-blockers or CCBs).
 Constrictive pericarditis.
 Severe valve stenosis.
 Wolf-Parkinson-White syndrome (abnormal conducting fibres).
j) Drug interactions:
 A-Pharmacokinetic interactions:
1) Absorption:
a) Drugs that decrease digitalis absorption:
Antacids (Mg. and Al. salts), Antiemetics (metoclopramide), Antidiarrheal
drugs (kaolin and pectin), Antibiotics (neomycin), and Antihyperlipidemic
drugs (cholestyramine).
b) Drugs that increase digitalis absorption:
Antimuscarinic drugs as atropine and propantheline. They may lead to digitalis
toxicity.
2) Distribution:
Many drugs displace digitalis from plasma proteins and may lead to digitalis
toxicity; as propranolol, NSAIDs as aspirin, CCBs as verapamil and nifedipine,
amiodarone, sulphonamides, and quinidine.
3) Metabolism:
a) -HME inducers as rifampicin, nicotine, phenytoin, and phenobarbitone
decrease bioavailability of digitalis.
b) -HME inhibitors as contraceptives and erythromycin increase bioavailability
and may induce digitalis toxicity.
4) Excretion:
Quinidine and CCBs especially verapamil decrease renal clearance of digoxin and
may cause toxicity.
N.B. Quinidine induces digitalis toxicity by displacing digitalis from plasma
proteins and decreasing its renal excretion.

 B-Pharmacodynamic interactions:
1) K+-losing diuretics as thiazides and loop diuretics cause hypokalemia and
hypomagnesemia which predispose to digitalis toxicity.
2) K+-sparing diuretics cause hyperkalemia which antagonizes digitalis.
3) β-blockers and verapamil antagonize inotropic action of digitalis but augment
bradycardia and AV block.
4) Sympathomimetics acting as β1-agonists as adrenaline may lead to ventricular
arrhythmia.
5) Ca2+ salts increase the action of digitalis and may lead to toxicity.
k) Digitalis Toxicity:
 Cardiac glycosides have low therapeutic index (narrow safety margin).
 The earliest manifestations of toxicity: nausea and vomiting, and bradycardia
below 60 beats /minute. Other manifestations of toxicity: see before.
 Digitalis toxicity is usually chronic (digitalis is a cumulative drug) and rarely acute
due to high loading dose especially in old age.
 Factors predisposing to digitalis toxicity:

1) Hypokalemia and hypomagnesemia due to concurrent use of thiazides or loop
diuretics with digitalis in treatment of heart failure. Corticosteroids and
carbenoxolone (aldosterone-like) also cause hypokalemia.
2) Hypercalcemia.
3) Sympathomimetics.
4) HME inhibitors (see before).
5) Drugs that displace digitalis from plasma proteins (see before).
6) Drugs that reduce renal clearance of digoxin (see before).
7) Acidosis, hypoxia, and ischemia: decrease activity of Na+/K+ ATPase and
increase the effect of digitalis.
8) Hypothyroidism decreases elimination of digitalis.
9) Old age: dimished liver and kidney functions reduce elimination of digitalis.
10) Hepatic insufficiency reduces metabolism of digitoxin and renal impairment
reduce renal excretion of digoxin.
l) Prevention of digitalis toxicity:

 Avoid and correct predisposing factors.
 Monitoring plasma level of digoxin (therapeutic level: 0.5-2ng./mL.) and digitoxin
(therapeutic level: 10-25 ng./mL).

m) treatment of digitalis toxicity:

1) Stop digitalis.
2) In case of hypokalemia: stop K+-losing diuretics and give KCl (syrup, sustained
release tablets, or slowliy IV infusion) except in case of renal impairment and AV
block.
3) In case of hypercalcemia: give Ca2+ chelating agent as disodium edetate IV.
4) To treat AV block use atropine.
5) To treat ventricular arrhythmias With AV block: Phenytoin.
To treat ventricular arrhythmias Without AV block: Lidocaine or β-blockers.
6) In case of acute toxicity: Digoxin antibodies (Fab fragments) are given, and
cholestyramine to decrease oral absorption of digitoxin.
n) Very important notes:

1) 1-DC shock (electric cardioversion) is contraindicated in digitalis toxicity as it may
lead to V.F.
2) 2-Quinidine is contraindicated in treatment of arrhythmias due to digitalis toxicity
(why?).
o) Methods of digitalization:
1) Loading dose method: a large dose is given to reach the steady state concentration
(Css) in a short period of time. It may lead to toxicity especially in old age. It is
followed by a small daily dose to maintain Css (maintenance dose).
2) Non-loading dose method: the small maintenance dose is given daily and Css is
reached after 4-5 half-lives; which equals about 1 week for digoxin (4 or 5 x 1.5)
and about 1 month for digitoxin (4 or 5 x 7).
Other Positive Inotropic Drugs:
1) Bipyridines:
a) Mechanism of action: inhibit PDE type 3 → increase in c-AMP.
b) Pharmacological actions: Positive inotropic action and V.D. which reduces pre-load
and after-load (they are known as "Ino-dilators").
c) Examples:
 Amrinone = Inamrinone: given IV for short-term treatment of acute heart failure. It
is highly toxic and may cause thrombocytopenia and hepatotoxicity.
 Milrinone: more potent and less toxic than amrinone.

2) Aminophylline:
a) Mechanism of action: inhibits PDE type 4 and increases c-AMP.
b) Pharmacological actions: positive inotropic + V.D. (also inodilator) + bronchodilator

+ Diuretic + CNS stimulant.
Given slowly IV in acute heart failure (increases COP for 30 minutes).
3) Β1-Agonists: Dopamine –Dobutamine –Prenalterol (see ANS).
The Role of β-Blockers in Heart Failure:
Traditionally β-blockers are contraindicated in heart failure because the have negative
inotropic action and may precipitate heart failure in compensated cases.
Recently some β-blockers as Bisoprolol, Metoprolol, and Carvedilol are given in small
doses to protect the heart against the mitogenic effect of catecholamines on cardiac cells
which induces remodeling and apoptosis.

RAAS & RAAS antagonists 2011/2012
Renin-Angiotensin-Aldosterone System (RAAS) and RAAS

Antagonists
• ANGIOTENSINOGEN (α2-globulin synthesized by the liver- synthesis is stimulated by
estrogen, cortisol, thyroxin and angiotensin II).
↓
↓ Renin from JGA of kidney
↓
• ANGIOTENSIN I (Inactive)
↓
↓ ACE in the lung
↓
• ANGIOTENSIN II (Very active)
↓
↓Aminopeptidase
↓
• ANGIOTENSIN III (Less active)
↓
↓ Angiotensinase
↓
Inactive Peptides
N.B.: JGA= Juxta-Glomerular Apparatus.

ACE=Angiotensin Converting Enzyme. It is identical to "Kininase II" enzyme which
metabolizes bradykinin into inactive fragments.
• Renin:
Glycoprotein protease enzyme synthesized by JGA of the kidney.
• Factors that stimulate renin release include:
1. Sympathetic stimulation of β1-receptors.
2. Decreased renal blood flow (due to low COP and hypotension).
3. Low Na+ reaching distal convoluted tubules (Macula densa).
4. Prostaglandin I2.
• Factors that inhibit renin release:
1. Angiotensin II (-ve feedback).
2. α2-Agonists (clonidine, alpha-methyldopa, guanfacin, guanabenz).
3. β1-Blockers.

Angiotensin II:
• Synthesis: see before.
• Mechanism of action:
Stimulates specific angiotensin receptors: AT1 (Gq-linked → activation of PLC →↑IP3 and
DAG→↑ Ca2+ and activation of protein kinases) and AT2 (in CNS and adrenal medulla).
• Actions:
1. Very potent V.C. of both arteries (pressor action) and veins. It is about 40 times more
potent than noradrenaline.
2. Stimulates synthesis and release of aldosterone from adrenal cortex causing Na+ and
water reabsorption and K+ secretion in urine.
3. Stimulates release of catecholamines from adrenal medulla and stimulates
transmission in sympathetic ganglia.
4. Positive inotropic action.
5. Spasmogenic action on smooth muscle fibres.
6. Inhibits renin release (-ve feedback) and increases angiotensinogen synthesis.
7. Stimulates drinking (dipsogenic action), ↑ACTH and ADH (vasopressin).
8. Hypertrophy and mitogenic action on the cardiac muscle and blood vessels.
N.B.: Actions 1, 2, 3, and 4 lead to elevation of ABP.
• Therapeutic use:
Treatment of severe hypotension given by I.V.infusion; especially if hypotension is due to
overdose of α1-blockers (α-agonists as noradrenaline and phenylephrine are not
effective, whereas adrenaline will lead to more hypotension..Why?).
Antagonists of the Renin-Angiotensin System:
a) Inhibitors of renin release:

• β-Blockers (both non-selective and cardioselective).
• α2-Agonists (Clonidine-Guanfacin-Guanabenz-α methyldopa).

b) Angiotensin Converting Enzyme Inhibitors

(ACE inhibitors-ACEIs)
• Chemistry:
1. Sulphhydryl-containing: Captopril –Active drug.
2. Non-SH -containing:
a) Lisinopril: Active drug.
b) Enalapril-Ramipril-Perindopril-Fosinopril-Benazepril-Quinapril: Prodrugs
• Pharmacokinetics:
1. Absorption:: Well absorbed orally, oral absorption of ACEIs is reduced by antacids.
Captopril is affected by presence of food, so it is better given on empty stomch (1-2
hours before meals).
Enalaprilat is also given I.V. in emergency hypertension.
2. Distribution: Pass placental barrier and are fetotoxic (teratogenic).
3. Fate:
a) Captopril (active drug) is partly metabolized by the liver into inactive metabolites
(50%) and partly excreted unchanged in urine (50%).
b) Lisinopril (active metabolite) is mostly excreted unchanged in urine, and so it has a
long half-life.
c) Most ACEIs are prodrugs: converted into active metabolites by the liver, e.g.
Enalapril is converted into enalaprilat, and these active metabolites are excreted in
urine, except Fosinopril which is excreted in bile, and it can be given in renal
impairment without dose adjustment.
• Pharmacodynamics:
1. Inhibit ACE leading to reduction of conversion of AT-I (inactive) into AT-II (the most
active angiotensin).
2. Inhibit inactivation of kinins (as bradykinin) resulting in accumulation of kinins which
induce powerful vasodilatation by: stimulation of vasodilator prostaglandin synthesis
as PGI, and by releasing nitric oxide.

1. V.D. of both arteries and veins (decreases after-load and pre-load; respectively).
N.B. ACEIs increase renal blood flow but may reduce glomerular filtration due to
dilatation of the efferent arterioles more than the afferent arterioles which decrease
intra-glomerular pressure.
2. Reduction of aldesterone synthesis and release → excretion of Na+ and water in urine,
and retention of K+(hyperkalemia).
3. Reduction of catecholamine release from adrenal medulla.
4. Reduction of bradykinin metabolism by inhibition of kininase II leading to
accumulation of bradykinin which causes potent V.D. but also produces dry persistent
cough due to its inflammatory reaction in the lung.
5. Reduction of sympathetic activity by decreasing release of adrenaline and
noradrenaline from the adrenal medulla and from adrenergic neurons, and inhibition
of transmission in sympathetic ganglia.
6. Decrease the positive inotropic action induced by AT-II.
(All previously mentioned actions ↓ABP).
7. Inhibit the mitogenic action and remodeling induced by AT-II.
8. Increase renin (no –ve feedback) but decreases angiotensinogen.
• Therapeutic uses:
1. Hypertension especially in:
a) Diabetic patients (drugs of choice, why?).
b) Hypertensive with heart failure.
c) High renin.
2. Congestive heart failure (decrease both pre-load and after-load).
3. To prevent remodeling after myocardial infarction.
4. Diabetic nephropathy.
• Advantages of ACEIs:
1. Mild venodilatation which explains the following:
a) The venous return, EDV, and COP are not markedly decreased. COP is maintained
and even increases in patients with heart failure.
b) No postural hypotension (except after the first dose).
2. No reflex tachycardia (due to reduction in sympathetic activity).
3. No change in blood glucose, no hyperuricemia, and no hyperlipidemia in contrast to
other antihypertensive drugs as beta blockers and thiazides and loop diuretics.

• Adverse effects:
1. 1st dose phenomenon: severe postural hypotension after the first dose especially in
sodium-depleted patients (due to the use of diuretics).
Avoided by starting treatment with small doses and giving the first dose at bed-time
(remember selective α1-blockers as prazosin). Diuretics may be stopped before
administration of ACEIs.
Treated by: saline (NaCl) IV infusion or oral salt intake.
2. Allergy (skin rash, angioneurotic edema, and rarely hepatotoxicity); especially
captopril (SH-containing).
3. Dry persistent cough.
4. Hyperkalemia especially in renal impairment.
5. Neutropenia.
6. Proteinurea (in large doses).
7. Dysgeusia (impaired taste sensation).
8. Fetotoxicity (teratogenicity) if ACEIs are administered in first trimester, and fetal
hypotension, fetal growth retardation, renal hypoplasia, oligohydramnios, and even
fetal death if they are given in second and third trimester.
9. Acute renal failure in "bilateral renal artery stenosis".
• Contraindications:
1- Pregnancy. 2- Bilateral renal artery stenosis.
3- Allergy. 4- Bronchial asthma.
• Drug interactions:
a) Pharmacokinetic interaction: Antacids decrease oral absorption of ACE inhibitors.
b) Pharmacodynamics interactions:
1. NSAIDs antagonize the antihypertensive effect of ACE inhibitors (due to inhibition
of bradykinin synthesis and due to Na+ and water retention).
2. With thiazide and loop diuretics: Synergism and maintain serum K+ normal.
However, they may aggravate first dose phenomenon if they cause severe
hyponatremia.
3. With K+-sparing diuretics and non-selective Beta blockers: Severe hyperkalemia
may occur.

c) Angiotensin Receptor Blockers (ARBs):
• Examples: Losartan, Valsartan, Candesartan, Telmisartan, Irbesartan.

• They are non-peptides and are given orally.
• They are competitive antagonists with AT II on AT1-receptors.
• Actions are identical to ACE inhibitors but they do not lead to accumulation of bradykinin
(because they do not inhibit kininase II).
• Uses: as ACEIs.
• Adverse effects: as ACE inhibitors Except cough, and less allergic reactions especially
angioneurotic edema.
• Drug interactions: ARBs correct the adverse effects caused by thiazides and loop
diuretics (hypokalaemia, hyperuricemia, and hyperglycemia).
N.B.:
1. ARBs inhibit release of noradrenaline from adrenergic nerves by blocking presynaptic AT1
receptors.
2. Saralasin: is a peptide so not given orally, given by I.V. injection – Partial agonist – not
used in treatment of hypertension but may be used to test the role of AT II in
hypertensive patients (it causes marked hypotension in high renin hypertension).
d) Renin Receptor Blockers:

as Aliskiren, Remikiren, and Enalkiren. They are used in treatment of hypertension, either
alone (monotherapy) or combined with diuretics. They may cause diarrhea.

AT II ACEIs (Captopril) and ARBs (Losartan)

1. Stimulates AT1 receptors. 1. ACEIs inhibit conversion of inactive AT I
into very active AT II.
ARBs competitively block AT1 receptors.
2. V.C. of arteries (more) and veins 2. V.D.of arteries (more) and veins (less),
(less), leading to increase in afterload leading to decrease in afterload and
and preload. preload.
3. Stimulates aldosterone synthesis and 3. Inhibit aldosterone synthesis and release

release leading to sodium and water leading to sodium and water excretion
reabsorption and potassium and potassium retention (hyperkalemia).
excretion.
4. Positive inotropic action. 4. Inhibit positive inotropic action of AT II.
5. Sympathetic stimulation. 5. Decrease sympathetic activity.
6. Elevates ABP. 6. Decrease ABP.
7. Hypertrophy of cardiac muscles but 7. Prevent hypertrophy and remodeling of

may lead to remodeling. cardiac muscles (cardioprotective action).
8. Inhibits renin release (negative 8. Increase renin release.

feedback).
9. Other actions: spasmogenic on SMF- 9. Other actions: ACEIs-but not ARBs-lead to

Dipsogenic-stimulates ADH and ACTH- accumulation of bradykinin by inhibition
stimulates angiotensinogen synthesis. of its degradation.
10.Used to elevate ABP in cases of severe 10.Uses: Hypertension-CHF-Diabetic

hypotension especially due to alpha nephropathy-After myocardial infarction.
blockers, given by IV infusion
(peptide).

Pharmacology of The C.N.S. 2011/2012
Pharmacology of C.N.S.
I-ANALGESICS
Definition: analgesics are drugs that relieve pain without loss of consciousness or loss of
other sensations (this is unlike general anaesthetics which relieve pain and other sensations
and cause loss of consciousness).
Classification: analgesics are classified into:
1. Central analgesics (proper analgesics):
They relieve pain by acting on CNS; and are further subdivided into:
a) Opioid analgesics (narcotic analgesics); e.g. morphine.
b) Antipyretic analgesics (Non-Steroidal Anti-inflammatory Drugs= NSAIDs); e.g. aspirin.
Morphine Aspirin
1. Potency Potent-relieves any type of pain Less potent-relieves mainly low
except itching. intensity pain.
2. Analgesic action Central on cortical and Central on subcortical level

subcortical levels. (thalamus) and peripheral (due
to anti-inflammatory action).
3. Other actions Narcosis-Drowsiness-Euphoria- Antipyretic-Antiinflammatory-

Tolerance-Dependence No narcosis, drowsiness,
(addiction) on prolonged use. euphoria, tolerance, or
dependence.
4. Analgesic in Deep visceral pain as cancer
pains-acute myocardial Superficial pain as headache-
infarction-Colics-Postoperative toothache-arthralgia-myalgia.
pain.
2. Peripheral analgesics (non-proper analgesics):

They relieve pain without acting on CNS; e.g.:
 Local anaesthetics.
 Counter-irritants.
 Physical agents as astringents (they precipitate surface proteins) and demulcents
(form a protective layer).
 Obtundants (they relieve pain of teeth, as oil of clover).
 Drugs that relieve specific types of pain: nitrates in anginal pain, atropine in colics,
colchicine in acute gout.

A-Opioid (Narcotic) Analgesics

Classification:
1. Opioid Agonists: they act as agonists on opiate (opioid) receptors and are subdivided
into:
a) Phenanthrene opium alkaloids: morphine and codeine.
b) They are obtained from plant origin (unripe fruit of Papaver somniferum).
c) Semisynthetic derivatives: e.g. diacetyl morphine (heroin).
d) Synthetic substitutes: meperidine, fentanyl, methadone, dextropropoxyphene.
2. Mixed Agonist-Antagonists: they act as agonists on some opioid receptors and as

antagonists on other types of opioid receptors, e.g. pentazocine, nalbuphine,
buprenorphine, and butorphanol.
N.B.:
Opium is the dried extract obtained by scratching the unripe fruits of Papaver somniferum.
Opium alkaloids are classified into:
1. Phenanthrene alkaloids: morphine (main constituent), codeine and thebaine. They are
opioid analgesics and spasmogenic on smooth muscle fibres.
2. Benzylisoquinoline alkaloids: papaverine and narcotine. They are not analgesics (almost
no CNS actions).
Morphine
 Source: plant origin (Papaver somniferum).
 Chemistry: phenanthrene opium alkaloid (the chief cons tuent, 10% of opium).
1. Absorption: morphine is well absorbed orally but it has low oral bioavailability (25%)
due to extensive 1st pass hepatic metabolism, so it is commonly given by injection
(S.C., I.M., and slowly diluted I.V.).
Give reason: in case of shock morphine is not given by S.C. injection.
2. Distribution:
 Morphine passes BBB (but not as rapid as heroin).
 Morphine passes the placental barrier and leads to fetal addiction (if given during
pregnancy) and neonatal asphyxia (if given during labor) which is treated by opioid
antagonists as naloxone (given I.M. to the mother before labor or intra-umbilical
to the fetus after labor).
3. Metabolism: conjugation with glucuronic acid by HME forming morphine -3-
glucuronide (inactive) and morphine -6- glucuronide (more active than morphine).

4. Excretion:
 Mainly in urine (both conjugated and small amounts of unchanged morphine).
 Small amounts of unchanged morphine are also excreted in:
1. Saliva (was used as a test for racing horses).
2. Stomach (that is why stomach wash should be performed in cases of acute
morphine toxicity although morphine is not orally administered in these cases).
3. Bile: entero-hepatic circulation of morphine prolongs the duration of action of
morphine compared to meperidine.
 Breast milk: morphine may affect suckling infants and is therefore contraindicated
in lactating females.
Pharmacodynamics:
 Mechanism of action: morphine acts as agonist on specific opiate (opioid) receptors in
brain and spinal cord →inhibi on of release of substance P (and other
neurotransmitters)→inhibi on of pain transmission.
Opiate receptors have the following characteristics:
1. They are present in CNS and in peripheral tissues as smooth muscle fibres –especially
GIT- and adrenal medulla.
2. They are activated by endogenous opio-peptides as endorphins, enkephalins,
endomorphins and dynorphins (pleasure substances released in large amounts during
stress and pain).
3. They are G-protein coupled leading to: inhibition of adenylate cyclase and decrease c-
AMP- inhibition of Ca2+ influx by blocking voltage-gated channels-opening of K+
channels causing K+ efflux and hyperpolarization.
4. Types of opiate receptors include:
 μ (Mu): induce analgesia –both supraspinal and spinal- euphoria, miosis, R.C.
depression, drowsiness, and constipation (due to reduced GIT peristalsis).
 κ (Kappa): induce analgesia-both spinal and supraspinal-less miosis, less
depression of R.C., and less drowsiness. Kappa receptors may induce dysphoria
and hallucinations (psychotomimetic action).
 δ (delta): induce analgesia (mainly spinal) and constipation.
 σ (sigma): induce dysphoria and hallucinations.

Morphine has the following actions:
1. CNS actions: both depressant and stimulant actions, but it is considered a CNS
depressant drug.
2. A.N.S.: morphine stimulates parasympathetic nervous system (C.I.C. mainly) and
inhibits sympathetic nervous system (V.M.C. mainly).
3. Eye: morphine causes miosis by central –not local- action.
4. Respiratory system actions.
5. CVS actions.
6. Actions on smooth muscle fibres: GIT-urinary system-Biliary tract-Bronchi.
7. Histamine release and action on skin: itching-sweating –wheal formation.
8. Lowers basal metabolic rate (B.M.R.).
a) CNS Actions:
1. Analgesia:
Relieves any type of pain especially deep visceral pain (dull aching, high intensity
pain), but does not relieve itching because morphine is a potent histamine releaser.
 Pain relief is due to supraspinal and spinal actions.
 It also reduces psychological reaction to pain by reducing anxiety and fear.
 Analgesia may be accompanied by drowsiness and stupor (mental clouding) and
narcosis.
2. Inhibition of repiratory centre (R.C.) and decreases the sensitivity of R.C. to CO2→ ↑
CO2 in blood → cerebral vasodilata on and increased CSF forma on → eleva on of
intra-cranial pressure (ICP) → more depression of R.C.
3. Inhibition of cough centre = central antitussive action.
4. Inhibition of V.M.C. occurs with large and toxic doses leading to vasodilatation and
hypotension.
5. Inhibition of heat regulating centre (H.R.C.) and lowering of basal metabolic rate
which may lead to hypothermia.
6. Euphoria (morphine may cause dysphoria if given in the absence of pain).
7. Miosis: morphine causes miosis by a central action (no miosis occurs if it is applied
locally to the eye) through stimulation of opiate receptors (mainly mu receptors) in
3rd nerve nucleus (Edinger-Westphal nucleus).
The miotic action of morphine can be antagonized by systemic antagonists as
naloxone or by local atropine.
In cases of acute morphine toxicity there is severe miosis referred to as "Pin-Point
Pupil = PPP" which is a very important diagnostic sign.
8. Excitation may occur in some human females and some animal species (as horses).
Morphine may cause seizures (convulsions) and trunkal rigidity which may be due to
inhibition of GABA release.

9. Stimulation of C.T.Z. causing nausea and vomiting.

10.Stimulation of C.I.C. causing bradycardia.
11.Hormonal actions: morphine inhibits the release of A.C.T.H. and gonadotrophins
(F.S.H. and L.H.) but stimulates the release of A.D.H. (may cause oligurea).
12.Spinal cord reflexes: morphine inhibits polysynaptic reflexes (withdrawal reflex) but
stimulates monosynaptic reflexes (stretch reflex).
Summary of C.N.S. actions of morphine:
Depressant actions Stimulant actions
1. Analgesia. 1. Euphoria.
2. Drowsiness, stupor, and narcosis. 2. Excitation, lowering of seizure threshold,
3. ↓ R.C. and trunkal rigidity.
4. ↓ cough center. 3. ↑ C.I.C.
5. ↓ V.M.C. 4. ↑ Edinger-Westphal nucleus.
6. ↓ A.C.T.H. and gonadotrophins (F.S.H. 5. ↑ C.T.Z.
and L.H.). 6. ↑ A.D.H.
7. ↓ polysynap c spinal reflexes. 7. ↑ monosynap c spinal reflexes.
b) Actions on Respiration:
1. Inhibition of R.C. and reduced sensitivity to CO2 (see before).
2. Bronchospasm (due to histamine release and spasmogenic action of morphine).
3. Inhibition of cough centre (see before).
Give reason: morphine is contraindicated in respiratory diseases as bronchial asthma
and chronic obstructive pulmonary disease (COPD).
c) Actions on CVS:
1. Small therapeutic doses cause only venodilatation which is beneficial in cases of
acute heart failure as it reduces preload but may lead to postural hypotension.
2. Large therapeutic doses (especially if given IV) and toxic doses cause hypotension due
to:
 Arteriodilatation by histamine release and inhibition of VMC.
 Bradycardia due to stimulation of CIC.
d) Action on Smooth Muscle Fibres:

Morphine is spasmogenic on smooth muscle fibres of GIT, urinary system, biliary system,
and bronchi but not spasmogenic on blood vessels or uterus.
1. GIT: morphine causes marked constipation due to:
 Spasmogenic action on smooth muscles.
 Inhibition of propulsive peristaltic movements.
 Inhibition of defecation reflex.

 Spasm of internal sphincter.

 Reduction of GIT secretions (except saliva)..
 The spasmogenic action of morphine is partially antagonized by atropine and
completely antagonized by naloxone.
2. Biliary tract: morphine causes spasm of the wall of gall bladder, the biliary duct and
the sphincter of Oddi; leading to increased intra-biliary pressure.
Give reason:
 Atropine is usually combined with morphine in treatment of biliary colic.
 Morphine is not preferred to relieve post-cholecystectomy pain.
3. Urinary tract:
 Spasm of the internal sphincter and inhibition of micturition reflex leading to
difficult micturition or urine retention.
 Spasm of the ureteric smooth muscles which is partially antagonized by atropine.
 Stimulation of ADH release leading to oligurea.
4. Uterus: no spasm on the uterus, but morphine causes fetal addiction and neonatal
asphyxia if given during pregnancy and labor; respectively (see before).
5. Bronchi: morphine causes bronchospasm which is also due to histamine release.
 Tolerance:
 Occurs a er 10:14 days of con nued administra on of morphine.
 It may be due to inhibition of release of endogenous opio-peptides or due to
down-regulation of opiate receptors.
 Tolerance occurs to analgesia, euphoria, and R.C. depression) and to euphoria; but
no tolerance occurs to miosis, constipation, and excitation (morphine addicts
always have miosis and constipation).
 Tolerance is followed by physical and psychic dependence (addiction).
 Cross tolerance and cross dependence occur between opioid analgesics and other
CNS depressants as barbiturates and alcohol.
1. Analgesic in cases of severe deep visceral pain as: acute myocardial infarction-Cancer
pain-Biliary and renal colic (combined with atropine)-Post-operative pain (except
after cholecystectomy and eye operations)-Bone fractures (except head injury).
N.B. morphine can be given intra-thecal or epidural to relieve chronic or post-
operative pain; this is known as "spinal analgesia".
2. Acute left ventricular failure (acute pulmonary edema): morphine is given IV, not as
analgesic (there is no pain in cases of acute left ventricular failure) but to reduce
anxiety and fear and to decrease sympathetic discharge leading to reduction of both
pre- and after-load (by vasodilatation).

3. Anaesthesia: morphine is given before general anaesthesia to reduce pain; this is

known as pre-anaesthetic medication.
Morphine has the following disadvantages: marked depression of R.C. – nausea and
vomiting – bronchospasm - post-operative constipation and urine retention-miosis
(which may interfere with stages of anesthesia).
That is why meperidine is preferred to morphine in pre-anaesthetic medication.
(Morphine may be used as IV anaesthetic).
4. Neurogenic shock (it is given diluted IV and not SC).
1. Nausea and vomiting (anti-emetics may be required).
2. Constipation and increased biliary pressure.
3. Urine retention.
4. Bronchospasm and depression of R.C.
5. Fetal addiction, delayed labor and neonatal asphyxia. It may affect suckling babies if
given to lactating women.
6. Bradycardia and hypotension in large doses.
7. Drowsiness and mental clouding and rarely dysphoria.
8. Itching (pruritus).
9. Tolerance and addiction = chronic toxicity.
10.Interferes with proper diagnosis of acute abdomen.
11.Acute morphine toxicity:
Manifestations: respiratory failure (central respiratory failure due to inhibition of R.C.) –
Coma – Hypotension and bradycardia – Miosis in the form of pin-point pupil (PPP) which
is a diagnostic sign.
Treatment:
a) Gastric lavage by potassium permanganate, followed by purgative as MgSO4.
b) Arificial respiration.
c) Specific Antidote: opioid antagonists as naloxone IV.
Give reason: stomach wash should be performed in acute morphine poisoning
although it is mostly administered intravenously.

 Treatment of morphine addiction:

Avoid sudden withdrawal of morphine for fear of severe withdrawal symptoms as
insomnia, dysphoria, excitation, yawning, mydriasis, body aches, rhinorrhea, lacrimation,
and diarrhea. Treatment includes:
1. Hospitalization and psychotherapy.
2. Gradual withdrawal of morphine until a stabilizing dose is reached (the smallest dose
that prevents withdrawal symptoms).
3. Substitution: Administration of other opioid agonists as methadone which has the
following advantages:
 Longer duration of action than morphine.
 Same potency as morphine.
 Less liable to tolerance and addiction.
 Less severe withdrawal symptoms.
4. Complete withdrawal of morphine followed by withdrawal of methadone. This is
known as "detoxification".
5. Clonidine is given to control withdrawal symptoms.
6. Acupuncture to stimulate release of endorphins.
7. After detoxification; opioid antagonists as naltrexone are given orally to maintain the
opioid-free state.
1. Head injury and other causes of increased intra-cranial pressure as brain tumours.
2. Hypothyroidism (myxedema).
3. Respiratory disease as bronchial asthma and COPD.
4. Pregnancy, labor and lactation.
5. Liver and kidney impairment.
6. Extremes of age (very young and very old patients due to deficient conjugation
leading to "supersensitivity").
7. Acute abdominal pain before diagnosis of the cause because morphine will mask pain
which is the diagnostic symptom.
8. After cholecystectomy.
9. Alone in renal and biliary colics (atropine is added).
10.Epilepsy and other convulsive states.
11.History of addiction to opiates.
12.Allergy to morphine.

Codeine
 Source: plant origin (from Papaver somniferum).
 Chemistry: phenanthrene opium alkaloid (1% of opium) - codeine is "methyl
morphine".
 Pharmacokinetics: given orally-metabolized by the liver-has higher oral bioavailability
than morphine-partially converted into morphine.
 Agonist on opiate receptors.
 Actions are similar to morphine but less potent analgesic-less R.C. depression-less
tolerance and addiction-may cause excitation in large doses. It is as potent as
morphine as cough centre depressant.
1. Central antitussive in treatment of dry cough (non-addictive antitussives are now
preferred).
2. Analgesic: may be combined with aspirin and paracetamol (APC).
Semi-Synthetic Derivatives (substitutes):

They are derived from morphine and codeine, examples include:
1. Diacetyl morphine=Heroin:
Opioid agonist- More potent than morphine as analgesic but is highly addictive-
Deacetylated into morphine in C.N.S.
2. Apomorphine:
Opioid agonist and dopaminergic agonist-Causes severe nausea and vomiting by
stimulation of CTZ (central emetic) –Given IV to induce vomiting in case of drug and food
poisoning (never used in comatose patients).
Synthetic Opioid Substitutes:

1-Meperidine (Pethidine):
 Chemistry: not a phenanthrene opium alkaloid.
 Absorbed orally, has higher bioavailability than morphine (50%). It is also given
parenterally. Meperidine has a rapid onset and short duration compared to
morphine.
 Passes BBB and placental barrier but causes much less depression of fetal R.C.
 Metabolized into normeperidine (active metabolite which may cause excitation and
convulsions) and meperidinic acid (inactive). Metabolites are excreted in urine.

 Mechanism of action: Agonist on opiate receptors (mainly κ).
1. Analgesic: less potent than morphine (1:10).
2. Less or no narcosis.
3. R.C. depression: less than morphine especially in newborn.
4. No depression of cough centre; i.e. meperidine is not antitussive.
5. Euphoria (less than morphine) and may cause excitation and seizures
(convulsions) if given in large and toxic doses or if given with MAO inhibitors.
6. No miosis; may even cause mydriasis due to atropine-like action.
7. Nausea and vomiting due to stimulation of CTZ: less than morphine.
8. Stimulates ADH release.
9. Less spasmogenic and less or no constipation due to atropine-like action.
10.Local anaesthetic action.
11.Tolerance and dependence: less than morphine.
1. Analgesic in deep visceral pain as acute myocardial infarction and cancer. It is
preferred to morphine in:
 Renal and biliary colics (given alone because of atropine- like action)
 Obstetric analgesia (less or no R.C. depression of newborn).
2. Pre-anaesthetic medication. It is preferred to morphine (less R.C. depression-less
emetic-less constipation).
With MAO inhibitors → severe R.C. depression, excita on, delirium, convulsions, and
hyperpyrexia.

Morphine Meperidine
1-Source: Natural from plant origin Synthetic.
(Papaver somniferum).
2-Chemistry: Phenanthrene opium alkaloid. Not an opium alkaloid.
3-Oral bioavailability: 25%. 50%.
4-Metabolism: Into morphine -6-glucuronide Into normeperidine (active)
(more active) and morphine - and meperidinic acid
3-glucuronide (inactive). (inactive).
5-Onset and duration: Delayed onset and longer Rapid onset and short
duration. duration.
6-Mechanism of action: Agonist on opiate receptors (μ Agonist on opiate receptors
and κ). (mainly κ).
7-Actions:
●Analgesic: Potent. Less potent (1/10).
●Narcosis: Narcotic. Less or no narcosis.
●R.C .depression: Potent. Less; especially in newborn.
●An tussive: Potent. Not antitussive.
●Euphoria: Potent. Less.
●Excita on: In some human females and In large and toxic doses (due
some animals. to normeperidine).
●Convulsions: In large and toxic doses due to In large and toxic doses or
inhibition of GABA release. with MAO inhibitors.
●Atropine-like action: No atropine-like action. Has atropine-like action.
●Pupil: Miosis (central). No miosis; may be mydriasis
(atropine-like)
●Eme c ac on (nausea Potent due stimulation of CTZ. Less
and vomiting):
●Spasmogenic ac on on Potent. Less or no action (atropine-
GIT and constipation: like).
●Addic on: Highly addictive. Less addictive.
8-Uses: -Analgesic in deep visceral -Analgesic in deep visceral

pain. pain.
-Acute heart failure. -Pre-anaesthetic medication.
-Pre-anaesthetic medication. Better than morphine in:
-Neurogenic shock. Colics-Obstetric analgesia-
-Insomnia due to pain. Preanaesthetic medication.

2-Fentanyl:
 Chemistry: derivative of meperidine.
 Pharmacokinetics: absorbed orally, given also by injection, transdermal patch and
intra-thecal.
-Mechanism of action: Agonist mainly on μ receptors.
-Pharmacological actions: as morphine but much more potent analgesic; about 80
times.
 Thearpeutic uses:
1. Analgesic in deep visceral pain.
2. Anaesthesia: combined with neuroleptics (major tranquilizer) as droperidol in short
painful operations. The emetic action of fentanyl (by stimulation of D2-receptors in
CTZ) is antagonized by the anti-emetic action of droperidol (blocks D2-receptors in
CTZ). This is known as "Neurolept-analgesia".
 Adverse effects: nausea and vomiting-depression of R.C.-addiction-trunkal rigidity.
Alfentanil: similar to fentanyl but more potent.

Sufentanil: similar to fentanyl but shorter in duration.
N.B.
Loperamide and Diphenoxylate: are meperidine derivatives but are not analgesics as they
very poorly penetrate BBB. They stimulate opioid receptors in GIT and are used in
treatment of diarrhea. Diphenoxylate is usually combined with atropine.
3-Methadone:
 Pharmacokinetics: given orally and by injection-higher oral bioavailability and longer
duration than morphine.
 Pharmacodynamics: agonist on opiate receptors, as potent as morphine but less liable
to tolerance and addiction and much less severe withdrawal symptoms.
 Therapeutic uses: Analgesic in deep visceral pain-To substitute morphine and heroin in
treatment of addicts.
4-D-Propoxyphene:
 Chemistry: derivative of methadone.
 Pharmacokinetics: given orally.
 Pharmacodynamics: opioid agonist-less potent analgesic than codeine.
 Therapeutic uses: analgesic in mild to moderate pain not relieved by aspirin.
 Adverse effects: addiction-depression of R.C. and excitation in toxic doses.

Mixed Agonist-Antagonists (Opioids with mixed action):

They include: Pentazocine – Nalbuphine – Butorphanol –Buprenorphine.
They act as antagonists on μ-receptors and agonists on κ-receptors, except Buprenorphine
which is a partial agonist on μ-receptors and antagonist on κ-receptors.
 Actions and uses:
1. Analgesics in deep visceral pain by stimulation of κ-receptors. They have the
following advantages:
a) Less liable to addiction.
b) "Ceiling effect" on R.C. depression; i.e. the dose can be increased to increase the
analgesic action without increase in R.C. depression because they act as μ-
antagonists.
2. Diagnosis of opioid addicts because they precipitate withdrawal symptoms by
blocking μ-receptors.
Pentazocine:
 Antagonist on μ and agonist on κ-receptors.
 Actions and uses: see before.
 Given orally and parenterally.
 Causes dyshoria and hallucination in large doses (due to stimulation of sigma receptors)
and increases blood pressure and heart rate (cardiac work).
Nalbuphine:
 As pentazocine (antagonist on μ and agonist on κ).
 Actions and uses: see before.
 Given parenterally.
 No increase in cardiac work.
Butorphanol: as pentazocine.
Buprenorphine: partial agonist on μ and antagonist on κ-receptors.
Indicate" true or false" and explain why:

It is advisable to combine morphine and pentazocine in treatment of severe visceral pains.
N.B.:
Tramadol:
 Central analgesic acting as a weak μ-agonist and by inhibi on of noradrenaline and 5-HT
uptake in CNS.
 It is used in chronic pain, given orally and parenterally.

Opioid Antagonists:
 They are competitive antagonists that block opiate receptors.
 They include:
a) Naloxone given IV and orally.
b) Naltrexone given orally.
c) Nalmefene given IV. Longer duration than naloxone.
 Actions depend on the patient receiving these drugs:
1. In normal individuals (in the absence of opioids): no effect, i.e. they are not
analgesics.
2. In cases of acute opioid toxicity: they reverse the actions of opioids as morphine (R.C.
depression, constipation, miosis, vomiting).
3. In opioid addicts: they induce withdrawal symptoms.
1. Treatment of acute opioid toxicity (naloxone or nalmefene IV).
2. Treatment of neonatal asphyxia (naloxone IM to the mother before delivery or intra-
umbilical after delivery).
3. Diagnosis of morphine and heroin addicts.
4. Treatment of morphine-induced paralytic ileus.
5. To maintain opioid-free state after treatment of addicts, i.e.to prevent return to
opioids (naltrexone oral).
N.B. Nalorphine is similar to mixed agonist-antagonists but is not used as analgesic because
it causes anxiety and visual hallucinations.
Levallorphan is a partial agonist on opiate receptors and is not used clinically.
Classify drugs acting on opiate receptors with examples:
Drug Example Therapeutic uses
1-Opioid Agonists: -Morphine. Analgesics in deep visceral pain.
-Codeine.
-Meperidine.
-Methadone.
-Fentanyl.
2-Mixed Agonist- -Pentazocine. 1-Analgesics in deep visceral pain.
Antagonists: -Nalbuphine. 2-Diagnosis of opioid addicts.
-Butorphanol.
-Buprenorphine.
3-Opioid Antagonists: -Naloxone. 1-Treatment of acute opioid (morphine)
-Nalmefene. toxicity.
-Naltrexone. 2-Neonatal asphyxia.
3-Opioid-induced ileus.
4-To maintain opioid-free state.
5-Diagnosis of opioid addiction.

B-Antipyretic Analgesics
 They are also known as "non-opioid analgesics" and more commonly as "Non-Steroidal
Anti-Inflammatory Drugs = NSAIDs".
 They inhibit prostaglandin synthesis and accordingly their actions are summarized as
follows:
Actions of PGs Actions of NSAIDs

1. Pain. 1. Analgesics in superficial pains.
2. Fever. 2. Anti-pyretics (non-specific).
3. Inflammation. 3. Anti-inflammatory.
4. Protection of mucosa of stomach and 4. Peptic ulceration.

duodenum against HCl and pepsin
(Cytoprotective by ↓HCl-↑mucus,
HCO3, and blood flow).
5. Increases renal blood flow (RBF). 5. Decreases RBF →Na+ and water retention
and even nephropathy.
6. Uterine stimulation (Oxytocics). 6. Uterine relaxants (Tocolytics).
7. Maintain patency of ductus arteriosus. 7. Closure of patent ductus arteriosus (PDA).
 They have the common characters:

a) Pharmacokinetic properties:
 Well absorbed orally.
 Highly bound to plasma proteins and displace other drugs from plasma protein
binding sites (as warfarin, oral hypoglycemics, digitoxin) leading to serious adverse
reactions by these drugs.
 Pass BBB.
 Pass placental barrier and may cause teratogenicity is given in early pregnancy
(aspirin is the safest anti-inflammatory during pregnancy) and premature closure
of DA if given in late pregnancy.
 The main fate is commonly hepatic metabolism, some are partly excreted in urine
unchanged (as aspirin), some are partly excreted in bile and undergo entero-
hepatic recycle leading to long duration of action (as indomethacin and oxicams),
and some are prodrugs (as sulindac and nabumetone).

b) Pharmacodynamics:
1. Mechanism of action:
They inhibit synthesis of prostaglandins (PGs) by inhibition of cyclo-oxygenase
(COX) enzymes.
All are "reversible" COX inhibitors except aspirin (=acetyl salicylic acid) which is
"irreversible" COX inhibitor by acetylation.
2. Pharmacological actions: see previous table.
N.B.: paracetamol has analgesic and antipyretic actions only.
c) Adverse effects:
1. Allergy.
2. Bronchospasm and precipitation of attacks in asthmatic patients.
3. Peptic ulcer.
4. Teratogenicity.
5. Decrease renal blood flow, cause Na+ and water retention, and may lead to renal
impairment (analgesic nephropathy).
6. Premature closure of DA.
d) 4-Contraindications:
1. Allergic patients.
2. Bronchial asthma.
3. Peptic ulcer.
4. Pregnancy.
Important note:
There are 3 types of COX enzymes:
 COX-1 (cons tu ve): present in the stomach where it stimulates synthesis of PGE2 and
PGI2 which are cytoprotective (↓HCl, ↑mucus, bicarbonate, and blood flow), in the
kidney stimulating synthesis of vasodilator PGs as PGE and I thus increasing renal blood
flow, and in platelets where it induces TXA2 synthesis that activates platelet aggregation.
 COX-2 (inducible): present in CNS and peripheral tissues inducing synthesis of PGs
causing pain, fever, and inflammation. It was recently found in the kidneys (as COX-1).
 COX-3: found only in CNS and stimulates of PGs causing pain and fever. (COX-3 may be a
variant of COX-1).

Classification of NSAIDs:
I-Non-selective COX inhibitors:
 They act as analgesics, antipyretics, and anti-inflammatory drugs through inhibition of
COX-2 and COX-3.
 Their main adverse effects are peptic ulcer and reduction of RBF due to inhibition of
COX-1 mainly.
 They include:
1. Salicylic acid derivates=Salicylates: e.g. aspirin and sodium salicylate.
2. Pyrazolone derivatives: e.g. phenylbutazone.
3. Indole derivatives: e.g. indomethacin, sulindac (prodrug) and Tolmetin.
4. Propionic acid derivatives: e.g. ibuprofen, ketoprofen, and naproxen.
5. Phenyl acetic acid derivatives: e.g. diclofenac.
6. Oxicams: e.g. piroxicam, Tenoxicam, and Meloxicam (inhibits COX-2 more than COX-1).
7. Nabumetone (prodrug).
8. Anthranilic acid derivatives = Fenamates: e.g. mefenamic acid and flufenamic acid.
II-Selective COX-2 inhibitors:

 Examples: meloxicam, celecoxib, rofecoxib, valdecoxib, eterocoxib.
 They act as analgesics, antipyretics, and anti-inflammatory as non-selective COX
inhibitors.
 The main advantage over non-selective drugs is much less incidence of peptic ulceration.
 They may cause less reduction of RBF compared to non-selective COX inhibitors.
 Some selective cox-2 inhibitors as rofecoxib (vioxx) were withdrawn from the market
because they caused cerebro-vascular strokes and cardiac toxicity (infarction and fatal
arrhythmias).
III-Selective COX-3 inhibitors:

Include Dipyrone (pyrazolone derivative) and Aniline derivatives e.g. paracetamol =
acetaminophen, and phenacetin (not commonly used). They are analgesics and antipyretics
but are not ant-inflammatory drugs (they act centrally and not peripherally).

SALICYLATES
 Chemistry: salicylates are derived from salicylic acid.
 Derivatives: salicylates include the following derivatives:
a) Derivatives for local use: they are not used systemically because they are highly
irritant on GIT. They include:
1. Salicylic acid: used locally as antiseptic-fungistatic– keratolytic.
2. Methylsalicylate: used locally as counter-irritant.
b) Derivatives for systemic use: they are used systemically as analgesics, antipyretics,
and anti-inflammatory drugs. They include:
1. Aspirin = Acetyl Salicylic Acid (ASA).
2. Sodium salicylate: given as "enteric-coated tablets".
3. Diflunisal: is a potent anti-inflammatory not it is not antipyretic or antiplatelet,
and has less adverse effects than aspirin.
 Pharmacokinetics of systemically administered salicylates (aspirin and sodium

salicylate):
a) Absorption: they are partially absorbed from the stomach and completely absorbed
from the upper intestine (why?).
b) Distribution: highly bound to plasma proteins and displace other drugs (see drug
interactions) – pass BBB – pass placental barrier and is not preferred in early and in
late pregnancy before labor (see adverse effects).
c) Metabolism: most of the drug (about 75%) is conjugated with glucuronic acid and
glycine and only 1% is oxidized into gen sic acid.
d) Excretion: renal excre on of metabolites and partly (about 25%) excreted
unchanged. Renal excretion is enhanced by NaHCO3 and reduced by vitamin C and
NH4Cl (why?).
e) N.B.: the elimina on t1/2 is variable according to the dose of aspirin because aspirin
in small doses (<5g. /day) obeys first-order kine cs; i.e. t1/2 is constant whereas
larger doses follow zero-order kine cs and t1/2 increases with increasing doses (due
to enzyme saturation).
 Mechanism of action: inhibition of PGs synthesis by non-selective COX inhibition.
Aspirin causes irreversible inhibition by acetylation but other salicylates –as all
NSAIDs- cause reversible inhibition.
Remember that very small doses; known as "pediatric or infan le doses" =75-150 mg.
/day, cause selective irreversible inhibition of thromboxane A2 (TXA2) synthetase
(may be called platelet COX) leading to inhibition of platelet aggregation.

a) Local actions:
1. Antiseptic-fungistatic- keratolytic actions by salicylic acid.
2. Counter-irritant action by methyl salicylate.
b) Systemic actions:
1. CNS actions: Analgesic action – Antipyretic action.
2. Anti-inflammatory (anti-rheumatic) action.
3. Action on respiration and acid-base balance.
4. Actions on CVS.
5. Actions on blood.
6. Action on serum uric acid.
7. Action on GIT.
8. Action on the kidney.
9. Metabolic action.
10.Endocrine actions.
11.Action on the liver.
1. CNS actions:
Analgesic action:
-By inhibition of PGs synthesis both centrally (subcortical on thalamus) and peripherally.
-Relieve superficial low intensity pains as headache, toothache, arthralgia, and myalgia.
-Not accompanied by euphoria, narcosis, tolerance, or addiction.
Antipyretic action:
a) In fever: IL1, IL6, and TNFα stimulate PG synthesis in the hypothalamic heat regulating
centre (HRC) leading to elevation of the set point, thus increasing heat production (by
shivering) and decreasing heat loss.
NSAIDs inhibit COX enzymes centrally leading to inhibition of PG synthesis with
consequent "re-setting" of HRC. This increases heat loss by sweating, V.D. of
cutaneous blood vessels, and mobilization of fluids from tissues to blood.
b) They have no effect on normal body temperature; i.e. they are not hypothermic
drugs.
c) In cases of acute salicylate toxicity, hyperthermia (hyperpyrexia) occurs due to
uncoupling of oxidative phosphorylation.
2. Anti-inflammatory (anti-rheumatic) action:

The anti-inflammatory action of NSAIDs is due to:
 Inhibition of PG synthesis peripherally mainly by inhibition of COX and indirectly by
stimulation of ACTH and cortisone release which inhibit phospholipase A2.
 Inhibition of hyaluronidase and fibrinolysin.
 Inhibition of kallikrein enzyme and accordingly inhibition of kinin synthesis.
3. Action on Respiration and Acid-Base Balance:

 The usual analgesic-an pyre c doses (< 5 g. /day) have no effect.

 Large doses (> 5 g. /day; used as an -inflammatory in rheumatoid arthritis (RA) and
rheumatic fever (RF)) stimulate R.C. and increase respiratory rate leading to wash of
CO2 from blood and respiratory alkalosis occurs.
The kidney compensates by increasing excretion of NaHCO3 in urine and
compensated respiratory alkalosis occurs.
 Larger doses-especially in children- cause metabolic acidosis (may be due to the
acidity of salicylates, reduction of the alkali reserve due to loss of NaHCO3 in urine,
and disturbance of carbohydrate metabolism increasing the blood levels of pyruvic
and lactic acids).
 In toxic doses R.C. depression occurs.
 NSAIDs induce bronchospasm and may precipitate asthmatic attacks in susceptible
patients due to inhibition of COX and shift of arachidonic acid into synthesis of
leukotrienes (sometimes referred to as aspirin-induced asthma).
Question:
How to treat inflammatory conditions as RF and RA in asthmatic patients?
4. Action on CVS:
Therapeutic doses of salicylates have no effect on CVS, but very large and toxic doses
cause V.D. both by peripheral action and centrally by inhibition of VMC, leading to
hypotension.
5. Action on Blood:
 Antiplatelet = An thrombo c ac on: very small doses of aspirin (75-150 mg. /day)
selectively inhibit platelet TXA2 synthesis leading to inhibition of platelet aggregation
which prolongs bleeding time.
 Anticoagulant action = dicuomarol-like action: large doses inhibit activation of
vitamin K leading to hypoprothrombinemia and bleeding. This prolongs coagulation
time and prothrombin time.
 Reduction of elevated sedimentation rate and leucocytic count to normal.
 Idiosyncracy: salicylates induce hemolysis of RBCs in patients with G6PD deficiency
leading to hemolytic anemia.
Question:
What are the possible mechanisms of aspirin-induced bleeding?

6. Action on serum uric acid:

 Usual doses (< 5 g. /day) increase serum uric acid by inhibi on of uric acid secre on
by proximal convoluted tubules (PCT); and accordingly are contraindicated in gout
and they antagonize the action of uricosurics as probenicid.
 Larger doses (> 5 g. /day) cause uricosuric ac on by inhibi on of uric acid
reabsorption from PCT; however they are not preferred in treatment of chronic gout
due to many adverse effects.
7. Actions on GIT:
 Nausea and vomiting due to both local irritant action and central action through
stimulation of CTZ.
 Ulceration and bleeding due to inhibition of synthesis of cytoprotective PGs (PGE2
and PGI2).
N.B.
 The irritant effect of salicylates can be reduced by giving them after meals, by adding
alkalis, or by giving enteric-coated tablets (sodium salicylate).
 Iatrogenic ulcers caused by NSAIDs are better prevented and treated by PG analogs
as misoprostol.
8. Action on the kidney:

 Inhibition of synthesis of vasodilator PGs decrease RBF leading to Na+ and water
retention and antagonize the anti-hypertensive action of diuretics, β-blockers and
ACE inhibitors.
 Chronic use of large doses of NSAIDs may cause renal impairment (analgesic
nephropathy).
9. Metabolic actions:
They are noticed with large and toxic doses of salicylates and include:
 Uncoupling of oxidative phophorylation and hyperthermia.
 Hyperglycemia due to increased release of ACTH, cortisol, and adrenaline.
 Protein catabolism (-ve nitrogen balance and increased amino acids in urine) due to
ACTH and cortisone.
 Increased Glutamate / GABA ratio in CNS which may lead to convulsions.
10.Endocrine actions:
 Increased release of ACTH, cortisone, and adrenaline.
 Displacement of bound T3 and T4 from plasma proteins →↑Free T3 and T4 →↓TSH by
negative feedback→↓ radioac ve iodine uptake and interference with thyroid
function tests.

11.Actions on the liver:

 Glycogenolysis and hyperglycemia (due to cortisone and adrenaline).
 Hydrochloretic action (increases water content of bile).
 Hepatotoxicity –and encephalopathy- if salicylates are administered to children
having fever due to viral infections especially influenza.
 This is known as Reye's syndrome which may be fatal.
Give reason:
Aspirin is absolutely contraindicated in children suffering from fever due to viral
infections. What is the alternative analgesic-antipyretic in such cases?
a) Local uses:
1. Antiseptic-fungistatic-keratolytic: salicylic acid is used.
2. Counter-irritant in arthritis: methylsalicylate is used.
b) Systemic uses:
1. Analgesic in superficial low intensity pains as headache, toothache, arthralgia,
myalgia, and common cold. Salicylates are not preferred in dysmenorrhea as they
may increase bleeding.
2. Non-specific antipyretics in fever.
3. Anti-inflammatory in RF, RA, osteoarthritis (OA).
4. Prophylaxis of thrombo-embolism (by pediatric=baby aspirin).
5. Other uses:
 Prophylaxis of cataract.
 Reduce the incidence of cancer colon.
 Symptomatic treatment of systemic mastocytosis (with anti-histaminics).
 Prevention of niacin-induced flushing.
 Chronic gout as uricosuric (not commonly used).
 Treatment of pre-eclampsia.
N.B.
1. Aspirin in acute RF relieves: fever, arthritis, reduces elevated sedimentation rate and
leucocytic count to normal, but has no effect on chorea and S.C. nodules.
2. In heart failure complicating RF aspirin is preferred to sodium salicylate (why?).


1. Hypersensitivity (allergic reactions) as skin 1. Allergy to salicylates.
rash, urticaria, angioedema.
2. Bronchospasm and precipitation of 2. Bronchial asthma.

asthmatic attacks in susceptible patients.
3. GIT disturbances: nausea, vomiting, ulcers 3. Peptic ulcers.

and bleeding (increased occult blood in
stools).
4. Bleeding. 4. Bleeding disorders as hemophilia

and purpura.
5. Hemolysis in idiosyncratic patients with 5. Idiosyncracy in G6PD deficiency

G6PD deficiency. (Favism).
6. Teratogenicity in early pregnancy (1st 6. Pregnancy (early and late).

trimester).
7. Increased post-partum hemorrhage,

delayed labor, and premature obliteration
of ductus arteriosus in late pregnancy.
8. Reye's syndrome: hepatocellular damage 7. Children with fever caused by viral

and encephalopathy in children with fever infections especially influenza.
due to viral infections.
9. Salicylism=chronic salicylate toxicity:

headache, nausea and vomiting, blurred
vision, vertigo and tinnitus (ringing in ears).
10. Acute salicylate toxicity (see later).
Important note:
Paracetamol is the analgesic-antipyretic of choice whenever aspirin is contraindicated in:
allergy-bronchial asthma-bleeding disorders-favism-peptic ulcer-pregnancy-children.

Acute salicylate toxicity:

 Manifestations:
Convulsions-Hypotension-Hemorrhage-Hyperglycemia-Hyperventilation, respiratory
alkalosis then metabolic acidosis especially in children -GIT disturbances
(nausea,vomiting and may be ulcerations and bleeding)-Hyperthermia-Dehydration-
finally R.C. depression occurs.
 Treatment:
1. Gastric lavage by NaHCO3.
2. Artificial respiration in case of depression of R.C.
3. Symptomatic treatment:
 NaHCO3 to correct systemic acidosis.
 Cold fomentations or ethyl alcohol fomentations to treat hyperthermia (no
antipyretics needed; why?).
 Anticonvulsant drugs (e.g. as diazepam IV) to control convulsions.
 Vitamin K to control hypoprothrombinemia and bleeding.
 IV fluids to correct hypotension and dehydration.
4. Increasing urinary excretion of salicylates by alkalinization of urine by NaHCO3, or by
potent diuretics as loop diuretics (frusemide) IV or mannitol IV infusion. This is known
as "forced diuresis".
5. Hemodialysis may be performed in severe cases.
N.B.: there is no specific antidote for aspirin but NaHCO3 may be considered as a non-
specific antidote because it decreases oral absorption, increases renal excretion, and
corrects acidosis.
a) Pharmacokinetics interaction:
 Absorption: NaHCO3 in antacids decreases oral absorption of aspirin.
 Distribution: salisylates displace digitoxin, warfarin, and oral hypoglycemic drugs
from plasma protein binding sites leading to serious adverse effects of these
drugs.
 Excretion: NaHCO3 promotes renal excretion of salicylates whereas vitamin C and
NH4Cl reduce excretion and may increase toxicity.
b) Pharmacodynamic interactions:
 Salicylates antagonize the antihypertensive action pf β-blockers, thiazides, and
ACE inhibitors by decreaseing RBF leading to salt and water retention (may
increase hyperkalemia caused by ACE Inhibitors).

 Small doses of salicylates antagonize the uricosuric action of "uricosuric drugs" as

probenicid, sulphinpyrazone, and benzbromarone and accordingly worsen gout.
 Alcohol and glucocorticoids (cortisone) increase the incidence of GIT ulcers and
bleeding caused by salicylates.
 Aspirin antagonizes the anti-inflammatory action of other NSAIDs as piroxicam and
diclofenac, because aspirin causes "irreversible" COX inhibition.
Indole Derivatives
 Include: Indomethacin and Sulindac (prodrug-less gastric irritation).
- Well absorbed orally.
- Pass BBB-pass placental barrier (teratogenic)-highly bound to plasma proteins.
- Metabolized by the liver, partly excreted unchanged in urine and bile and undergo
entero-hepatic circulation (long acting).
- Mechanism of action: inhibition of PG synthesis by reversible non-selective COX
inhibition.
- Pharmacological actions: Anti-inflammatory (mainly) – Analgesic –Antipyretic.
1. Anti-inflammatory in acute gouty arthritis -RF- pericarditis- OA-RA.
2. Patent ductus arteriosus.
1. Allergy: skin rash.
2. Bronchospasm and precipitation of asthmatic attacks.
3. Peptic ulceration.
4. Teratogenicity in early pregnancy, delayed labor and premature closure of ductus
arteriosus in late pregnancy.
5. Renal impairment.
6. Bone marrow depression (blood dyscrasias).
7. CNS disturbances: confusion, hallucinations, psychotic manifestations, seizures, and
frontal headache.
8. Corneal opacities.
1-Allergy. 2-Bronchial asthma. 3-Pep c ulcer. 4-Pregnancy.
5-Psychosis. 6-Epilepsy.

Pyrazolone Derivatives
 Include: Phenylbutazone, Azaprpazone (Apazone), Sulphinpyrazone (uricosuric only).
Other pyrazolone derivatives as dipyrone, antipyrine, aminopyrone are not used because
they may cause severe bone marrow depression.
- Well absorbed orally.
- Pass BBB- pass placental barrier (teratogenic)- highly bound to plasma proteins and
displace other drugs as oral anticogulants, oral hypoglycemics, and thyroid hormones.
- Metabolized by the liver, and metabolites are excreted in urine.
- Mechanism of action: inhibit prostaglandin synthesis by reversible non-selective COX
inhibition.
- Pharmacological actions: Anti-inflammatory (mainly)- Analgesic- Antipyretic-
Uricosuric.
N.B. only salicylates and pyrazolone derivatives are uricosurics but other NSAIDs have no
uricosuric action.
Anti-inflammatory in acute gouty arthritis- OA- RA.
1. Allergic reactions as skin rash.
2. Bronchospasm and induction of asthmatic attacks.
3. Peptic ulcer.
4. Teratogenicity.
5. Salt and water retention leading to edema, elevation of ABP, and worsening of heart
failure. Renal impairment may occur.
6. Bone marrow depression.
1. Allergy.
2. Bronchial asthma.
3. Peptic ulcer.
4. Pregnancy.
5. Hypertension and heart failure.
1. Displacement of other drugs from plasma proteins.
2. Antagonize the action of diuretics and antihypertensive drugs.

Propionic Acid Derivatives:

 Include: Ibuprofen, ketoprofen, naproxen, flurbiprofen, tiaprofenic acid, and fenoprofen.
Oxicams:
 Include: Piroxicam and tenoxicam.
 They have entero-hepatic circulation and long duration of action.
Aryl acetic acid Derivatives:

 Include: Diclofenac, tolmetin, and ketorolac.
Anthranilic Acid Derivatives = Fenamates:

 Include: Mefenamic acid, and flufenamic acid.
All these derivatives have the common characters of NSAIDs (page 18 and 19).
Aniline Derivatives:
 Include: Paracetamol = Acetaminophen, and phenacetin (not commonly used due to its
serious adverse effects).
 Chemistry: aniline derivatives.
- Absorption: well absorbed orally (paracetamol is rapidly disintegrated in the
stomach, and the more rapid the gastric emptying the better the absorption).
- Distribution: pass BBB – pass placental barrier but not teratogenic- slight binding to
plasma proteins (much less liable to drug interactions than other NSAIDs as aspirin).
- Metabolism:
Phenacetin (active) → paracetamol (ac ve).
About 95% of paracetamol is metabolized by the liver mainly by conjuga on with
glucuronic acid and sulphate (major pathway) and to a less extent by oxidation by
CYP450 (minor pathway) into a toxic metabolite known as NAPQI (N-Acetyl –Para-
Benzo-Quinone-Imine) which is detoxified by SH donors in the liver as glutathione.
- Excretion: metabolites and unchanged paracetamol (about 5%) are excreted in urine.

a) Mechanism of action: inhibit prostaglandin synthesis centrally only by reversible
selective COX-3 inhibi on.
b) Pharmacological actions: Analgesic and antipyretic actions only.
1. NO (or very weak) anti-inflammatory action.
2. NO anti-platelet action and NO anticoagulant action, and accordingly NO bleeding.
3. NO uricosuric action.
4. NO peptic ulceration.
5. NO renal impairment (except in acute toxicity).
6. NO bronchospasm or precipitation of asthmatic attacks.
7. NO uterine relaxation and NO closure of ductus arteriosus.
1. Analgesic in superficial low intensity pains as headache, arthralgia, common cold,
toothache, myalgia.
2. Antipyretic (non-specific) in fever.
3. Paracetamol is especially indicated in patients allergic or intolerant to aspirin (i.e.
whenever aspirin is contraindicated) as in:
Bronchial asthma – peptic ulcer- bleeding disorders as hemophilia – pregnancy (early
and late) –children with fever due to viral infections as influenza.
 Adverse effects: "paracetamol is well-tolerated by most patients except in case of

allergy or acute toxicity". Adverse reactions include:
1. Allergic reactions: rash, fever, and rarely blood dyscrasias (bone marrow depression).
2. Phenace n causes methemoglobinemia, hemoly c anemia in G6PD deficiency
(idiosyncracy)-cyanosis- cardiac arrest and respiratory failure in case of acute toxicity.
3. Acute paracetamol toxicity:
Cause: occurs with toxic doses (10-15 g. in adults) due to satura on of conjuga on
pathway and formation of NABQI which is not detoxified due to depletion of SH; or in
chronic alcoholism (induces enzyme responsible for oxidation of paracetamol into
toxic NABQI).
Manifestations: early symptoms: nausea, vomiting, diarrhea, and abdominal pains.
Later; there is hepatotoxicity (hepatic necrosis) causing jaundice- nephrotoxicity
(renal tubular necrosis) causing hematuria, oliguria and anuria- hypoglycemic coma.
Treatment: mainly by SH donors as N-acetylcysteine, and supportive treatment.
 Contraindications: allergy to aniline derivatives.
N.B.: Benoral (benorylate) is a combination of aspirin and paracetamol.

Aspirin Paracetamol
 Chemistry: Salicylic acid derivative. Aniline derivative.
 Pharmacokinetics: - Well absorbed orally, partially - Well absorbed orally.
absorbed from the stomach. - Passes BBB.
- Passes BBB. - Passes placental barrier.
- Passes placental barrier. - Slightly bound to plasma
- Highly bound to plasma proteins. proteins.
- 75% is metabolized mainly by - 95% is metabolized by:
conjugation with glucuronic acid conjugation with glucuronic
and glycine, 1% oxidized into acid and sulphate (major
gentisic acid. pathway), and oxidation
- 25% is excreted unchanged in into NABQI (minor
urine (excretion is enhanced by pathway).
alkalinization of urine). - 5% excreted unchanged.
 Mechanism of Inhibition of PG synthesis centrally Inhibition of PG synthesis

action: and peripherally by irreversible centrally by reversible
non-selective COX inhibition. selective COX-3 inhibi on.
 Pharmacological Analgesic – Antipyretic – Analgesic –Antipyretic only.

actions: Antiinflammatory – Antiplatelet –
Uricosuric.
 Indications: 1. Analgesic in superficial pains. 1. Analgesic in superficial

2. Antipyretic in fever. pains.
3. Anti-inflammatory in RF, RA, OA. 2. Antipyretic in fever.
4. Antiplatelet for prophylaxis of
thrombo-embolic diseases.
 Adverse effects: Allergy –Bronchospasm –Gut upset Allergy – Acute toxicity.

and ulceration –Bleeding-
Teratogenicity, delayed labor, and
premature closure of DA –Salicylism
–Hemoly c anemia in G6PD
deficiency – Reye's syndrome –
Acute toxicity.
 Contraindications: Allergy-bronchial asthma-peptic

ulcer-pregnancy-favism-bleeding
disorders –children with viral
infections (as influenza).

Treatment of Gout
 Gout is a disease characterized by: hyperuricemia (serum uric acid > 6 mg. %),
precipitation of mono-sodium urate crystals in the synovium of joints causing recurrent
acute attacks of gouty arthritis which may affect any joint but more commonly occurs in
the metatarso-phalangeal joint of the big toe. Gout may lead to the formation of renal
urate stones which may cause urate (gouty) nephropathy .
 Causes:
1. Primary metabolic disorder in purine metabolism leading to excessive synthesis of
uric acid.
2. Cancer: causing increased turn over of purines into uric acid.
3. Drugs that increase serum uric acid as thiazide and loop diuretics, diazoxide, cancer
chemotherapy, some anti-tuberculous drugs as pyrazinamide and ethambutol, and
clofibrate (anti-hyperlipidemic drug).
 Uric acid is synthesized from purines by the action of xanthine oxidase as follows:
X.O. X.O.
Purines---------►Hypoxanthines---------►Xanthines---------►Uric acid
(X.O.: Xanthine Oxidase).
 Uric acid undergoes 3 processes in the nephrons: filtra on, reabsorp on, and tubular
secretion.
 Pathogenesis of acute gouty arthritis:

1. Precipitation of mono-sodium urate crystals (insoluble) in the synovial membrane of
joints causes inflammatory reaction.
2. Migration of phagocytic cells (polymorpho-nuclear leucocytes = PMNL) towards the
inflamed joint (chemotaxis).
3. Phagocytosis of mono-sodium urate crystals by the phagocytic cells.
4. Rupture of the phagocytic cells and release of glycoprotein (the main inflammatory
mediator) and lactic acid which causes acidity of the joint thus favoring more
precipitation of mono-sodium urate crystals and a vicious circle goes on.

Drug Therapy of gout:

I. Treatment of acute gouty arthritis:
Anti-inflammatory drugs:
1. Colchicine and demecolcine (drugs of choice because they are specific anti-
inflammatory in acute gouty arthritis).
2. NSAIDs as indomethacin, diclofenac, ibuprofen, piroxicam, and others. They are used
in patients who can not tolerate colchicine.
3. Glucocorticoids (cortisone) and ACTH: if NSAIDs are ineffective.
II. Treatment of chronic gout (Prophylactic treatment):
a) Uricosuric drugs:
1. Probenicid.
2. Sulphinpyrazone.
3. Benzbromarone.
4. Aspirin (> 5 g. / day): not commonly used because of serious adverse effects.
b) Uricostatic drug:
Allopurinol inhibits uric acid synthesis by inhibition of xanthine oxidase enzyme.
N.B.:
1. Colchicine is also used in prophylaxis of gout.
2. Rasburicase:
 It is a recombinant urate oxidase enzyme.
 It oxidizes uric acid (insoluble) into allantoin (soluble).
 It is used in hyperuricemia due to cancer chemotherapy and radiotherapy.
 Adverse effects: Allergy (anaphylaxis) – hemolysis in G6PD deficiency – GIT
disturbance- expensive.
Colchicine:
 Source: plant origin (colchicum).
 Chemistry: alkaloid.
- Absorbed orally, may be given IV.
- Passes BBB and may cause severe CNS depression in toxic doses.
- Passes placental barrier and may cause teratogenicity.
- Excreted in urine and bile.

- Mechanism of action: binds to microtubular protein (tubulin) of phagocytic cells
leading to inhibition of: migration, phagocytosis, rupture of phagocytic cells, release
of glycoproteins and lactic acid. This breaks the vicious circle occurring in acute gouty
arthritis.
1. Specific anti-inflammatory in acute gouty arthritis.
2. Antimitotic by binding to and inhibition of the mitotic spindle.
1. Acute gouty arthri s (1mg. = 2 tablets at the start of therapy followed by 0.5 mg. = 1
tablet every 2 hours un l pain is relieved or diarrhea occurs).
2. Prophylac c treatment in gout (0.5 mg. 2-3 mes / week).
3. Prophylaxis against attacks of Mediterranean fever = familial paroxysmal
polyserositis.
4. To improve liver functions in liver cirrhosis (?).
5. Treatment of psoriasis.
1. GIT disturbances are the most common adverse effects: nausea, vomiting, and
diarrhea.
2. On chronic use: alopecia (reversible)-bone marrow depression-myopathy-
nephrotoxicity-hepatotoxicity.
3. In acute toxicity: hemorrhagic gastro-enteritis (bloody diarrhea)-nephrotoxicity
(hematuria and anuria)-vascular damage-CNS depression.
Uricosuric drugs:
They increase uric acid excretion in urine by inhibition of uric acid reabsorption from PCT.
They should be given in large doses because small doses inhibit uric acid secretion and will
worsen gout.
1. Probenicid:
 Adverse effects: allergic reactions (rash or fever) and GIT disturbances.
a) Inhibits tubular secretion of penicillin→longer duration of action.
b) Inhibits tubular secretion of thiazides and loop diuretics→antagonism of their
diuretic action (they act from the inner side of the nephron).

2. Sulphinpyrazone.
 It is a pyrazolone derivative.
 It has uricosuric and antiplatelet actions bou no analgesic, antipyretic, or anti-
inflammatory actions.
 Drug interaction: displaces warfarin and oral hypoglycemic drugs from plasma
proteins.
3. Benzbromarone.
4. Aspirin (> 5 g. / day): not commonly used because of serious adverse effects.
Important notes:
1. Patients treated with uricosurics should drink plenty of fluids and receive NaHCO3 to
render the urine alkaline to avoid precipitation of urate crystals in the nephrons which
may lead to the formation of urate stones and may end in urate nephropathy.
2. Uricosuric drugs should be avoided in patients already excreting large amounts of uric
acid in urine and in patients with history of recurrent urate stones or urate nephropathy.
Inhibitor of uric acid synthesis (uricostatic):

Allopurinol (Zyloric):
 Pharmacokinetics: absorbed orally –passes BBB- metabolized into alloxanthine (active
metabolite) - excreted in urine.
 Pharmacodynamics: inhibits uric acid synthesis from xanthines and hypoxanthines by

competitive inhibition of xanthine oxidase (xanthines and hypoxanthines are increased
but they are soluble).
 Therapeutic uses: prophylaxis of gouty attacks in chronic gout, especially in the following
conditions:
1. Gouty (urate) nephropathy.
2. Recurrent urate stones.
3. Patients who cannot tolerate uricosurics.
4. Failure to reduce hyperuricemia by uricosurics.
1. Hypersensitivity reactions: rash, fever, bone marrow depression.
2. GIT upsets: nausea, vomiting, diarrhea.
3. CNS disturbances: headache, vertigo.
4. Precipitation of acute gouty arthritis at the start of treatment, so colchicines is added.
5. Others: peripheral neuritis, malaise.

1. Decreases metabolism of warfarin and may cause bleeding (allopurinol is a HME
inhibitor).
2. Decreases metabolism of mercaptopurine (anti-cancer) - which is metabolized by
xanthine oxidase – and may cause toxicity.
N.B. Reduce the dose of warfarin and mercaptopurine in patients treated with allopurinol.
Drugs causing hyperuricemia:

1. Thiazides and loop diuretics.
2. Diazoxide (antiy-hypertensive arteriodilator-thiazide like).
3. Some anti-tuberculous drugs as: pyrazinamide and ethambutol.
4. Clofibrate (anti-hyperlipidemic).
5. Anticancer drugs.
6. Uricosuric drugs in small doses.
Gouty patients should avoid eating red meat, liver, fava beans, and nuts. However;
methyxanthine beverages as coffee, tea, and cola are allowed because they are
metabolized into "methyl" uric acid which is a soluble compound.
Anti-Parkinsonian Drugs
 Parkinsonism (Parkinson's disease):
It is a neuro-degenerative disorder of the basal ganglia leading to disturbance of the
voluntary motor activity characterized by: hypokinesia =bradykinesia (difficulty to start
voluntary movements), rigidity (causes kyphosis, shuffling gate, and mask face), static
tremors, postural instability, salivation, and may be accompanied by depression.
 Parkinsonism is considered as imbalance between dopamine (deficient) acting on D2-
receptors, and acetylcholine (relatively increased) acting on M-receptors in basal ganglia
(nigrostriatum).
 Causes:
I. Idiopathic degeneration of dopaminergic neurons in the basal ganglia (may be related
to atherosclerosis, repeated trauma, environmental pollutants, or genetic
predisposition).
II. Secondary: following encephalitis and drugs (iatrogenic Parkinsonism):

1. D2- blockers as:
a) Typical Anti-psychotics (phenothiazines as chlorpromazine, and
butyrophenones as haloperidol and droperidol).

b) Anti-emetics as metoclopramide.
These drugs induce Parkinsonism if administered for large doses for about 3
months. Iatrogenic Parkinsonism due to D2 blockers can be prevented and
treated by anticholinergic drugs.
2. Drugs that deplete dopamine in CNS as reserpine.
3. Drugs that inhibit synthesis of dopamine as α-methyl dopa.
4. MPTP (Methyl Phenyl Tetrahydro Pyridine) which destroys dopaminergic neurons
(MPTP is a narcotic drug related to meperidine which is now used to induce
Parkinsonism in experimental animal models).
III. Wilson's disease.

 Aim of treatment is to restore the balance between dopamine and acetylcholine by
stimulation of D2-receptors (by increasing the level of dopamine or by other D2-agonists)
and / or by blocking M-receptors by anti-muscarinic drugs.
Accordingly; anti-parkinsonian drugs are classified into:
a) Dopaminergic drugs: they stimulate D2-receptors and include:
1. L-dopa in combination with peripheral dopa decarboxylase inhibitors (PDD-I) as
Carbidopa and Benserazide.
2. Direct Dopamine (D2) Agonists, which are either:
a) Ergolines (ergot derivatives): Bromocriptine -Pergolide-Lisuride.
b) Non-ergolines: Pramipexole and Ropinirole.
3. Deprenyl = Selegiline: selective MAO-B inhibitor.
4. COMT Inhibitors as Tolcapone and Entacapone.
5. Amantadine.
b) Anti-muscarinic (anti-cholinergic drugs):
1. Natural belladonna alkaloids: atropine and hyoscine (not used due to various
adverse effects).
2. Synthetic atropine substitutes: Benztropine- Benzhexol (trihexphenidyl)-Biperiden.
3. Seda ng (1st generation) anti-histaminics having potent atropine-like action:
diphenhydramine-orphenadrine.
Important notes:
1. Anti-muscarinic drugs are more effective in treating tremors, rigidity, and salivation but
have little or no effect on bradykinesia.
2. They prevent and treat Parkinsonism caused by typical anti-psychotics (dopaminergic
drugs would be ineffective).
3. They may be added to dopaminergic drugs (add on therapy)
4. Adverse effects: tachycardia-dry mouth-constipation-urine retention-blurred vision and
glaucoma-may cause CNS disturbances as confusion and hallucination.
5. They are contraindicated in glaucoma and benign prostatic hyperplasia.
N.B.: Beta-blockers as Propranolol may be used to control Parkinsonian tremors.

Dopaminergic Drugs:
1. L-Dopa:
 Dopamine itself is ineffective in treatment of Parkinsonism as it can not penetrate BBB.
 L-dopa is used because it is the precursor of dopamine but only 5 % of L-dopa is
converted into dopamine in CNS by the action of central dopa decarboxylase (CDD)
enzyme.
 About 95 % of L-dopa is converted into dopamine by the action of peripheral dopa
decarboxylase (PDD) enzyme in GIT (90%), blood and peripheral ssues (5%) into
dopamine which in turn can not pass BBB.
That is why L-dopa should be combined with peripheral dopa decarboxylase inhibitors
(PDD-I) as carbidopa or benserazide in a "fixed combina on" in a ra o of 10:1 or 4:1 as
follows:
L-dopa (100 mg. or 250 mg.) + carbidopa (10 mg. or 25 mg.) = Sinemet®
L-dopa (100 mg.) + benserazide (25 mg.) = Madopar®
 Part of L-dopa is converted by COMT into 3-O-methyl dopa which competes with L-dopa
for active uptake into CNS (uptake of L-dopa occurs by a transporter known as L-amino
acid transporter = LAT).
 That is why COMT inhibitors as tolcapone and entacapone may be given with L-dopa /
carbidopa combination.
- Absorption: L-dopa is absorbed orally by active transport which is decreased by the
presence of food especially amino acids which compete with L-dopa for the active
transporter LAT.
That is why it is better administered on empty stomach.
- Distribution: L-dopa passes BBB (see before).
- Fate: L-dopa is converted into dopamine inside CNS by the action of CDD. Dopamine
is metabolized by:
1. MAO-B and COMT into an inactive metabolite known as homo-vanillic acid (HVA)
which is excreted in urine.
2. MAO-B metabolizes dopamine into another inactive metabolite known as Di-
hydroxy-phenyl-acetic acid (DOPAC) which is also excreted in urine.
DOPAC interacts with H2O2 leading to formation of toxic oxidative metabolites
which destroy dopamine storage vesicles and loss of response to L-dopa therapy
with continous use (see adverse effects).
L-dopa is decarboxylated into dopamine by the action of dopa decarboxylase in CNS.
Dopamine stimulates D2-receptors in basal ganglia.
Give reason: L-dopa is considered as a "prodrug".

 Therapeutic use:
Treatment of Parkinsonism; it improves rigidity and bradykinesia better than tremors.
Treatment is usually started with small doses then gradually increased. Best results are
obtained in the first 3-4 years.
a) CNS manifestations:
1. Euphoria, anxiety, agitation, insomnia, psychological disturbances as confusion,
delusions, hallucinations, and aberrant (abnormal) sexual behaviour.
This requires either reduction of the dose of L-dopa, or adding an "atypical"
antipsychotic as Clozapine.
2. Dyskinesia (abnormal involuntary movements as chorea and athetosis which is
corrected by dose reduction).
b) CVS manifestations: postural hypotension (D1 stimulation), tachycardia (direct β1

stimulation and reflexly due to hypotension), arrhythmias (extrasystoles).
Hypertension occurs with large doses or with non-selective MAO inhibitors (α1
stimulation).
c) GIT manifestations: anorexia, nausea, and vomiting due to stimulation of D2-

receptors in CTZ. Tolerance may develop to this adverse effect, but if nausea and
vomiting persist, antiemetics are given; e.g. domperidone (D2 antagonist which does
not pass BBB) but not metoclopramide (why?).
Constipation and bleeding peptic ulcer may occur.
d) Eye: active mydriasis and increased IOP which may precipitate glaucoma.
e) Fluctuation in drug response:

1. On-Off phenomenon: may be due to variable levels of dopamine in CNS (rapid rise
→ the drug is "on", rapid fall → the drug is "off").
2. Wear off phenomenon: no more response to the drug following several years of
continous treatment. This may be due to the interaction of DOPAC with H2O2
leading to formation of toxic oxygen free radicals which destroy dopamine storage
vesicles (this can be prevented by adding selective MAO-B inhibitors as deprenyl).
3. End of dose Akinesia.
Management of fluctuation of drug response:

1. Increase the frequency of L-dopa intake.
2. Use slow release (controlled release) preparations as Sinemet CR®.
3. Add long acting direct dopamine agonists as bromocriptine and pergolide.
4. Drug holiday for 3-21 days.

f) Sudden withdrawal of L-dopa leads to severe rebound Parkinsonian rigidity.
1. Psychosis.
2. Glaucoma (especially narrow angle).
3. Peptic ulcer.
4. CVS diseases (arrhythmias).
5. Unfavorable drug interactions (see later).
a) Favorable (desirable) drug interactions:
1. L-dopa is potentiated by ant-muscarinic drugs.
2. With PDD inhibitors as cabidopa and benserazide (PDD-I allowed the use of smaller
doses of L-dopa leading to reduction in peripheral adverse effects but increased
central adverse effects) .
3. With COMT inhibitors as tolcapone and entacapone: inhibit synthesis of 3-o-methyl
dopa which competes with L-dopa for CNS uptake.
4. With selective MAO-B inhibitor (selegiline) which increases CNS levels of dopamine
and prevents synthesis of DOPAC (see before).
b) Unfavorable (undesirable) drug interactions:

1. L-dopa / carbidopa is antagonized by vitamin B6 (pyridoxine) which stimulates
peripheral dopa decarboxylase.
2. L-dopa is antagonized by drugs inducing iatrogenic Parkinsonism as D2-antagonists
and drugs decreasing dopamine in CNS (reserpine and α-methyl dopa).
3. With non-selective MAO inhibitors: severe hypertension may occur due to reduced
metabolism of noradrenaline, adrenaline, and dopamine (treated by alpha blockers
as Prazosin).
4. Non-selective MAO inhibitors should be stopped 2 weeks before giving L-dopa.
5. Foods rich in amino acids interfere with absorption of L-dopa from GIT (drug-food
interaction).
2. Bromocriptine:
 Chemistry: ergoline = ergot derivative.
- Absorbed orally.
- Passes BBB.
- Extensively metabolized by the liver.

- Mechanism of action: agonist on D2 and partial agonist on D1.
1. Anti-parkinsonian.
2. Inhibits prolactin release.
3. Inhibits growth hormone and ACTH release.
1. Parkinsonism (alone =monotherapy, or with sinemet=add on therapy).
Advantages over L-dopa/Carbidopa:
 Longer t 1/2 and less fluctua on in response.
 Not affected by presence of food as it does not compete with amino acid for
active transport carriers.
 No synthesis of toxic oxidative metabolites.
 No need for metabolizing enzymes (dopa decarboxylase).
 More specific action on D2 receptors.
2. Treatment of hyperprolactinemia (hyperprolactinemia causes galactorrhea-
amenorrhea syndrome in females, and loss of libido-gynecomastia-impotence in
males).
3. Suppression of lactation (safer than estrogen).
4. Acromegaly and ACTH-dependent tumors.
1. CNS: anxiety, insomnia, and hallucinations. Dyskinesia is less marked than with L-
dopa.
2. CVS: first-dose hypotension and collapse (especially if the patient is receiving anti-
hypertensive drugs)-digital vasospasm.
3. GIT: anorexia, nausea, vomiting, dyspepsia, constipation, and sometimes bleeding
peptic ulcer.
4. Allergy: skin eruption.
5. Erythromyalgia: painful, tender, red, hot, swollen feet.
3. Pergolide-Lisuride: ergolines (ergot derivatives) – act as agonists on D2 and D1

receptors.
4. Pramipexole and Ropinirole: non-ergot dopaminergic agonists.

5. Amantadine:
 Anti-viral used in prophylaxis of influenza A.
 Anti-parkinsonian by increasing dopamine release and inhibiting neuronal reuptake.
1. CVS: Ankle edema, hypotension, CHF.
2. CNS: Ataxia, confusion, hallucination, insomnia, irritability, and even acute toxic
psychosis.
3. GIT upset.
6. Selegiline (Deprenyl):
selective MAO-B inhibitor usually added to L-dopa/carbidopa to enhance its action and to
prvent formation of DOPAC.
7. Tolcapone and Entacapone:

They are COMT inhibitors which inhibit synthesis of 3-O-methyl dopa which competes
with L-dopa for uptake into CNS.
They are used in combination with L-dopa/carbidopa.
Tolcapone may cause serious fulminating hepatic necrosis, but entacapone is less toxic
(no hepatotoxicity).
Drugs contraindicated in Parkinsonism =Iatrogenic Parkinsonism:

1. D2-antagonists that block D2-receptors in CNS:
a) Neuroleptics (anti-psychotics): Phenothiazines (e.g.chlorpromazine) and
Butyrophenones (as haloperidol).
b) Anti-emetics as metoclopramide.
2. Reserpine: inhibits storage of dopamine causing its depletion.
3. Alpha-methyl dopa: inhibits dopa decarboxylase and accordingly inhibits synthesis of
dopamine.
4. Muscarinic agonists that can pass BBB as physostigmine and pilocarpine.
5. MPTP.
Psychotropic Drugs
Psychotropic drugs include all drugs that affect mood, psychology (behavior, thoughts, and
emotional state), and CNS activity, they include:
I. Tranquillizers (Psycholeptics):
They are further subdivided into:
a) Minor tranquillizers = Anxiolytics = Antianxiety drugs:
These drugs are used in treatment of anxiety disorders as panic disorders, phobias,
and stress disorders. Examples include Benzodiazepines (e.g. Diazepam), Zolpidem,
Buspirone.

b) Major tranquillizers = Neuroleptics = Antipsychotics:

These drugs are used in treatment of psychotic disorders as schizophrenia. They are
subdivided into:
1. Typical Antipsychotics: they act mainly by blocking D receptors (mainly D2) in the
limbic system but also block D2 receptors in other areas of CNS leading serious
adverse effects as Parkinsonism and hyperprolactinemia.
Typical antipsychotics include the following chemical derivatives:
Phenothiazines as Chlorpromazine, Thioridazine, and Trifluperazine.
Butyrophenones as Haloperidol, and Droperidol.
Thioxanthenes as Thiothixene.
2. Atypical Antipsychotics: they act by more selective block of D2 receptors in limbic
system, and/ or by blocking 5-HT2 receptorsin limbic system and accordingly they
have much less adverse effects.
Examples include: Pimozide, Sulpiride, Clozapine, Risperidone, Olanzepine.
II. Antidepressants (Psychanaleptics) and Lithium (Antimanic and mood stabilizer).

These drugs elevate mood in patients with psychic depression. They are classified –
according to the mechanism of action -into:
1. Tri-cyclic Antidepressants (TCAs).
2. MAO-Inhibitors.
3. Selective Serotonin Reuptake Inhibitors (SSRIs).
4. Atypical Antidepressants.
III. Psychotomimetics = Hallucinogenics = Psychedelics:

e.g. LSD.
IV. Psychomotor stimulants = Psychostimulants:

These drugs induce euphoria, wakefulness, alertness, and antifatigue actions. Examples
are: Methylxantines (as Caffeine), Cocaine, Amphetamine and amphetamine derivatives,
Atropine (Datura).

Anti-Psychotic Drugs
(Neuroleptics –Major Tranquillizers)
 Anti-psychotic drugs are used in treatment of psychotic disorders as schizophrenia.

 Psychosis: disorder in thoughts, behavior, and emotions characterized by positive signs
as hallucinations (usually auditory) and delusions (fixed false belief commonly paranoid),
and negative signs as emotional dullness (emotional blunting), dementia, and social
withdrawal (poor socialization).
 Psychosis may be due to increased activity of dopamine-stimulating D2-receptors- and /
or serotonin-s mula ng 5-HT2-receptorsin the limbic system.
 Dopaminergic receptors:
- There are 5 subtypes of dopaminergic receptors.
- D1 and D5 are coupled to Gs→ s mula on of adenyl cyclase → increase c-AMP
synthesis.
- D2,3,4 are coupled to Gi → inhibi on of adenyl cyclase and reduc on of c-AMP,
increase in K+ efflux, and decrease in Ca2+ influx.
Site D2-Agonists D2-Antagonists

(Dopamine)
1-Limbic system: Euphoria-Anxiety-Psychosis. Anti-Psychotic.
2-C.T.Z.: Nausea and vomiting (except Anti-emetics except in motion
motion sickness). sickness.
3-Basal ganglia: Anti-Parkinsonism. Induce iatrogenic Parkinsonism or
extrapyramidal manifestations.
4-Hypothalamus: - Inhibit prolactin. - Hyperprolactinemia.
- Increase heat formation - Decrease heat formation and

(increase body temperature). may lower normal body
temperature (Hypothermia).
- Reduce appetite. - Increase appetite and may cause

weight gain.

Classification of Anti-Psychotic Drugs:

a) Typical Antipsychotics:
They are non-selective D2-antagonists, used as anti-psychotic and anti-emetic drugs
except in motion sickness, and may lead to Parkinsonism (extrapyramidal
manifestations) and hyperprolactinemia.
1. Phenothiazines: e.g. chlorpromazine, thioridazine , and trifluperazine.
2. Butyrophenones: e.g. haloperidol, and droperidol..
3. Thioxanthenes: e.g. thiothixene, chlorprothixene, zuclopenthixol, and flupenthixol.
b) Atypical Anti-psychotics: e.g. clozapine (may cause agranulocytosis), risperidone,

sulpiride, loxapine, pimozide and molindone.
 They cause less extrapyramidal manifestations.
 They are more effective in refractory cases of schizophrenia.
 They improve the negative signs of schizophrenia.
Pimozide and Sulpiride: block D2 selectively in the limbic system.
Clozapine: blocks D4 and 5-HT2, but it has a high incidence of agranulocytosis (1-2% of
patients).
Risperidone: blocks equally D2 and 5-HT2.
Olanzepine: blocks 5-HT2 more than D2.
Chlorpromazine
 Chemistry: phenothiazine derivative.
- Absorbed orally.
- Passes BBB.
- Metabolized by the liver and metabolites are excreted in urine.
- Mechanism of action: as anti-psychotic it acts mainly by blocking D2-receptors in the
limbic system.

The pharmacological actions of chlorpromazine can be expected from the following
information:
1. Blocks D2-receptors in the limbic system→Anti-psychotic action.
2. Blocks D2-receptors in CTZ→Anti-emetic action except in motion sickness.
3. Blocks D2-receptors in basal ganglia→induce iatrogenic Parkinsonism
and other extrapyramidal manifestations.
4. Blocks D2-receptors in the hypothalamus→Hyperprolacinemia, Hypothermia, and
increased appetite.
5. Blocks α1-receptors→postural hypotension, reflex tachycardia, and delayed
ejaculation.
6. Blocks 5-HT2 receptors in CNS→Anti-psychotic and increased appetite.
7. Blocks H1-receptors→ Anti-allergic action.
8. Blocks M-receptors = Atropine-like action →tachycardia, dry mouth, cons pa on,
urine retention, and elevation of IOP.
9. Blocks Nn-receptors = ganglion blocking action →postural hypotension and
tachycardia.
10.Blocks Nm-receptors = Skeletal muscle weakness (curare-like action).
11.Blocks Na+-channels = Membrane stabilization →Quinidine-like action on the heart
and local anaesthetic action.
12.Inhibits neuronal uptake (uptake I) of noradrenaline.
(Chlorpromazine is a potent D2, α1, and 5-HT2 blocker and weak H1, M, and N-
blocker).
 The pharmacological actions of chlorpromazine are classified into:

a) CNS actions:
1. Anti-psychotic action (by blocking D2-receptors in limbic system).
2. Anti-emetic action (by blocking D2-receptors in CTZ) except in motion sickness.
3. Induction of Parkinsonism and other extrapyramidal manifestations (due to block of
D2-receptors in basal ganglia).
4. Increase in prolactin release (hyperprolactinemia) (due to block of D2-receptors in
hypothalamus).
5. Hypothermia due to increased heat loss (by inhibition of the hypothalamic heat
regulating centre and V.D. of skin blood vessels) and decreased heat formation (by
inhibition of shivering).
6. Increases appetite and causes weight gain (by blocking D2-receptors in
hypothalamus).
7. May cause seizures (convulsions) in epileptic patients.
8. Potentiates CNS depressants as analgesics, sedatives (as benzodiazepines), and
alcohol.

b) CVS actions:
1. Heart: tachycardia (reflex due to hypotension, due to atropine-like action, and
ganglion blocking action) – negative inotropic action (myocardial depression) due to
quinidine-like action.
2. Blood vessels: vasodilatation of both veins and arteries due to α1-blocking action,
ganglion blocking action, inhibition of VMC and direct vasodilatation.
3. Increases coronary flow.
4. BP: postural hypotension due to V.D. and myocardial depression.
c) Receptor blocking action:

1. Potent D2-blocker.
2. Potent α1-blocker.
3. Potent 5-HT2-blocker.
4. Weak M-blocker (atropine-like action).
5. Weak H1-blocker (anti-histaminic action).
6. Weak ganglion blocker.
7. Weak neuro-muscular blocker (curare-like action).
d) Endocrine actions:
1. Increases prolactin release by blocking D2-receptors in hypothalamus.
2. Decreases ACTH, FSH, and LH (may lead to amenorrhea and infertility in females).
e) Other actions:
1. Na+-channel blocker = membrane stabilization (local anaesthetic action and
quinidine-like action).
2. Inhibits neuronal uptake (uptake I) of noradrenaline (and drugs that undergo uptake I
as guanethidine).
1. Anti-psychotic in treatment of schizophrenia. Typical antipsychotics improve mainly
the positive signs of schizophrenia as delusions and hallucinations.
2. Anti-emetic in treatment of nausea and vomiting except in motion sickness (not
effective) and in vomiting of pregnancy (contraindicated as it may cause
teratogenicity).
3. The anti-emetic doses are lower than the doses used as anti-psychotic.
4. Treatment of intractable (severe and persistent) hiccough.
5. Pre-anaesthetic medication (to reduce anxiety and inhibit vomiting).
6. Hypothermic agent during cardio-pulmonary surgery.
7. Anti-pruritic in treatment of itching.


1. Allergic reactions: dermatitis- photosensitivity- 1. Allergy and liver diseases.
blood dyscrasias-corneal and skin deposits-
cholestatic jaundice (allergic obstructive hepatitis).
2. Parkinsonism and extrapyramidal manifestations 2. Parkinsonism.

as: akathisia (restless involuntary movements)-
acute dystonia-tremors. This can be prevented by
antimuscarinic drugs.
3. Tardive dyskinesia (abnormal involuntary

movements on prolonged use of chlorpromazine,
may be due to up-regulation of D receptors.There
is no specific treatment but can be prevented by
lithium).
4. Seizures in epileptic patients. 3. Epilepsy.
5. Teratogenicity. 4. Pregnancy.
6. Hyperprolactinemia leading to galctorrhea-

amenorrhea in females, gynecomastia, impotence,
and loss of libido in males.
7. Increased appetite and weight gain.
8. Atropine-like adverse effects: tachycardia, dry 5. Glaucoma and enlarged prostate.

mouth, constipation, urine retention, and
elevation of IOP.
9. Postural hypotension. 6. Hypotension.
10. Neuroleptic Malignant Syndrome: idiosyncratic 7. Idiosyncracy.

reaction similar to malignant hyperthermia,
treated by cooling and IV dantrolene..
11. Delayed ejaculation.

1. Potentiates the actions of:
- Sedatives as alcohol, benzodiazepines, and barbiturates.
- Analgesics as morphine.
- Anticholinergic drugs as atropine.
- Vasodilators and other hypotensives.
- Skeletal muscle relaxants as curare.
2. The hypotensive action of chlorpromazine is mainly due to its α1-blocking action and
accordingly is not treated by adrenaline (more hypotension will occur = adrenaline
reversal).
3. Antagonizes the anti-hypertensive action of guanethidine (chlorpromazine inhibits
neuronal uptake of guanethidine).
Other Phenothiazines:
Trifluperazine:
Similar to chlorpromazine but is a more powerful D2 antagonist and accordingly is a more
potent antipsychotic but with more extrapyramidal manifestations.
Thioridazine:
Similar to chlorpromazine but is less potent D2 antagonist.
1. Not antiemetic.
2. Rare extrapyramidal manifestations.
3. Side effects: as chlorpromazine + Cardiotoxicity + Retinopathy.
Anti-Convulsant Drugs (Anti-Epileptic)

Epilepsy: is a CNS disorder due to the presence of hyper-excitable neurons-known as
epileptic focus-leading to abnormal behavior, loss of consciousness, and / or convulsions.
Types of epilepsy:
1. Generalized tonic-clonic seizures (grand mal epilepsy).
2. Absence seizures (petit mal epilepsy).
3. Myoclonic seizures.
4. Partial seizures.
5. Status epilepticus (severe sustained seizures which may be fatal).
General principles in treatment of epilepsy:

1. Use the minimal number of anti-epileptic drugs to avoid drug interactions.
2. Treatment should be con nued for 2-3 years a er the last seizure.
3. Anti-epileptic drugs should be gradually withdrawn to avoid status epilepticus.

Mechanism of action of anti-epileptic drugs:

1. Block of Na+-channels: by Phenytoin, Carbamazepine, and Valproic acid.
2. Block of voltage-gated Ca2+-channels (T-type): by Ethosuximide, and Valproic acid.
3. Blocking the receptors of excitatory transmitters as glutamate and aspartate: by
Felbamate.
4. Potentiation of the inhibitory action of GABA: by Benzodiazepines, Barbiturates, Valprioc
acid, and Vigabatrin.
1. Phenytoin (Diphenylhydantoin):
 Chemistry: hydantoin derivative.
- Well absorbed orally and can be given by injection.
- Passes BBB.
- Passes placental barrier and cause teratogenicity
- Bound to plasma proteins (displaces thyroxin and tri-cyclic antidepressants = TCAs;
but is displaced by aspirin, sulphonamides, and valproic acid).
- Metabolized by the liver by hydroxylation and conjugation. Saturation of
metabolizing enzymes occurs with large doses and elimination will follow "zero
order kinetics" and t 1/2 increases (remember aspirin).
- Metabolites are excreted in urine.
- Mechanism of action: Na+-channel blocker (membrane stabilization).
1. Anti-epileptic action.
2. Anti-arrhythmic action (class I-B anti-arrhythmic).
3. Hepatic microsomal enzyme (HME) inducer.
1. Treatment of epilepsy: in grand mal epilepsy, partial seizures, and may be used in
status epilepticus. It is not effective in petit mal epilepsy and may even worsen it.
2. Treatment of ventricular arrhythmias especially with heart block as in cases of
digitalis toxicity.
3. Treatment of neuropathic pains as trigeminal neuralgia.

1. Gingival (gum) hyperplasia especially in children (irreversible).
2. GIT irritation (better given with meals).
3. Hypersensitivity reactions: rash, blood dyscrasias, and cholestatic hepatitis.
4. Teratogenic (fetal hydantoin syndrome: cleft lip, cleft palate, and cardiac septal
defect).
5. Cerebello-vestibular dysfunction: vertigo-ataxia-nystagmus-diplopia.
6. Hirsutism (may be due to increased androgen release).
7. Inhibits ADH and insulin release (may cause hyperglycemia).
- Induces its own metabolism → tolerance to the anti-epileptic action.
- Induces metabolism of other drugs as digitoxin, theophylline, cortisone, and oral
contraceptives.
- Displaces thyroxine and TCAs from plasma proteins but is displaced by aspirin,
sulphonamides, and valproic acid.
- Other HME inducers as barbiturates and carbamazepine increase its metabolism.
- HME inhibitors as valproic acid and cimetidine decrease its metabolism and may
lead to phenytoin toxicity.
- Increases metabolism of vitamin K leading to hypoprothrombinemia and bleeding.
- Increases metabolism of vitamin D leading to hypocalcemia and osteoporosis.
- Increases metabolism of folic acid leading to folic acid deficiency anemia
(megaloblastic anemia) and increases toxicity of methotrexate (anticancer folate
antagonist).
1. Pregnancy.
2. Allergy to hydantoins.
2. Carbamazepine (Tegretol):
 Chemistry: related to tri-cyclic antidepressants (TCAs).
- Absorbed orally.
- Passes BBB.
- Bound to plasma proteins.
- Metabolized by the liver.

- Mechanism of action: Na+-channel blocker.
1. Antiepilectic action.
2. HME inducer.
3. Stimulates ADH release (anti-diuretic action).
1. Treatment of epilepsy: grand mal and partial seizures but not in petit mal epilepsy.
2. Treatment of trigeminal neuralgia.
3. Treatment of central (pituitary) diabetes insipidus.
1. GIT irritation: nausea, vomiting, and diarrhea.
2. Hypersensitivity reactions: rash, blood dyscrasias, and cholestatic hepatitis.
3. Cerebello-vestibular dysfunction: ataxia, diplopia, nystagmus, and vertigo.
4. Fluid retention and dilutional hyponatremia due to anti-diuretic action.
5. Teratogenic (similar to fetal hydantoin syndrome).
6. Drug interactions: HME induction.
1. Pregnancy.
2. Allergy.
3. Valproic acid (Sodium valproate):

- Absorbed orally.
- Passes BBB.
- Passes placental barrier and causes teratogenicity (Spina bifida).
- Highly bound to plasma proteins and displaces other drugs as phenytoin.
- Metabolized by the liver.
- Mechanism of action:
1. Inhibits GABA transaminase –the enzyme responsible for degradation of GABA-
leading to increase in the level of GABA.
2. Blocks Na+-channels.
3. Blocks voltage-gated Ca2+-channels (T-type).

1. Anti-epileptic.
2. HME inhibitor.
Treatment of all types of epilepsy (broad-spectrum anti-epileptic).
1. GIT irritation.
2. Transient alopecia.
3. Teratogenicity (spina bifida).
4. Bone marrow depression (thrombocytopenia).
5. CNS: ataxia and sedation.
6. Cholestatic jaundice (and may lead to hepatotoxicity).
- HME inhibition leading to decreased metabolism of phenytoin.
- Displaces phenytoin from plasma protein binding sites and increases its plasma
level.
4. Ehtosuximide:
- Absorbed orally.
- Passes BBB.
- Mainly metabolized by the liver (75%) and partly excreted unchanged in urine
(25%).
- Mechanism of action: blocks voltage gated Ca2+-channels (T- type).
- Pharmacological actions: Anti-epileptic.
Drug of choice in absence seizures (petit mal epilepsy.
1. GIT upset.
2. Allergy.
3. Drowsiness and mood changes.
4. Blood dyscrasias.

Chemotherapy 2011/2012
CHEMOTHERAPY
Definition: It is the use of a drug (chemotherapeutic agent) to kill or stop growth and
multiplication of infective microbes (anti-microbial chemotherapy), or to kill cancer cells
(anti-cancer chemotherapy).
Anti-Microbial Chemothearpy:
Anti-microbial chemotherapeutics are further classified into:
a) Anti-Bacterial chemotherapy (including Anti-Tuberculous Drugs).
b) Anti-Fungal chemotherapy.
c) Anti-Viral chemotherapy.
d) Anti-Protozoal chemotherapy: include Anti-amoebic and Anti-malarial chemotherapy.
e) Anti-Helminthic chemotherapy.
Anti-Bacterial Chemotherapy
Scheme for studying anti-bacterial chemotherapy:
1) Source:
Chemotherapeutic agents are either:
a) Natural : from microorganism source as fungi = Antibiotics.
b) Semisynthetic.
c) Synthetic (sulphonamides and fluroquinolones).
2) Chemistry:
3) Pharmacokinetics:
a) Absorption:
I. Poorly absorbed chemotherapeutics as Aminoglycosides should be given
parenterally to treat systemic infections, but are given orally to treat local GIT
infections.
II. Broad spectrum antibiotics, especially if incompletely absorbed, lead to
Superinfection and Vitamin B and K deficiency (they affect bacterial flora).
III. Antacids containing Mg2+ and Al3+ reduce oral absorption of Quinolones and
Tetracyclines.
IV. Food decreases absorption of penicillins especially Ampicillin.
Ca2+ in milk and other dairy products as well as oral iron preparations decrease oral
absorption of Tetracyclines.

b) Distribution:
I. Plasma protein binding: Sulphonamides are highly bound to plasma proteins and
they displace other drugs as warfarin and oral hypoglycemics, and displace
bilirubin in neonates leading to hyperbilirubinemia (jaundice and Kernicterus may
occur).
II. Chemoterapeutics that pass BBB and achieve high level in CSF are useful in
treatment of meningitis. Some chemotherapeutics cannot penetrate normal
meninges but penetrate inflamed meninges in case of meningitis, as penicillins.
Drugs that cannot penetrate even inflamed meninges may be given intrathecal as
Aminoglycosides.
III. Some chemotherapeutics may be teratogenic (as Aminoglycosides, Tetracyclines,
Quinolones, Sulphonamides, and Chloramphenicol) whereas others are safely
used in pregnancy (as Penicillins and Erythromycin).
c) Fate:
I. Some chemotherapeutics are metabolized in the liver and are not effective in
treatment of urinary tract infections (UTIs), and are better avoided in patients
with hepatic insufficiency.
II. Other chemotherapeutics are excreted unchanged in urine (by glomerular
filtration or active secretion) and are accordingly useful in UTIs. They are better
avoided in renal impairment, or the dose may be adjusted according to renal
functions (creatinine clearance).
III. Few chemotherapeutics are excreted in bile and are very effective in treatment of
GIT infections as typhoid fever and in biliary tract infections. They usually undergo
"entero-hepa c recycle" and have long dura on of ac on, may be given once / 24
hours which results in excellent compliance.
4) Pharmacodynamics:
a) Action on bacteria: chemotherapeutics may be either:
I. Bactericidal: they kill "active growing and multiplying bacteria", e.g. β-lactam
antibiotics (penicillins-cephalosporins-monobactams-carbapenems), vancomycin,
co-trimoxazole, polypeptide antibiotics. They should be used in immuno-
compromised patients and in serious infections as endocarditis, septicemia, and
meningitis.
II. Bacteriostatic: they stop growth and multiplication of bacteria, e.g.
sulphonamides, chloramphenicol, tetracyclines, trimethoprim. Bacteriostatic
drugs should not be given to immuno-compromised patient (due to D.M., AIDS,
patients treated by immunosuppressive drugs as cortisone and cancer
chemotherapy).
N.B.: few chemotherapeutics may be bacteriostatic or bactericidal according to their
concentration or the state of activity of bacteria, e.g. erythromycin and isoniazid.

Chemotherapeutic agents may act by the following mechanisms:
Mechanism of Action Chemotherapeutic

1-Inhibition of cell wall synthesis: 1) β-Lactam antibiotics:
Penicillins-Cephalosporins-
Carbapenems-Monobactam.
2) Vancomycin.
3) Cycloserine.
4) Bacitracin.
2-Interference with cell membrane: Polymyxins.
3-Inhibition of Protein synthesis:

A-Inhibi on of 30 S ribosomal subunit: 1) Aminoglycosides.
2) Tetracyclines.
B-Inhibi on of 50 S ribosomal subunit: 1) Chloramphenicol.

2) Macrolides (as Erythromycin)
and Clindamycin.
4-Inhibition of DNA synthesis by Fluroquinolones.
inhibition of DNA gyrase:
5-Inhibition of RNA synthesis by Rifampicin.
inhibition of DNA –dependent RNA
polymerase:
6-Inhibition of folic acid synthesis: 1) Sulphonamides.
2) Trimethoprim.
3) Co-trimoxazole.
5) Spectrum of activity:
Chemotherapeutic agents are broadly classified according to spectrum of activity into:
a) Narrow Spectrum.: e.g. Aminoglycosides and some penicillins.
b) Broad (Wide) Spectrum: e.g. Chloramphenicol, Tetracyclines, and some penicillins.

Microorganism Infection
Gram positive cocci
1-Staphylococci: a) Pyogenic infections; e.g. of skin
(abscess) and bone (osteomyelitis).
b) Endocarditis.
2-Streptococci: a) Upper respiratory tract infections

(RTIS): tonsillitis, pharyngitits, otitis,
sinusitis.
b) Lower respiratory tract infections:
bronchitis and pneumonia.
c) Rheumatic fever.
enoxaprin
Gram positive bacilli
1-Clostridia Tetanus and gas gangrene.
2-Corynebacterium diphtheria Diphtheria.
3-Bacillus anthracis Anthrax.

Gram negative cocci:
1-Neisseria gonorrhea Gonorrhea.
2-Neisseria meningitidis Meningitis.

Gram negative bacilli: a) GIT infections (Typhoid, Bacillary
E.coli, Proteus, Klebsiella, dysentery, Cholera).
Pseudomonas, H.pylori, b) Peptic ulcer (by H.pylori).
Salmonella, Shigella, Vibrio c) Urinary tract infections (UTIs).
cholera. d) Meningitis.
e) Septicemia.
f) Pneumonia.
g) Endocarditis.
Chlamydia: a) Pneumonia.
b) Uro-genital infections.
c) Eye infections (trachoma).
Mycoplasma: Pneumonia (Atypical).
Mycobacterium tuberculosis: T.B.
Treponema pallidum: Syphilis.
Pneumocystis cainii: Pneumonia in AIDS.

6) Indications:
a) Treatment of infections: according to spectrum.
b) Prophylaxis against infections (Chemoprophylaxis): for example:
I. Prophylaxis against rheumatic fever (by benzathine penicillin).
II. Prophylaxis against endocarditis (by procaine penicillin or vancomycin).
III. Prophylaxis against meningococcal meningitis (by rifampicin).
7) Adverse (toxic) effects:
Chemotherapeutic Adverse Effects

1) Penicillins: Hypersensitivity (rash, urticaria, angioedema, and
anaphylactic shock).
2) Cephalosporins: a) Hypersensitivity and cross allergy with penicillins.
b) Nephrotoxicity.
3) Aminoglycosides: a) Ototoxicity (damage of 8th cranial nerve)
b) Nephrotoxicity.
4) Erythromycin: a) Gut upsets (nausea, vomiting, colics, and diarrhea).
b) Cholestatic hepatitis.
c) HME inhibition.
5) Chloramphenicol: a) Bone marrow depression.
b) Grey baby syndrome.
c) Diarrhea and superinfection.
d) HME inhibition.
6) Tetracyclines: a) Gut upsets (nausea, vomiting, hyperacidity,
ulcerations).
b) Chelation with Ca2+ in bone and teeth.
c) Fanconi syndrome (nephrotoxicity by outdated
tetracyclines).
d) Teratogenicity.
7) Sulphonamides: a) Hypersensitivity reactions.
b) Crystalluria.
c) Blood dyscrasias (bone marrow depression and
hemolysis in pa ents with G6PD deficiency).
d) Hyperbilirubinemia and kernicterus (in neonates), and
displacement of other drugs from plasma proteins.
8) Fluroquinolones: a) Arthropathy (damage of growing articular cartilage).
b) HME inhibition.
c) Seizures especially with NSAIDs.
9) Vancomycin: a) Red man syndrome
b) Ototoxicity -Nephrotoxicity.

8) Drug interactions:
a) Drug interaction before administration:
Anti-Pseudomonal penicillins (acidic) should not be mixed with Aminoglycosides
(basic) in the same syringe or infusion bottle to avoid chemical antagonism.
b) Pharmacokinetic interactions:
I. Absorption: see before.
II. Distribution: see before.
III. Metabolism:
1. Erythromycin, chloramphenicol, and fluroquinolones are HME inhibitors.
2. Rifampicin is a HME inducer.
IV. Excretion:
Probenicid decreases renal tubular secretion of penicillins and cephalosporins
leading to increased duration of action.
c) Pharmacodynamic interactions:
I. Bactericidal drug + Bactericidal drug → Synergism.
II. Bacteriostatic drug + Bacteriostatic drug → Synergism or Addi on.
III. Bactericidal drug + Bacteriostatic drug → Antagonism (cidal drugs act on ac ve
growing and multiplying bacteria).
d) Benefits of Anti-microbial Combinations:
I. To achieve synergism (see before).
II. To reduce the incidence of bacterial resistance.
III. To reduce toxic effects of individual drugs.
IV. To broaden the spectrum.
V. To treat mixed infections.
VI. To treat serious infections as septicemia before diagnosis (empiric therapy).
Inhibitors of Cell Wall Synthesis:

I-β-Lactam Antibiotics:
They have the following common characteristics:
a) Contain β-Lactam ring which is essential for anti-bacterial activity. Bacteria producing β-
lactamases as Staph. aureus destroy β-lactam ring and show resistance to some
penicillins.
b) Bactericidal.
c) Inhibit cell wall synthesis by inhibition of transpeptidase enzyme.
They include:
I. Penicillins.
II. Cephalosporins (and Cephamycins).
III. Carbapenems.
IV. Monobactams.

1. PENICILLINS:
a) Source:
I. Natural from fungi (moulds): benzyl penicillin (penicillin G) and phenoxymethyl
penicillin (penicillin V).
II. Semi-synthetic.
b) Chemistry:
I. Deriva ves of 6-Amino Penicillanic acid.
II. Contain β-Lactam ring.
I. Absorption:
1) Some penicillins are "Acid-Sensitive": destroyed by gastric acidity and
accordingly not given orally; e.g. benzyl penicillin –procaine penicillin –
benzathine penicillin – methicillin –carbenicillin.
2) Other penicillins are "Acid-Resistant": not destroyed by HCl and are given
orally; e.g. phenoxymethyl penicillin- ampicillin- amoxycillin.
3) Ampicillin is incompletely absorbed orally especially in the presence of food.
II. Distribution:
1) Bound to plasma proteins.
2) Pass placental barrier and are safe in pregnancy.
3) Penicillins cannot penetrate normal meninges but penetrate well inflamed
meninges in case of meningitis. They can also be given intra-thecal but may
cause convulsions.
III. Fate:
Penicillins are excreted unchanged (active) in urine by tubular secretion mainly
and to a much lesser extent by glomerular filtration.
1) They are effective in treatment of UTIs.
2) The dose should be adjusted in cases of renal impairment according to kidney
functions.
3) Benzyl penicillin is rapidly excreted and has short duration of action. Probenicid
reduces the rate of urinary excretion and accordingly prolongs the duration of
action of penicillins.
4) Nafcillin is excreted in bile and undergoes entero-hepatic circulation and has
long duration of action.

IV. Antibacterial Activity:

1) Action on bacteria: Bactericidal.
2) Mechanism of action:
a) Penicillins bind to specific penicillin binding proteins (PBPs) → inhibi on of
transpeptidase enzyme→ inhibi on of cross linking between pep doglycan
layers → inhibition of cell wall synthesis.
b) Penicillins activate bacterial autolytic enzymes (autolysins) → cell wall lysis.
c) Bacteria imbibe water by its high osmotic pressure leading to rupture and
cell death.
N.B.: penicillins act on active growing bacteria not on resting ones.
3) Selectivity: Penicillins have selective toxicity, they act on bacteria but do not
affect human cells due to the lack of peptidoglycan cell wall in human cells.
4) Resistance: resistance shown by some microorganisms to penicillins may be:
a) Natural: due to absence of peptidoglycan cell wall as in Mycoplasma.
b) Acquired (plasmid-mediated) by:
I. Synthesis of enzymes that destroy the β-lactam ring of penicillins, these
enzymes are known as "β-lactamases" or penicillinases.
II. Alteration in the binding site of penicillins (PBP).
III. Decreased permeability (influx) to penicillins.
IV. Increased efflux (extrusion) of the antibiotic from the inside of the
bacterial cells to the outside.
Give reason:
1) Penicillins have "selective toxicity" and are considered safe antibiotics.
2) Penicillins are inactive against Mycoplasma, Mycobacteria, Fungi, and Viruses.
d) Spectrum:
Penicillins are classified according to their spectrum into:
1) Narrow spectrum penicillins.
2) Broad spectrum penicillins.
3) Extended spectrum penicillins (known as Anti-Pseudomonal penicillin).

Type of Penicillin Active Against Examples

1) Narrow spectrum: a) Gram positive bacteria a) Benzyl penicillin.
(cocci and bacilli). b) Procaine penicillin.
b) Gram negative cocci c) Phenoxymethyl penicillin.
Not active against Gram d) Benzathine penicillin.
negative bacilli.
d) Broad spectrum: a) Gram positive bacteria a) Ampicillin.
(cocci and bacilli). b) Ampicillin esters =
b) Gram negative cocci. Ampicillin prodrugs = Pro-
c) Gram negative bacilli ampicillins: Bacampicillin,
Except Pseudomonas, Pivampicillin,
Proteus, and Klebsiella. Talampicillin, Epicillin.
c) Amoxycillin.
e) Extended spectrum a) Gram positive bacteria Carboxy-penicillins:
=Anti-Pseudomonal (cocci and bacilli). a) Carbenicillin.
penicillins: b) Gram negative b) Carbenicillin indanyl.
bacteria (cocci and
bacilli including a) Ureido-penicillins:
Pseudomonas, b) Piperacillin.
Proteus, and c) Azlocillin.
Klebsiella). d) Mezlocillin.
e) Ticarcillin.
N.B.: Penicillins are also active against anaerobes except β-lactamase producing Bacteroides
fragilis, Spirochaetes (Treponema pallidum and acute ulcerative gingivitis), and Actinomyces
israelii (actinomycosis).
e) Indications:
I. Chemoprophylaxis:
1) Prophylaxis against streptococcal infections in patients with rheumatic fever by
benzathine penicillin (1,200.000 units IM every month for 5 years or un l
reaching 20 years of age; which is ever longer. Some physicians advise life-long
therapy).
2) Prophylaxis against endocarditis in patients with valve disease or prosthetic
valves before dental procedures. Procaine penicillin (300,000 – 600,000 units
IM) is used.

II. Treatment of:

1) Respiratory tract infections: pharyngitis, tonsillitis, otitis, sinusitis, bronchitis,
and pneumonia.
2) Urinary tract infections.
3) GIT infections as typhoid fever and bacillary dysentery and eradication of
H.pylori in peptic ulcer.
4) Meningitis.
5) Gonorrhea.
6) Pyogenic infections as abscess, osteomyelitis.
7) Endocaditis.
8) Diphtheria, tetanus, gas gangrene, anthrax.
9) Actinomycosis.
10) Syphilis.
f) Adverse effects: (Penicillins are among the safest antibiotics)

I. Hypersensitivity (allergic reactions):
1) It is due to "penicilloic acid" which acts as a hapten.
2) It is manifestsed as rash, urticaria, angioedema, or anaphylactic shock (treated
by adrenaline IM, cortisone IV, and antihistaminics).
3) It is prevented by asking the patient for previous history and by skin test.
4) The patient should never re-use penicillins.
5) There is "cross allergy" between penicillins and other β-lactam antibiotics as
cephalosporins in about 10% of popula on , due to similarity in the chemical
structure.
6) Ampicillin causes "maculopapular rash" in case of:
a) Allergy.
b) Leukemia.
c) Infectious mononucleosis (diagnostic test).
d) Patients treated by allopurinol.
II. Diarrhea and superinfection especially with ampicillin. Superinfection may be
caused by monilia (candida) and is treated by Nystatin orally, or by Staph. or by
Clostridium difficile which is treated by oral Vancomycin or Metronidazole.
III. Local pain and induration due to IM injection (benzathine penicillin), and
thrombophlebitis after IV injection.
IV. Seizures and epileptic fits in case of large doses or intrathecal injection.
V. Penicillins are given in the form of Na+ or K+ salts, which may lead to
hypernatremia or hyperkalemia especially in cardiac and renal patients.
VI. Platelet dysfunction leading to bleeding (by carbenicillin, ticarcillin, and rarely
benzyl penicillin).
VII. Acute interstitial nephritis by methicillin (not used clinically).

VIII. Jarisch-Herxheimer reaction: due to release of toxins from dead Treponema in

syphilitic pa ents treated by 1st dose of penicillin. The manifestations are similar
to allergic reactions and are treated by cortisone. In contrast to allergy; penicillin
therapy should be continued.
I. Allergy.
II. Epilepsy.
h) Penicillin Preparations (Classification):

I. Benzyl Penicillin (Penicillin G):
1) Natural.
2) Acid-sensitive: not given orally, given by IV and IM injection.
3) β-Lactamase (penicillinase)-sensitive: inactive against bacteria that produce β-
lactamase as Staph.aureus.
4) Narrow spectrum (see before).
5) Short acting due to rapid excretion in urine.
II. Long-Acting Penicillins:

1) Procaine Penicillin.
2) Fortified Procaine Penicillin: combination of benzyl penicillin (rapid onset) and
procaine penicillin (long duration).
3) Benzathine Penicillin: used only for chemoprophylaxis against Rheumatic fever,
and not for treatment of infections.
They all have the following characteristics:
a) Acid-sensitive.
b) β-Lactamase-sensitive.
c) Narrow spectrum.
III. Acid-Resistant Penicillin: Phenoxymethyl Penicillin (Penicillin V):

1) Natural.
2) β-Lactamase-sensitive.
3) Narrow spectrum.
4) Short duration of action.
IV. β-Lactamase (Penicillinase) Resistant Penicillins:

1) Oxacillin.
2) Cloxacillin.
3) Dicloxacillin.
4) Flucloxacillin.
5) Nafcillin: excreted in bile and has entero-hepatic circulation.

All are acid-resistant.

6) Methicillin: acid-sensitive -nephrotoxic (causes acute interstitial nephritis) –
obsolete- some strains of Staph. aureus became resistant to methicillin and are
known as MRSA. They are treated by vancomycin.
V. Broad Spectrum Penicillins:

Active against Gram positive and Gram negative bacteria except Pseudomonas,
Proteus, and Klebsiella.
1) Ampicillin:
a) Acid-resistant (given orally).
b) β-Lactamase-sensitive (inactive against Staph.).
c) Incompletely absorbed orally especially in the presence of food, causing
diarrhea and superinfection.
d) May cause maculo-papular rash (see adverse effects).
2) Ampicillin Esters (Pro-Ampicillins = Ampicillin Prodrugs):
a) They are better absorbed orally than ampicillin and accordingly cause
minimal diarrhea and superinfection.
b) They are de-esterified in the liver and gut mucosa into "active" ampicillin.
c) They include: Bacampicillin – Talampicillin – Pivampicillin.
3) Amoxycillin:
a) Acid-resistant (given orally).
b) β-Lactamase sensitive.
c) Absorption is much better than ampicillin and not affected by food.
VI. Extended Spectrum = Anti-Pseudomonal Penicillins:

a) They are active against Gram positive and negative bacteria including
Pseudomonas.
b) They are β-lactamase sensitive.
c) They are acid sensitive (except carbenicillin indanyl).
d) They are given with aminoglycosides in treatment of serious infections to
achieve synergism but should not be mixed in the same syringe or bottle
(why?).
e) They are subdivided into:
Carboxypenicillins: Carbenicillin – Carbenicillin indanyl.
Ureidopenicillins: Azlocillin – Mezlocillin – Piperacillin – Ticarcillin.
How To Treat β-Lactamase Producing Bacteria?:

1) By β-Lactamase resistant penicillins as oxacillin, cloxacillin, dicloxacillin, and nafcillin.
2) By combination of β-lactamase resistant penicillin with broad spectrum penicillin, e.g.:
Ampicillin + Cloxacillin =Ampiclox®

3) By combination of broad spectrum penicillin or anti-pseudomonal penicillin with β-

lactamase inhibitors (suicide inhibitors) as clavulanic acid- sulbactam – tazobactam:
Examples: Ampicillin + sulbactam = Unasyn®.
Amoxycillin + clavulanic acid = Augmentin®
2. Cephalosporins:
a) Source: Natural and semisynthetic.
b) Chemistry: β-Lactam antibiotics.
I. Absorption: they may be given orally and parenterally (IV and IM).
II. Distribution: bound to plasma proteins-pass placental barrier and are safe in
pregnancy- 1st and 2nd genera ons cannot pass BBB whereas 3rd (except
Cefoperazone) and 4th generations easily penetrate BBB into CSF.
III. Fate: most cephalosporins are excreted unchanged in urine mainly by tubular
secretion and adding probenicid prolongs their action (as penicillins).
Ceftriaxone and Cefoperazone are excreted in bile and undergo entero-hepatic
circulation (long duration and very effective in GIT infections as typhoid fever).
d) Pharmacodynamics: As penicillins:
I. Action on bacteria: Bactericidal.
II. Mechanism of action: Inhibit cell wall synthesis.
e) Spectrum:
Gram positive, Gram negative, and anaerobes (especially Cefoxitin).
I. Activity on Gram positive: 1st genera on > 2nd genera on > 3rd and 4th
generations.
II. Activity on Gram negative: 3rd and 4th genera ons > 2nd genera on > 1st
generation.
III. Β-Lactamase Resistance: all cephalosporins are resistant to β-lactamases but
resistance increases from 1st to 4th generations.
f) Indications:
I. Respiratory tract infections.
II. Urinary tract infections.
III. Meningi s (3rd and 4th generations except cefoperazone).
IV. Gonorrhea.
V. Typhoid fever (especially cefoperazone and ceftriaxone).
VI. Anaerobic infections (especially cefoxitin).
VII. Pyogenic infections especially if due to penicillin-resistant bacteria.
VIII. Serious infections by Gram negative bacteria as endocarditis and septicemia.
IX. Prophylaxis against surgical wound infections.

g) Adverse effects:
I. Hypersensitivity: allergy to cephalosporins is less frequent than penicillins. In
about 10% of people there is "cross allergy" with penicillins.
II. Nephrotoxicity; especially if given with aminoglycosides (also nephrotoxic) and
with loop diuretics (increase renal concentration of cephalosporins).
III. Diarrhea and superinfections with oral administration.
IV. Pain and induration after IM injection.
V. Thrombophlebitis after IV injection.
VI. Hypoprothrombinemia and bleeding due to vitamin K deficiency (by
cefoperazone and cefamandole).
VII. Disulfiram-like action in alcoholic patients (disulfiram inhibits aldehyde
dehydrogenase leading to accumulation of acetaldehyde after alcohol injestion
causing nausea, vomiting, bronchospasm, and hypotension).
h) Classification of Cephalosporins:
3.
Character 1st Generation 2nd Generation 3rd Generation 4th
Generation
Spectrum: Broad: G+ve > G- Broad:more active on Broad:more active on G- Broad: as
ve. G-ve and less on ve than on G+ve. 3rd
G+ve. generation.
Resistance to β- Resistant. More resistant than More resistant than 2nd More
lactamase: 1st generation. generation. resistant
than 3rd
generation.
Passage across Cannot pass BBB Cannot pass BBB Excellent passage except Excellent
BBB: cefoperazone. passage
across BBB.
Routes of a) Oral: a) Oral: a) Oral: Cefipime:
administration: Cephradine Cefaclor- Cefpodoxime- only IV.
(velosef®) – Cefuroxime. Cefixime.
Cephadroxil-
Cephalexin. b) Parenteral; b) Parenteral:
a) Cefamandole I. Cefoperazone
b) Parenteral: b) Cefoxitin (cannot pass BBB,
Cefazolin- (most active excreted in bile)
Cefapirin- against II. Ceftriaxone
Cephalothin. anaerobes). (excreted in bile)
III. Cefotaxime
IV. Moxalactam.

4. Carbapenems:
a) Examples: Imipenem – Meropenem – Ertapenem.
b) Source: Synthetic.
c) Chemistry: β-Lactam antibiotics.
d) Pharmacokinetics:
I. Given IV.
II. Pass BBB during meningitis.
III. Pass placental barrier (safe in pregnancy).
IV. Excreted unchanged in urine by tubular secretion. Imipenem is metabolized in
renal tubular cells of PCT by "dihydropeptidase" into an inactive and
nephrotoxic metabolite. That is why imipenem should be combined with a
dihydropeptidase inhibitor as cilastatin.
(Imipenem + Cilastatin = Tienam®).
N.B.: the dose should be adjusted in renal impairment.
e) Action on bacteria:
Bactericidal.
f) Mechanism of action:
Inhibit cell wall synthesis (as penicillins).
g) Spectrum:
Active on Gram positive, Gram negative (including Pseudomonas), and anaerobes.
h) Indications:
II. Urinart tract infections.
III. Anaerobic infections.
IV. Mixed infections.
V. Serious and resistant infections.
i) Adverse effects:
I. Nausea, vomiting, and diarrhea.
II. Seizures (in large doses).
III. Neutropenia and eosinophilia.
IV. Skin rash.
5. Monobactam:
a) Aztreonam
I. Source: synthetic.
II. Chemistry: β-lactam antibiotic.
III. Pharmacokinetics: given IM and IV-excreted in urine.
IV. Pharmacodynamics: bactericidal- inhibits cell wall synthesis.
V. Spectrum: active on Gram negative only (including Pseudomonas), inactive
against Gram positive and anaerobes.

VI. Adverse effecst: thrombophlebitis- superinfection with Staph.-elevates hepatic

serum transaminases- skin rash.
b) Vancomycin:
a) Source: natural.
I. Not absorbed orally, given by IV infusion to treat systemic infection but is
given orally to act locally on GIT.
II. Poorly penetrates BBB except in meningitis.
III. Passes placental barrier and may cause deafness of fetus.
IV. Excreted unchanged in urine by passive glomerular filtration (useful in UTIs
and dose should be adjusted in renal impairment).
I. Action on bacteria: bactericidal.
II. Mechanism of action: inhibits cell wall synthesis.
d) Spectrum: Gram positive bacteria (including MRSA and Clostridium difficile).
e) Indications:
I. Chemoprophylaxis against endocarditis in penicillin- allergic patients.
II. Treatment of pseudomembranous colitis (given orally).
III. Treatment of MRSA infections.
IV. Urinary tract infections.
f) Adverse effects:
I. Ototoxicity.
II. Nephrotoxicity.
III. "Red man syndrome": rapid IV infusion leads to histamine release causing V.D.
of cutaneous blood vessels and flushing.
IV. Allergy: rash and fever.
V. Thrombophlebitis.
6. Bacitracin:
a) Polypeptide antibiotic (ineffective orally).
b) Bactericidal-inhibits cell wall synthesis.
c) Spectrum: Gram positive bacteria especially Staph. aureus (β-lactamase
producing).
d) Indications: used topically only in treatment of skin and wound infections; never
used systemically because it is extremely nephrotoxic.
7. Cycloserine:
a) Bactericidal by inhibition of cell wall synthesis.
b) Used as a 2nd line drug in T.B.
c) adverse effects: CNS manifeststions as headache, drowsiness, convulsions and
toxic psychosis.

Inhibitors of Protein Synthesis
A- Aminoglycosides:
a) Source: most aminoglycosides are natural.
b) Chemistry: Polar (highly ionized and poorly lipid soluble) –strongly basic.
a) Absorption: poorly absorbed orally, given orally only for treatment of GIT
infections and bowel sterilization. They must be given IM or IV for treatment of
systemic infections. They may be also given topically as skin ointments, by
inhalation in treatment of respiratory tract infections, and intra-thecally in
treatment of meningitis.
b) Distribution:
I. Minimal plasma protein binding (only 10%).
II. Cannot pass BBB even in meningitis (and cannot enter the eye).
III. Concentrated in renal cortex and in endolymph of inner ear.
IV. Pass placental barrier and may induce fetal deafness.
c) Fate:
Aminoglycosides are excreted unchanged in urine mainly by glomerular filtration.
I. Action on bacteria:
Bactericidal (but bacteriostatic on T.B. bacilli).
II. Mechanism of action:
1) Aminoglycosides diffuse into bacterial cell by an active oxygen-dependent
transport.
2) They bind to 30 S ribosomal subunit leading to inhibition of the codon-
anticodon recognition (interfere with the initiation complex of peptide
formation) and misreading of m-RNA with consequent inhibition of protein
synthesis.
N.B.:
1) Aminoglycosides are more active in alkaline medium.
2) Aminoglycosides are inactive against anaerobes (why?).
3) β-Lactam antibiotics enhance diffusion of aminoglycosides.
e) Spectrum:
1) Gram negative bacilli including Pseudomonas.
2) Some Gram positive cocci especially Staph.aureus and Strept.viridans and fecalis
(cauing endocarditis).
3) Mycobacteria T.B.

f) Indications:
1) Endocarditis.
2) Meningitis.
3) Respiratory tract infections.
5) Septicemia.
6) T.B. by streptomycin (1st line) and kanamycin, viomycin, and amikacin (2nd line).
7) Gentamycin is used topically in wound and burn infection and to prevent catheter
infection.
8) GIT infections by neomycin and streptomycin orally.
9) Neomycin is used:
a) Orally: Treatment of GIT infection-Bowel sterilization before surgery and
endoscopy-Treatment of ammonia encephalopathy in hepatic insufficiency
(hepatic coma). It was used orally to decrease cholesterol absorption in
treatment of hyperlipidemia.
b) Topically on skin: treatment of wound infections.
c) Inhalation: treatment of respiratory tract infection.
g) Toxic effects:
I. Ototoxicity: aminoglycosides achieve high levels in endolymph and cause damage
of 8th cranial nerve leading to deafness and vertigo, especially if given frequently
for long periods and with other ototoxic drugs as loop diuretics (frusemide).
II. Nephrotoxicity: aminoglycosides are concentrated in renal cortex and may cause
renal impairment or acute tubular necrosis, especially if given frequently for long
periods and with other nephrotoxic drugs as cephalosporins.
III. Skeletal muscle weakness due to inhibition of acetylcholine release from somatic
nerves and decreased sensitivity of Nm-receptors (curare-like action). This was
particularly dangerous after intra-pleural and intra-peritoneal injection of
streptomycin in treatment of T.B. as it lead to respiratory paralysis.
IV. Neomycin is extremely toxic and is used locally (never used systemically) and may
cause contact dermatitis-when applied to skin-and diarrhea and malabsorption if
given orally.
Examples of Aminoglycosides:
Streptomycin. Gentamicin. Amikacin (used in gentamicin-resistant bacteria).
Tobramycin. Kanamycin. Viomycin.
Paromomycin (amoebicidal). Netilmicin.

h) Precautions to reduce toxicity:

I. Adjust the dose in patients with renal impairment.
II. Prolong the intervals between doses (40 mg. / 12 hours is less toxic than 20 mg. /
8 hours).
III. Avoid using other nephrotoxic drugs as cephalosporins.
IV. Avoid loop diuretics because they are ototoxic and also increase the level of
aminoglycosides in renal cortex.
V. Follow up by frequent kidney function tests and frequent audiogram in cases of
long duration of treatment with aminoglycosides.
VI. Never use aminoglycosides in pregnancy.
Give Reason:
Aminoglycosides are usually combined with extended spectrum penicillins in treatment of
serious infections but should not be mixed in the same syringe or container?
B- Macrolides:
1. Erythromycin:
a) Source: natural.
I. Absorbed orally but is destroyed by gastric acidity (acid-sensitive) and is
given"enteric coated" with estolate ester. It may be given IV.
II. Poor penetration of BBB into CSF.
III. Passes placental barrier and is safe in pregnancy.
IV. Extensively metabolized by the liver and metabolites are excreted in urine and
bile.
I. Mechanism of action:
Macrolides bind reversibly to 50 S ribosomal subunits and inhibit transloca on
of amino acids, thus inhibiting protein synthesis.
They are more active in alkaline medium.
II. Action on bacteria:
Macrolides are bacteriostatic or bactericidal according to their concentration.
d) Spectrum:
I. Gram positive bacteria; both cocci and bacilli.
II. Gram negative cocci and some Gram negative bacilli as H.influenza and
Legionella.
III. Mycoplasma pneumoniae, Chlamydia, and Spirochaetes.

e) Indications:
I. Treatment of Respiratory tract infections: diphtheria, atypical pneumonia
caused by Mycoplasma and Legionella especially in pregnant and neonates
(tetracyclines are contraindicated).
II. Treatment of Chlamydia infections: pneumonia, uro-genital, and eye infections.
III. Treatment of sexually transmitted diseases: gonorrhea and syphilis.
IV. Alternative to penicillin in penicillin-allergic patients as in cases of prophylaxis
in rheumatic fever and endocarditis.
V. Topically in treatment of Acne vulgaris.
VI. Erythromycin acts as "prokinetic" in cases of diabetic gastroparesis by
stimulating "motilin" receptors in GIT.
f) Adverse effects:
I. GIT disturbances: anorexia, nausea, vomiting, epigastric pain, colics and
diarrhea.
II. Cholestatic hepatitis (jaundice) caused by estolate ester.
III. Allergic reactions: fever, rash, and eosinophilia.
IV. Drug interactions: Erythromycin (and Clarithromycin but not Azithromycin)
inhibit CYP 450 3A4 and decreases clearance of theophylline and warfarin and
may cause toxicity by these drugs.
g) Contraindications: liver diseases.
2. Clarithromycin:
a) As erythromycin but more active against atypical bacteria.
b) Better oral absorption and less gut upset.
c) Used in peptic ulcer to eradicate H.pylori.
d) HME inhibitor (as erythromycin).
3. Azithromycin (Zithromax®):
a) As erythromycin but more active on mycobacteria and Chlamydia and less active
on Staph. and Strept.
b) High tissue concentration (exceeding blood concentration) except CSF then slowly
released from the ssues leading to long t 1/2 and long dura on of ac on, and is
given once daily.
c) Not HME inhibitor.

C- Ketolides:Telithromycin
a) Semi-synthetic macrolide.
b) Given orally once daily due to high tissue concentration.
c) Active against Gram positive, Gram negative, and Chlamydia.
d) HME inhibitor (inhibits CYP 450 3A4 as erythromycin and clarithromycin).
e) Useful in cases of bacterial resistance to macrolides.
D- Lincocamines:
Clindamycin and Lincomycin
a) Pharmacokinetics:
I. Absorbed orally and can be given IV.
II. Highly bound to plasma proteins.
III. Poor penetration into CSF but highly concentrated in teeth and bone.
IV. Metabolized by the liver and excreted in urine and bile.
b) Mechanism of action:as macrolides.
c) Spectrum: as macrolides but much more active against anaerobes except Clostridium
difficile.
d) indications:
1) Treatment of anaerobic infections as dental infections (usually with
metronidazole).
2) Prophylaxis against endocaditis.
3) Tretment of intra-abdominal and female genital infections in combination with
aminoglycosides or cephalosporins.
4) Combined with primaquine (anti-malarial) in treatment of Pneumocystis carinii
pneumonia as alternative to Co-trimoxazole (drug of choice).
e) Adverse effects:
1) Superinfection by Clostridium difficile leading to serious and may be fatal
pseudomembranous colitis treated by oral vancomycin and metronidazole.
2) GIT disturbances.
3) Impaired liver functions.
4) Allergy: skin rash.
5) Neutropenia.

V- Broad Spectrum Antibiotics:

1) Chloramphenicol:
a) Source: natural.
I. Well absorbed orally, and may be given by injection and topically.
II. Passes BBB and attains high level in CSF.
III. Fate: mainly metabolized by the liver by conjugation with glucuronic acid,
excreted in urine mainly as metabolite.
I. Action on bacteria: Bacteriostatic.
Binds to 50 S ribosomal subunit and inhibits pep dyl transferase leading to
inhibition of protein synthesis.
d) Spectrum: Gram positive, Gram negative, Rickettsia, and anaerobes.
e) Indications:
II. Typhoid fever (in acute stage and not in carriers).
III. Meningitis (especially H.influenza).
IV. Rickettsial infections as Typhus.
V. Anaerobic infections (as brain abscess).
VI. Topically in eye and ear infections.
f) Adverse effects:
I. Bone marrow depression (blood dyscrasias): usually in the form of
agranulocytosis, and is either:
1. Toxic = Dose-Dependent: chloramphenicol inhibits mitochondrial protein
synthesis in bone marrow. It is usually reversible after stoppage of the drug.
2. Idiosyncratic = Dose-Independent: is irreversible and may be fatal.
II. Gray Baby Syndrome: occurs in newborn and especially if premature due to
failure to conjugate chloramphenicol. It is characterized by ash color of the skin,
vomiting, hypothermia, hypotension, collapse and shock (treated by HME
inducers as phenobarbitone).
III. Diarrhea, superinfection, and vitamin K deficiency.
IV. HME inhibition and decreases clearance of theophylline, warfarin, phenytoin, and
oral hypoglycemic drugs as tolbutamide.

2) Tetracyclines:
a) Source: natural and semisynthetic.
I. Absorption:
1) Tetracycline-Chlortetracycline-Oxytetracycline are incompletely absorbed
orally especially in the presence of food.
2) Doxycycline is completely absorbed orally and not affected by food.
3) All tetracyclines are "chelated" with Ca2+ (in milk and other dairy products and
in some antacids), Al3+ (in most antacids), Mg2+ (in most antacids), and iron (in
oral iron preparations used in treatment of iron deficiency anemia). This
decreases absorption and oral bioavailability of tetracyclines (and iron).
II. Distribution:
1) Poor penetration of BBB except Minocycline which may reach an adequate CSF
concentration and was used in eradication of meningococci in meningococcal
carriers (Rifampicin is better).
2) Pass placental barrier and are teratogenic.
3) Tetracyclines are concentrated bone and teeth, and in calcified tumors, where
they are precipitated with Ca2+. Tetracyclines are also concentrated in liver and
kidney.
III. Fate:
1) All tetracyclines are excreted mainly unchanged in urine (useful in treatment of
UTIs but the dose should be adjusted in renal impairment) except Doxycycline
which is eliminated in bile and can be used in renal impairment without dose
adjustment. Doxycycline undergoes entero-hepatic circulation and is given
once daily.
2) All tetracyclines are excreted in breast milk and are accordingly contraindicated
during lactation.
I. Action on bacteria: Bacteriostatic.
II. Mechanism of action: Bind to 30 S ribosomal subunit and inhibit protein synthesis
by inhibition of aminoacyl t-RNA from reaching
III. m-RNA –ribosomal complex.
d) Spectrum:
Tetracyclines have the broadest spectrum but are not commonly used because of
serious toxic effects.
I. Gram positive and Gram negative bacteria (very active against vibrio cholera).
II. Chlamydia, Mycoplasma, and Rickettsia.
III. Spirochaetes (Treponema pallidum).
IV. Amoeba (luminal amoebicidal).

e) Indications:
I. Respiratory tract infections: especially if caused by Chlamydia and Mycoplasma
(Atypical Pneumonia) but are contraindicated in newborn and pregnant females
II. Urinary tract infections (except doxycyline).
III. GIT infections as Cholera and eradication of H.pylori in peptic ulcer and amoebic
dysentery.
IV. Minocycline was used in eradication of meningococci in meningococcal carriers
but is now replaced by rifampicin.
V. Demiclocycline decreases renal action of ADH and is used in patients with
excessive ADH release known as Syndrome of Inappropriate ADH (SIADH).
f) Toxicity:
1. GIT disturbances: anorexia, nausea, vomiting, hyperacidity, esophagitis,
esophageal ulcerations and bleeding.
2. Diarrhea, superinfection (by candida, Staph. or Clostridium difficile), and vitamin K
and B deficiency especially with poorly absorbrd tetracyclines.
3. Teratogenicity.
4. Chelation with Ca2+ in bone and teeth leading to defective growth (enamel
hypoplasia), yellow-brown discoloration, and dental caries.
5. Allergy: rash and photosensitivity.
6. Hepatotoxicity and pancreatic toxicity is more common in pregnant
7. Fanconi syndrome: the use of outdated (expired) tetracyclines causes
nephrotoxicity (glucosuria, aminoaciduria, polyuria, proteinuria).
8. Minocycline causes CNS disturbances as dizziness and vertigo.
9. Demiclocycline causes nephrogenic diabetes insipidus.
10.Thrombophlebitis.

Inhibitors of Nucleic Acid Synthesis

1. Quinolones:
a) Source: all quinolones are synthetic.
b) Chemistry: all quinolones are 4-fluorinated except Nalidixic acid and Cinoxacin.
I. Absorption:
Quinolones are well absorbed except in the presence of antacids containing Al3+ and
Mg2+ salts.
II. Distribution:
1) Bound to plasma proteins.
2) Poor passage across BBB and thus they have low CSF levels.
3) Pass placental barrier and are contraindicated in pregnancy as they may cause
fetal arthropathy (see adverse effects).
4) Highly concentrated in prostate.
III. Fate:
1) Nalidixic acid and cinoxacin have very low blood levels and very high urine levels
because they are rapidly excreted unchanged in urine.
2) Fluoroquinolones are partly metabolized by the liver and mainly excreted
unchanged in urine, and are excreted in breast milk.
1) Action on bacteria: bactericidal.
2) Mechanism of action: inhibit DNA synthesis by inhibition of DNA gyrase
(Topoisomerase II) which is responsible for supercoiling of bacterial DNA.
e) Spectrum:
1) Nalidixic acid and cinoxacin are active against Gram negative bacteria causing
urinary tract infections as Pseudomonas and Hemophilus.
2) Old fluoroquinolones are active against Gram negative cocci (gonococci), Gram
negative bacilli (Pseudomona, Hemophilus, Salmonella, Shigella, E.coli, Proteus),
Mcoplasma, Chlamydia, Mycobacteria T.B., some Gram positive cocci as Staph.
but are inactive against Strept. and anaerobes. Examples: Ofloxacin Norfloxacin
Ciprofloxacin.
3) New fluoroquinolones have similar spectrum to old fluoroquinolones and are
more active against Gram positive including Strept. and MRSA, and are active
against anaerobes.

4) Examples: Levofloxacin Gatifloxacin Moxifloxacin Sparfloxacin (may cause

phototoxicity and cardiac arrhythmias as prolonged QT)
5) Trovafloxacin (hepatotoxic).
f) Indications:
2) Prostatitis.
3) Gonorrhea.
4) GIT infections as Typhoid fever and bacillary dysentery.
5) Respiratory tract infections including Mycoplasma pneumonia.
6) Chlamydial infections.
7) Multi-drug resistant T.B.
8) Pyogenic infections of skin, soft tissues, and bones.
g) Adverse effects:
1) Arthropathy (damage of growing articular cartilage of bones), tendonitis, and joint
swelling.
2) Allergy: skin rash and photosensitivity.
3) Gut upsets: nausea, vomiting, and abdominal pain.
4) CNS disturbances: headache, dizziness, and seizures which may occur if given with
NSAIDs.
5) Hepatotoxicity: with trovafloxacin.
6) Phototoxicity and prolonged QT interval in ECG: with sparfloxacin.
h) Drug interactions:
1) HME inhibition: decreases clearance of theophylline.
2) Seizures in some patients treated with NSAIDs.
i) Contraindications:
1) Pregnancy and lactation.
2) Pre-pubertal children.
3) Allergy.
4) Epilepsy.

Interference with metabolic pathway:

1. Sulphonamides:
b) Chemistry: derivatives of Para-Amino Benzene Sulphonamide (Sulphanilamide) which is
structurally similar to Para Amino Benzoic Acid (PABA).
Different sulphonamides are obtained by substitution at N1 and N4.
I. Absorption:
a) Some sulphonamides are poorly absorbed and are used for local GIT diseases, e.g.
Sulphaguanidine used in bacillary dysentery, and Sulphasalazine (Salazopyrine)
used as anti-inflammatory in treatment of ulcerative colitis.
b) Other sulphonamides are well absorbed orally and used in treatment of systemic
infections (see later).
II. Distribution:
a) Sulphonamides are highly bound to plasma proteins leading to serious drug
interactions, and may lead to displacement of bilirubin causing
hyperbilirubinemia, jaundice, and Kernicterus if used before labor and in
neonates.
b) They pass BBB.
c) They pass placental barrier and may lead to hyperbilirubinemia and
"Kernicterus" if given in late pregnancy.
III. Fate:
Sulphonamides used for treatment of systemic infections are partly excreted
unchanged in urine (are used in treatment of UTIs, need dose adjustment in renal
impairment, and are more soluble and more active in alkaline urine), and partly
metabolized in the liver by acetylation. The acetylated metabolite is inactive and
insoluble in acidic urine leading to "crystalluria". This is avoided by proper hydration
and by urine alkalinizers as NaHCO3.
d) Classification on Sulphonamides:
Sulphonamides are classified according to their pharmacokinetic properties into:
I. Poorly Absorbed Sulphonamides:
Sulphaguanidine, Sulphathalidine,Sulphasuxidine: treat bacillary dysentery.
Sulphasalazine (Salazopyrine): Anti-inflammatory in Ulcerative colitis.
II. Rapidly (Completely) Absorbed Sulphonamides:

They are subdivided according to rate of excre on and t 1/2 into:
a) Short Acting (Rapidly excreted): are given every 6 hours and include:Sulphadiazine
and Sulphisoxazole.
b) Intermediate Acting: are given every 12 hours and include:
c) Sulphamethoxazole.

d) Long Acting: are given every 24 hours and include:

e) Sulphadoxine and Sulphamethoxypyridazine.
N.B.: Short acting are bound to plasma proteins, intermediate acting are more bound, and
long acting are the most bound.
III. Sulphonamides for Topical Use:
Silver Sulphadiazine: used as ointment for treatment of burn infections.
Sulphacetamide: used as eye drops in treatment of eye infections.
Mafenide: used as ointment in treatment of wound infections but is ineffective in the
presence of pus which contains high level of PABA which antagonizes sulphonamides.
e) Pharmacodynamics:
I. Action on bacteria: bacteriostatic.
Sulphonamides compete with bacterial PABA (due to structural similarity) for
bacterial dihydropteroate synthetase leading to inhibition of folic acid synthesis.
dihydropteroate dihydrofolate
PABA----------------------------► dihydrofolic acid ----------------------►tetrahydrofolic acid
synthetase reductase
Inhibited by sulphonamides inhibited by:

-Trimethoprim.
-Proguanil.
- Pyrimethamine.
N.B. human cells get preformed dihydrofolic acid in diet which is converted into "active"
tetrahydrofolic acid (folinic acid) necessary for synthesis of purines which are in turn
required for DNA and RNA synthesis.
III. Synergism: by drugs that inhibit dihydrofolate reductase: trimethoprim,

pyrimethamine and proguanil (anti-malarial drugs).
IV. Antagonism: by PABA, Pus (has high content of PABA), and drugs that release PABA
as Procaine.

f) Spectrum:
1. Sulphonamides are active mainly against Gram positive bacteria.
2. They are active against some Gram negative bacteria as Hemophilus and E.coli.
3. Spectrum also involves: Spirochaetes (Treponema), Chlamydia, and Nocardia.
4. Combination with pyrimethamine → ac vity against Toxoplasma and malaria.
g) Indications:
1. Urinary tract infections.
2. GIT infections as bacillary dysentery (use poorly absorbed sulphonamides as
sulphaguanidine).
3. Ulcerative colitis by sulphasalazine.
4. Respiratory tract infections.
5. Treatment and prophylaxis of meningococcal meningitis (by sulphadiazine); but
rifampicin is considered the drug of choice in prophylaxis.
6. Prophylaxis against streptococcal infections in rheumatic fever as an alternative to
penicillin as in penicillin allergic patients.
7. Locally in treatment of eye infections by sulphacetamide.
8. Locally for treatment of wound and burn infections by mafenide and silver
sulphadiazine.
9. Treatment of Toxoplasmosis, malaria, chlamydial infections, and nocardiosis.
h) Adverse effects:
1. Hypersensitivity reactions: rash, photosensitivity, urticaria, angioedema, erythema
(Stevens-Johnson syndrome), fever, anaphylaxis.
2. There is cross allergy between sulphonamides and thiazides and some loop diuretics
as frusemide and sulphonylureas (oral hypoglycemics).
3. Blood dyscrasias: Bone marrow depression (leucopenia or thrombocytopenia) and
idiosyncratic hemolytic anemia in patients with favism due to G-6-PD deficiency.
4. Crystalluria due to precipitation of acetylated metabolites in acidic urine causing
renal colics, hematuria, and anuria. It is prevented by proper hydration and
alkalinization of urine by NaHCO3, or by using a mixture of soluble sulphonamides.
5. GIT disturbances: nausea, vomiting, diarrhea, and superinfection.
6. Hyperbilirubinemia, jaundice, and kernicterus in newborn.
7. Hepatotoxicity.
i) Drug interactions:
Sulphonamides (especially long acting) displace other drugs as oral anticoagulants, oral
sulphonylureas hypoglycemics, and digitoxin from plasma protein binding sites and may
cause serious toxic effects of such drugs.

j) Contraindications:
1. Allergy to sulphonamides.
2. Favism.
3. Newborn and pregnancy especially last 2 weeks.
II- Trimethoprim:
I. Absorbed orally.
II. Bound to plasma proteins.
III. Concentrated in prostate and vaginal fluid.
IV. Excreted in urine and is intermediate acting.
I. Action on bacteria: bacteriostatic.
Inhibits dihydrofolate reductase and inhibits synthesis of folinic acid with
consequent inhibition of purines, DNA, and RNA synthesis.
d) Spectrum:
I. Gram negative cocci (Neisseria gonorrhea and meningitides) and bacilli (E.coli,
Hemophilus, Proteus, Salmonella, Shigella, Legionella)
II. Pneumocystis carinii (causing fatal pneumonia in AIDS patients).
e) Indications:
I. Urinary tract infections.
II. Respiratory tract infections.
III. GIT infections as typhoid fever.
IV. Gonorrhea.
V. Pneumocystis carinii pneumonia.
f) Adverse effects:
Megaloblastic anemia due to folinic acid deficiency.

III-Co-Trimoxazole (Sutrim®):
a) Combination of Sulphamethoxazole (intermediate sulphonamide) and Trimethoprim
in a ra o of 5 : 1 (400 mg. sulpha + 80 mg. trimethoprim in adults, and 100 mg.
sulpha + 20 mg. trimethoprim in children. Given every 12 hours).
b) Action on bacteria: bactericidal.
c) Mechanism of action:
Sulphamethoxazole inhibits dihydropteroate synthetase and trimethoprim inhibits
dihydrofolate reductase; leading to sequential block of the enzymes responsible for
synthesis of folinic acid.
d) Spectrum:
I. Sulphamethoxazole is active mainly on Gram positive, Chlamydia, Spirochaetes,
and Nocardia.
II. Trimethoprim is active mainly on Gram negative bacteria and Pneumocystis
carinii.
Accordingly Co-trimoxazole acts on all the previous microorganisms.
e) Indications:
I. Drug of choice in Pneumocystis carinii in AIDS.
II. Typhoid fever (both acute stage and carriers).
III. Respiratory tract infections.
IV. Urinary tract infections.
V. Gonorrhea.
VI. Prostatitis.
VII. Chlamydial infections.
VIII. Treatment of Nocardiosis.
f) Adverse effects:
As sulphonamides but less toxic + megaloblastic anemia.
g) Benefits of Combination:
I. Achieves synergism: each drug alone is bacteriostatic but co-trimoxazole is
bactericidal.
II. Broadens the spectrum.
III. Reduces toxicity caused by each drug alone.
IV. Reduces the incidence of bacterial resistance.
V. Treatment of mixed infections.
Treatment of Typhoid Fever:
Acute Stage:Co-Trimoxazole, Ciprofloxacin, Ceftriaxone and Cefoperazone (third
generation cephalosporins excreted in bile)are the first choice drugs. Ampicillin and
Amoxycillin are the second choice drugs. Chloramphenicol is the third choice due to
toxicity and bacterial resistance.
Carrier Stage: Ampicillin, Amoxycillin, or Co-trimoxazole.

Special Chemotherapy
I. Anti-Tuberculous Drugs
Drugs used for chemotherapy against T.B. are classified into 2 lines:
a) First Line Drugs: are more effective and less toxic than second line drugs and include:
1) Isoniazid (Isonicotinic acid hydrazide = INH).
2) Rifampicin.
3) Ethambutol.
4) Pyrazinamide.
5) Streptomycin.
b) Second Line Drugs: are less effective and more toxic than the first line drugs and are
used as alternative to first line drugs especially in case of development of bacterial
resistance, they include:
1) Para amino salicylic acid (PAS).
2) Ethionamide.
3) Cycloserine.
4) Aminoglycosides: viomycin, kanamycin, amikacin, and capreomycin.
5) Fluoroquinolones as ciprofloxacin or ofloxacin in "multi-drug resistant T.B".
6) Clofazimine.
First Line Drugs:

1) Rifampicin:
A. Pharmacokinetics:
I. Absorption:
Well absorbed orally but absorption is affected by food, so it is given on empty
stomach (before breakfast).
II. Distribution:
Distributed to all tissues including CSF.
III. Fate:
Partially metabolized by the liver and partially excreted in: bile (undergoes entero-
hepatic circulation and has long duration so it is given once daily) – urine – sweat
– saliva – tears (causes orange-red discoloration of all these fluids).
B. Pharmacodynamics:
I. Action on Mycobacteria: bactericidal (tuberculocidal). It acts both intra- and extra-
cellular.
II. Mechanism of action: inhibits DNA-dependent RNA polymerase leading to
inhibition of RNA synthesis.

C. Spectrum:
I. Mycobacteria T.B.
II. Mycobacteria leprae.
III. Gram negative bactertia as meningococci and H.influenza.
IV. Gram positive bacteria as Staph.
V. Pox viruses.
D. Indications:
I. T.B. (combined with isoniazid ± pyrazinamide or ethambutol).
II. Leprosy.
III. Chemoprophylaxis against meningococcal meningitis; rifampicin is the drug of
choice and has replaced sulphonamides.
IV. To eradicate memingococci in carriers, rifampicin has replaced minocycline (a
tetracycline).
V. Treatment of endocarditis by Staph., in combination with a β-lactam antibiotic or
vancomycin.
E. Adverse effects:
1. Cholestatic hepatitis and jaundice.
2. Flu-like syndrome at the start of treatment.
3. CNS disturbances: headache, confusion, and ataxia.
5. Allergy: fever, rash, and blood dyscrasias (thrombocytopenia).
6. Orange-red discoloration of urine.
7. Drug interaction: rifampicin is a hepatic microsomal enzyme inducer and thus
increases clearance of theophylline, warfarin, oral hypoglycemics, digitoxin, and
oral contraceptives.
2) Isoniazid (I.N.H.):
I. Absorption:
Well absorbed orally but Al3+-containing antacids decrease its absorption.
II. Distribution:
Distributed to all tissues including CSF.
III. Fate:
Mainly metabolized in the liver by acetylation which is genetically determined;
patients are either slow or fast acetylators. Metabolites are excreted in urine.
I. Action on Mycobacteria: bacteriostatic in resting bacteria (stationery phase) and
bactericidal in active rapidly dividing bacteria. It acts both intra- and extra-cellular.
II. Mechanism of action: inhibits mycolic acid synthesis leading to inhibition of cell
wall synthesis.

c) Spectrum: Mycobacteria T.B. only.
d) Indications: treatment of T.B. (in combination with rifampicin ± pyrazinamide or

ethambutol).
e) Adverse effects:
1. Peripheral neuritis especially in slow acetylators due to competition between
vitamin B6 (pyridoxine) and INH-due to structural similarity- which impairs
myelination of peripheral nerves. That is why B6 should be prescribed
prophylactically with INH.
2. Hepatitis and hepatotoxicity especially in fast acetylators.
3. Hemolysis is patients with G-6-PD deficiency (idiosyncracy).
4. Allergy: rash, fever, blood dyscrasias.
5. Drug interaction: INH inhibits metabolism of phenytoin and may lead to toxicity.
3) Ethambutol:
Absorbed orally – distributed to all tissues including CSF – excreted in urine and
decreases uric acid excretion.
1. Action on Mycobacteria: bacteriostatic.
2. Mechanism of action: unknown.
c) Toxicity:
1. Optic neuritis which decreases visual acuity and failure to discriminate between
red and green.
2. Hyperuricemia and may precipitate gouty attacks.
4) Pyrazinamide:
Absorbed orally – distributed to all tissues including CSF – extensively metabolized by
the liver and metabolite is excreted in urine and decreases uric acid excretion
1. Action on Mycobacteria: bactericidal.
2. Mechanism of action: unknown.
c) Toxicity:
1. Hepatotoxicity.
2. Hyperuricemia and may precipitate gouty attacks.

5) Streptomycin: (see Aminoglycosides).

N.B.: all first line drugs –except streptomycin- may cause liver impairment and follow up
by liver function tests is required.
Second Line Drugs:

1) Para Amino Salicylic acid (PAS):
Absorbed orally – metabolized by acetylation- metabolite is excreted in urine and is
insoluble in acidic urine causing crystalluria (as sulphonamides).
1. Action on Mycobacteria: bacteriostatic.
2. Mechanism of action:competes with PABA and inhibits folic acid synthesis (as
sulphonamides).
c) Toxicity:
1. Hepatotoxicity.
2. Allergy.
3. Gut upsets.
4. Crystalluria (prevented by proper hydration and alkalinization of urine by
NaHCO3).
2) Ethionamide:
a) Chemically related to INH.
b) Given orally and passes into CSF.
c) Toxicity: peripheral neuropathy –optic neuritis- allergy –gut upsets.
3) Aminoglycosides: Kanamycin- Capreomycin – Viomycin – Amikacin.

a) Given IM.
b) Toxicity: Ototoxic and nephrotoxic.
4) Cycloserine:
a) Inhibits cell wall synthesis.
b) Toxicity: CNS manifeststions as headache, drowsiness, vertigo, seizures, and toxic
psychosis.
5) Fluoroquinolones: Ciprofloxacin- Ofloxacin

Used in multi-drug resistant T.B. (see Quinolones).
6) Clofazimine:
Inhibits DNA.
Other actions: Anti-leprotic and Anti-inflammatory.

Regimens of treatment of T.B.:

1) Rifampicin + INH + Pyrazinamide or Ethambutol for 6 months.
2) Rifampicin + INH for 9 months.
Treatment of Leprosy:
1) Rifampicin.
2) Clofazimine.
3) Sulphones as Dapsone: compete with PABA (as sulphonamides).
4) All are given orally.
II. Anti-Amoebic Drugs

Drugs used in treatment of amoebiasis are classified into:
a) Luminal Amoebicides: they kill cyst form and include:
1. Diloxanide furoate.
2. Paromomycin (aminoglycoside antibiotic).
3. Tetracyclines.
4. Halogenated hydroxyquinolines.
b) Tissue Amoebicides: they kill trophozoits causing intestinal and hepatic amoebiasis
and include:
1. Nitroimidazoles: Metronidazole and Tinidazole.
2. Chloroquine.
3. Emetine and dehydroemetine.
Metronidazole (Flagyl®):
 Absorption:
Absorbed orally and also given by IV infusion.
 Distribution:
1) Passes BBB and may cause serious CNS disturbances.
2) Passes placental barrier and induces teratogenicity.
3) Concentrated in vagina, seminal fluid, and saliva.
 Fate:
Metabolized by the liver and is excreted in breast milk.
1. Action on bacteria and protozoa: cidal (bactericidal and amoebicidal)
2. Mechanism of action:
Metronidazole is reduced inside bacteria and protozoa by ferrodoxin into an
active metabolite which binds to DNA and inhibits nucleic acid synthesis.

c) Spectrum:
1. Amoeba (tissue more than luminal).
2. Giardia.
3. Trichomonas vaginalis.
4. H.pylori.
5. Anaerobic bacteria including Clostridium difficile.
d) Indications:
1. Treatment of amoebiasis especially acute tissue amoebiasis (intestinal and
hepatic).
2. Treatment of giardiasis.
3. Treatment of uro-genital trichomoniasis in females and males.
4. Eradication of H.pylori in peptic ulcer.
5. Treatment of anaerobic infections as acute ulcerative gingivitis, peritonitis, female
genital tract infections, brain abscess, septic shock.
6. Treatment of pseudomembranous colitis caused by antibiotics as clindamycin,.
Metronidazole is usually given with oral vancomycin.
e) Adverse effects:
1. GIT disturbances: anorexia, nausea, vomiting, and metallic taste.
2. Allergic reactions.
3. Teratogenicity.
4. CNS disturbances: headache, dizziness, parasthesia. If vertigo occurs the drug
should be stopped to avoid CNS toxicity.
5. Intensification of moniliasis (candidiasis) which should be treated by nystatin.
6. Dark color of urine.
7. Disulfiram-like action in alcoholics.
f) Drug interactions:
HME inhibitor and decreases clearance of warfarin.

III. Anti-Malarial Drugs

Classification:
Anti-malarial drugs can be classified according to the chemical structure and according
to their action on malaria.
A-Chemical classification:
Anti-malarial drugs are classified chemically into:
1) Aminoquinolines: Chloroquine – Amodiaquine.
2) Aminoquinolines: Primaquine.
3) Pyrimethamine and Proguanil.
4) Quinine
5) Mefloquine.
B- Classification according to action:
Drugs Action in malaria Indication in malaria

Aminoquinolines: Blood shizonticidal (act on 1-Clinical cure.
Chloroquine and erythrocytic stage). 2-Suppressive prophylaxis.
Amodiaquine. 3-Radical cure in P.falciparum
and P.malariae (no relapse).
Aminoquinolines: 1-Primary tissue shizonticidal 1-Causal prophylaxis (unsafe).
Primaquine. (1ry exo-erythrocytic stage).
2-Secondary tissue
schizon cidal (2ry exo- 2-Radical cure and Anti-relapse
erythrocytic stage). in P.ovale and P.vivax.
3-Gametocidal.
3-Prevents transmission.
Proguanil and 1-Primary tissue 1-Causal prophylaxis.
Pyrimethamine. shizonticidal.
2-Blood shizonticidal (much 2-Suppressive prophylaxis.
weaker than chloroquine).
3-Sporonticidal. 3-Prevents transmission.
Quinine. Blood shizonticidal. As 4-Aminoquinolines.

Mefloquine
(for chloroquine-
resistant P.falciparum).

N.B.: there is no "true prophylaxis" against malaria because no drug can kill sporozoits
injected by bite of female Anopheles mosquito.
1-Chloroquine:
a) Chemistry: 4-aminoquinoline.
I. Absorbed orally.
II. Passes BBB and cause CNS disturbances.
III. Passes placental barrier and is teratogenic.
Concentrated in liver, RBCs, retina, kidney, and spleen.
Excreted in urine, excretion is enhanced by acidification of urine.
Binds to and inhibits synthesis of DNA and RNA.
1) Anti-malarial: blood shizonticidal.
2) Antiamoebic.
3) Anti-giardiasis.
4) Anti-inflammatory.
1. Malaria: clinical cure – suppressive prophylaxis – radical cure in P.falciparum and
malariae (no secondary tissue shizont and accordingly no relapse).
2. Treatment of hepatic amoebiasis.
3. Treatment of giardiasis.
4. Anti-inflammatory in RA and SLE (given in large doses and for long periods).
e) Adverse effects:
1. GIT upsets.
2. Blood dyscrasias (bone marrow depression).
3. Teratogenic.
4. Retinopathy: blurred vision, retinal vasoconstriction, and macular degeneration.
5. Skin manifestations: eruption, dermatitis, alopecia, graying of hair, and pruritus.
6. CNS disturbances: headache, peripheral neuritis.
7. (Adverse effects are more common in patients treated with chloroquine in cases
of RA and SLE).
f) Contraindications:
1. Pregnancy.
2. Psoriasis.
3. Porphyria.
4. With gold salts (used in RA) and phenylbutazone (NSAIDs also used in RA) to avoid
severe dermatitis.

2- Primaquine:
a) Chemistry: 8-Aminoquinoline.
Absorbed orally – Metabolized by the liver into 6-hydroxy derivative (active
metabolite) and then into quinonimine which causes hemolysis in G-6-PD deficiency.
 Mechanism of action: unknown.
 Actions: Antimalarial by: primary tissue shizonticidal – secondary tissue
shizonticidal (in P. ovale and vivax) – gametocidal.
I. Causal prophylaxis of malaria (unsafe).
II. Radical cure and anti-relapse in P. ovale and vivax.
III. Prevention of spread by gametocidal action.
IV. Combined with clindamycin as an alternative to co-trimoxazole in treatment of
pneumocystis carinii in AIDS.
N.B.: primaquine is not used in treatment of acute malarial attacks because it is not blood
shizonticidal.
e) Adverse effects:
1. GIT upsets.
2. Blood dyscrasiasis: Methemoglobinemia- hemolytic anemia in favism (G-6-PD
deficiency).
N.B.: Toxicity of primaquine increases if combined with proguanil.
3- Proguanil and Pyrimethamine:

a) Pharmacodynamics:
 Mechanism of action: inhibit dihydrofolate reductase leading to inhibition of
folinic acid synthesis.
 Actions:
1) Primary tissue shizonticidal.
2) Sporontocidal: inhibits sexual cycle inside mosquito.
3) Blood shizon cidal (much less potent than 4-aminoquinolines and act before
rupture of RBCs).
b) Therapeutic uses:
1) Causal prophylaxis.
2) Prevention of spread.
3) Suppressive prophylaxis.
4) (Pyrimethamine + sulphdoxine = Fansidar).
5) Pyrimethamine + sulphdiazine in treatment of toxoplasmosis.

c) Adverse effects:
2. Blood dyscrasias: megaloblastic anemia – granulocytopenia.
4- Quinine:
a) Plant origin: from cinchona bark (as quinidine).
b) Blood shizonticidal used in clinical cure in chloroquine-resistant malaria.
c) Adverse effects: Cinchonism (headache, nausea and vomiting, blurred vision, and
tinnitus) – Gut upset – Blood dyscrasias as hemolysis – Abortion due to oxytocic
action.
5- Mefloquine:
Blood shizonticidal – used for suppressive prophylaxis and clinical cure in chloroquine-
resistant P. falciparum.
IV. Anti-Bilharzial Drugs :

Praziquantel Oxamniquine Metrifonate
Mechanism of Increases Ca+ influx Inhibit DNA in male Irrevesible anti-
action: into worm leading to worm leading to cholinesterase
severe contraction and hepatic shift and (organophosphorou
spastic paralysis. death. Female s compound) leading
worms fail to lay to paralysis of the
eggs. worm.
Indications: 1) S.hematobium. S.mansoni only. S. hematobium only.
2) S.mansoni.
3) Taeniasis.
4) Hymenoepis nana.
5) Heterophes.
Adverse effects: 1) Abdominal pain, 1) Convulsions and 1) Colics and
diarrhea,nausea, drowsiness. diarrhea.
anorexia, and 2) Orange-red 2) Vertigo.
vomiting. discoloration of 3) Increases action
2) Headache and urine and of
dizziness. proteinuria. succinylcholine.
3) Fever, pruritus 3) Low grade fever.
arthralgia, and
myalgia (due to
release of dead
worm contents).
Contraindications Pregnancy. Pregnancy. Pregnancy.
Epilepsy.

Other Anthelmintic Drugs:

1) Mebendazole and 2) Albendazole
They decrease glucose uptake and inhibit microtubular synthesis.
3) Pyrantel pamoate: depolarizing neuro-muscular blocker.
a) Used in round worms-pinworms-hookworms-taeniasis-hydatid disease-
whipworms.
b) They are contraindicated in pregnancy.
c) They are known as Broad-spectrum anthelmintics.
4) Levamisole:
a) Anthelmintic against round worm by depolarizing neuromuscular blocking action.
b) Immunostimulant.
V. Anti-Fungal Drugs
I. Polyene Antibiotics:
1-Amphotericin B:
a) Chemistry: Polyene antibiotic.
1. Not absorbed orally, given by I.V. infusion, intra-thecal, and topical on eye,
nose, intra-articular, and to irrigate the bladder.
2. Cannot pass BBB, so must be given intra-thecal in fungal meningitis.
3. Excreted in bile and urine.
 Action on fungus: Fungicidal.
 Mechanism of action: binds to ergosterol in the fungal cell membrane leading
to formation of channels and leakage of fungal cell content as electrolytes. This
causes death of fungal cells.
(Human cell membrane contains cholesterol not ergosterol).
Systemic fungal infections.
e) Adverse effects:
"Amphotericin has low therapeutic index" so start by small dose.
1. Allergic reactions and anaphlaxis.
2. Fever and chills.
3. Convulsions especially if given intra-thecal.
4. Hypokalemia and nephrotoxicity.
5. Bone marrow depression (aplastic anemia).
6. Thrombophlebitis.

2-Nystatin:
a) Chemistry: Polyene antibiotic.
Nystatin should never be given systemically because of its toxicity especially
nephrotoxicity. It is given orally (not absorbed) and locally on skin and vagina.
 Mechanism of action: as amphotericin.
Nystatin is the drug of choice in treatment of candidiasis (moniliasis) which is
common in D.M., due to steroids (oropharyngeal candidiasis in asthmatics treated by
inhaled steroids) and due to superinfection by antibiotics.
II. Azoles:
A- Azoles for Systemic Fungal Infections:
1) Ketoconazole (Nizoral®):
I. Absorbed from the stomach (in the presence of HCl), absorption is
impaired in the presence of food and by drugs that decrease gastric
acidity as antacids and anti-secretory drugs as cimetidine and
omeprazole.
II. Cannot pass BBB.
III. Extensively metabolized by the liver,metabolites are excreted in bile.
 Mechanism of action:Inhibits synthesis of cell membrane by inhibition of
ergosterol synthesis.
CYP 450
Lanosterol------------------►Ergosterol
N.B.: ketoconazole inhibits synthesis of testosterone and cortisol.
1. Systemic fungal infections but not in fungal meningitis.
2. Local fungal infections as hair dandruff (nizoral shampoo).

d) Adverse effects:
1. Hepatotoxicity.
2. Inhibits synthesis of testosterone leading to gynecomastia, impotence,
loss of libido, and infertility.
3. Allergy.
4. Gut upsets.
e) Drug interactions:
I. Ketoconazole is a hepatic microsomal enzyme inhibitor and reduces
clearance of theophylline and cyclosporine (immunosuppressive drug
used after renal transplantation).
II. Azoles as ketoconazole antagonize polyene antibiotics (how?).
III. Antacids, H2-blockers (as cimetidine), and Proton pump inhibitors (as
omeprazole) decrease oral bioavailability of ketoconazole.
2) Itraconazole: as ketoconazole but less adverse effects.
3) Fluconazole: as ketoconazole but:

a) Absorption is not affected by food or drugs.
b) Passes BBB and is the drug of choice in fungal meningitis in immunocompromised
patients.
c) Less hepatic toxicity.
d) No inhibition of testosterone synthesis and accordingly no gynecomastia or
infertility.
e) Not HME inhibitor.
B- Azoles for Topical Use:

1) Miconazole.
2) Clotrimazole.
They are never used systemically because of severe toxicity and are used only
for local fungal infections including moniliasis.

III. Flucytosine:
Absorbed orally – passes BBB – excreted in urine.
 Mechanism of action: converted inside fungal cell into 5-Flurouracil which
inhibits DNA synthesis.
Systemic fungal infections.
d) Adverse effects:
1. Bone marrow depression: thrombocytopenia and neutropenia.
2. Hepatotoxicity.
3. Gut upsets and severe entero-colitis.
e) Drug interaction:
Flucytosine + Azoles → synergism (both are fungicidal and act by different
mechanisms).
IV. Griseofulvin:
Absorbed orally especially in the presence of fats in diet – Concentrated in
keratinized tissues: hair and nails – Extensively metabolized by the liver.
1. Action on fungus: Fungistatic.
2. Mechanism of action: Binds to and inhibits microtubular protein of the
mitotic spindle and accordingly inhibits mitosis.
3. It inhibits infection of newly synthesized keratin of hair and nails but does
not affect already infected tissues which must be shed. This requires long
term therapy before cure.
Treatment of muco-cutaneous fungal infection of hair and nail
(dermatophytes).
d) Adverse effects:
1. Hepatotoxicity.
2. Teratogenicity.
3. Gut upsets.
4. Headache.
5. Precipitation of acute porphyria.

e) Contraindications:
1. Pregnancy.
2. Porphyria.
f) Drug interaction:
Griseofulvin is a HME inducer.
V. Terbenafine:
a) Action on fungus: Fungicidal.
b) Mechanism of action: inhibits ergosterol synthesis and thus inhibits cell
membrane synthesis (as azoles but by a different mechanism).
c) Therapeutic uses: Treatment of muco-cutaneous infections of hair and nails, it is
given orally and topically.
d) Adverse effects: Rash – Headache – Gut upsets (it is much safer than griseofulvin).
Anti-Viral Drugs
I. Inhibitors of DNA-Polymerase:
1) Acyclovir (Zovirax®):
a) Given orally, IV, and topical on eye and skin.
b) Drug of choice in herpes simplex infection (HSV) of: skin, cornea (keratitis),
genitals, and encephalitis. Used also in varicella-zoster viral infections (VCV). Not
effective against cytomegalovirus (CMV) and Epstein Barr virus (EBV).
c) Adverse effects: nephrotoxicity – gut upset- local irritation.
2) Vidarabin: used topically in HSV infections.
3) Idoxuridine: used only topically in HSV keratitis and never used systemically because
of its toxicity.
4) Gancyclovir: used in treatment of cytomegalovirus (CMV) infection of respiratory
system in immunocompromised patients.
5) Foscarnet: as gancyclovir but inhibits both DNA and RNA polymerases.
II. Reverse Transcriptase Inhibitors (RTIs):

a) They inhibit reverse transcriptase = RNA-dependent DNA polymerase in HIV.
b) They are used in treatment of AIDS.
c) They include:
d) Nucleoside RTIs as Zidovudine which causes bone marrow depression and viral
resistance has developed.
e) Non-Nucleoside RTIs as Nevirapine which is less toxic and less virus resistance.

III. HIV Protease Inhibitors:

a) They inhibit HIV protease enzyme necessary for synthesis of mature proteins of
virus coat.
b) They are combined with RTIs in treatment of AIDS.
c) Examples: Indinavir –Saquinavir –Ritonavir.
d) They may cause bone marrow depression (thrombocytopenia).
IV. Other Anti-viral drugs:

1) Amantadine:
a) Anti-viral: in prophylaxis of influenza A by inhibition of viral uncoating.
b) Anti-parkinsonian: by stimulation of release and inhibition of reuptake of
dopamine.
c) Ataxia and Ankle edema are characteristic adverse effects.
2) Rimantadine: as amantadine but has no CNS actions (not antiparkinsonian and no

ataxia).
3) Neuraminidase inhibitors: inhibit neuraminidase enzyme leading to inhibition of viral

assembly (clumping) - used in treatment of avian flu - examples include Oseltamivir
and Zanamivir.
4) Ribavirin: inhibits DNA and RNA viruses – used in treatment of hepatitis C virus
(HCV)–causes bone marrow depression, hepatotoxicity, and teratogenicity.
5) Rifampicin: inhibits pox virus by inhibition of assembly and release.
6) Interferons:
a) Polypeptides, so are not given orally, but must be given by injection.
b) Types: alpha, beta, and gamma interferons.
c) Inhibit m-RNA and viral protein synthesis.
d) Used with ribavirin in HCV.
e) Toxicity: bone marrow depression – alopecia – flu like syndrome- anorexia and
weight loss – confusion, ataxia, and seizures.

Pharmacology of GIT 2011/2012
Pharmacology of GIT
1- Peptic Ulcer (see Clinical Pharmacology).

2- Emetics and Anti-emetics.
3- Intestinal evacuants (Purgatives and treatment of constipation).
4- Treatment of diarrhea.
5- Miscellaneos.

Peptic Ulcer
Peptic ulcer is a damage of the mucosal lining of the stomach (gastric ulcer) or the
duodenum (duodenal ulcer) due to imbalance between:
Mucosal attacking (aggressive, offensive) agents: HCl, Pepsin, and H.pylori. and
Mucosal protective agents: Prostaglandins E2 and I2 which are "cytoprotective" by
decreasing HCl, increasing mucus, stimulating bicarbonate synthesis to neutralize HCl, and
increasing mucosal blood flow to help regeneration of the damaged mucosa.
Clinical picture:
1- Epigastric pain and tenderness.
2- Nausea and vomiting.
3- Complications: bleeding, perforation and peritonitis, pyloric obstruction.
Diagnosis:
By the clinical picture and investigations as: X-ray (barium meal) – abdominal
ultrasonography – and most importantly Endoscopy and biopsy (to diagnose H.pylori and to
exclude malignancy in gastric ulcers). H.pylori is also diagnosed by "ammonia breath test".
Treatment:
The aim of treatment of peptic ulcer is to restore the balance between the mucosal
offensive agents (HCl, pepsin, and H.pylori) and the mucosal protective agents (PGs mainly).
The goals of therapy are:
1- To promote healing of the ulcer (by antisecretory drugs mainly).
2- To prevent recurrence of the ulcer (by antisecretory drugs mainly).
3- To relieve pain (by antacids mainly).
4- To prevent complications.
Drugs used include:

1- Anti-secretory drugs: they reduce HCl secretion, and are used for "healing of the ulcer".
2- Anti-microbial drugs: to eradicate H.pylori.
3- Mucosal protective agents.
4- Antacids: to relieve pain and hyperacidity, i.e they are used only for "symptomatic
treatment" and not for healing of the ulcer.
N.B.: Corticosteroids (glucocorticoids) and NSAIDs –except paracetamol- cause peptic ulcer
by inhibition of PG synthesis; this is known as Iatrogenic ulcer and is best prevented and
treated by PG analogues as Misoprostol.

I- Anti-secretory Drugs:
These drugs reduce HCl secretion from the parietal cell of the stomach and are classified
according to the mechanism of action into:
1- H2-Antagonists: Cimetidine, Ranitidine, Nizatidine, Famotidine.
2- Proton Pump Inhibitors (PPIs): Omeprazole, Esomeprazole, Lansoprazole,
Pantoprazole, Rabeprazole.
3- Anti-Muscarinic Drugs (Anticholinergic drugs = Muscarinic antagonists): Pirenzepine,
Telenzepine (selective M1-blockers).
• They decrease HCl secretion and also decrease motility of GIT.
4- Prostaglandin Analogues: e.g. Misoprostol.
 It is a prostaglandin E1 analogue.
 It acts both as anti-secretory drug and mucosal protective agent.
 It is the drug of choice in prophylaxis and treatment of iatrogenic ulcers caused by
glucocorticoids and NSAIDs.
 It causes abdominal cramps and diarrhea.
 It is contraindicated in pregnancy because it is a powerful oxytocic and may lead to
abortion.
5- Gastrin Antagonists:
1- Gastrin receptor blockers: Proglumide.
2- Inhibitors of gastrin release: Somatostatin and Octreotide (synthetic somatostatin
analogue used also in treatment of bleeding esophageal varices).
1- H2-Antagonists:
Cimetidine – Ranitidine – Nizatidine – Famotidine.
Pharmacokinetics:
Absorption:
Absorbed orally and can also be given by IV injection (in upper GIT bleeding).
Distribution:
 Pass BBB and may cause CNS adverse effects especially in old age and in renal
impairment.
 Pass placental barrier and may cause teratogenicity.
 Bound to plasma proteins.
Fate:
Partly (1/3) metabolized by the liver and mainly excreted in urine unchanged (2/3) and as
metabolites. They are also excreted in breast milk.

Pharmacodynamics:
Competitive antagonists with histamine released from enterochromaffin-like cells (ECL) at
H2-receptors in gastric parietal cells.
1- Reduction of HCl secretion (basal, nocturnal, and stimulated by histamine, food, gastrin,
vagus, insulin, and drugs as methylxanthines and muscarinic agonists).
2- Reduction of both volume and H+ ion concentration of gastric juice.
3- Reduction in pepsin secretion (↓ daily amount not concentration).
4- Mild reduction of intrinsic factor without impairment of vitamin B12 absorption, so no
incidence of pernicious anemia.
5- No effect of gastric emptying or GIT motility (in contrast to antimuscarinic drugs).
6- Block the actions of histamine on the heart and blood vessels mediated by H2 receptors.
Therapeutic uses:
1- Peptic ulcer; both gastric and duodenal ulcers. They are given in a dose of 2 tablets / day
for 6-8 weeks until healing of the ulcer. This is followed by a maintenance dose of 1
tablet / day for 6 months to prevent recurrence of the ulcer.
2- Zollinger – Ellison syndrome: gastrin-secreting tumor of the pancreas accompanied with
peptic ulcers.
3- Gastro-Esophageal Reflux Disease (GERD) = Reflux esophagitis.
4- Prevention and treatment of upper GIT bleeding following severe trauma, burns, and
acute renal failure. They are given IV.
5- Treatment of stress ulcers and iatrogenic ulcers.
6- Treatment of hiatus hernia.
7- Other uses: combined with H1-blockers (antihistaminics) and NSAIDs in treatment of
symptoms of systemic mastocytosis – combined with antihistaminics in treatment of
resistant urticaria.
Adverse effects:
1- Recurrence of the ulcer in case of sudden stoppage of H2-antagonists.
2- Allergic reactions: skin rash and urticaria (itching).
3- GIT disturbances: diarrhea or constipation.
4- Blood dyscrasias: bone marrow depression as aplastic anemia, granulocytopenia
(agranulocytosis), and thrombocytopenia.
5- Liver: cholestatic hepatitis and jaundice, reduce hepatic blood flow, and HME inhibition
by cimetidine.
6- Kidney impairment leading to elevation of serum creatinine.

7- CNS disturbances: drowsiness, confusion, tremors, slurred speech, delirium and

hallucinations. They are more common in old age and in renal impairment (dose should
be adjusted according to renal function).
8- Teratogenicity and affect nursing babies.
9- Rarely CVS manifestations as bradycardia and hypotension.
10- Cimetidine causes sexual dysfunctions in males (gynecomastia, impotence, loss of libido
and decreased sperm count causing infertility), and in females (galactorrhea and breast
tenderness). This is probably due to hyperprolactinemia and due to anti-androgenic
effect in males.
11- Muscle pain.
Drug interactions:
1- Cimetidine is a hepatic microsomal enzyme inhibitor (inhibitor of CYP 450) and
decreases clearance of theophylline, warfarin, phenytoin, diazepam, digitoxin, and
propranolol and may cause serious adverse effects by these drugs.
2- Decreased gastric acidity may decrease the effect of clorazepate (prodrug activated by
gastric acid) and sucralfate (see later).
N.B.:
1- Ranitidine and nizatidine have the same potency, and are more potent and have longer
duration than cimetidine.
2- Nizatidine is not metabolized and has 100% oral bioavailability.
3- Famotidine is more potent than ranitidine and nizatidine.
4- Ranitidine, famotidine, and nizatidine have the following advantages over cimetidine:
 Stronger.
 Longer duration.
 No HME inhibition and accordingly no drug interactions.
 No passage across BBB and accordingly no CNS disturbances.
 No antiandrogenic effect and no hyperprolactinemia, and accordingly no sexual
disturbances in males or females.

2- Proton Pump Inhibitors (PPIs):

Omeprazole – Esomeprazole – Lansoprazole- Pantoprazole – Rabeprazole.
Chemistry: PPIs are basic drugs.

Pharmacokinetics:
Absorption:
Absorbed orally and are given in the form of "enteric-coated tablets" to prevent
degradation by HCl. Omeprazole and pantoprazole may be given IV.
Distribution:
 Pass BBB and may cause CNS disturbances.
 Highly bound to plasma proteins.
Fate:
Metabolized in the liver by CYP 450 and metabolites are excreted in urine, they have short
t1/2 but their action may last for 2-3 days (why?). Metabolites are excreted in urine.
Pharmacodynamics:
PPIs are concentrated in the acidic secretory canaliculi of parietal cell because they are
basic drugs, then they are activated (they are "prodrugs") into active metabolites which
cause "irreversible inhibition of H+/K+ ATPase", also known as the proton pump. That is why
they have long duration of action.
1- Reduction of HCl secretion up to 100%, they reduce basal, nocturnal, and stimulated
HCl.
2- Reduction of H+ ion concentration with minimal effect on volume of gastric juice, pepsin
secretion, and intrinsic factor secretion.
3- No effect on gastric emptying and GIT motility.
4- Gastrin secretion may increase (see adverse effects).
Therapeutic uses:
1- Peptic ulcer (considered as the drugs of choice): given for 4 weeks in duodenal ulcer, and
for 8 weeks in gastric ulcer.
2- Zollinger – Ellison syndrome.
3- GERD.

Adverse effects:
1- Allergy: skin rash.
2- GIT disturbances: nausea, abdominal pains, diarrhea.
3- CNS disturbances: headache, dizziness, drowsiness, and somnolence.
4- Decreased gastric acidity may lead to:
 GIT infections.
 Increased gastrin secretion = hypergastrinemia (no negative feedback of HCl) which
may lead to gastric carcinoid tumor. However; this was found to occur in rats and not
in humans.
 Colonization of bacteria producing carcinogenic nitrosamines.
Drug interactions:
Omeprazole is a HME inhibitor (inhibit CYP 450) and decrease clearance of warfarin,
theophylline, phenytoin, and diazepam.

II- Mucosal Protective Agents:

1-Prostaglandin Analogues: e.g. Misoprostol (see before) and rebampide (stimulates
PG synthesis).
2-Sucralfate (Aluminium sucrose sulphate):

1- Sucralfate is given orally and dissociates in the presence of HCl into Al3+ and sucrose
sulphate (negatively charged) which adheres to the positively charged proteins in the
base of the ulcer forming a protective layer against HCl and pepsin.
2- It adsorbs pepsin.
3- It stimulates synthesis of PGs → ↑mucus, ↑ bicarbonate, ↓ HCl and pepsin.
Role in peptic ulcer:
Stimulates healing and prevents recurrence. It is given orally on an empty stomach (at least
1 hour before meals) in a dose of 1 g. 4 times daily.
Adverse effects: (most adverse effects are due to aluminium)
1- Constipation.
2- Decreases absorption (and oral bioavailability) of many drugs given orally at the same
time as quinolones, tetracyclines, digitalis, ketoconazole, and phenytoin.
Important note: Sucralfate should not be given with anti-secretory drugs as H2-antagonists
and PPIs or with antacids because it is "activated" in the acidic medium of the stomach.
3- Carbenoxolone:
Chemistry:
 Derivative of glycyrrhizic acid which is obtained from liquorice.
 Aldosterone –like structure.
Pharmacokinetics: absorbed orally – highly bound to plasma proteins –eliminated in
bile.
Pharmacodynamics:
Stimulates healing of the ulcer and protects mucosa by increasing mucus and stimulating
PG synthesis (it acts on aldosterone receptors).
Adverse effects: are due to aldosterone-like action:
1- Na+ and water retention leading to elevation of ABP, edema, and heart failure in cardiac
patients.
2- Hypokalemia.
Contraindications:
Hypertension – Congestive heart failure-Edema-Hypokalemia.

Important note:
To correct Na+ and water retention and hypokalemia caused by carbenoxolone: amiloride
and triamterene (non-aldosterone K+ sparing diuretics) are used but spironolactone
(aldosterone antagonist) is avoided because it will antagonize the ulcer healing action of
carbenoxolone.
4- Colloidal Bismuth Compounds: e.g. Bismuth subcitrate (tripotassium-dicitro-

bismuthate).
Pharmacodynamics:
1- Mucosal protective action by: coating the ulcer and stimulating PG synthesis leading to
increased mucus secretion and ↓decreasing pepsin.
2- Anti-microbial action against H.pylori.
Adverse effects:
Black discoloration of mouth, tongue, teeth, and stools.
III- Antacids:
 Antacids are used for symptomatic treatment to relieve ulcer pain and hyperacidity and
are not useful for healing of ulcers. They are also useful in gastritis and GERD.
 Antacids are classified into:
A) Physical antacids: they adsorb HCl and pepsin and form a protective coat on the ulcer
= demulcent action.
B) Chemical antacids: they chemically neutralize HCl and are further subdivided into:
1- Systemic antacids: NaHCO3 which causes "systemic alkalosis".
2- Local (non-systemic) antacids: Aluminium and magnesium salts which do not
cause systemic alkalosis.

Sodium Magnesium Aluminium Salts

Bicarbonate Salts
Advantages: 1- Rapid onset. 1- No systemic 1- No systemic alkalosis.
2- No diarrhea or alkalosis. 2- No CO2 release.
constipation. 2- No CO2 release. 3- Long duration.
3- Alkalinize the urine in: 3- Long duration. 4- Al hydroxide gel acts
• treatment of acute 4- Mg trisilicate acts both chemically and
toxicity by acidic both chemically physically.
drugs as salicylates and physically.
• with uricosuric
drugs in prophylaxis
of gout
• prevention of
crystalluria caused
by some drugs as
sulphonamides.
Disadvantages: 1- Systemic alkalosis. 1- Delayed onset. 1- Delayed onset.
2- Releases CO2 leading 2- Diarrhea. 2- Constipation.
to distension, 3- Decreases oral 3- Decreases oral
discomfort, rebound absorption of absorption of
acidity, and may be quinolones, quinolones,
rupture (perforation). tetracyclines, tetracyclines,
3- Hypernatremia which warfarin, digoxin, warfarin, digoxin,
may cause edema, ketoconazole, ketoconazole,
elevate ABP, and theophylline, theophylline,
heart failure. ranitidine. ranitidine.
4- Short duration. 4- Hypophosphatemia
5- Alkalinization of urine (except Al phosphate
may precipitate gel).
phosphate stones and
decreases renal
excretion of basic
drugs as ephedrine
and amphetamine.

Important Notes:
1. NaHCO3 is also used:
 To treat systemic acidosis.
 To dissolve thick mucus and facilitate expectoration (alkaline expectorant).
2. Magnesium salts include: Mg oxide- Mg hydroxide – Mg trisilicate which is both a

chemical and physical antacid.
3. Aluminium salts include: Al hydroxide gel which acts both physically and chemically- Al
Phosphate gel which acts both physically and chemically and has the advantage that it
does not decrease absorption of dietary phosphate and accordingly does not cause
hypophosphatemia.
4. Calcium carbonate:
Advantages: rapid onset- long duration.
Disadvantages:
 Releases CO2 leading to distension, discomfort, rebound acidity, and may be rupture
(perforation).
 Systemic alkalosis.
 Hypercalcemia and hypercalciuria.
 Constipation.
 Milk-alkali syndrome.
5. Magaldrate = Mg hydroxide + Al hydroxide (no diarrhea or constipation).
IV- Anti-Microbials To Eradicate H.pylori:

Combination of 2 or 3 of the following anti-microbials are used for 2 weeks in cases of
peptic ulcers associated with H.pylori infection:
1. Clarithromycin (Macrolide antibiotic).
2. Amoxycillin (broad spectrum penicillin).
3. Metronidazole.
4. Tetracyclines.
5. Colloidal Bismuth compounds.

Emetics
Emetics are drugs that induce vomiting. They may be used in treatment of food and drug
poisoning, but are contraindicated in comatosed patients for fear of aspiration pneumonia.
They are divided into:
1. Central Emetics: they induce vomiting by stimulation of CTZ, as Apomorphine S.C.
2. Peripheral (local) Emetics: they induce vomiting reflexly by inducing gastric irritation,
they are either:
a. Rapidly acting: hypertonic salt solution (but if it fails to induce vomiting it may cause
hypernatremia).
b. Slowly acting: Tincture ipecacuanha, tincture senega, ammonium chloride and
ammonium carbonate.
They may be given in sub-emetic doses to act as expectorants in treatment of
productive cough and are known as "nauseant expectorants" (nausea → vagal
stimulation → increase watery secretion in bronchi).
Anti-Emetic Drugs
Anti-emetics are used in treatment of nausea and vomiting which may be caused by:
1. GIT diseases.
2. Pregnancy.
3. Motion sickness, labyrinthitis, Meniere's disease.
4. Severe pain as acute myocardial infarction and renal colic.
5. Stress and psychological disorders.
6. Drugs:
 Opioid analgesics: morphine, fentanyl, methadone…
 Cardiac glycosides.
 Theophylline and Aminophylline.
 Estrogen (oral contraceptives).
 D2-Agonists as L-dopa and Bromocriptine (antiparkinsonian drugs).
 Cancer chemotherapy and radiotherapy.

Classification of Anti-emetic Drugs:

I. D2-Antagonists (see later).
II. 5-HT3-Antagonists e.g. Ondansetron and Granisetron given orally or IV to treat nausea
and vomiting induced by cancer chemotherapy.
III. Anti-muscarinic drugs(Anti-cholinergic): Hyoscine (drug of choice in prophylaxis of

motion sickness-especially air sickness due to short duration- given as transdermal
patch).
Adverse effects: tachycardia-dry mouth-constipation-urine retention-blurred vision,
xerophthalmia, and elevation of IOP.
Contraindications: Glaucoma- Benign Prostatic Hyperplasia (BPH).
IV. Antihistaminics: only sedating (1st generation) antihistaminics have antiemetic action
by blocking H1 and muscarinic receptors in vomiting centre and vestibular system,
and are accordingly useful in motion sickness -especially sea sickness due to their
long duration-, e.g. Diphenhydramine, Dimenhydrinate, Promethazine Cyclizine, and
Meclizine (cyclizine and meclizine are contraindicated in pregnancy).
Adverse effects: atropine-like + sedation and drowsiness + teratogenicity (cyclizine
and meclizine).
Contraindications: as atropine + pregnancy + car drivers.
V. Other Anti-emetics:
1- Pyridoxine (vitamin B6): useful in vomiting of pregnancy.
2- Glucocorticoids: as dexamethasone in vomiting due to cancer chemotherapy. (It
may be combined with B6 =Cortigen B6®).
3- Benzodiazepines: they are used before cancer chemotherapy to reduce anxiety-
induced vomiting.
4- Cannabinoids: as Dronabinol which is used in vomiting due to cancer
chemotherapy and radiotherapy.
5- Neurokinin receptor blockers: e.g. Aprepitant used to inhibit cancer
chemotherapy-induced vomiting (it blocks neurokinin receptors in vomiting center
which are stimulated by substance P causing vomiting).

D2- Antagonists:
They act by blocking D2-receptors in CTZ so they are useful as anti-emetics except in motion
sickness.
1. Antipsychotic drugs = Neuroleptics = Major tranqillizers:
 Phenothiazines: Chlorpromazine, Trifluperazine.
 Butyrophenones: Droperidol and Haloperidol.
These drugs are used mainly in treatment of psychosis by blocking D2-receptors in the
limbic system.
Adverse effects:
1. Extrapyramidal manifestations and Parkinsonism due to blocking D2-receptors in the
basal ganglia.
2. Hyperprolactinemia leading to gynecomastia, impotence, and loss of libido in males,
and galactorrhea-amenorrhea and menstrual disturbances in females due to blocking
D2 receptors in hypothalamus.
3. Teratogenicity.
4. Other adverse effects: see CNS pharmacology.
Contraindications:
1. Parkinsonism.
2. Pregnancy.
2. Metoclopramide (Primperan):
 Central action: Blocks D2-receptors in CTZ → anti-emetic except in motion sickness.
 Peripheral action: Stimulates (modulates) 5-HT4 receptors in GIT → release of
acetylcholine from cholinergic neurons → Prokinetic action: stimulates gastric
motility and emptying, increases tone of lower esophageal sphincter (LES), and
stimulates peristalsis.
This action is blocked by atropine.
1. Anti-emetic except in motion sickness.
2. Prokinetic action.
3. Blocks D2-receptors in basal ganglia → extrapyramidal effects and Parkinsonism.
4. Blocks D2-receptors in hypothalamus → Hyperprolactinemia.
Metoclopramide has no action on GIT secretions (no atropine-like action)

Therapeutic uses:
1) Anti-emetic in cancer chemotherapy and radiotherapy, post-operative vomiting,
hiccough but not effective in motion sickness.
2) Prokinetic in:
 GERD.
 Gastric hypomotility as in diabetic gastroparesis.
 Before emergency operations (anaesthesia may cause vomiting and aspiration
pneumonia).
3) Treatment of hiccough (hiccup).
Adverse effects:
1. Extrapyramidal manifestations as akathisia- dystonia- tremors-and Parkinsonism.
2. Hyperprolactinemia (gynecomastia, impotence, and loss of libido in males,
galactorrhea-amenorrhea and menstrual disturbances in females).
3. Dizziness, restlessness, insomnia, anxiety, ataxia.
4. Increases absorption of concomitantly administered drugs except digoxin (being
slowly disintegrated in the stomach).
3. Domperidone (Motilium – Motinorm):

Central action:As metoclopramide; it blocks D2 receptors in CTZ, but poorly penetrates
BBB and does not markedly block D2-receptors in basal ganglia, so it is much less liable to
cause extrapyramidal manifestations but still can cause hyperprolactinemia.
Peripheral action: blocks α1 receptors in the stomach leading to stimulation of gastric
motility and emptying (prokinetic action).
This action is not blocked by atropine.
Prokinetic Drugs
1. Metoclopramide (Primperan): see before.
2. Domperidone (Motilium –Motinorm): see before.
3. Itopride and Mosapride:
 Prokinetic by activation of 5-HT4 receptors leading to release of acetylcholine and
stimulation of gastric motility and emptying.
 No D2 blocking action and accordingly it is not an antiemetic.
 Used in treatment of GERD in addition to PPIs.
4. Muscarinic agonists (parasympathomimetics): as bethanechol used in non-obstructive
paralytic ileus. Unlike metoclopramide; bethanechol increases GIT secretions as well as
motility.
5. Erythromycin: has "motilin-like action" as it stimulates motilin receptors in GIT. It is used
in diabetic gastroparesis.

Intestinal Evacuants
Intestinal evacuants include:
A) Purgatives.
B) Glycerin suppository: causes mild irritation of the colon and rectum, and softens the
stools. It is used in children mainly.
C) Evacuant (cleansing) enema: large volume of fluids used under high head pressure and
usually contains irritant substances as chamomile.
This is in contrast to "retention enema" as glucose (nutrient), barium (for radiology),
corticosteroids (anti-inflammatory in ulcerative colitis), thiopentone (basal anaesthesia),
MgSO4 (dehydrating agent), and anti-parasitic drugs. Retention enemata contain small
volume of non-irritant drugs given under low head pressure.
Therapeutic uses of intestinal evacuants:

1. Treatment of constipation.
2. Treatment of drug and food poisoning (see acute morphine toxicity).
3. Before GIT surgery, endoscopy, and radiography.
4. After treatment of helminths by anthelmintic drugs.
5. To prevent straining in patients with CHF, hernia, and after eye surgery.
Purgatives (Laxatives)
Purgatives are drug that are given orally to evacuate the bowel.
I. Physical purgatives (Luminally active purgatives):
a) Bulk purgatives:
1) Hydrophilic colloids and undigestible fibres:
They increase bulk of intestinal contents → stretch the wall of colon → stimulation
of peristalsis → evacuation of the colon.
Examples: bran- agar- methylcellulose- plantago (psyllium seeds).
2) Saline purgatives (Osmotic purgatives):

They increase water in GIT by their osmotic action → increase bulk of intestinal
contents → stretch the wall of colon → stimulation of peristalsis → evacuation of
the colon.
Examples: Magnesium sulphate, sodium sulphate.
Act after 1-2 hours so should be given in the morning before breakfast (on empty
stomach) - solution should be isotonic.

Contraindications:
1. Pregnancy; as it causes pelvic congestion → uterine stimulation and abortion.
2. Chronic habitual constipation; as increased bulk of stools may cause stool
impaction and intestinal obstruction.
N.B.: The actions of magnesium sulphate depend on the route of administration as
follows:
 Orally in small concentration → cholagogue (stimulates gall bladder contraction
and evacuation).
 Orally in high concentration → saline osmotic purgative.
 Rectal retention enema → dehydrating agent as in acute glaucoma.
 IV infusion → anticonvulsant.
3) Lactulose: a synthetic disaccharide made up of fructose and galactose. It is not

absorbed orally and due to osmotic action it retains water in GIT → increase bulk
of intestinal contents → stretch the wall of colon → stimulation of peristalsis. It
also stimulates release of cholecystokinin which evacuates bile from the bladder
which also stimulates peristalsis.
Lactulose is split by the action of bacteria in the colon into lactic acid which
softens stool and inhibits ammonia producing proteolytic bacteria.
Uses of lactulose:
1. Treatment of constipation.
2. Given with neomycin (aminoglycoside antibiotic) in hepatic encephalopathy to
reduce formation of ammonia.
b) Lubricant Purgatives (Emolients):
Liquid Parffin:
1. Lubricates hard stools leading to softening and easy evacuation.
2. Acts after 10-12 hours so they should be given at night.
3. Allowed in chronic habitual constipation.
4. Adverse effects:
 Bad consistency, avoided by adding fruit juice or using an emulsion.
 Inhibits absorption of fats and fat-soluble vitamins as vitamin K leading to
hypoprothrombinemia and increases the action of oral anticogulants as
warfarin, and vitamin D leading to reduced Ca2+ absorption and impairs growth
and teething in children.
 Decreases oral absorption of some drugs as oral contraceptives.
 Systemic absorption leads to foreign body reaction (in the liver) and lipoid
pneumonia.
 Leakage outside the anus causes: severe itching (pruritus ani)- anal polypi-
delayed healing of ano-rectal wounds so not allowed after ano-rectal surgery
(piles and anal fissures).

c) Surfactants (Surface active agents =Wetting Agents):

They decrease surface tension of hard stools (surfactant =detergent action) and allow
water penetration, e.g. Di-octyl sodium sulphosuccinate
II. Irritant (Chemical or Stimulant) Purgatives:

They induce chemical irritation of nerve endings → stimulation of peristalsis →
evacuation of the colon.
Disadvantages:
1. Colics, diarrhea, and may be dehydration (avoided by adding small doses of
anticholinergic drugs as atropine or hyoscine).
2. Interfere with absorption of drugs and food.
3. Pelvic congestion may lead to uterine contractions causing dysmenorrhea and
abortion, so they are contraindicated in menstruation and in pregnancy.
4. Partly excreted in breast milk and affect suckling babies.
Classification:
A) Mild irritants:
1. Figs and Prunes (act also as bulk purgatives).
2. Castor oil:
 Hydrolysed by biliary lipase enzyme into glycerol and ricinoleic acid leading to
chemical irritation →stimulation of peristalsis.
 Ineffective in obstructive jaundice (due to lack of lipase in GIT).
 Acts after 2-6 hours and is accordingly given in the morning.
 Contraindicated in pregnancy and menstruation.
B) Moderate irritants:
1. Anthracene derivatives: Senna-Cascara-Aloe-Rhubarb: release emodin which
chemically irritates the colon.
Adverse effects: Colics-Excreted in breast milk-Discoloration of urine (red
discoloration if urine is alkaline).
2. Phenolphthalein: chemically irritate the colon –has enterohepatic circulation and
long action-given at night-alkaline urine becomes reddish in color and may cause
liver damage and skin rash.
3. Bisacodyl: related to phenolphthalein but no enterohepatic circulation, given
orally or rectally (suppository).
N.B.: sodium picosulfate is related to bisacodyl.
C) Severe irritants =Cathartics: are obsolete.
Types of Enemata:
1. Evacuant Enema (cleansing enema).
2. Retention Enema.
Stool softeners: glycerine suppository –liquid paraffin –dioctyl sodium sulfosuccinate.

Treatment of Diarrhea
A) Causal Treatment: specific treatment of the causative infective organism (by
antibacterial drugs as ciprofloxacin in bacillary dysentery, and anti-amebic drugs as
metronidazole in amebic dysentery).
B) Rehydration therapy: to correct dehydration, electrolyte and acid/base disturbance

by oral rehydration therapy (ORT) or parenteral rehydration therapy in severe cases.
C) Symptomatic treatment: non-specific treatment that includes:

1. GIT Protectives:
 Adsorbants: "adsorb" toxins and form a protective coat that decreases mucosal
irritation, e.g. Kaolin, Bismuth, Chalk, Charcoal.
 Absorbents: Pectin (in rice, carrot, apple).
 Astringents: precipitate surface proteins and decrease the effect of toxins on GIT
mucosa, as tannic acid released from Tincture krameria and Tincture catecho.
2. Anti-motility drugs:
 Anticholinergic drugs: atropine and synthetic antisecretory-antispasmodic
atropine substitutes as atropine methyl nitrate –propantheline- hyoscine butyl
bromide.
 Mebeverin: direct smooth muscle relaxant used also in irritable bowel syndrome
(IBS).
 Other spasmolytics: as papaverine-nitrates-methylxantines-peppermint oil-khellin.
 Opiate agonists: treat diarrhea with minimal CNS actions, as Loperamide and
Diphenoxylate (combined with atropine =Lomotil).
Antispasmodic drugs = Treatment of colics:

1. Anticholinergic drugs: atropine and synthetic antisecretory-antispasmodic substitutes
as atropine methyl nitrate –propantheline- hyoscine butyl bromide.
2. Other spasmolytics: as papaverine-nitrates-methylxantines-peppermint oil-khellin.
3. Mebeverin: direct smooth muscle relaxant used also in irritable bowel syndrome
(IBS).
Treatment of biliary colic:

1. Anticholinergic drugs.
2. NSAIDs as diclofenac IM.
3. Opioid analgesics: morphine (must be combined with atropine) or
meperidine alone.

Cholagogues: drugs that release cholecystokinin that stimulates contraction of the wall and
relaxation of sphincter of Oddi leading to evacuation of bile:
1. MgSO4 orally before breakfast.
2. Fats and oils.
Chloretics: stimulate bile synthesis by the liver:

1. Natural bile salts: cholic and desoxycholic acids.
2. Synthetic derivatives: sodium glycocholate and taurocholate.
Hydrochloretics: increase water content of bile, as salicylates.
Cholagogues and chloretics are useful in constipation, flatulence, indigestion, and to
increase absorption of fats and fat-soluble vitamins.
They are contraindicated in obstructive jaundice and acute hepatitis.
Sialagogues: drugs that increase salivary secretion as pilocarpine, used in treatment of dry
mouth (xerostomia).
Anti-sialagogues: drugs that reduce salivary secretion as atropine, useful in excessive
salivation in Parkinsonism, and as pre-anaesthetic medication to avoid aspiration.
Carminatives: drugs that help eructation (expulsion of gases through the mouth) as anise-
carawy-peppermint-cinnamon-carbonated water.
Treatment of Hepatic Encephalopathy:

1. Neomycin: aminoglycoside antibiotic given orally to sterilize the bowel from ammonia-
producing bacteria.
2. Lactulose: it is an artificial sugar degraded in the colon into lactic acid and other organic
acids that increase GIT motility and decrease formation of ammonia by bacterial flora. It
is also used as "osmotic laxative" in treatment of constipation.
Treatment of Inflammatory Bowel Disease (IBD) =Ulcerative colitis

1. Glucocorticoids: systemically (orally or IV) or as retention enema.
2. Sulphasalazin: combination of sulphonamide (sulfapyridine) and 5-amino salicylic acid. It
is given orally and split in the colon into sulfapyridine which is absorbed and causes
most of the adverse effects, and 5-aminosalicylic acid which acts as anti-inflammatory by
blocking leukotriene B4 receptors.
Mesalazine (5-aminosalicylic acid) and olsalazine (2 molecules of aminosalicylic acid
linked together) are safer than sulfasalazine.
3. Immunosuppressive drugs as methotrexate and azathioprine.
4. Monoclonal antibodies: Anti -TNFα (infliximab).

Treatment of Cholesterol Gall stones:

Chenodeoxycholic acid and Ursodeoxycholic acid dissolve cholesterol gall stones and also
decrease hepatic synthesis of bile. They may cause diarrhea.
Hepatotoxic drugs:
1. Cholestatic hepatitis (jaundice): chlorpromazine-TCAs-carbamazepine-erythromycin-
rifampicin-estrogen-testosterone-carbimazole-cimetidine-chlorpropamide
2. Viral hepatitis-like: phenytoin-isoniazid-halothane .Alpha-methyldopa causes chronic
hepatitis-like.
3. Centrilobular (zonal) necrosis: paracetamol toxicity.
4. Fatty liver: tetracycline-valproic acid.
Management of obesity:
1. Treatment of the underlying cause (if any), psychotherapy may be needed in some
cases.
2. Regular physical exercise.
3. Low calorie diet rich in bran and undigested fibers as methylcellulose, which are bulk
forming, giving the sense of satisfaction and also reduce oral glucose and cholesterol
absorption.
4. Acupuncture.
5. Drugs:
 Orlistat: reduces fat digestion and absorption by irreversible inhibition of gastric and
pancreatic lipases. Adverse effects include fatty diarrhea and impaired absorption of
fat-soluble vitamins.
 Octopamine: fat burner by stimulation of β3 receptors in adipose tissues leading to
lipolysis.
 Leptin: hormone secreted by adipocytes.
 Anorexigenic drugs:
 Sibutramine: inhibits uptake of serotonin and noradrenaline.
 Amphetamine derivatives: as phenmetrazine, fenfluramine, and diethylpropion (not
preferred as they may cause addiction).
 Metformin: oral anti-diabetic which decreases appetite and helps weight loss in type
2 obese diabetics.

Endocrine Pharmacology 2011/2012
Endocrine Pharmacology
1 www.medadteam.org
Endocrine Pharmacology
Mechanism of action of Hormones:
Hormone Mechanism of Action

1-Polypeptide hormones Activation of cell membrane receptors (G-protein linked)
(glucagon- → increased synthesis of 2ry messenger as c-AMP.
parathormone-ACTH- The onset of action is immediate.
TSH-ADH-Oxytocin).
2-Adrenaline.
3-Steroid hormones Activation of cytoplasmic receptors →activation of the
(cortisol-aldosterone-sex hormone-receptor complex which enters the nucleus and
hormones). binds to DNA (nuclear receptors)→ synthesis of m-RNA→
4-Vitamin D. synthesis of specific proteins (gene expression) and/or
inhibition of other proteins (gene repression).
They have delayed onset of action (lag period of several
hours).
5-Thyroid hormones. Activation of nuclear receptors → synthesis of m-RNA and

proteins. They have intermediate onset of action.
6-Insulin (polypeptide Activation of specific "tyrosine kinase-linked" receptors.

hormone). Insulin has very rapid onset of action.
N.B.: All polypeptide hormones are never given orally because they are destroyed by
proteolytic enzymes in GIT whereas steroid and thyroid hormones are given orally.
2 www.medadteam.org
DIABETES MELLITUS
Definition: Diabetes Mellitus (D.M.) is a chronic metabolic disorder affecting carbohydrate,
fat, and protein metabolism and is characterized by hyperglycemia and glucosuria, due to
absolute or relative insulin deficiency, or decreased sensitivity of insulin receptors.
Types of D.M.:
Type I: Insulin-Dependent D.M. (IDDM): known as (Juvenile) D.M.-it occurs in
young age (< 30 years) and is characterized by severe or absolute insulin deficiency- patients
are non obese (underweight)- and diadetic ketoacidosis (DKA) is common.
Treatment is by insulin replacement for life.
Type II: Non Insulin Dependent D.M.: known as (Maturity onset) D.M.- it occurs in
older patients (> 40 years) and is characterized by relative insulin deficiency or a defect in the
biological effect of insulin (insensitivity)-85% of patients are obese and only 15 % are non-
obese and DKA is rare.
Treatment does not necessarily require insulin.
Type III (secondary D.M.): it occurs due to:
1- Drugs (iatrogenic D.M.) as thiazides, diazoxide, phenytoin, and CCBs as verapamil. These
drugs inhibit insulin release.
2- Counter-regulatory hormones (anti-insulins) including glucagon, growth hormone,
glucocorticoids, thyroxin, and catecholamines (adrenaline and noradrenalin).
3- Immunosuppressive drugs (inhibit insulin synthesis).
4- Pancreatic diseases as pancreatitis, or after pancreatectomy.
5- Cytotoxic drugs that destroy B-cells as streptozotocin and alloxan.
Type IV (gestational D.M.): which occurs for the first time during pregnancy, and is mostly
due to placental hormones with anti-insulin effect.
Anti-Diabetic Drugs
Anti-diabetic drugs can be classified into the following groups:
I-Insulin: given S.C. in all type I patients and in some type II patients. Only soluble regular
insulin can be given I.V. only in emergencies as diabetic ketoacidosis (D.K.A.) and
hyperosmolar non-ketotic coma.
II-Oral anti-diabetic drugs: these drugs are given orally in treatment of type II D.M. They
are subdivided into:
A-Insulin secretagogues: their main action is to stimulate insulin release from B-cells of islets
of Langerhan. That is why they may cause hypoglycemia and are sometimes referred to as
"oral hypoglycemics". According to their chemical structure they are classified as:
1. Sulfonylureas (SU): these drugs are chemically related to sulfonamides, and are divided
into 2 generations:
3 www.medadteam.org
First generation SU: as Tolbutamide (short acting)- Acetohexamide (intermediate acting)-

Chlorpropamide (long acting).
Second generation SU: as Glibenclamide (Glyburide)- Glipizide- Gliclazide- Glimepiride.
They have the following advantages over the first generation:
a. Less adverse effects (better tolerated).
b. More potent.
c. Intermediate duration of action (12-24 hours) and can be given once or twice daily.
2. Meglitinides: as Repaglinide.
3. D-phenylalanine derivatives: as Nateglinide.
B-Insulin sensitizers: they improve the action of insulin on insulin receptors in the liver,
adipose tissue, and skeletal muscles mainly.
They do not stimulate insulin release and never induce hypoglycemic when used alone; that is
why they are referred to as "oral euglycemics".
Insulin sensitizers include:
1-Biguanides: only Metformin is available (phenformin was withdrawn because of severe
lactic acidosis).
2-Thiazolidinediones (Tzds) = Glitazones: as Rosiglitazone and Pioglitazone (Troglitazone
was withdrawn due to serious hepatotoxicity).
C-Alpha Glucosidase Inhibitors:

These drugs inhibit α-glucosidase enzymes in the brush border of intestinal mucosa leading to
inhibition digestion of dietary carbohydrates (poly-, oligo- and di-saccharides) into glucose.
They are used to reduce "post-prandial" increase in blood glucose.
Examples are Acarbose and Miglitol (which is about 5 times more potent than acarbose).
III-New Antidiabetic Drugs:

A- GLP-1* receptor agonists: Exenatide and Liraglutide (given S.C.).
B- DPP-IV** inhibitors: Sitagliptin, Vildagliptin, and Saxagliptin (given orally).
C- Synthetic Amylin*** analogues: Pramlintide (given S.C.).
Important notes:
1. GLP-1: Glucagon-Like Peptide 1 which is an incretin (GIT hormone released after
meals).
2. DPP-IV: Di-Peptidyl Peptidase-4 which is the enzyme responsible for degradation of
GLP-1.
4 www.medadteam.org
3. Amylin: is a polypeptide hormone (37 amino acids) stored and released with insulin
from B-cells.
GLP-1 receptor agonists DPP-IV inhibitors Amylin analogues

Examples: 1-Exenatide (short duration). 1-Sitagliptin (Januvia™). Pramlintide.
2-Liraglutide (long duration). 2-Vildagliptin.
3-Saxagliptin.
Route: S.C. injection. Oral. S.C. injection.
Mechanism and Stimulate Glucagon-Like Inhibit Di-Peptidyl- Stimulates amylin
actions: Peptide-1 (GLP-1) receptors Peptidase-4 (DPP-IV) receptors leading to:
leading to: enzyme→ ↑ endogenous 1. Decrease glucagon
1. Stimulation of insulin GLP-1 → stimulation of release from A-cells.
release from B-cells. GLP-1 receptors leading to: 2. Delay gastric
2. Decrease glucagon release 1. Stimulation of insulin emptying (to prevent
from A-cells. release from B-cells. sudden elevation of
3. Delay gastric emptying (to 2. Decrease glucagon blood glucose after
prevent sudden elevation of release from A-cells. meals).
blood glucose after meals). 3. Delay gastric emptying 3. Suppress appetite
4. Suppress appetite (CNS (to prevent sudden (CNS action).
action). elevation of blood N.B. amylin does not
glucose after meals). stimulate insulin release
4. Suppress appetite (CNS (it may even reduce
action). insulin release but this is
insignificant).
Indications: Type II D.M.step 4. Type II D.M. step3 and 4 Type I and Type II D.M.
(Sitagliptin is available in to prevent post-prandial
combination with metformin hyperglycemia.
and is known as Janumet™).
Adverse effects 1. Hypoglycemia (when
(Disadvantages): combined with SU).
2. Nausea is very common.
3. Decreased absorption of
some drugs as paracetamol
due to delayed gastric
emptying.
4. Given only by injection.
INSULIN
Source:
1. Animal insulin: from animal pancreatic extracts and is either:
• Bovine: differs from human insulin in 3 amino acids and is highly antigenic.
5 www.medadteam.org
• Porcine: differs from human insulin in 1 amino acid and is less antigenic than bovine
insulin.
2. Human insulin: obtained by 2 different techniques:
• Synthesis by recombinant DNA technology (Bio-synthetic insulin).
• Enzymatic modification of animal insulins (Semi-synthetic insulin).
Human insulin is the least antigenic but is much more expensive.
Chemistry:
Insulin is composed of 2 polypeptide chains: A chain made up of 21 amino acids, and B chain
made up of 30 amino acids. Both chains are connected by 2 disulphide links which are
essential for the biological activity of insulin.
Factors Affecting Insulin Release:
Factors Stimulating Insulin Release Factors Inhibiting Insulin Release
1. Glucose (the most potent stimulus): glucose 1. Fasting and starvation: increase sympathetic
enters B-cells by GLUT 2 and undergoes activity leading to release of adrenaline and
glycolysis to form ATP, which in turn noradrenaline which stimulate α2-receptors
blocks ATP-sensitive K+ channels → thus inhibit insulin release.
depolarization → opening to voltage- 2. Somatostatin (inhibits glucagon release
dependent Ca2+ channels → influx of Ca2+ more than its inhibitory action on insulin).
→ insulin release. 2-PG E1.
2. Amino acids (leucine and arginine) and 3. Autonomic innervation and receptors:
fatty acids in diet. α2 stimulation, β2 block, and muscarinic
3. GIT hormones (incretins) as Glucagon-like block.
peptide 1 (GLP-1) and Gastrin inhibitory 4. Drugs:
peptide (GIP). • Thiazides, Loop diuretics, and Diazoxide:
4. Systemic Hormones: Glucagon and growth open ATP-sensitive K+ channels in B-cells
hormone (secondary to increased blood leading to hyperpolarization.
glucose). • Phenytoin (Na+ channel blocker).
5. Autonomic innervation and receptors: • CCBs as Verapamil.
Muscarinic stimulation, β2 stimulation, and
α2 block increase insulin release.
6. Insulin secretagogues (Oral hypoglycemic
drugs, e.g. sulfonylureas and meglitinides).
Pharmacokinetics:
• Insulin is never given orally because it is a polypeptide; i.e. it is destroyed by proteolytic
enzymes in GIT.
• All insulin preparations are given by S.C. injection.
• Only regular (soluble) insulin is given IV Only in case of diabetic ketoacidosis (D.K.A.).
• Insulin is distributed to all tissues.
• Fate: insulin is metabolized by glutathione insulin transhydrogenase (insulinase) in liver
and kidney which breaks the disulphide links, then the polypeptide chains are degraded
by polypeptidases.
Pharmacodynamics:
6 www.medadteam.org
• Insulin acts by stimulation of specific insulin receptors.
• Insulin receptors are "Tyrosine Kinase linked".
• Each receptor is composed of 2 α-subunits on the cell membrane, and 2 β-subunits that
transfix the cell membrane (partly extracellular and partly intracellular). These subunits are
linked by disulphide links.
• Insulin molecule binds to α-subunits of insulin receptors which then activate β-subunits
leading to activation of tyrosine kinase and phosphorylation of different enzymes which
initiate the biological actions of insulin; e.g. ↑glucose transporters (GLUT) which ↑glucose
uptake.
• The insulin receptor then undergoes "conformational change" and "internalization", then it
is either degraded or "recycled" to the cell membrane.
"Remember that insulin is an anabolic hormone".
1. Action on Carbohydrate Metabolism:
Insulin tends to reduce blood glucose by the following mechanisms:
• Stimulation of glucose uptake by formation of "glucose transporters" as GLUT 4 which
is responsible for glucose uptake into skeletal muscles and adipose tissue.
• Stimulation of glucose utilization by glycolysis (glucose by glucokinase → glucose 6
phosphate → ATP).
• Stimulation of glycogenesis and inhibition of hepatic glycogenolysis.
• Inhibits gluconeogenesis.
2. Action on Protein metabolism:
• ↑Amino acid transport and stimulates synthesis of proteins.
• Inhibits gluconeogenesis (↓ protein degradation).
3. Action on Fat Metabolism:
• Stimulates lipogenesis by stimulating lipoprotein lipase and↑adipocyte fat storage.
• Inhibits lipolysis by inhibition of triglyceride lipase.
• ↓Free fatty acids in blood.
• ↓Fatty acid oxidation and inhibits ketone bodies synthesis (inhibits ketogenesis).
4. Stimulates transport of K+, Mg2+, and phosphate and decreases their plasma level.
Insulin deficiency in D.M. is characterized by:

1. Hyperglycemia and glucosuria due to:
• ↓Glucose uptake and utilization.
• ↓Glycogenesis.
• ↑Glycogenolysis.
• ↑Gluconeogenesis.
2. ↑Free fatty acids in blood due to:
• ↑Lipolysis.
• ↓Lipogenesis.
7 www.medadteam.org
3. ↑Oxidation of free fatty acids and formation of ketone bodies (ketogenesis).

4. ↓Amino acid uptake and protein synthesis and ↑protein catabolism.
5. Weakness, immunocompromization and recurrent infections.
Indications of insulin:
A- Diabetic indications:
1. Treatment of Type I (IDDM): replacement therapy from the time of diagnosis and
throughout life.
2. Treatment of Diabetic Keto-Acidosis (DKA) by soluble insulin IV.
3. Temporarily in Type II (NIDDM) in cases of "stress" due to: infections –surgery –
pregnancy -trauma.
4. Permanently in Type II (NIDDM) in cases of:
• Failure to control hyperglycemia by diet + exercise + oral anti-diabetics.
• Development of renal or hepatic impairment.
• After recovery from DKA.
B- Indications of insulin in "non-diabetic cases":
Treatment of hyperkalemia due to renal impairment (glucose should be given with insulin to
avoid hypoglycemia).
Adverse effects:
A-Local Adverse Effects:
1- Lipodystrophy: either hypertrophy (more common due to insulin-induced lipogenesis) or
atrophy of subcutaneous fats. It is prevented by changing (rotating) the site of injection.
2- Local allergic reactions; they are rare nowadays due to the use of human insulin instead of
animal insulin.
3- Localized infections (very rare).
B-Systemic Adverse Effects:

1- HYPOGLYCEMIA:
Hypoglycemia is the most dangerous adverse effect of insulin therapy.
Causes:
1- Insulin overdose (too much insulin).
2- Ommission of meals (too little food).
3- Exhaustive physical exercise (too much exercise).
Manifestations:
• Sympathetic stimulation: tachycardia and palpitations (the most important warning
symptoms) – tremors – sweating – pallor.
• Neuroglycopenia: headache – blurred vision and diplopia – confusion – convulsions,
coma and may end in death.
Treatment:
• If the patient is conscious: treatment by oral glucose or sweets (candy, juice, chocolate,
etc.).
8 www.medadteam.org
• If the patient is comatose: treatment by IV glucose (50-100 mL. of 25-50% glucose) or

by glucagon (1mg.) given IM or SC followed by oral glucose. Adrenaline SC is used
only if there is no alternative and no contraindication (as hypertension, angina,
arrhythmia).
2- Systemic allergic reactions (uncommon because human insulin has largely replaced animal
insulins). Allergy may be due to protamine-containing isulins as N.P.H and P.Z.I., and they
should be replaced by zinc-containing insulins (as Lente insulin).
3- Insulin resistance (daily insulin requirements exceed 200 Units, common in obese non-
exercising patients, and may improve by adding insulin sensitizers as metformin or
glitazones). Insulin resistance was also common with animal insulin due to the formation of
insulin antibodies.
4- Hypokalemia may occur especially with IV insulin therapy in DKA.
Methods of Administration:
1- Disposable plastic syringes.
2- Insulin pen (more accurate dosage and less painful).
3- Insulin pump.
N.B.: insulin in the form of nasal inhalation will be available soon.
Insulin Preparations:
Insulin Preparation: Onset Peak Duration

Rapid acting insulin analogs (Ultra-
short acting): rapid onset + short
duration.
1- Insulin Lispro. 5-15 min. 30-90 min. 5 hours.
2- Insulin Aspart. 5-15 min. 30-90 min. 5 hours.
3- Insulin Glulisine. 5-15 min. 30-90 min. 1-2 hours.
Short acting: (slower onset + longer

duration than ultra-short)
1- Soluble = Regular =Crystalline 30-60 min. 2-3 hours. 5-8 hours.
insulin zinc.
2- Semilente (prompt insulin zinc 30-60 min. 4-6 hours. 12-16 hours.
suspension).
Intermediate acting:
1- Isophane insulin (NPH). 2-4 hours. 4-10 hours. 10-18 hours.
2- Lente (insulin zinc suspension). 2-4 hours. 4-10 hours. 10-18 hours.
9 www.medadteam.org
Long acting:
1- Protamine zinc insulin (PZI). 4-6 hours. 16-18 hour 20-36 hours.
2- Ultralente (insulin zinc 6-10 hours. 10-16 hour 18-24 hours.
suspension). 2-4 hours. No peak. 18-24 hours.
3- Insulin Glargine (peakless 1-4 hours. Dose- 6-23 hours
insulin). dependent (dose-
4- Insulin Detemir. peak. dependent).
Pre-mixed:
70% NPH/30% regular (Humulin 30-60 min. 2 Peaks (1-3 24 hours.
70/30). hours and 4-
10 hours).
Insulin analogs:
• Prepared by recombinant DNA technology.
• Synthesized by substitution of one or more amino acids in insulin molecule (modified
amino acid sequence or composition).
• They show different pharmacokinetic properties and accordingly have different onset and
duration.
• Examples include: insulin glargine- insulin lispro- insulin aspart-insulin detemir-insulin
glulisin
Oral Anti-Diabetic Drugs
Oral anti-diabetic (anti-hyperglycemic) drugs are classified into:
I- Insulin Secretagogues:
These drugs stimulate insulin release from pancreas in Type II diabetes and accordingly may
cause "Hypoglycemia" in large doses and are called "Oral Hypoglycemic drugs". They include:
A- Sulphonylureas: sulphonamide derivatives and accordingly may cause severe allergic

reactions, and there is an incidence of acute myocardial infarction causing sudden death.
B- Meglitinides: they have the same mechanism of action as sulphonylureas but are non-
sulphonamides and are less allergic and not associated with risk of acute myocardial
infarction. They include Repaglinide and Nateglinide.
II- Insulin Receptor Sensitizers:

These drugs do not stimulate insulin release but increase sensitivity of insulin receptors and
never cause hypoglycemia but "normalize high blood sugar" so they are known as
"Euglycemics".They include:
10 www.medadteam.org
A- Biguanides: only Metformin(Glucophage®) is available and phenphormin is obsolete

because it may cause fatal "lactic acidosis".
B- Thiazolidinediones: also known as "Glitazones", for example:Rosiglitazone, Pioglitazone,
and Troglitazone which was withdrawn due to hepatic toxicity.
Mechanism of action: They stimulate Perixosome Proliferator Activated Receptor -Gamma
(PPAR- γ) which is a nuclear receptor that stimulates synthesis of lipoprotein lipase and
GLUT-4 in skeletal muscles and adipose tissues, thus increasing glucose uptake and utilization.
Indications: Indicated in type 2 diabetes in addition to dietary control
and exercise, either alone (monotherapy) or in combination with sulphonylureas,
metformin, or insulin.
Adverse effects:
1- Na+ and water retention leading to edema, weight gain, and may cause CHF.
2- Hepatitis and elevation of liver enzymes (transaminases). Hepatotoxicity is rare but may be
fatal and frequent monitoring by liver function tests is needed (troglitazone was withdrawn).
3- Mild anemia.
4- Teratogenicity.
5- May increase the risk of: osteoporosis and bone fractures, myocardial infarction and sudden
death, and cancer bladder.
Contraindications: pregnancy- liver impairment-hypertension and heart failure.
III- Alpha Glucosidase Inhibitors:

• They act by inhibition of α-glucosidase enzymes in the brush border of intestinal mucosa
leading to inhibition of digestion of complex carbohydrates and accordingly inhibition of
dietary glucose absorption.
• They are used to control=blunt "Post-Prandial hyperglycemia" in type II DM, they can be
given with SU but not with metformin (see later).
• They cause GIT disturbances: bloating, flatulence, abdominal pain, diarrhea, malabsorption
of dietary carbohydrates, and decrease absorption of metformin.
N.B.: in case of hypoglycemia, they will interfere with oral absorption of sucrose, and glucose
should be given.
• They include: Acarbose and Miglitol (5-6 times more potent).
Sulfonylureas (SU)
Source: synthetic.
Chemistry: sulfonamide derivatives.
Classification:
• First Generation: they are less potent than the second generation and not used clinically
anymore in D.M.:
Tolbutamide: metabolized mainly by the liver and is "short acting".
Acetohexamide: metabolized into active metabolite and excreted mainly in urine and is
"intermediate acting".
Chlorpropamide: about 80% excreted in urine and 20% metabolized by the liver, and is
"long acting" (action lasts up to 60 hours).
It stimulates secretion and action of ADH and is used in pituitary (central) diabetes
insipidus.
• Second Generation: they are more potent and well tolerated (less adverse effects) than the
first generation and all are "intermediate acting", i.e. act for about 12 to 24 hours. They
include:
Glibenclamide (also known as Glyburide and is contraindicated in patients with creatinine
clearance less than 50 ml. / min.) -Glipizide –Gliclazide- Glimeperide (most potent).
Pharmacokinetics:
• Well absorbed orally.
• Bound to plasma proteins, and may be displaced by many drugs as NSAIDs and
sulfonamides.
• Pass BBB and may cause CNS adverse effects.
• Pass placental barrier and may cause teratogenicity and fetal hypoglycemia.
• Fate: extensive hepatic metabolism, metabolites are excreted in urine.
They are partly excreted in breast milk.
Pharmacodynamics:
Sulfonylureas block ATP-sensitive K+-channels in pancreatic cells → depolarization and influx
of Ca2+ → release of insulin from pancreatic B cells of islets of Langerhans.
(SU act on specific receptors in ATP-sensitive K+ channels, known as SUR).
1. Stimulation of insulin release from pancreas. This is the main action of sulphonylureas, and
depends on the presence of some insulin in the pancreas.
2. Inhibition of glucagon release from pancreas.
3. Increase sensitivity of β-cells to glucose.
4. (Actions 1, 2, and 3 are known as "Pancreatic actions").
5. Increase tissue sensitivity to insulin.
6. Suppress hepatic gluconeogenesis.
(Actions 4 and 5 are known as "Extra-pancreatic action".
Indications:
1-NIDDM: alone in non-obese patients, or in combination with metformin if one drug can not
control hyperglycemia.
2-Chlorpropamide is used in pituitary diabetes insipidus because it has an antidiuretic action
(may be through stimulation of ADH release).
Adverse effects:
1- Hypoglycemia: is the most serious adverse effect. The causes, manifestations, and treatment
are identical to insulin-induced hypoglycemia.
2- Hypersensitivity reactions: skin rash and photosensitivity, and cross allergy with
sulphonamides and thiazides.
3- Gut upsets: nausea, vomiting, diarrhea.
4- Stimulation of appetite and weight gain.
5- Cholestaic jaundice especially with chlorpropamide.
6- Disulfiram-like action (alcohol-intolerance) especially with chlorpropamide.
7- Edema and dilutional hyponatremia with chlorpropamide due to its antidiuretic action.
8- Teratogenicity and fetal hypoglycemia.
9- High incidence of acute myocardial infarction and sudden death especially with first
generation sulphonylureas.
10- CNS disturbances: drowsiness, confusion, and ataxia.
11- Bone marrow depression (blood dyscrasias).
12- Failure of therapy: either "primary" failure (no response to sulphonylureas from the start
of therapy), or "secondary" failure (failure to control hyperglycemia after 1-2 years of initial
improvement, which may be due to refractoriness of β-cells or loss of dietary compliance).
Contraindications:
1-Type I D.M.
2-Allergy.
3-Pregnancy and lactation.
4-Renal and hepatic impairment.
5-After recovery from DKA.
6-NIDDM in conditions of stress: pregnancy-infections-surgery.
N.B.: SU are contraindicated whenever insulin is indicated + allergy to sulfa.
*Drug interactions:
Pharmacokinetic interactions:
1- Sulphonylureas displace oral anticoagulants as warfarin from plasma proteins leading to
bleeding.
2- Sulphonylureas are displaced by NSAIDs as aspirin and phenylbutazone, and
sulphonamides from plasma proteins and may augment the hypoglycemic effect of
sulphonylureas.
3- Dicoumarol (oral anticoagulant) decreases renal excretion of chlorpropamide and may

augment its hypoglycemic effect.
4- Alcohol may cause hypoglycemia and thus augments the effect of sulfonylureas.
Pharmacodynamic interactions:
1- Thiazide diuretics, loop diuretics, diazoxide, CCBs as Verapamil, and phenytoin antagonize
the hypoglycemic effect of sulphonylureas because they inhibit insulin release (thiazides,
loop diuretics, and diazoxide open ATP-sensitive K+-channels and phenytoin blocks Na+-
channels).
2- Glucocorticoids (cortisol), Catecholamines (adrenaline) and oral contraceptives (estrogen)
cause hyperglycemia and antagonize the hypoglycemic effect of sulphonylureas.
3- Non-selective β-blockers as propranolol inhibit β2-mediated hepatic glycogenolysis thus
may augment the hypoglycemic effect of sulphonylureas by inhibition of compensatory
glycogenolysis, and all β-blockers mask the warning symptoms of hypoglycemia –
especially tachycardia and palpitations- and may lead to "silent hypoglycemia". They do not
inhibit sweating, which is a cholinergic action not mediated by β-receptors.
4- Sympathomimetics cause hyperglycemia by stimulation of hepatic glycogenolysis (β2).
Questions:
1- Enumerate drugs that augment the hypoglycemic action of sulphonylureas.
2- Enumerate drugs that antagonize the hypoglycemic action of sulphonylureas.
Drugs that Augment the Drugs that Antagonize the

hypoglycemic action of SU hypoglycemic action of SU
1- NSAIDs as salicylates (aspirin), 1- Thiazide diuretics
indomethacin, phenylbutazone… (Hydrochlorothiazide), and to a less
2- Sulfonamide. extent loop diuretics (Frusemide).
3- HME inhibitors as Cimetidine, 2- Diazoxide.
Allopurinol, Chloramphenicol, MAO 3- Phenytoin.
inhibitors… 4- HME inducers as Phenytoin,
4- Beta blockers as Propranolol. Rifampicin, Phenobarbitone…
5- Alcohol. 5- Estrogen (oral contraceptives).
6- Dicoumarol (augemts chlorpropamide- 6- Glucocorticoids (cortisol).
induced hypoglycemia). 7- Catecholamines as Adrenaline.
Biguanides = Metformin
Pharmacokinetics: absorbed orally and excreted unchanged in urine.

Pharmacodynamics:
Mechanism of action: unclear but may act through:
1. Increases insulin sensitivity by stimulation of binding to its receptors.
2. Decreases oral absorption of glucose from GIT.
3. Decreases glucagon release from pancreas.

4. Increases action of insulin in peripheral tissues and thus stimulates glucose uptake and
utilization by skeletal muscles and adipose tissues.
5. Stimulates anaerobic glycolysis.
6. Inhibits hepatic gluconeogenesis (↓ hepatic glucose output).
7. Decreases appetite leading to weight reduction.
(Remember that metformin does not stimulate insulin release, this is why it is euglycemic not
hypoglycemic).
Indications:
1. NIDDM especially in obese patients, and may be combined with sulphonylureas.
2. Treatment of diabetes insipidus.
3. Polycystic ovary with anovulatory cycles (often in obese diabetic females).
Adverse effects:
1. Lactic acidosis: it is the most serious adverse effect and may lead to coma and death in 50%
of cases. It is common in cases of: renal impairment-hepatic insufficiency and alcoholism-
congestive heart failure (CHF)-chronic obstructive pulmonary disease (COPD)-old age.
2. GIT upsets (most common): anorexia, nausea, vomiting, bloating, colics and diarrhea.
3. Prolonged use decreases GIT absorption of vitamin B12 and may lead to macrocytic
hyperchromic anemia.
Contraindications:
Metformin is contraindicated in conditions that increase lactic acidosis:
1. Renal impairment (↓elimination of metformin and lactic acid).
2. Hepatic insufficiency and alcoholism (↓elimination of lactic acid).
3. CHF (causes hypoxia).
4. COPD (causes hypoxia).
5. Old age (associated with renal and hepatic dysfunction).
Diabetic Keto-Acidosis (DKA)

Causes:
Too little insulin-Too little exercise-Too much food-Poor patient's compliance.
DKA is more common in type 1 D.M. and may be the first manifestation.
Manifestations Treatment
1-Marked insulin deficiency. 1. Soluble insulin IV (20-50 units).
2. KCl IV infusion to avoid insulin-induced
2-Hyperglycemia and glucosuria. hypokalemia (with ECG monitoring to
avoid arrhythmias).
3-Ketone bodies in blood 3. NaHCO3 IV infusion to correct acidosis.
(ketonemia) leading to acidosis and 4. Isotonic saline (0.9% NaCl) by IV
acetone odor, and ketonuria. infusion; followed by glucose 5% IV

4-Dehydration due to glucosuria infusion when blood glucose is less than
and ketonuria. 300 mg. % to avoid insulin-induced
hypoglycemia.
5-Infections especially RTI. 5. Antibiotics as Azithromycin.
Adrenocortical Hormones (Corticosteroids)

The adrenal (suprarenal) gland is formed of cortex and medulla. The adrenal medulla secretes
catecholamines (adrenaline and noradrenaline) and the cortex secretes steroid hormones
including:
1. Glucocorticoids: cortisone (corticosterone) and cortisol (hydrocortisone).
2. Mineralocorticoids: aldosterone and desoxycorticosterone (DOC).
3. Sex hormones: estrogens and androgens are secreted in small amounts.
Glucocorticoids are synthesized by the adrenal cortex from cholesterol (steroidogenesis)
under control of "Hypothalamic-Pituitary-Adrenocortical Axis" (HPA axis).
HPA Axis:
1. Corticotropin releasing hormone (CRH): synthesized and released from the
hypothalamus.
2. Adrenocorticotrophic hormone (ACTH): synthesized and released from the anterior
pituitary under the influence of CRH.
3. Cortisol (active) and cortisone (inactive and converted by the liver into active cortisol):
synthesized and released from the adrenal cortex under the influence of ACTH.
4. Cortisol exerts negative feed-back effect on CRH and ACTH and causes suppression of
HPA axis.
5. HPA axis is
• Stimulated by:
1. Stress (infection, surgery, trauma, and pregnancy).
2. Day-light (circadian rhythm).
3. Hormones: A.D.H., adrenaline, and estrogen.
4. Low plasma cortisol level.
• Inhibited by:
1. Negative feedback effect of cortisol.
2. Night.
3. Hormones: androgens.
4. Opiopeptides (endorphins and enkephalins).
ACTH:
• Polypeptide released from the anterior pituitary.
• Release is controlled by CRH, negative feed-back by cortisol, stress, and circadian rhythm
(see before).
• Mechanism of action: stimulates membrane receptors→ activation of adenylyl cyclase
→synthesis of c-AMP.
• Action: stimulates synthesis and release of cortisol (steroidogenesis) but minimal action on
mineralocorticoid synthesis and release.
• Indications:
1. Diagnostic: diagnosis of adrenocortical function: ACTH→ release of cortisol from
"healthy" cortex → eosinopenia and increased metabolites as 17-keto-steroids in urine.
2. Therapeutic: same indications as cortisol with the advantage of less catabolic effect in
old patients and less growth retardation in children.
3. During gradual withdrawal of steroids after long use to avoid acute addisonian
insufficiency.
• Preparations:
1. ACTH (corticotrophin) prepared from animals and is highly antigenic.
2. Synthetic tetracosactrin which is less antigenic.
Glucocorticoids (Cortisol)
Chemistry: steroid.
Pharmacokinetics:
Absorption:
• Well absorbed orally.
• Given also: IV, IM, intra-thecal, topical on skin, eye, ear, and nose, intra-articular, by
inhalation, and as rectal retention enema.
Distribution:
• Pass BBB.
• Pass placental barrier and cause teratogenicity.
• Highly bound to plasma proteins; mainly to globulin known as corticosteroid binding
globulin = CBG (75%), and to albumin (20%), only 5% is in the free form.
Metabolism:
• Cortisol (= Hydrocortisone) is active whereas cortisone is inactive and is converted by
the liver into cortisol.
• Give reason: cortisol is used locally (as skin cream or intra-articular injection) and
systemically but cortisone is used only systemically?
• Glucocorticoids are metabolized in the liver by reduction and conjugation with
glucuronic acid and sulfate.
Excretion:
Metabolites are excreted in urine and may be measured to assess function of HPA axis.
Pharmacodynamics:
1- Genomic mechanism:
Cortisol passes easily the cell membrane by simple diffusion being lipophilic. Then cortisol
binds to cytoplasmic receptors →activation of the hormone-receptor complex which enters

the nucleus and binds to nuclear receptors (a specific site on DNA strands) leading to:
a. Gene expression: synthesis of m-RNA (transcription)→ synthesis of specific proteins (
after translation) as Lipocortin I (Annexin 1) and catabolic enzymes.
b. Gene repression: inhibition of synthesis of certain proteins as COX-II, Nitric oxide
synthase (NOS), and antibodies (immunoglobulins).
The genomic mechanism shows a delayed onset of action (lag period of several hours).
2- Non-genomic mechanism: few actions of cortisol are due to stimulation membrane
receptors, such as the action on HPA axis. These actions are rapid in onset.
1. Negative feed-back inhibition of hypothalamic-pituitary-adrenal cortical axis leading to
inhibition of CRH and ACTH, with suppression of endogenous glucocorticoid synthesis.
Long use of exogenous glucocorticoids may lead to atrophy of the adrenal cortex may occur
due to inhibition of ACTH.
2. Metabolic Actions:
A- On Carbohydrate metabolism:
• Anti-insulin actions: stimulate gluconeogenesis (mobilization of amino acids from
skeletal muscles to the liver and synthesis of carbohydrates) and inhibit glucose uptake
and utilization by tissues.
• Stimulate synthesis of glycogen from pyruvate (glycogenesis) in the liver, and prevent
glucose output from the liver.
• The net result is Hyperglycemia and glucosuria (glucose intolerance).
B- On Protein metabolism:
Glucocorticoids cause protein catabolism in most tissues –except few tissues as the liver- as
skeletal muscles, bone, lymphoid tissue, and connective tissue leading to muscle wasting
and myopathy, osteoporosis, growth retardation in children, and delayed wound healing.
Amino acids are converted into urea which is excreted in urine, this is known as "negative
nitrogen balance".
C- On Fat metabolism:
• Lipolysis of fats in limbs, thighs, and buttocks.
• Lipemia: cortisol increases free fatty acids (FFA) in blood.
• Lipogenesis in face, back, and trunk leading to "moon face", "buffalo hump", and
trunkal obesity. This is known as Fat Redistribution.
3. Mineralocorticoid action: glucocorticoids have aldosterone-like action causing Na+ and
water reabsorption and hypokalemia. This may lead to edema, elevation of ABP, and may
dangerous in patients with CHF. Severe hypokalemia occurs if given with thiazides and
loop diuretics.
In addition; they are essential for diuresis of excess water (may be through inhibition of ADH).
N.B.: Cortisol is essential to get rid of excess water and prevention of water intoxication.
This is a "glucocorticoid" not a "mineralocorticoid" action and may be due to antagonism of
ADH effect on the nephrons, and this action is known as "free water clearance".
4. On vitamin D and Ca2+: glucocorticoids have anti-vitamin D action and accordingly

decrease Ca2+ absorption from GIT and increase Ca2+ excretion by the kidney, leading to
Hypocalcemia (negative calcium balance).
5. Anti-inflammatory action:
• By inhibition of phospholipase A2 (through synthesis of lipocortin I –also known as
Annexin
-by neutrophils and macrophages leading to inhibition of synthesis of inflammatory
mediators: PGs, leukotrienes, and platelet activating factor (PAF).
• Gene repression leading to inhibition of synthesis of COX-II, NOS, adhesion molecules,
and complement components.
• Inhibit migration of neutrophils.
• Decrease circulating lymphocytes, eosinophils, monocytes, basophils.
• Decrease synthesis of inflammatory cytokines as interleukins, TNFα, and colony
stimulating factor (CSF).
• Stabilize lysosomal membrane and inhibit release of lysosomal enzymes thus preventing
cell death and tissue destruction.
• Decrease capillary permeability thus decreasing inflammatory edema and joint effusion.
N.B.: Cortisol is a non-specific anti-inflammatory, and is sometimes described as a
"deceiver" as it masks the signs of infection and inflammation without treating the cause.
6. Immunosuppression and Anti-allergic actions:
Through inhibition of antibody (immunoglobulins) formation, inhibition of antigen-antibody
reaction, and ↓tissue response to inflammatory mediators.
7. Actions on blood:
• Increased number of RBCs due to increased release from bone marrow (polycythemia).
• Increased number of neutrophils (PMNLs)due to inhibition of migration and increase
output from the bone marrow (neutrophilia).
• Increased number of platelets (thrombocytosis).
• Increased blood coagulability.
• Decreased number of lymphocytes due to catabolic effect on lymphoid tissue
(lymphopenia).
• Decreased number of eosinophils (eosinopenia).
8. Action on Serum Uric Acid:
Uricosuric action and decrease serum uric acid.
9. Action on CNS: cortisol has a stimulant action on the CNS causing euphoria and may even
lead to psychosis.
10.Action on Respiratory system:
• Anti-inflammatory and stabilization of the membrane of mast cells to prevent the release
of "allergotoxins" in bronchial asthma.
• Increase number of β2-receptors and prevents down regulation by β2-agonists as
salbutamol.
• Stimulate production of surfactant in neonates.
11.Action on GIT: inhibit synthesis of cytoprotective PGE2 and

PGI2and accordingly increase HCl and decrease mucus leading to peptic ulcer. This iatrogenic
ulcer is best prevented and treated by misoprostol.
12.Anti-stress and Anti-shock: (by increasing blood volume and BP by hypernatremia, by
increasing blood sugar, and by CNS action).
13.Action on CVS: cortisol elevates blood pressure by the following mechanisms:
1. I-Sodium and water retention by its mineralocorticoid (aldosterone-like) action which
increases cardiac output.
2. Potentiation of the vasoconstrictor action of noradrenaline and angiotensin II, which
increases total peripheral resistance.
3. Decrease in capillary permeability thus maintaining blood volume.
14.Antiemetic action.
Therapeutic uses:
A- Replacement Therapy:
Physiological doses of glucocorticoids are used which minimizes the adverse effects.
1. Acute adrenocortical insufficiency (acute Addisonian crisis) due to sudden withdrawal
of exogenous steroid therapy, or due to stress (trauma or infection). Treatment by
Hydrocortisone sodium succinate IV +
0.9% NaCl IV infusion + glucose 5% IV infusion. Blood transfusion and vasopressor
drugs are sometimes needed.
2. Chronic adrenocortical insufficiency (chronic Addison's disease): treated by oral steroids
having both gluco- and mineralocorticoid actions as cortisol or fludrocortisone (see
preparations).
(Gluco: cortisone acetate orally + generous salt and sugar diet.
Mineralo: DOCA SL, IM, or SC implantation).
B- Suppressive and Supplementary Therapy:
Pharmacological (supra-physiological)doses are used, which may lead to many and serious
adverse effects. Glucocorticoids with no mineralocorticoid activity are needed
1. Suppression of ACTH in treatment of adrenogenital hyperplasia.
2. Anti-allergic in angioneurotic edema, dermatitis, allergic rhinitis, allergic conjunctivitis,
anaphylactic shock.
3. Anti-inflammatory and anti-allergic in bronchial asthma (inhaled steroids as
beclomethasone in prophylaxis, and hydrocortisone sodium succinate IV in status
asthmaticus).
4. Anti-inflammatory and immunosuppressive in auto-immune diseases (collagen diseases)
as rheumatic carditis, R.A., S.L.E., nephrotic syndrome, chronic hepatitis, and ulcerative
colitis (may be given as retention enema).
5. Anti-inflammatory in: acute gouty arthritis resistant to NSAIDs, osteoarthritis (may be
given intra-articular), and cerebral edema (avoid glucocorticoids with salt-retaining
effect).
6. Immunosuppressive after organ transplantation to prevent rejection.
7. Blood diseases as: leukemia (acute lymphocytic leukemia), thrombocytopenic purpura,

agranulocytosis, and hemolytic anemia.
8. Hypercalcemia and hypervitaminosis D (vitamin D intoxication).
9. Shock.
10.Hypertrophic scars and keloids.
11.Respiratory distress syndrome in neonates.
12.Antiemetic.
Preparation Glucocorticoid Mineralocorticoid

(Anti-inflammatory) (Salt retaining) action
action
Short acting glucocorticoids:
1. Cortisone (inactive converted 0.8 0.8
into active cortisol).
2. Cortisol = Hydrocortisone. 1 1
Intermediate acting
glucocorticoids:
1. Prednisone (inactive converted 5 0.8
by the liver into active
prednisolone).
2. Prednisolone and 5 0.8
methylprednisolone. 5 0.5
3. Triamcinolone. 5 0
4. Paramethasone. 10 0
Long acting glucocorticoids:
1. Betamethasone. 30 0
2. Dexamethasone. 30 0
Inhaled Steroids:
1. Beclomethasone.
2. Fluticasone.
3. Budesonide.
Mineralocorticoids:
1. Aldosterone. ± 500
2. Fludrocortisone. 10 150
3. Desoxycorticosterone (DOC). 0 50
4. Desoxycorticosterone acetate 0 50
(DOCA).
DOC and DOCA are ineffective
orally (extensively metabolized);
given IM and SL and DOCA is
given by SC implantation.
1. Cortisone and Prednisone are used only systemicall. Hydrocortisone, prednisolone,

methylprednisolone, triamcinolone, betamethasone, and dexamethasone are given orally,
topically, and by injection.
2. Triamcinolone, Paramethasone, Betamethasone, and Dexamethasone are fluorinated
prednisolone derivatives with very potent anti-inflammatory action and almost no Na+ and
water retention.
Adverse Effects Contraindications
Toxic effects from sudden withdrawal: 1. Sudden withdrawal of

1. Suppression of HPA axis and adrenal atrophy which glucocorticoids after
leads to acute adrenocortical insufficiency if prolonged use.
exogenous steroids are suddenly stopped after 2. Cushing syndrome.
prolonged therapy. 3. Peptic ulcer.
2. Corticosterone withdrawal syndrome: fever, myalgia, 4. Diabetes mellitus.
arthralgia, and malaise. 5. Osteoporosis.
Toxic effects due to continued use of large doses: 6. Repeated intra-articular
1. Iatrogenic Cushing' syndrome: moon face-buffalo injections.
hump-trunkal obesity- wasting of limbs. 7. Hypertension.
2. Iatrogenic peptic ulcer and acute pancreatitis. 8. CHF.
3. Hyperglycemia and glucosuria. 9. In digitalis toxicity and
4. Skeletal muscle wasting and myopathy- osteoporosis- with K+ losing
sublaxation of joints-delayed wound healing-growth diuretics.
retardation in children.
5. Na+ and water retention leading to edema and weight 10.Uncontrolled
gain, elevation of ABP, and may cause HF. infections.
6. Hypokalemia (hypokalemic alkalosis). 11.Thrombo-embolic
7. Hypocalcemia. diseases.
8. Immunosuppression and masking of inflammation 12.Glaucoma.
leading to infection by T.B., viral and fugal infections 13.Psychotic patients.
(as candidiasis). Inhaled steroids cause oropharyngeal 14.Pregnancy.
candidiasis and dysphonia.
9. Increased blood coagulability and thrombo-embolic

manifestations.
10. Catarct and glaucoma.
11. Hirsutism and menstrual disturbances.
12. CNS manifestations: psychosis.

13. Teratogenicity.
*Precautions during long-term therapy:

1. Never stop glucocorticoids suddenly after long term therapy to avoid acute adrenal
insufficiency. Glucocorticoids should be gradually withdrawn; the longer the duration of
therapy the slower must be the withdrawal.
2. Increase the dose during periods of stress as infections.
3. Diet should be rich in proteins, Ca2+, and K+ but low in Na+.
Anabolic steroids may be added.
4. Follow up:
• A.B.P.
• Body weight.
• Glucose in blood and urine.
• Hidden infections.
• Peptic ulcer (ask about heartburn and other symptoms).
• Osteoporosis (X-ray of the spine every 6 months).
5. Use the smallest effective dose.
Mineralocorticoids
1. Aldosterone:
• Synthesized by the adrenal cortex (zona glomerulosa).
• Synthesis and release are not controlled by HPA but is controlled by:
1. Renin-Angiotensin system.
2. Na+ and K+ levels in blood (low Na+ and high K+ stimulate aldosterone release
directly).
• Mechanism of action: as steroid hormones.
• Actions:
1. On the kidney: aldosterone acts on the distal convoluted tubules (D.C.T.) leading to salt
and water reabsorption (retention) and excretion of potassium (and to a less extent H+
and Mg2+) in urine.
2. On GIT, salivary glands, and sweat glands: the same action as on the kidney but much
weaker.
N.B.:
• In cases of prolonged hypervolemia due to hyperaldosteronism there is decreased
sensitivity of D.C.T. to the salt-retaining action of aldosterone (as a compensatory
mechanism to correct hypervolemia) but K+ excretion persists. Escape phenomenom
does not occur in other tissues (GIT, salivary and sweat glands).
• The action of aldosterone is potentiated by Cortisol and Estrogen, and is antagonized by

Progesteron and Spironolactone.
• Aldosterone has no therapeutic uses but aldosterone-like drug "Carbenoxolone" is a
mucosal protective agent in treatment of peptic ulcer, and aldosterone antagonists as
"Spironolactone and Eplerenone" are used as K+-sparing diuretics (spironolactone is
steroid in structure and may cause sexual dysfunction in males and females).
2. Synthetic Mineralocorticoids:
• Fludrocortisone. -DOC -DOCA (see table of preparations).
Inhibitors of Steroid Synthesis (Adrenostatics)

Adrenostatics are used mainly for treatment of Cushing\s disease, which is either ACTH-
dependent or ACTH-independent.
A- ACTH-dependent Cushing: treated by drugs that inhibit release of ACTH from the anterior
pituitary:
1. Bromocriptine:
• Direct Dopaminergic (D2) agonist.
• Therapeutic uses:
1. Parkinsonism.
2. Hyperprolactinemia.
3. Suppression of lactation (much safer than estrogen).
4. ACTH-dependent Cushing's disease.
5. Acromegaly (bromocriptine inhibits release of growth hormone).
2. Cyproheptadine: it has additional antihistaminic (antiallergic) and antiserotonin actions.
B- ACTH-independent Cushing's disease:

1. Metyrapone (metopyrone):
• Inhibits synthesis of cortisol by inhibition of 11-β hydroxylase.
• Uses:
1. Treatment of ACTH-independent Cushing's disease.
2. To test the ability of the anterior pituitary to secrete ACTH.
2. Mitotane: antimitotic used in inoperable tumors of the adrenal cortex.
3. Aminoglutethimide and 4-Ketoconazole inhibit conversion of cholesterol into
pregnenolone which is the first step in steroidogenesis. Ketoconazole is used mainly as
an antifungal drug, it also inhibits androgen synthesis (may cause gynecomastia) and is a
potent HME inhibitor and may markedly decrease metabolism of other drugs as
theophylline leading to toxicity.
The most serious adverse effect of ketoconazole is hepatotoxicity.
Thyroid Hormones and Antithyroid Drugs

Thyroid Hormones
Thyroid gland secretes thyroid hormones (thyroxin) from follicular cells, and calcitonin from
parafollicular C cells.
Steps of synthesis of thyroid hormones:

1. Dietary iodine is absorbed as iodide.
2. Iodide trapping: active uptake of iodide into follicular cells which requires energy obtained
by Na+ / K+ ATPase. Iodide trapping is stimulated by TSH and is inhibited by cardiac
glycosides as ouabain, and by ionic inhibitors as thiocyanate and perchlorate.
3. Oxidation: Iodide is oxidized into iodine by peroxidase enzyme.
4. Organification of iodine: iodine binds to tyrosine in thyroglobulin to form "mono-
iodotyrosine" (MIT) and "di-iodotyrosine" (DIT) which are biologically inactive.
5. Coupling: MIT is coupled to DIT to form "tri-iodothyronine" =T3, and DIT is coupled to
DIT to form "tetra-iodothyronine" =T4.
6. Storage: T3 and T4 are stored within thyroglobulin of thyroid follicles in a ratio of 1:5.
7. Proteolysis and release: proteolysis of thyroglobulin by protease enzyme and free T3 and T4
are released into the circulation. MIT and DIT are also released from thyroglobulin into
follicular cells where they are de-iodinated by thyroid de-iodinase and iodine is re-utilized
to synthesize T3 and T4 (congenital deficiency of thyroid de-iodinase may lead to
hypothyroidism).
Control of thyroid hormones:

1. Thyrotropin releasing hormone (TRH) from the hypothalamus stimulates the anterior
pituitary to synthesize thyroid stimulating hormone (TSH).
2. TSH is a polypeptide acting on cell membrane receptors and increases c-AMP leading to
stimulation of iodide trapping and synthesis of thyroid hormones, and increases the size and
vascularity of the gland.
3. T3 and T4 exert a negative feed-back inhibition on TRH and TSH.
4. Autoregulation: the thyroid gland regulates iodide uptake and hormone synthesis by an
"intrathyroid mechanism" according to the level of iodide in the blood: excess iodide
decreases iodide uptake (trapping) and inhibits organification if the gland is exposed to such
excess iodide for a period not more than 2 weeks.
If the gland is exposed to iodide excess for longer periods this autoregulatory mechanism
"wears off" (thyroid adaptation).
5. Thyroid stimulating immunoglobulin (TSI): is synthesized by lymphocytes in patients with

hyperthyroidism and it stimulates TSH receptors on thyroid gland leading to release of huge
amounts of thyroid hormones. It was known as "long acting thyroid stimulator" (LATS).
Pharmacokinetics:
Absorption: thyroid hormones are well absorbed orally; about 95% of T3 and 65% of T4 are
absorbed orally. Absorption of both T3 and T4 is reduced in myxedema, and absorption of T4 is
reduced in the presence of food, antacids, and iron.
Distribution:
• Thyroid hormones are distributed to all tissues.
• They are highly bound to plasma proteins (>99%) mainly to globulin known as
thyroxine binding globulin (TBG) and to a lesser extent to thyroxine binding prealbumin
(TBPA).
Only 0.04% of T4 and 0.4% of T3 are free.
• TBG increases by estrogen therapy and during pregnancy and is reduced by
hypoproteinemia.
• Drugs as salicylates and phenytoin displace thyroid hormones from plasma globulin and
may increase free hormones which reduces TSH by negative feed-back and may
interfere with radioactive iodine uptake test.
Fate:
1. Peripheral (Tissue) De-iodination: is the primary pathway.
T4 is de-iodinated into more active T3 (30%) into reverse T3 (40%) which is biological inactive,
and the liberated iodine is re-trapped by the thyroid gland.
N.B.: peripheral de-iodination is inhibited by:
• Propranolol.
• Propylthiouracil.
• Ipodate sodium: iodinated contrast medium used in radio-diagnosis. It also inhibits
release of T4 and T3.
• Hydrocortisone.
2. Conjugation: with glucuronic acid and sulphate, and the conjugated metabolites are
excreted partly in bile (and undergo entero-hepatic circulation) and partly in urine.
Pharmacodynamics:
Thyroid hormones enter the cell and bind to nuclear receptors, and thyroid hormone-receptor
complex binds to DNA and induce transcription of DNA into m-RNA thus inducing synthesis
of various enzymes.
1. Calorigenic action: increase oxygen consumption, heat production, basal metabolic rate, and
sweating (as adrenaline but more potent and slower onset of action).
2. Growth: essential for mental, physical, and sexual development both directly and indirectly
by stimulation of release and effect of growth hormone.
3. CVS: increase number and sensitivity of β1-receptors (supersensitivity and upregulation)

leading to cardiac stimulation.
4. GIT: increase cholinergic activity of GIT leading to stimulation of motility and secretion.
5. CNS stimulation.
6. Metabolic actions: glycogenolysis and increase glucose absorption, uptake and utilization,
decrease lipogenesis, and decrease cholesterol level in blood.
Therapeutic uses:
1. Replacement therapy in hypothyroidism: myxedema and myxedema coma in adults, and
cretinism in children. Treatment of cretinism should be started as early as possible.
2. Suppressive therapy: to suppress TSH to reduce size of the gland in puberty goiter and
Hashimoto's disease, and to inhibit growth of TSH-dependent follicular carcinoma.
3. Treatment of hypercholesterolemia in euthyroid patients by D-thyroxine which is
biologically inactive.
Preparations:
1. Levothyroxine =synthetic L-T4: less potent than T3-delayed onset because of long t 1/2 (7
days)-low cost- and not antigenic.
It is the preparation of choice: cheap –stable –well absorbed –long acting.
2. Liothyronine = synthetic L-T3: 4 times as potent as T4-rapid onset because of shorter t 1/2
(1.5 days) so it is used in emergencies as myxedema coma I.V. and acute psychosis -high
cost-and not antigenic.
3. Liotrix = synthetic mixture of T4 and T3 in a ratio of 4:1, it is potent, high cost, and not
antigenic.
4. Dried thyroid extract obtained from animals is obsolete as it was highly antigenic.
Adverse effects:
1. Tachycardia, palpitation, arrhythmia, and anginal pains.
2. Diarrhea.
3. Nervousness, tremors, and insomnia.
Contraindications:
1. Angina pectoris.
2. Arrhythmias.
Antithyroid Drugs
Antithyroid drugs are used in treatment of hyperthyroidism (thyrotoxicosis) which results from
a hyperplastic thyroid nodule or due to diffuse hyperplasia of the gland (Grave's disease). It is
not controlled by TSH but is controlled by TSI (LATS).
Hyperthyroidism is more common in females and is characterized by: nervousness, tremors,

insomnia, tachycardia, palpitations, anginal pains, increased appetite with weight loss,
sweating and heat intolerance, and exophthalmos in Grave' disease.
Antithyroid drugs: they include the following groups:

1. Thioamides: Carbimazole-Methimazole-Propylthiouracil (PTU).
2. Ionic Inhibitors: Potassium Perchlorate- Thiocyanate. They inhibit iodide trapping and
are obsolete due to the high incidence of fatal aplastic anemia.
3. Iodides: Potassium iodide- Lugol's iodine.
4. Radioactive Iodine: I131.
5. Adjuvant Drugs: β-Blockers especially Propranolol. It is used to control CVS and CNS
symptoms of hyperthyroidism. Propranolol is also given IV in treatment of thyrotoxic crisis
(storm) and is "life-saving".
Advantages of Propranolol:
1. It is given both orally and parenterally (in thyrotoxic crisis).
2. It inhibits peripheral de-iodination.
3. It has no ISA (proranolol is a pure antagonist).
4. It is lipophilic, i.e. it can pass BBB and controls CNS manifestations of thyrotoxicosis as
tremors and insomnia.
1. Thioamides
Carbimazole –Methimazole -Propylthiouracil (PTU).
Source: synthetic.
Chemistry: thiourea derivatives.
Pharmacokinetics:
Absorption:
Absorbed orally. PTU is incompletely absorbed and can also be given IV in thyrotoxic crisis.
Distribution:
• Highly bound to plasma proteins.
• Concentrated in thyroid gland.
• Pass BBB.
• Pass placental barrier and may cause fetal goiter or cretinism. PTU is the safest thioamide in
pregnancy (PTU does not cross placental barrier).
Fate:
• Carbimazole is a prodrug and is metabolized into active methimazole.
• Thioamides are metabolized by the liver by conjugation and metabolites are excreted in
urine. They are excreted in breast milk and affect suckling infants.
Pharmacodynamics:
1. Inhibit peroxidase enzyme and accordingly inhibit oxidation of iodide into iodine.
2. Inhibit organification of iodine and formation of MIT and DIT.
3. Inhibit coupling of MIT with DIT and DIT with DIT thus inhibiting synthesis of T3 and T4.
4. PTU also inhibits peripheral de-iodination.
5. Inhibition of iodine absorption from GIT.
Inhibition of synthesis of "new" thyroid hormones but no effect on iodide uptake and no effect
on release of already formed and stored hormones. That is why they have delayed onset of
action (about 2 weeks) until the stored hormones are depleted and ☻due to long t1/2 of thyroid
hormones.
Therapeutic uses:
1. Treat mild cases of hyperthyroidism. They are given until the patient is "euthyroid" then a
smaller maintenance dose is given to prevent recurrence.
2. Temporary control of hyperthyroidism in patients treated by radioactive iodine which has
very delayed onset of action (about 2-3 months).
3. Pre-operative preparation before subtotal thyroidectomy to decrease the stored hormones
before operation, but they have the disadvantage of increasing the size and vascularity of
the gland (corrected by iodides before thyroidectomy).
4. PTU is also used in thyrotoxic crisis.
Adverse effects:
1. Allergy: is common and may manifest as skin rash, pruritis, fever, cholestatic hepatitis and
jaundice, or nephritis.
2. Bone marrow depression (blood dyscrasias): is the most dangerous and is usually in the
form of toxic (dose-dependent) agranulocytosis. Frequent blood count should be performed
to detect agranulocytosis. Low-grade fever and sore throat are the earliest manifestations of
agranulocytosis which is treated by: Stopping the drug- fresh blood transfusion-broad
spectrum penicillins-anabolic steroids.
3. Arthralgia and joint stiffness.
4. Gut upsets: anorexia, nausea, vomiting, and diarrhea.
5. Increase size and vascularity of the gland: thioamides ↓ T3 and T4 → ↑TSH (reduced
negative feed-back inhibition) → increased size and vascularity of the gland.
6. Goitre and hypothyroidism in fetus and suckling infants if given during pregnancy and
lactation.
7. Other adverse effects: headache-depigmentation and loss of hair –aggravate exophthalmos.
Contraindications:
1. Pregnancy and lactation.
2. Allergy to thioamides.
2. Iodides
Include: potassium iodide and Lugol's iodine (5% iodine in 10% potassium iodide).
Mechanism of action and actions:
1. Antagonizes the action of TSH and decreases iodide trapping and reduces the size and
vascularity of the gland if given for 10-15 days (see autoregulation).
2. Iodide also inhibits protease enzyme and inhibits release of stored hormones and so it has a
rapid onset of action.
3. Inhibition of iodide organification.
Therapeutic uses:
1. Pre-operative preparation before subtotal thyroidectomy.
2. Treatment of thyrotoxic crisis (with PTU and Propranolol).
3. Prophylaxis of goiter (added to salt, bread, and water).
N.B.: iodine is also used as "saline expectorant" in treatment of productive cough.
Adverse effects:
1. Allergy: skin rash, angioedema, and anaphylaxis.
2. Iodism: iodide is concentrated in exocrine glands as the salivary glands, nasal glands,
lacrimal glands, and bronchial glands leading to irritation and increased secretion which
causes: metallic taste-sialadenitis and salivation-rhinorrhea (runny nose)- lacrimation-
productive cough.
It also causes nausea, vomiting, and diarrhea.
3. Long use may lead to goiter.
3- Radioactive Iodine (I131)

• I131: given orally and is trapped by -and stored in- the thyroid gland.
• It emits destructive β- and γ particles which have low penetrability and lead to
destruction of follicular cells without damaging surrounding tissues.
• The onset of action is very delayed (1-2 months) and maximal response appears after
another 2 months, and the patient is temporarily treated by thioamides and propranolol
until its effect appears.
Indications:
1. Hyperthyroidism in patients who are unfit for surgery as old patients and cardiac patients.
2. Recurrence of hyperthyroidism after surgery.
3. Failure to control hyperthyroidism by long term therapy with thioamides.
4. Metastatic follicular carcinoma of the thyroid gland. Radioactive iodine uptake can be
increased by TSH or by decreasing the size of the gland by surgery or irradiation.
5. I132 is used only for diagnosis of thyroid function.
Adverse effects:
1. Hypothyroidism due to excessive destruction of thyroid follicles (the main adverse effects).
2. Induces fetal and neonatal hypothyroidism (cretinism) if given in pregnancy and lactation as
it passes placental barrier and is excreted in breast milk.
3. Induce carcinogenicity in thyroid gland after several years (15-20 years).
4. Delayed onset of action.
5. Thyroid storm due to release of thyroid hormones.

6. Leukemia.
7. Repeated doses may be required.
Contraindications:
1. Pregnancy and lactation.
2. Young patients (below 40 years).
Treatment of thyrotoxic crisis (storm):

It usually occurs in patients undergoing thyroidectomy who are not adequately prepared.
Manifestations include CVS stimulation, CNS stimulation (convulsions), hyperpyrexia, and
dehydration.
Treatment:
1. Propranolol IV (life saving).
2. PTU IV.
3. Potassium iodide IV.
4. Hydrocortisone IV (antistress and inhibits peripheral de-iodination).
5. Symptomatic treatment: IV fluids as 0.9% NaCl to correct dehydration – cold fomentations-
anticonvulsants as diazepam IV.
Pre-operative Preparation:
1. Thioamides until the patient is "euthyroid".
2. Iodide for 10-15 days to reduce size and vascularity of the gland.
3. Propranolol.
Sex Hormones
All sex hormones are steroid in nature and act on "nuclear" receptors.
I. I-Androgens:
Testosterone and androsterone. Used as replacement therapy in male hypogonadism.
Contraindicated in cancer prostate.
Anabolic steroids:
Examples: nandrolone – methandrostenolone.
Indications:
1. Aplastic anemia.
2. Anemia associated with acute renal failure .
3. Osteoporosis.
4. General wasting.
Adverse effects:
1. Precocious puberty in children.
2. Virilization in females (deepening of voice, hirsutism, and acne).
3. Testicular atrophy in adult males.
Anti-Androgens:
1. Flutamide and Cyproterone: competitive antagonists on androgen receptors. Used in: cancer
prostate-hirsutism-male hypersexuality.
2. Finasteride: inhibits 5-α reductase and thus inhibits conversion of testosterone into more
active dihydrotestosterone in prostate and other tissues except skeletal muscles. Used in
benign prostatic hyperplasia (BPH).
3. Ketoconazole: Antifungal and also inhibits synthesis of androgens and cortisol.
4. Spironolactone: K+-sparing diuretic-aldosterone antagonist.
5. Cimetidine: H2-antagonist.
Male contraceptives:
1. Gossypol: it destroys seminiferous tubules and decreases sperm count. The main adverse
effect is hypokalemia (may cause transient paralysis).
2. Testosterone in large doses.
3. Cyproterone (anti-androgen) + levonorgestrel (progestogen).
II. II-Progestogens:
Therapeutic uses:
1. Contraception; either alone (minipill) or combined with estrogen.
2. Dysmenorrhea and premenstrual tension.
3. Endometriosis and endometrial carcinoma.
4. Threatened and habitual abortion.
Adverse effects:
1. Sodium and water retention.
2. Weak androgenic effect of some preparations leading to acne vulgaris, hirsutism, and
deepening of voice.
3. Psychic depression.
4. Elevation of LDL-cholesterol and atherosclerosis.
Anti-Progesterones:
1. Mifepristone:
• Blocks progesterone receptors and in large doses it blocks also glucocorticoid (cortisol)
receptors.
• Uses:
1. Termination of early pregnancy given with PG analog as misoprostol, as it sensitizes
the uterus to prostaglandins.
2. Post-coital contraceptive as it inhibits implantation.
2. Danazol:
• Binds to progesterone, androgen, and glucocorticoid (cortisol) receptors.
• It inhibits the mid-cycle surge of FSH and LH.
• It inhibits steroid synthesis in the ovaries leading to reduced ovarian function and
endometrial atrophy.
Uses: Endometriosis – Fibrocystic disease of breast – Menorrhagia-Gynecomastia.
Adverse effects:
1. Deepening of voice, decrease breast size, and changes in libido in females.
2. Edema and weight gain due to salt and water retention.
3. Hot flushes and headache.
4. Hepatic impairment.
5. Teratogenic.
Contraindications: Pregnancy – Liver diseases.
III. Estrogens:
Being a steroid; estrogen is lipid soluble and crosses the cell membrane by simple diffusion.
Estrogen binds to "nuclear" estrogen receptors (ER) which are of 2 subtypes: ERα and ERβ.
ERα stimulates gene transcription whereas ERβ inhibits transcription.
(The actions of estrogen are mostly due to stimulation of ERα).
Indications:
1. Replacement therapy in primary hypogonadism.
2. Hormonal Replacement Therapy (HRT) in postmenopausal syndrome (climacteric
syndrome) to prevent osteoporosis, hot flushes, atrophic or senile vaginitis, and
hyperlipidemia causing atherosclerosis and ischemic heart diseases.
3. Dysmenorrhea (with progestins to suppress ovulation).
4. Endometriosis.
5. Oral Contraception.
6. Suppression of lactation (bromocriptine is safer).
7. Functional uterine bleeding.
8. Postmenopausal cancer breast (some cases).
9. Acne vulgaris and Hirsutism.
10.Cancer prostate.
N.B.: Treatment of dysmenorrhea: 1-oral contraceptives 2-NSAIDs (avoid aspirin as it may
increase bleeding) 3-β2-agonists as ritodrine
4-CCBs as nifedipine.
Preparations:
1. Steroidal preparations:
• Estradiol (most potent), estriol, and estrone (natural): ineffective orally due to extensive
hepatic metabolism. Estradiol is given by IM injection.
• Premarin is a sulphate-conjugated estrogen which is effective orally
• Ethinyl estradiol and Mestranol (semisynthetic): effective orally.

2. Non-Steroidal: Diethylstilbosterol (synthetic) effective orally.
N.B.: estrogens may be given as vaginal pessaries or creams, and also as transdermal patches
as they are well absorbed from the skin.
Adverse effects:
1. Nausea mainly and less commonly vomiting.
2. Breast tenderness (mastalgia).
3. Salt and water retention leading to edema, weight gain, hypertension, and heart failure.
4. Decreased libido (corrected by adding progestins).
5. Headache and increased frequency of migraine.
6. Increase TBG and CBG, and elevate sedimentation rate.
7. Failure of withdrawal bleeding (misinterpreted as pregnancy).
8. Hyperglycemia and impaired glucose tolerance.
9. Fibroids and Endometrial carcinoma (corrected by adding progestins).
10.Premenopausal breast carcinoma (estrogen-dependent tumors).
11.Vaginal carcinoma in females whose mothers received estrogen (diethylstilbestrol) as post-
coital pills (see later).
12.Thromboembolism and antagonizes the action of oral anticoagulants as warfarin due to
increase in hepatic synthesis of coagulation factors II (prothrombin), VII, IX, and X. This
may cause deep venous thrombosis (DVT) leading to pulmonary embolism. Acute
myocardial infarctions and cerebrovascular strokes may also occur.
The risk of thromboembolism is higher in females over 35 years and in smoker females.
13.Cholestatic hepatitis and jaundice, gall stones, cholangitis, and cholecystitis.
14.Depression.
15.Feminization in males with cancer prostate treated by estrogen.
Contraindications:
1. Hypertension, ischemic heart disease, and heart failure.
2. Migraine.
3. Diabetes mellitus.
4. Fibroids and endometrial carcinoma (estrogen-dependent).
5. Pre-menopausal breast carcinoma (estrogen-dependent).
6. Thromboembolic diseases.
7. Liver and gall bladder diseases.
8. Depression.
9. Females over 35 years to avoid thromboembolism, hypertension, DM, especially in obese
and smokers.
10.Undiagnosed vaginal bleeding (which may be due to endometrial carcinoma).
Drug interactions:
A-Pharmacokinetic interactions:
1. HME inducers as rifampicin, phenytoin, and phenobarbitone increases clearance of
estrogens (contraceptives) and cause failure of therapy (conception).
2. HME inhibitors as cimetidine decrease clearance of estrogens and may increase adverse
effects.
3. Estrogens have mild HME inhibitory action and may reduce clearance of other drugs as
digitoxin and aminophylline.
4. Mineral oils as paraffin oil (lubricant purgative used in treatment of constipation) reduce
oral absorption of steroid hormones.
B-Pharmacodynamic interactions:
1. Estrogens antagonize the action of: anticoagulants, diuretics, antihypertensives and
antidiabetics.
2. Tobacco smoking and anti-fibrinolytics (as aminocaproic acid and tranexamic acid)
increase the incidence of thromboembolism in patients receiving estrogens.
Anti-Estrogens:
I-Selective Estrogen Receptor Modulators (SERMs):
These drugs are "tissue-selective", i.e they stimulate ERα in the bone, lipoproteins, blood
coagulation, and endometrium leading to "estrogen-like actions" in these tissues. On the other
hand; they stimulate ERβ in the anterior pituitary and breast leading to "anti-estrogen" actions.
1. Clomiphen: was previously considered a "partial agonist" on estrogen receptors in
anterior pituitary, but mow it is considered a SERM that stimulates ERβ in the anterior
pituitary → inhibition of negative feed-back inhibition on FSH and LH → increase in FSH
and LH → induction of ovulation.
It may cause multiple ovulations and multiple twins –hot flushes –nausea –constipation –
headache –reversible hair loss –visual disturbances.
2. Tamoxifen: was also considered as a "partial agonist" on estrogen receptors in the breast,
but now it is regarded as a SERM that stimulates ERβ in the breast and is accordingly used
in treatment of estrogen-dependent (pre-menopausal) breast carcinoma.
It may cause hot flushes and nausea.
3. Raloxifen: a SERM which stimulates ERα in bone and lipids and is accordingly used in
prevention and treatment of postmenopausal osteoporosis and hyperlipidemia without
inducing breast carcinoma.
4. Toremifene: a SERM used in cancer breast.
II-Aromatase inhibitors (AIs): inhibit synthesis of estrogen from androgen precursor by

inhibition of aromatase enzyme.
A- A-Steroids: irreversible aromatase inhibitors (suicide inhibitors) as Exemestane. Used in
cancer breast resistant to tamoxifen.
B- B-Non-steroids: reversible aromatase inhibitors used to induce ovulation, as Letrozole.
Contraceptives
Methods of contraception:
1. Hormonal contraceptives: either orally or parenterally.
2. Intrauterine device (IUD).
3. Mechanical contraceptives (male condom and vaginal diaphragm).
4. Chemical contraceptives (spermicides).
5. Physiological methods (safe period).
6. Sterilization in females or males.
1-Hormonal Contraceptives:
They are administered either: orally, IM, or by S.C. implantation.
ORAL CONTRACEPTIVES:
They contain estrogen alone, progestin alone, or more commonly combination of estrogen and
progestin in the same "pill".
A- Combined Method:
Pills contain combination of estrogen (ethinyl estradiol) and progestin (norethindrone,
levonorgestrel, or desogestrel which is less androgenic). They are started at the 5th day of the
menstrual cycle and used continuously for 21 days then stopped to allow menstruation and are
subdivided into:
1. Monophasic pills:
Pills contain fixed amount of estrogen (0.035 mg. ethinyl estradiol) and progesterone (0.5 mg.
norethindrone).
2. Biphasic pills:
There are 2 types of pills:
• Pills containing 0.035 mg. ethinyl estradiol + 0.5 mg. norethindrone given for 10 days
(from day 1 till day 10).
• Pills containing 0.035 mg. ethinyl estradiol + 1 mg. norethindrone for the next 11 days
(from day 11 till day 21).
3. Triphasic pills:
There are 3 types of pills:
• Pills containing 0.03 mg = 30 µg. ethinyl estradiol + 0.05mg. = 50 µg. norgestrel given
from day 1 till day 6 (for 6 days).
• Pills containing 0.04 mg. =40 µg. ethinyl estradiol + 0.075 mg. =75µg. norgestrel given
from day 7 till day 11 (for 5 days).
• Pills containing 0.03 mg. =30 µg. ethinyl estradiol + 0.125 mg. =125 µg.
norgestrel given from day 12 till day 21 (for 10 days).
Advantages:
1. Most effective.
2. Lower amounts of hormones are used.
3. Similar to the natural menstrual cycle.
4. Less adverse effects than other oral contraceptive methods.
B- Minipill:
Pills contain progestogen only (norethindrone or levonorgestrel) given continuously without
stop.
Disadvantages: "Break-through bleeding" is common, irregular menstrual cycles, and less
effective than combined method.
N.B.: Continous progestin only contraceptives include:
1- Minipills orally.
2- Medroxyprogesterone 150 mg. is given IM every 3 months (depot therapy), used in
lactating females as it does not suppress lactation.
3- L-norgestrel is given as SC implant which lasts about 5 years (6 capsules are placed SC in
upper arem).
a. Advantages: effective –cheap-does not depend on patient's compliance-reversible.
b. Disadvantages: irregular menstruation-headache.
4- I.U.D.: release progestin locally.
C-Post-Coital Pills (Emergency Pills =Morning after = Rape pills):

1. Estrogen only (diethylstilbestrol) is given within 72 hours after coitus (sexual intercourse)
and for 5 days.
2. Estrogen + progestogen given twice (every 12 hours) within 72 hours after intercourse.
3. Mifepristone + Misoprostol once (see before).
1. Inhibition of FSH release by estrogen and inhibition of ovarian follicle development.
2. nhibition of LH release by progestins mainly and accordingly inhibition of ovulation.
3. ncrease the viscosity of cervical mucus which prevents sperm penetration (by progestins
mainly).
4. Induce endometrial changes which interfere with implantation (by both estrogen and
progestins).
5. Interfere with coordinated contraction of the uterus, cervix, and Fallopian tubes which
interferes with fertilization and implantation (by both estrogen and progestins).
Adverse effects:
1. Nausea.
2. Breast tenderness (mastalgia).
3. Salt and water retention leading to edema and weight gain.
4. Decreased libido (corrected by adding progestins).
5. Headache and increased frequency of migraine.
6. Increase TBG and CBG, and elevate sedimentation rate.
7. Failure of withdrawal bleeding.
8. Break-through bleeding due to using progestin only or small doses of combination pills.
9. Skin pigmentation, hirsutism, and acne due to progestins having androgenic effects.
10.Vaginal infections and bacteruria.
11.Amenorrhea.
12.Hyperglycemia and impaired glucose tolerance.

13.Fibroids and Endometrial carcinoma.
14.Premenopausal breast carcinoma.
15.Thromboembolism (due to inhibition of anti-thrombin III) which may cause deep venous
thrombosis (DVT), acute myocardial infarctions, and cerebrovascular strokes. Progestins
increase LDL-cholesterol and triglycerides and increase the risk of atherosclerosis.
16.Cholestatic hepatitis and jaundice, gall stones, cholangitis, and cholecystitis.
17.Depression.
Contraindications:
1. Hypertension, ischemic heart diseases, and heart failure.
2. Migraine.
3. Diabetes mellitus.
4. Fibroids and Endometrial carcinoma.
5. Pre-menopausal breast carcinoma.
6. Thromboembolic diseases.
7. Liver and gall bladder diseases.
8. Depression.
9. Females over 35 years to avoid thromboembolism, hypertension, DM, especially in obese
and smokers.
10.Undiagnosed vaginal bleeding (which may be due to endometrial carcinoma).
Drug interactions: see estrogen.
Pituitary Hormones
Anterior Pituitary Hormones
1. Growth Hormone (GH) = Somatotropin: polypeptide –synthesized by recombinant
DNA technology-used in treatment of dwarfism (replacement therapy, given before closure
of epiphyses).
2. Gonadotrophins = FSH and LH: used to induce ovulation. They are prepared as
human menopausal gonadotrophoins (hMG contains both FSH and LH) and human
chorionic gonadotrophins (hCG contains LH).
3. Prolactin: inhibited by the action of hypothalamic dopamine on D2-receptors (dopamine =

PIF). D2-agonists as bromocriptine are used in treatment of hyperprolactinemia and to
suppress lactation. D2-antagonists as chlorpromazine and metoclopramide, and drugs
reducing dopamine level in CNS as α- methyldopa and reserpine cause hyperprolactinemia.
Drugs used to induce ovulation:

1. Clomiphen (anti-estrogen).
2. Bromocriptine.
3. Gonadotrophins (hMG and hCG).

4. Gonadotrophin releasing hormone = GnRH (released from hypothalamus) and its synthetic
analogues (leuprolide and nafarelin). GnRH are also used to induce spermatogenesis.
They should be given "intermittently" or as "pulsatile" therapy to induce release of
gonadotrophins.
It should be noted that "continous" administration of GnRH causes "desensitization" of the
anterior pituitary leading to inhibition of gonatrophins, androgens, estrogens and progesterone,
and endometrial atrophy. That is why continous GnRH analogues are used in treatment of
endometriosis, ovarian cysts, uterine fibroids, central precocious puberty, as well as in cancer
prostate.
N.B.: Cancer prostate is treated by:
1. Anti-androgens as Flutamide and Cyproterone.
2. GnRH analogues as Leuprolide and nafarelin (continuously).
3. estrogen.
4. T.S.H.
5. A.C.T.H.
Posterior Pituitary Hormones

1-Oxytocin: polypeptide- causes uterine contraction and contraction of myo-epithelial cells
of breast.
Uses: induction of labor in uterine inertia – control post partum hemorrhage-milk ejection in
breast engorgement.
Syntocinon is a synthetic drug.
Oxytocic Drugs= Uterine Stimulants:
1. Oxytocin and syntocinon.
2. PG analogs as misoprostol and dinaprostone.
3. Ergometrine and methylergometrine.
They are used in induction of labor and abortion, and to control postpartum hemorrhage.
Tocolytic Drugs= Uterine Relaxants:
1. NSAIDs.
2. β2-agonists as ritodrine.
3. CCBs as nifedipine.
They are used in dysmenorrhea, premature labor, threatened abortion, and contraction ring of
the uterus.
2-Anti-Diuretic Hormone (ADH) = Vasopressin:

Polypeptide- acts on specific V-receptors:
• V1-receptors in smooth muscles → contraction (as V.C. and spasmogenic on smooth

muscles of GIT).
• V2-receptors in collecting tubules → facultative water reabsorption.
Indications:
1. Replacement therapy in pituitary (central) type of diabetes insipidus.
2. To stop bleeding in esophageal varices in patients with portal hypertension.
3. Paralytic ileus.
It is given by injection or by nasal spray (may cause nasal ulcers).
N.B.: Types and treatment of diabetes insipidus:

1. Pituitary type: treated by ADH- carbamazepine-chlorpropamide-metformin.
2. Nephrogenic type: caused by ADH antagonists as demeclocycline-lithium-
methoxyflurane, and treated by thiazides (amiloride is used in treatment of lithium-
induced nephrogenic diabetes insipidus).
Hypothalamic Hormones
1. Gonadotrophin releasing hormones: see before.
2. Somatostatin (GH inhibitory hormone): also secreted in gut and pancreas. In addition to
its inhibitory effect on GH; it also inhibits insulin, glucagon, HCl, and gut motility.
Octreotide is a synthetic analog used in treatment of bleeding esophageal varices.
Factors Affecting Calcium Homeostasis

Serum calcium (Ca2+) is maintained at a normal range of 9-11 mg. % by the action of
parathyroid hormone (parathormone), calcitonin, and vitamin D mainly and to a less extent by
the effect of glucocorticoids and estrogen. Some and drugs as thiazide and loop diuretics,
biphosphonates may affect serum calcium.
Hormone Actions Indications Routes of
administration
1. Parathormone • Activation of 1. Treatment of I.M. (ineffective
(polypeptide): Gs coupled hypoparathyroidism orally).
membrane causing
receptors and hypocalcemia and
increase c- tetany.
AMP. 2. Intermittent use of
• Increases small doses
serum Ca2+ stimulates bone
and decreases growth in
phosphate. osteoporosis.
(Teriparatide is a
recombinant
parathormone).
2. Calcitonin • Activation of 1. treatment of I.M., S.C., nasal

(polypeptide): membrane hypercalcemia. spray (ineffective
receptors. 2. Post-menauposal orally).
• Decreases osteoporosis.
serum Ca2+ 3. Paget's disease of
and phosphate. bone.
3. Vitamin D • As steroid 1. Hypocalcemia and Oral and I.M.
(steroid): hormones. tetany.
• Increases 2. Rickets and
serum Ca2+ osteomalacia.
and phosphate. 3. Post-menauposal
osteoporosis with
dietary Ca2+.
Other Factors Affecting Calcium Homeostasis:

1. Bisphosphonates: inhibit bone resorption- used in: osteoporosis- Paget's disease –
hypercalcemia associated with malignancy. Examples: sodium etidronate , alendronate,
risedronate and pamidronate.
2. Estrogens and SERM as Raloxifen: inhibit parathormone-induced bone resorption in
menopause, used it treatment and prophylaxis of postmenopausal osteoporosis.
3. Thiazide diuretics: decrease Ca2+ excretion in urine and cause hypercalcemia, used in
hypocalcemia and idiopathic hypercalciuria.
4. Loop diuretics: decrease blood Ca2+ and are used in hypercalcemia.
5. Glucocorticoids: antagonize vitamin D and decrease Ca2+ absorption from GIT leading
to hypocalcemia, and are used in hypercalcemia.
6. Fluoride: increases bone Ca2+ deposition and prevents dental caries, and is used in
postmenopausal osteoporosis.
7. Mithramycin (Plicamycin): cytotoxic antibiotic that prevents bone resorption, used in
hypercalcemia due to malignancy and Paget's disease.
Treatment of Osteoporosis:
Osteoporosis occurs in post-menopausal females- due to long treatment with glucocorticoids,
hyperparathyroidism, thyrotoxicosis, and alcoholism. Treatment includes:
1. Ca+ and vitamin D.
2. Bisphosphonates.
3. Estrogen and Raloxifen (better than estrogen to reduce the risk of breast and endometrial
carcinoma).
4. Calcitonin.
5. Fluoride sustained release.
6. Teriparatide: recombinant parathormone given in small pulse doses.
Treatment of Hypocalcemia:
1. Ca2+ and vitamin D.
2. Parathormone.
3. Thiazides.
Treatment of Hypercalcemia:
1. Biphosphonates.
2. Mithramycin.
3. Calcitonin and phosphate.
4. Glucocorticoids.
5. Ca2+-chelating agents as disodium edetate IV.
6. Phosphate.
Treatment of hypoparathyroidism:
Hypoparathyroidism is either idiopathic or following thyroidectomy. It is characterized by low
serum calcium and high phosphate leading to tetany.
Treatment by:
1. Parathormone (resistance occurs).
2. Calcium gluconate slowly IV.
3. Vitamin D.
4. Dihydrotachysterol (AT 10) to elevate serum calcium.
This chapter deals with the following drugs:
I- Drugs used to stop bleeding.
II-
Drugs used in prevention and treatment of thromboembolic diseases in
vivo and are particularly effective in venous thrombosis. They are also
used to prevent blood clotting in blood samples and during blood
transfusion (in vitro).
A
III-
Drugs used to prevent platelet aggregation.They are particularly effective
in prophylaxis against arterial thrombosis as coronary thrombosis
causing acute myocardial infarction. N.B.: arterial thrombi are formed of
platelet aggregation mainly and are thus known as "white" thrombus,
whereas venous thrombi are formed of fibrin mainly which entangles
RBCs and are called "red" thrombi. A part of venous thrombi may detach
forming an embolus (floating thrombus).
IV-
Drugs used to dissolve (lyse) already formed thrombi and emboli, mainly
arterial thrombi as in acute myocardial infarction due to coronary
thrombosis.
V- Drugs used
in treatment of hypelcholesterolemia and / or hypertriglyceridemia.
VI- Drugs used to treat anemias.

A-Local Hemostatics (styptics):
application of pressure (compression),

cold, or cautery (e.g. by diathermy).
as adrenaline and ephedrine locally
in cases of epistaxis (contraindicated in hypertension and bleeding
from fingers, toes and during male circumscision).
as tannic acid and alum, which precipitate
surface proteins at sites of bleeding.
to stop bleeding from
minute vessels:
a-Thrombin and thromboplastin.

b-Human fibrin foam (sponge)
used in surgery.
c-Absorbable gelatin sponge.
d-Oxidized cellulose (oxycel): surgical gauze which acts
mechanically but should not be left for long time as it
prevents epithelization.
t
B-Systemic Coagulants:
• It is obtained from diet and is also synthesized by bacterial flora.

• It is a fat-soluble vitamin, so absorption is impaired in cases of
obstructive jaundice and by liquid paraffin (lubricant purgative).
• It is reduced in the liver into an active form. Reduced vitamin K is active
and is essential for activation - by carboxylation- of coagulation factors II
(prothrombin),VII, IX, and X, and of anticoagulation proteins C and S. After
carboxylation of these factors, reduced active vitamin K is converted into
inactive vitamin K epoxide which is transformed again into active reduced
vitamin K by vitamin K epoxide reductase which is inhibited by oral
anticogulants as warfarin and by large doses of salicylates (aspirin).
Vitamin K -------------► reduced active vitamin K -------- Carboxylation

t "
(activation) of coagulation factors + inactive vitamin K epoxide.

i
Vitamin K epoxide reductase

Vitamin K epoxide --------------------------------------------- ► reduced active vit.K
(inhibited by warfarin and large doses of aspirin)
• Vitamin K is the specific antidote of oral anticoagulants.
• Vitamin K is used in treatment of bleeding due to hvpoprothrombinemia
which is caused by:
-Drugs: Overdose of oral anticoagulants and salicylates.
-Decreased synthesis of vitamin K by flora: Prolonged use of oral

broad spectrum antibiotics especially if incompletely absorbed as
ampicillin,
. . A
cefadroxyl, and tetracycline.

-Excessive metabolism of vitamin K: Antiepileptics as phenytoin,
phenobarbitone, primidone (partially converted into phenobarbitone),
and carbamazepine (all are HME inducers).
-Decreased absorption of vitamin K: Liquid paraffin (decreases
vitamin K absorption), obstructive jaundice, malabsorption syndrome, and
by drugs as neomycin.
-Decreased utilization of vitamin K in liver: Liver diseases and
neonates especially if premature.
basic and electropositive drug -chemically antagonizes heparin (which is

strongly acidic and electronegatively charged) -specific antidote of
heparin used to control bleeding due to overdose of heparin-given IV.
as Tranexamic acid and Aminocaproic acid
which are used to control bleeding due to overdose of fibrinolytics
as streptokinase and alteplase (see later).
Adverse effects: intravascular thrombosis.
IM.
Antihemophilic globulin (AHG) IV in treatment of hemophilia.
in treatment of scurvy.
blocks plasmin, used for prophylaxis in cardiopulmonary

bypass surgery.
 ® Sclerosing agents: as sodium morhuate-sylnasol-sodium

ricinoleate, used to induce coagulation, and permanent obliteration
of varicose veins.
4
(Antithrombotic Drugs = Platelet Aggregation Inhibitors)
Factors stimulating aggregation Factors inhibiting aggregation

1-Thromboxane A2 (TXA2). 1- Prostacyclin (PGI?).
2-ADP. 2- c-AMP.
3-Glycoproteins (act on specific 3- c-GMP.
GPIIb/IIIa receptors on platelets
and stimulate binding of
fibrinogen to platelets).
4-Ca2+. ‘
5-Serotonin (5-HT).
6-Collagen
Mechanism of action of Antithrombotics:

A-Inhibition of TXA2 synthesis
by inhibition of TXA2 synthetase (platelet COX):
infantile (pediatric) doses of aspirin (75- 150 mg. / day) cause irreversible
inhibition of TXA2 by acetylation of the enzyme. Other NSAIDs are
reversible inhibitors and have short duration. Adverse effects: increases
incidence of hemorrhagic strokes-bleeding (as from GIT)-allergy.
1-
usually combined with aspirin.
4
:
B-Inhibition of ADP-dependent pathway:
these drugs inhibit binding of ADP to ADP receptors on platelets and so

inhibit activation of GP Ilb/IIIa receptors and inhibit binding of platelets to
fibrinogen and to each other. Examples include: Ticlopidine and
Clopidogrel (ticlopidine analogue). They are used during stent insertion
( * maximum effect after 3-5 days). Adverse effects: bleeding (no specific
antidote).
Ticlopidine may cause neutropenia' but clopidogrel is safer.
C-Blockers of GP Ilb/IIIa receptors:
these drugs inhibit binding of fibrinogen to GP Ilb/IIIa receptors on

platelets and thus inhibit platelet aggregation. They include:
Abciximab (monoclonal antibodies of GP Ilb/IIa receptors) - Tirofiban -
Epitifibatide.
They are given by IV infusion during surgery and catheterization (oral
drugs are too toxic).
Adverse effects: bleeding especially if given with anticoagulants.
D-Prostacyclin analogue: Epoprostenol (short acting, given IV).
E-Drugs increasing platelet c-AMP:
Dipyridamole -Cilostazole -Pentoxyphylline: inhibit phosphodiesterase

leading to iijcreased platelet c-AMP.
* Dipyridamole is ineffective alone and is used in combination with

aspirin. It also a vasodilator (* coronary vasodilators) and myocardial
stimulant both directly due to increased cardiac c-AMP and reflexly
following vasodilatation and hypotension.
Cilostazole and pentoxyphylline are used mainly in treatment of
5
:
intermittent claudication.
Indications of Antithrombotics:
Prophylaxis against thrombo-embolism (especially arterial) in old age,

stable and unstable angina, after myocardial infarction and cerebro-
vascular thrombosis.
Common adverse effect:

bleeding, no specific antidote, blood transfusion may be required.
5
Anticoagulants and antithrombotics (antipiateiets)
are used for prophylaxis of thrombo-embolism but they have no effect on
already formed thrombi and emboli.
Fibrinolytics dissolve (lyse) already formed thrombi and emboli.
Stimulate conversion of inactive plasminogen (pro-fibrinolysin) into
active plasmin (fibrinolysin) which dissolves (lyses) already formed
thrombi and emboli.
Indications:
Recently formed thrombi and emboli as in coronary thrombosis causing
acute myocardial infarction, cerebro-vascular thrombosis, pulmonary
embolism, some cases of deep venous thrombosis (DVT).
They should be given as early as possible before irreversible tissue
damage (better results within 3-6 hours).
Examines of Fibrinolytics:
Streptokinase:
• Synthesized by streptococci and is highly antigenic.
• Stimulates'systemic plasminogen (non selective) causing high
incidence of bleeding.
•It is given by IV drip (for 1 hour and used within 4 hours, not effective in
older thrombi).
• Streptokinase does not directly stimulate conversion of plasminogen
into plasmin, it stimulates "proactivator" into "activator which stimulates
plasminogen conversion into plasmin.
6
Urokinase:
a human enzyme synthesized by the kidney. It is much less antigenic that
streptokinase.
Recombinant tissue Plasminogen Activator (r-tPA=Alteplase):
• It is a protease enzyme synthesized by recombinant DNA technology
so it is much less antigenic but expensive.
• It binds specifically to local plasminogen bound to fibrin of thrombus
or embolus (clot-selective) so it has the advantage of minimal systemic
bleeding.
• Shorter 11/2 than streptokinase but more effective in older clots.
Adverse effects:
1- Bleeding:
more common with streptokinase, and is treated by anti fibrinolytics as
tranexamic acid and aminocaproic acid.
Cerebral and GIT bleeding may occur.
2- Allergic reactions and fever: commonly with streptokinase.
3- Antibodies
to streptococci (due to repeated infections) may inhibit the action of
streptokinase.
4-Microemboli.
5-Re-perfusion arrhythmias.
6
Anticoagulants are classified into the following groups:
A- Anticogulants used in vitro only:
They decrease ionized Ca2+ in blood either by precipitation as NaT and K+

oxalate or By de-ionization as Na+ and K+ citrate, and EDTA. They are used
in blood samples and blood banks during transfusion.
B- Anticoagulants in vivo only (= Indirect acting):
They include oral anticoagulants which interfere with vitamin K activation

in the liver: coumarin derivatives: warfarin, dicuomarol, and tromexan.
C- Anticoagulants both in vivo and in vitro (Direct acting):
1-Direct thrombin inhibitors (DTIs): hirudin and lipirudin.

2-In direct thrombin inhibitors: act via activation of antithrombin III and
include heparins: unfractionated heparin (UFH) and low molecular weight
heparin (LMWH).
*Anticoagulants are classified clinically into:
1- Parenteral anticoagulants: heparin- hirudin - lipirudin.

2- Oral anticoagulants: warfarin.
7
Also known as "High Molecular Weight Heparin" (HMWIT).
*Source:
Animal origin: heparin is naturally present in mast cells with histamine
and it is prepared from bovine lung and porcine intestine.
* Chemistry:
Mucopolysaccharide - strongly acidic (it is the strongest organic acid) -
electro-negatively charged (acidity and negative charge are essential
for the anticoagulant activity of heparin).
*Pharmacokinetics:
•Absorption: heparin is not absorbed orally.
•Route of administration: heparin is given IV (bolus and infusion) and
SC but never IM to avoid hematoma.
•Distribution: cannot pass placental barrier and is safe during

pregnancy.
•Fate: heparin is rapidly cleared by reticulo-endothelial system (RES),
metabolized by the liver and partly excreted unchanged in urine.
It is not excreted in breast milk and so it is not contraindicated in
lactation.
7
-Mechanism action
Heparin activates "antithrombin III" known as heparin cofactor which in
turn inhibits thrombin and other coagulation factors as factor Xa.
Heparin is an indirect thrombin inhibitor.
1- Direct anticoagulant characterized by the following:
o Rapid onset: 1-acts directly on coagulation factors in blood
2- given IV or SC.
o Acts both in vivo and in vitro.
o Not contraindicated in pregnancy or lactation.
o Not liable to drug interactions.
* Short duration: due to rapid clearance by RES.

1- Given only by injection and requires careful monitoring of the dose
(see later) and accordingly the patient must be hospitalized.
2- Lipemic clearing effect: reduces plasma turbidity after fatty meals
due to liberation of lipoprotein lipase.
3- Antiplatelet action (inhibits platelet aggregation) in large doses.
Control of Dose:
- Normal: atjout 30-40 seconds.

- After heparin: should be 2-2.5 times the normal value.
- Normal: 5-7 minutes.

- After heparin: should be 2-2.5 times the normal value.
Adverse effects:
1- Hemorrhage is the most serious adverse reaction and it may

occur from any site as epistaxis, hematuria, etc. Treated by: stopping
heparin + specific antidote (protamine sulphate) + fresh blood
transfusion.
2- Hypersensitivity reactions.
3- Thrombocytopenia: which may be mild transient reversible, or severe

due to heparin-induced platelet aggregation or heparin-induced
antiplatelet antibodies. This may lead to "paradoxical embolism"Heparin
should be stopped and direct thrombin inhibitors as hirudin and lepirudin
are used.
4- Thrombosis: chronic use of heparin reduces antithrombin III

activity leading to increased risk of thrombosis.
5- Transient teversible alopecia.
6- Transient reversible osteoporosis (may cause spontaneous

fractures).
7- Hyperkalemia: due to inhibition of aldosterone release.
Reversal of action:
1- Stop heparin.
2- Protamine sulphate is the "specific antidote" of heparin:
-It is strongly basic and electro-positively charged (acts by "chemical
antagonism"), 1 mg. protamine IV reverses the action of 100 I.U. heparin.
3- Fresh blood transfusion.
Contraindications:
1- Hypersensitivity.
2- Severe uncontrolled hypertension.
3- GIT ulcerations: peptic ulcer and ulcerative colitis.
4- Threatened abortion.
5- Subacute bacterial endocarditis.
6- During and after eye, brain, or spinal cord surgery, or lumbar
puncture.
7- Bleeding disorders as hemophilia, thrombocytopenia, and purpura.
8- Active T.B.
9- Intracranial hemorrhage, head injury, and brain tumors.
10- Visceral carcinoma.
11- Advanced liver and kidney diseases.
: Enoxaparin – Daltaparin - Tinzaparin.

They are obtained by enzymatic depolymerization of UFH.
Advantages over UFH:
1- High bioavailability after SC injection and long duration allowing

single daily injection.
2- Potentiate the action of antithrombin III mainly on activated factor X
9
(Xa) andhave less effect on other coagulation factors; so they are less
liable to induce hemorrhage.
3- Equal efficacy as UFH.
4- Predictable pharmacokinetics, so the doses are easily calculated and
no need for monitoring by aPTT, and can be used as out-patient therapy.
1- Hirudin: obtained from medicinal leech. Given by IV infusion.

2- Lipirudin: chemically related to hirudin but it is synthesized by
recombinant DNA technology. Given IV.
DTIs are indicated in patients with heparin-induced thrombocytopenia,
and the main adverse effect is bleeding especially if used with fibrinolytics
as streptokinase and alteplase.
9
*Fondaparinux:
selective factor Xa inhibitor-given SC once / day-more effective than

LMWH in prophylaxis of venous thrombo-embolism as DVT-long tl/2-no
need to use antidote (anticoagulation reversal) before stopping (before
neurosurgery or if spinal cord injury is suspected).
Source: Synthetic.
*
*Chemistry:■ Coumarin derivative.
* Pharmacokinetics:
•Absorption: absorbed orally.

•Distribution:
highly bound to plasma proteins (99%)- passes placental barrier and
may cause teratogenicity.
•Fate: metabolized by FIME and very small amounts are excreted in

breast milk (© not secreted in breast milk).
*Pharmacodynamics:
-Mechanism of action: inhibit vitamin K epoxide reductase thus

inhibiting regeneration of active reduced vitamin K - from vitamin K
epoxide- needed for carboxylation of prothrombin (factor II), factors VII,
IX, and X.
-Pharmacological actions:
Indirect anticoagulant acting in vivo only, characterized by the following:
10
Advantages.:
1- Easy route of administration.
2- Long duration of action (4-7 days).
Disadvantages:
1- Delayed onset (1-2 days): it does not act on already formed active
(carboxylated) coagulation factors present in blood but act by inhibiting
release of "new" active factors, so the action is delayed until
disappearance of the already formed coagulation factors which may take
several days.
2- Liable to several drug interactions (see later).
3- Contraindicated in pregnancy.
*Control dose:
1- Prothrombin time (PT):
-Normal: 12-15 seconds.
-After oral anticoagulants: PT should be 2-2.5 times the normal value.
2- International Normalized Ratio (INR): it is a ratio between PT of the
patient / PT of control. It should be 2-3 after oral anticoagulation.
10
Adverse effects:
1- Hemorrhage from any sits is the most serious Adverse effects.

2- Gut upsets: anorexia, nausea, vomiting, and diarrhea.
3- Allergic reactions: skin rash.
4- Teratogenicity (abnormal bone development).
5- Skin necrosis is rare but serious (may be due to rapid elimination of
anticoagulant proteins C and S before coagulation factors are eliminated
leading to liability of formation of thrombi in skin blood vessels, it is
prevented by co-administration of heparin).
6- Drug interactions (see later).
Reversal of action:
1- Stop the drug.

2- Vitamin K is the specific antidote, e.g. vitamin K1 IV.
Contraindications:
As heparin + Pregnancy.
Drug interactions:
A-Pharmacokinetic interactions:
•Absorption: cholestyramine decreases absorption of oral

anticoagulants. •Distribution: several drugs displace oral anticogulants
from plasma proteins as NSAlDs (aspirin, phenylbutazone, indomethacin),
sulphonamides, sulphonylureas, propranolol, verapamil, loop diuretics as
frusemide, and clofibrate.
11
Metabolism:
-HME inducers as phenobarbitone, phenytoin, rifampicin, and tobacco

smoking increase clearance of oral anticoagulants and may lead to
decreased PT and the patient is at risk of thrombo-embolism.
-HME inhibitors as cimetidine, erythromycin, ketoconazole,
chloramphenicol, and allopurinol decrease clearance of oral
anticoagulants and may lead to excessive prolongation of PT and
bleeding.
Drugs that increase the effectiveness of oral anticoagulants:
1- Inhibition of vitamin K synthesis by gut bacterial flora: broad

spectrum antibiotics especially incompletely absorbed: ampicillin and
tetracyclines.
2- Inhibition of vitamin K absorption by liquid paraffin.
3- Inhibition) of vitamin K activation as aspirin (large and toxic doses),
and cephalosporins.
These drugs as well as some pathological conditions as liver diseases,
obstructive jaundice, and hyperthyroidism (increase catabolism of
coagulation factors) increase PT and subject the patient to bleeding.
11
• Drugs that decrease the effectiveness of oral anticoagulants:
1- Excess vitamin K (in green vegetables).

2- Estrogen (oral contraceptives) increases synthesis of coagulation
factors II, VII, IX, X, and inhibits antithrombin III.
These drugs as well as some pathological conditions as

hypothyroidism (decreases turnover of coagulation factors) and
hereditary resistance to oral anticoagulants decrease PT and subject
the patient to thromboembolism.
Factors increasing PT Factors decreasing PT

(Increase activity of warfarin) (Decrease activity of warfarin)
1-Drugs that displace warfarin 1 -Drugs that decrease oral
from plasma proteins. absorption
2-HME inhibitors. of warfarin as cholestyramine.
3-Liquid paraffin. 2-HME inducers.
4-Broad spectrum antibiotics. 3-Excess vitamin K.
5-Aspirin (large and toxic doses) 4-Estrogen.
and cephalosporins. 5-Pathological conditions as
6-Pathological conditions as liver hypothyroidism and hereditary
diseases, obstructive jaundice, and resistance.
hyperthyroidism.
Uses of Anticoagulants:
1- Anticoagulants are now used primarily in prophylaxis of DVT and

pulmonary embolism in high risk patients (smokers-obese-recumbent as
postoperative patients-hyperlipidemia and atherosclerosis).
2- Unstable angina.
3 - Treatment of pulmonary embolism.
4- Treatment of acute myocardial infarction.
5- Treatment of cerebral thrombosis
A
12
6- Heparin is used in:
•Disseminated intravascular coagulation (DIC).

• Prevention of blood clotting during blood transfusion and dialysis.
• Hyperlipidemia.
Choice of Anticoagulants:
Start by co-administration of heparin and warfarin for about 4-5 days then
heparin is stopped and warfarin, is continued alone after being sure of its
anticoagulant action (PT should be 2-2.5 times its normal value).
Remember that during pregnancy heparin is used alone.
Endogenoul anticoagulants: .1-Proteins C and S. 2-Antithrombin III.
3-Fibrinolysin.
12
HEPARIN WARFARIN
Source: Animal origin. Synthetic.
Mucopolysaccharide-Strongly Coumarin derivative.
Chemistry:
acidic-Eiectronegative.
Absorbed oraliy-highly bound to plasma
-Not absorbed orally-given only IV or SC proteins-pass placental
but never IM. barrier-metabolized by the liver and
Pharmacokinetics: -Does not pass placental barrier and not minimally excreted in breast milk.
excreted in breast milk. -Rapidly cleared
by RES and metabolized by the liver.
-Activates antithrombin III and inhibits Inhibits vitamin K epoxide reductase

Pharmacodynam ics: active factor X, thrombin and other thus inhibiting carboxylation of
-Mechanism: factors. prothrombin and factors VII, IX, and X.
Anticoagulant in vivo only-

1- Anticoagulant both in vivo and in
Indirect-Slow onset and long duration,
vitro-Direct-Rapid onset and short
duration.
Actions: 2- Lipemia clearing factor.
3- Slight V.D.
4- Inhibits platelet aggregation.
ii:
1-aPTT. 1- PT.
Control of dose:
2- Coagulation time. 2- INR.
1 -Hemorrhage. 1 -Hemorrhage.
2- Hypersensitivity. 2- Hypersensitivity.
3- Osteoporosis. 3- Gut upsets.
4- Alopecia. 4- Teratogenic and affects suckling
Adverse effects: babies.
5- Thrombocytopenia and paradoxical
thrombosis. 5- Skin necrosis.
6- Hyperkalemia.
1 -Stop the drug. 1- Stop the drug.
Reversal of action: 2- Protamine sulphate IV ( specific 2- Vitamin K IV (specific antidote).
antidote). 3- Fresh blood transfusion.
13
1 -Treatment of Iron Deficiency Anemia:
♦ Dietary iron is better absorbed from the duodenum in the form of

ferrous iron.
♦ Absorption is enhanced by gastric HC1 and vitamin C and reduced
by phytate and phosphate.
♦ Iron deficiency anemia occurs due to dietary deficiency,
decreased absorption, and chronic blood loss.
* Examples:
Ferrous gluconate, Ferrous fumarate, and iron choline citrate which is the
least irritant (Ferrous sulphate is not used as it is very irritant on GIT).
* Adverse effects:
1- Gut upset: epigastric pain, colics, diarrhea or constipation

2- Acute iron toxicity: manifestations include nausea, vomiting,
severe colics, hematemesis, and black or bloody diarrhea.
It may cause hypotension, collapse, and finally coma.
* Treatment of acute iron toxicity:
- Stomach wash by NaHC03.

-Iron chelating agent as Desferrioxamine given orally or parenterally.
-Symptomatic treatment as IV fluids.
14
* Examples:
- Iron dextran: IV or IM.

- Iron sorbitol citric acid complex: IM only.
* Toxicity of parenteral iron:
-Local effects: pain and skin discoloration at the site of injection.

-Systemic effects: headache-malaise-muscle and joint pain-
bronchospasm-hemolysis-fainting-hypotension-encephalopathy.
* Treatment of toxicity:
-Iron chelating agent as Desferrioxamine given parenterally.

-Symptomatic treatment as IV fluids.
14
♦ Pernicious anemia is commonly due to deficiency of intrinsic factor
required for absorption of vitamin B12 (extrinsic factor).
♦Drugs that decrease absorption of B12 and may cause pernicious anemia
include:Metfonnm, Neomycin, and Para-amino salicylic acid.
♦ Manifestations of pernicious anemia include: macrocytic anemia + CNS

disturbances (peripheral neuritis and subacute combined degeneration of the
spinal cord) + GIT manifestations (glossitis, achlorhydria, gastritis and
diarrhea).
♦Treatment:
1- Cyanocobalamin (lmg. IM may be used for life).
2- Hydroxocobalamin (also used in treatment of cyanide poisonings cyanide
chelating agent).
N.B.:
1- Never treat pernicious anemia by folic acid alone as it will correct blood
picture but aggravates CNS and GIT manifestations.
2- Neomycin, metformin, and PAS reduce oral absorption of Bi2.
15
Causes:
-Pregnancy: increases requirements for folic acid.
-Decreases GIT absorption.
Drugs:
1- Dihydrofolate reductase inhibitors: Trimethoprim Proguanil
Pyrimethamine.
2- Antiepileptic drugs with potent HME induction: Phenytoin Carbamazepine
Barbiturates.
3- Methotrexate (antimetabolite anticancer drug).
Treatment:
Folinic acid (active tetrahydrofolic acid = leucovorin).
15
4
Blood Disorder Causes Treatment
1-Anti-cancer drugs. 1- Stop the drug.

1- Anti-fungal drugs as Amphotericin. 2- Fresh blood transfusion.
2- Anti-viral drugs as Zidovudine. 3- Broad spectrum
3- Anti-thyroid drugs: Thioamides penicillins.
as methimazole and-carbimazole. 4- Anabolic steroids and
4- Anti-inflammatory drugs: glucocorticoids.
Pyrazolone derivatives (phenylbutazone), 5- Hematopoeitic growth
Indole derivatives (indomethacin), factors as erythropoietin,
gold salts (used in rheumatoid arthritis). granulocyte colony
5- Anti-bacterial drugs: chloramphenicol stimulating factor (G- CSF),
and sulphonamides. or granulocyte /
6- Anti-epileptic drugs: carbamazepine. macrophage colony
stimulating factor (GM-
CSF).
Ionic inhibitors as perchlorate (were used as 1- Stop the drug.
antithyroid drugs) + most of the drugs 2- Fresh blood transfusion. •
causing granulocytopenia. 3- Anabolic steroids and
glucocorticoids.
4- Hematopoeitic growth
factors as erythropoietin.
5- B 12 , folic acid, and
vitamin C.
1-Primaquine. Reducing agents as vitamin

2- Sulphonamides. C (ascorbic acid) or
3- Phenacetin. methylene blue.
4- Nitrites (more than nitrates).
1 -Aspirin. 1- Avoid drugs inducing
2- Sulphonamides. hemolysis.
3- Primaquine. 2- Fresh blood transfusion or
4- Phenacetin. packed RBCs.
5- Isoniazid.
16
Bile acid
STATINS FIBRATES sequestrants
(bile acid-binding
resins)
Simvastatin- Clofibrate- Cholestyramine-
Fenofibrate- Colestipol
Examples Lovastatin-
Gemfibrozil
Pravastatin-
Atorvastatin.
1- decrease 1- decrease 1- Bind to (sequester)
cholesterol Triglycerides by bile salts in the
synthesis by decrease VLDL intestine inhibiting
inhibition of HMG synthesis and output their entero-hepatic
Co-A reductase. from the liver (by recycle
decrease lipolysis in ….compensatory
2- decrease LDL in adipose tissues and increase in hepatic
blood decrease FFA supply LDL receptors
….compensatory to the liver) and …increase uptake of
Actions
increase in hepatic increase VLDL cholesterol by
LDL receptors—» clearance from hepatocytes to
increase uptake of plasma (increase synthesize bile salts.
cholesterol by activity of lipoprotein
hepatocytes. lipase). 2- Decrease LDL.
3- increase HDL 3-No effect on HDL or

2- decrease LDL.
triglycerides.
4- decrease
Triglycerides.
3-increase HDL (most
effective, especially
gemfibrozil).
All types of Hypertriglyceridemia- Hypercholesterolemia
Uses hyperlipidemias Mixed in patients intolerant
(the most effective hyperlipidemia. to other drugs.
drugs).
1 -increase liver 1-increase liver 1- Constipation and
enzymes enzymes and may be distension (may be
(transaminases) hepatotoxic. used in treatment of
Adverse effects and may be refractory diarrhea,
hepatotoxic. 2- increase creatine see GIT
kinase (CK) and may pharmacology).
2- increase creatine cause myopathy.
kinase (CK) and 3- Gut upset. 2-Decreasc
may cause absorption of most
myopathy. 4- Gall stones drugs as digitalis,
(cholelithiasis) and warfarin, and fat-
soluble vitamins
3- Gut upset. cholecystitis.
4- Headache. 5- Displace oral

anticoagulants and
5- Teratogenic. sulphonylureas from
plasma proteins.
6-Displace oral 6-Allergy and blood

anticoagulants dyscrasiasis.
from plasma
proteins.
Contra- 1-Pregnancy and 1-Pregnancy-
indications lactation. lactation.
2-Liver diseases. 2-Liver diseases.
3-Gall bladder
diseases
Niacin (nicotinic acid): as fibrates (decrease LDL and VLDL synthesis by
the . liver and increase lipoprotein lipase —>decrease cholesterol and
triglycerides).
Adverse effects:
1- flushing due to PG release, this is prevented by aspirin

administration before niacin.
2- GIT disturbances.
3- Hyperuricemia and hyperglycemia.
4- Elevation of serum transaminases.
Ezetimibe: decreases absorption of dietary and biliary cholesterol.
18
Pharmacology
A-Drugs acting by enzyme inhibition:
1-α-methyldopa : inhibits dopa-decarboxylase enzyme

(Used in treatment of hypertension, it is the drug of choice in hypertension during
pregnancy).
2-Anti-cholinesterase: either reversible as physostigmine and neostigmine, or
irreversible as organophosphorous compounds.
3-Glucocorticoids (cortisone): inhibits phospholipase A2.
4-NSAIDS e.g. Aspirin, phenylbutazone, Diclofenac....., inhibit cyclooxygenase
enzymes (COX).
5-Zileuton: inhibits 5-lipooxygenase enzyme → ↓ leukotriene synthesis, used in
prophylaxis of bronchial asthma.
6-Dazoxiben: Antiplatelet by inhibition of thromboxane A2 synthase (same
mechanism as aspirin as antiplatelet).
7-Methylxanthines e.g. theophylline and aminophylline, inhibit P.D.E
(phosphodiesterase) type IV (4) → ↑ c-AMP → CNS stimulation, cardiac
stimulation, V.D. and bronchodilation.
8-Disodium cromoglycate and Nedocromil sodium: (mast cell stabilizers)
Used in prophylaxis of bronchial asthma, given by inhalation, inhibit P.D.E in mast
cell.
9-Warfarin: "oral anticoagulant", inhibits vitamin k reductase →
↓ Synthesis of prothrombin ii (2) and other coagulation factors (vii,ix,x).
10-Dipyridamole: Antiplatelet, ↓ PDE → ↑ c-AMP.
11-pentoxyphylline: methylxanthine, antiplatelet, as dipyridamole.
12-Statins: antihyperlipidaemics, ↓ HMG.COA reductase enzyme.
13-Carbonic anhydrase inhibitors: e.g. acetazolamide (diamox) used as diuretic
(self-limiting), ↓ IOP in glaucoma, treatment of petit-mal epilepsy, as alkalinizer of
urine.
14-Angiotensin converting enzyme (ACE) inhibitors: e.g. captopril, lisinopril,
enalopril, used in treatment of hypertension (drugs of choice in hypertension +
diabetes mellitus), and in congestive heart failure.
15-Digitalis (cardiac glycosides): inhibit Na+/K+ ATPase (Na+ pump), used in
treatment of heart failure.
16-Bipyridines: e.g. amrinone, milrinone, eroximore, inhibit P.D.E type iii (3) , used
in resistant heart failure as short term therapy.
17-Proton pump inhibitors: e.g. dmeprazole, lansoprazole. Inhibit H+/K+ ATPase
(proton pump) in partial cells, used as antisecretory (↓ HCl) in treatment of peptic
ulcer.
18-Allopurinol: xanthine oxidase inhibitors, ↓ uric acid synthesis in prophylaxis of
gout.
19- MAO Inhibitors.
20-peripheral dopa-decarboxylase inhibitors (PDDI) e.g. carbidopa and
beuserazide, combined with L-dopa in treatment of Parkinsonism.
21- COMT-Inhibitors: tolcapone and entacapone, given with L-dopa/carbidopa in
treatment of Parkinsonism.
22-Sodium valproate and vigabartin: Inhibit GABA transaminase, used in epilepsy
(broad-spectrum anti epileptics).
23-β-lactamase inhibitors: e.g. clavulanic acid, sulbactum and tazobactam,
combined with penicillin to treat β-lactamase producing bacteria e.g. staph.
24-Cilastatin: inhibits dipeptidase enzyme in renal cells to inhibit metabolism of
imipenem into nephrototic metabolite (imipenem + cilastatin = tienam).
25-sulphonamides: inhibit dihydropteroate enzyme → ↓ synthesis of dihydrofolic
acid from PAPA by bacteria.
26-Trimethoprim
27-pyrimethamine
28-proguanil:
29-Methotrexate: anticancer, inhibits dihydrofolate reductase, causes

megaloblastic anemia, treated by folinic acid (=leukovorin).
30-Rifampicin: inhibits DNA-dependent RNA polymerase.
31-Quinolones and fluroquinolones: inhibits DNA-gyrase.
32-Acyclovir: Antiviral inhibits DNA polymerase.
33-Zidovudine: Antiviral, used in treatment of AIDS, inhibits reverse
transcriptase enzyme.
B-Drugs that inhibit phosphodiesterase enzymes (P.D.E Inhibitors)

:
1 Selective α1-blockers (e.g. prazosin , they do not cause reflex
tachycardia as they increase cAMP & cGMP)
2 Bipyridines (Amrinone , Milrinone , Enoximone) :Inhibit PDE III (3)
3 Methyl Xanthines (Aminophylline , caffeine , theophylline ,
theobromine): Inhibit PDE IV (4)
4 Sildenafil (Viagra) , Tadafil , Valdenafil used in erectile dysfunction :
Inhibit PDE V (5)
5 Dipyridamole : anti platelet
Drugs & git:
A-Drugs causing Hepatotoxicity:
1. α-methyl dopa(α2-agonist-antiadrenergic-used in treatment of hypertension,

is the drug of choice in hypertension during pregnancy).
2. Dantrole (direct skeletal muscle relaxant, ↓Ca release from sarcoplasmic
reticulum, life-saving in malignant hyperthermia and neuroleptic malignant
syndrome , given I.V).
3. Statins e.g; simvatatin (anti-hyperlipidemics).
4. Fibrates e.g; clofibrate (anti-hyperlipidemic).
5. Toxic doses of paracetamol (or if given with HME inhibitors as alcohol and
phenobarbitone) due to accumulation of NABQI.
6. Colchicine (anti-inflammatory in gout).
7. Tolcapone( COMT-inhibitor used in parkinsonism with L-dopa).
8. Phenytoin( anti-epileptic+anti-arrhythmic).
9. Oxazolidinediones( anti-epileptic in petit-mal epilepsy).
10. Sodium Valproate (broad-spectrum antiepileptic).
11. MAO-inhibitors (anti-depressants).
12. Halothane (inhaled general anaesthetic).
13. Tetracyclines( antibiotics).
14. Sulphonamides( anti-bacterial).
15. Isoniazid.
16. Pyrazinamide.
17. Ethionamide.
18. Para-amino-salicylic acid.
19. Ketoconazole.
20. Griseofulvin.
21. Cis-platin (anti-cancer).
B-Drugs causing Diarrhea:
1-Parasympathomietics: e.g Carbachol – Bethanecol -Neostigmine

(Stimulate M Receptors in Small Intestine)
2-Adrenergic Neurone Depressants : e.gGuanethidine –Reserpine
(They causes Parasympathetic Predominance)
3-Dantrolene which is direct skeletal muscle Relaxant
4- Oral Iron : e.g Ferrous Fermanate & Gluconate ,May cause black or bloody
diarrhea
(Some oral iron causes constipation )
5-Magansium Oxide –Hydroxide –Trisilicate :used as Chemical antacids
6-Metoclopramide : Antemitic & Prokinitic
7-Domperidone: Antiemitic & Prokinitic
8-Purgatives (chemical & physical)
9-Colchicine : used in Acute gouty anthritis, may causes bloody diarrhea
10- Erthromycin : Anthmicrobial (Diarrhea is due to prokinietic
11-Broad Spectrum Antimicrobials (especially if not completely absorbed )
e.g Ampicillin –Tetraglclines- Chloramphenicol –Cophalosporins
(Due to Superinfection)
12-PG-Analogues :e.g Misoprostol (see Peptic ulcer)
C-Drugs Causing Constipation:
1-Antimuscarinic Drugs (Anticholinergic Drug =Parasympatholytics)

e.g: Atropine –Hyoscine-Antisecretory –Antispasmodic –Atropine substitutes
2-Opiod Analgesics: e.g Morphine –Mepridine –Loperamide-diphenoxylate (note that
lopramide and diphenoxylate are not analgesics) they stimulate opioid receptors in
GIT
3-Aluminum Hydroxide Gel :Act as Chemical & physical Antiacid
4-Calcium Carbonate :chemical Antacid
5-Calcium channel blockers :e.g Nifedipine –Veraparmil
6-Drugs Having marked ” Atropie-like Action”;e.g
-1st Generation (=sedating ) Anti-histaminics as Diphenhydramine
-Disopyramide : class I-Anti-arrhythmic
-Tricyclic anti-depressants as imipramin
-Carbamazepine : Anti-epileptic
D-Drugs Causing Nausea &Vomiting:
1-Opioid Analesics :e.g Morphine ,Methadone ,Meperidine

2-Cardiac Glycosides (Digitalis ) :e.g Digoxin ,digitoxin
3-Methylxanthin :e.g Aminophylline , Theophyline
4-D2-Agonists :e.g L-Dopa , Bromocriptine
5-Estrogen (oral contraceptive) causes mainly nausea
6-Cancer chemotherapy
E-Drugs causing Allergic Cholestatic Hepatitis :
1. Carbamazepine(anti-epileptic).
2. Tricyclic antidepressants (TCA's).
3. Chlorpromazine (anti-psychatic).
4. Erythromycin (antibiotic).
5. Chlorpromazine (anti-diabetic).
6. Oral contraceptives.
7. Rifanpicin(anti-T.B)
8. H2-blockers as Cimetidine (anti-ulcer).
F-Drugs activated by gastric acidic medium:
1-Chlorazepate (Benzodiazepine: anxiolytic &hypnotic)

2-Proton Pump Inhibitors e.g. Omeprazole (Antisecretory drugs used in
treatmentof peptic ulcer)
3-Sucralfate (mucosal protective agent, used to prevent recurence)
N.B.:
Ketoconazole (Antifungal) absorption increases in acidic medium
G- Drugs destroyed by gastric acid:

1-Acid-sensitive penicillins(e.g. benzyl penicillinG, procaine penicillin , benzathine
penicillin , methicillin , cabencillin , ureido-penicillins)
2- Erythromycin (to protect against HCL, erythromycin is given as enteric-coated
tablets, or estolate ester is added to erythromycin)
H-Drugs destroyed by proteolytic enzymes: (Not

effective orally)
1- Polypeptide antibiotics: Bacitracin & Polymixins

2- Polypeptide hormones: e.g. Insulin, Growth hormone, Glucagon, ACTH, ADH
(vasopressin)
3-Drugs and cardiovascular system:
A-Drugs Causing Bradycardia:
1-β-blocker: e.g Propranolol ,Nadolol , Atenolol …..etc

2-Parasympathomimetics (Muscrinic Agonists ):e.g Methocholidine ,Carbachol ,…
3-Digitalis (The Earlist manifestion of toxicity are nausea & vomiting +Bradycardia
below 60 beats /min)
4- α1 –Agonists causes reflex Bradycardia (α1 stimulation ➔V.C ➔ increase B.P
➔reflex bradycardia through baro receptors action)
5-General Anasthesia :e.g Halthone due to increase vagal tone
6-Some calcium channel blockers :e.g Verapamil (due to Blocking Voltage-gated Ca
channels in heart)
B-Drugs causing Postural Hypotention (Orthostatic

Hypotention OR Syncope) :
1. Nitrates as Nitroglycerine (used in treatment of Angina pectoris)
2. α1-blockers (phentolamine , phenoxybenzamine , BUT selective α1-blockers as
prazosine cause “1st dose phenomenon”)
3. Ganglion blockers (they cause Atropine like side effect + postural
hypotention + sexual dysfunction in males)
4. Adrenergic neurone blockers: (Guanithidine , reserpine , α-methyl dopa which
causes minimal hypotension)
C-Drugs used in treatment of Postural Hypotention :

1. Noradrenaline ( IV infusion ) Catecholamine
2. Ephedrine ( oral & IV )
3. Phenylepherine ( oral & IV ) Non-catecholamine
4. Methooxamine (oral & IV )
5. Midodrine ( oral )
N.B. : - All previous drugs are α1-agonists

-They are given by I.V. injection in case of “Acute” postural
hypotension due to spinal anesthesia
-They are given orally (except noradrenaline) in case of “chronic” postural
hypotension
D-Drugs used in treatment of PVD :
1. a1-blockers (except ergotamine , ergotoxine , dihydroergotamine , yohimbine

)
2. β2-Agonists (e.g. Nylidrin , isoxsuprine)
3. M3-Agonists = parasympathomimetics (e.g. Methacholine)
4. Calcium channel blockers e.g. Nifidipine
5. PGI2 : Epoprostenol
6. Dihydroergotoxine (the only ergot alkaloid useful in PVD)
E-Drugs contraindicated in PVD :

1. a1-Agonists
2. Ergot alkaloids (except dihydroergotoxine)
3. Non selective β-blockers
F-Drugs used in treatment of paroxysmal atrial

tachycardia (PAT) :
1. β-blockers
2. M2-Agonists (e.g Methacholine , Edrophonium , Neostigmine)
3. Digitalis (cardiac glycosides)
4. Anti Arrhythmic drugs : quinidine , Ca2+-channel blockers (e.g. verapamil)
5. a1-Agonists: e.g. Noradrenaline , phenylepherine , Methoxamine (causes
reflex bradycardia following elevation of blood pressure & contraindicated in
hypertensive patients )
G-Drugs contraindicated in PAT :
1. β1-Agonists: e.g. Adrenaline , isoprenaline , ephedrine

2. M2-antagonists: e.g. Atropine , Gallamine
3. a1-antagonists: due to hypotention followed by reflex tachycardia (except
selective a1-blockers as prazosin)
4. Arteriodilators (e.g. Hydralazine , Minoxidil , β2-agonists due to reflex
tachycardia following hypotention)
(Atropine is non-selective muscarinic antagonist whereas Gallamine is a competitive
neuromuscular blocker that block Nm receptors and also blocks cardiac M2-
receptors)
H-Drugs cuasing Tachycardia:
1- B1-agonists : e.g. Adrenaline , Isoprenaline , Ephedrine

2-B2- agonist : e.g. Salbutamol , Ritodrine
B2-stimulation lead to :V.D :dcrease B.P :reflex tachycardia &may be due
to B1 stimulation by large doses because Selectivity is not absolute
3-Atropine(antimuscarinic =parasympatholitic) , note that atropine may
Cause initial bradycardia due to block of presynaptic M-receptors
that cause increasing release of acetylcholine or due to stimulation of
C.I.C
4-Methylxanthines : e.g. Aminophylline , theophylline , by inhibition of
P.D.E type 4 & increase C-AMP
5-Arteriodialators : e.g. nifedipine (and other dihydropyridine Ca2+
Chanel blockers ) , hydralazine , minoxidil , (nitrates are mainly
Venodilatores but may cause arteriodilatation) . Arteriodialators
Cause reflex tachycardia
6-Glucagon hormone (increase C-AMP by stimulation of adenylcyclase )
7-Alpha 1-blockers : e.g. phentolamine , phenoxybentamine , they cause
reflex tachycardia due to arteriodilatation , note that selective alpha1-
blockers as prazosin cause no (or minimal ) tachycardia.
8-Ganglion blockers : e.g. Trimethaphan
I- Drugs causong hypokalemia :

1- Thiazide diuretics
2- Loop diuretics
3- C.A. Inhibitors
4- Steroids (Aldosterone - cortisone)
5- Adrenaline (and other drugs acting as β2-Agonists) due to uptake of K+ from
blood into skeletal muscles.
J-Drugs causing hyperkalemia :
1 K+-sparing diuretics
2 ACE-Inhibitors (Captopril , ………)
3 ARBs (Losartan , ………)
4 Drugs that inhibit Aldosterone synthesis (e.g. Metyropone , see hormones)
5 Succinycholine
6 Non-seletive β-Blocker (e.g. propranolol)
N.B. Digitalis does not cause hypokalemia , but hypokalemia induces digitalis
toxicity.
K-Drugs that are contraindicated in porphyria
:
1-Barbiturates (phenobarbitones , thiopentone …)

2-Primidone (antiepileptic , partially metabolized into phenobarbitone )
3- Eriseofulvin (antifungal used for treatment of muco-cutaneous fungal
infection
4-Chloroquine (anti-malarial + anti –ameobic + anti-giardiasis
+anti-inflammatory in R.A .)
4-Drugs and nervous system:
A-Therapeutic uses of sympathomimetics :

1. Shock : Adrenaline is life-saving in anaphylactic shock ,
Dopamine in hypovolemic & cardiogenic shock ,
Dobutamine in cardiogenic shock
(in Hypovolemic shock fill up then open up)
2. Acute attacks of bronchial asthma :
Adrenaline , isoprenaline (non selective) salbutamol ,terbutaline , fenoterol ,
reproterol
(short acting selective B2 agonists)
3. Prophylaxis of Bronchial asthma :
Ephedrine (non selective & CNS stimulant) ,
Hexoprenaline & Isoetharine (catecholamines)-selective B2-agonists ,
Salmetrol & formoterol (long acting selective B2-agonists)
4. Peripheral Vascular Diseases (PVD) e.g. Raynauld’s diseases
Nylidrin , Isoxsuprine
5. Uterine relaxants (tocolytics) in contraction ring of the uterus , premature
labor , threatened abortion , dysmenorrhea :
Ritodrine, salbutamol , isoxsuprine : Selective B2-agonists
Adrenaline : Non-selective
6. Vasopressors in treatment of hypotension (see above)
7. Nasal decongestants : Naphazoline , tetrahydrozoline, xylometazoline ,
phenyl propanolamine , ephedrine (causes rebound congestion) ,
pseudoephedrine , phenylephrine , methoxamine
8. AV block (Heart block) : Isoprenaline (S.L.) , Dobutamine (I.V. infusion)
9. Nocturnal Enuresis : Ephedrine
10. Narcolepsy (Hypersomnia ): Amphetamine
11. Attention Deficit Hyperkinitic Disorder (ADHD) :
Methylphenidate , Amphetamine
12. Anorexigenic drugs in obesity : phenmetrazine , diphenmtrazine ,
diethyproprion , amphetamine (not used)
13. Acute heart failure :
Dopamine , Dobutaxmine , Dopexamine : I.V. infusion
14. Chronic heart failure : Prenaterol (oral)
15. Glucoma (open-angle) :
Adrenaline , Dipivefrin (prodrug , better than adrenaline)
16. Cardiac resuscitation in cardiac arrest : Adrenaline (intra cardiac)
17. Mydriatics for fundus examination : (α1-agonists as Ephedrine-Phenylephrine)
18. Paroxysmal atrial tachycardia : (α1-agonists as phenylephrine)
19. Hemostatics in cases of bleeding as Epistaxis but not in hypertensive
patients (adrenaline-ephedrine-phenylephrine-methoxamine)
20. To prolong duration of local anesthetics but not in fingers , toes &
circumcision : Adrenaline , Ephedrine , phenylephrine , methoxamine
21. Acute hypoglycemia due to overdose of insulinor oral hypoglycemic drugs:
Adrenaline (I.V. glucose is better)
B-Drugs causing Convulsions (Seizures):

1-CNS stimulants: a-Methylxanthines (Theophylline)
b-Amphetamine
c-Cocaine
d- Atropine
e-Araleptics (brain stem stimulants )
f- Strychnine (spinal cord stimulant)
2- Morphine (by decrease release of GABA)
3-Meperidine (metabolized into normeperidine +atropine like action)
4-Aspirin (acute toxicity) due to increase Glutamate /GABA ratio
5-Chlorpromazine (major tranquilizer = Antipsychotic = Neuroleptic)
6-MAO-inhibitors
7-Lithium (anti-manic, mood stabilizer in bipolar disorders)
8-Penicillins (if large dose or intrathecal injection)
9-Carapenem e.g. Imipenem (B-lactam antibiotics)
10-Cycloserine (antibacterial _ inhibits cell wall synthesis)
11-Fluoroquinolones especially with NSAIDS &theophyllin
12-Amphotericin B (polyere –antifungal)
13-Oxamniquine (Anti bilharzial)
14-Cardiac glycosides
C-Drugs causing psychosis:
1-D2-Agonist e.g. L-dopa , bromocriptine (antiparkinsonian drugs )

2-Indomethacin (NSAID)
3-Glucocorticoides
4-Cycloserine
5-Cardiac glycosides
D-Drugs causing Depression:
1- Estrogen (oral contraceptives)

2-Reserpine (adrenergic neurone depressant, depletes the brain from
monoamins :5HT , noradrenaline &dopamine )
3- Alpha –methyldopa (decrease synthesis of monoamines by decrease
dopa decarboxylone )
4-Chlorpromozine (causes pseudo-depression)
5- Drugs and the urinary system:
A-Drugs causing Nephrotoxicity

:
1-NSAIDs except paracetamol(cause "analgesic nephropathy" due to renal V.C. by
↓ PGE and PGI synthesis.
2-Colchicine(+ hematuria).
3-Gold salts(in treatment of rheumatoid arthritis).
4-Vancomycin.
Anti-Bacterial
5-Aminoglycosides.
6-Cephalosporins.
7-Methicillin.
8-Sulphonamides.
9-Tetracyclines(especially of expired = Fanconi syndrome).
10-Amphotericin B (Anti-fungal).
11-Acyclovir(Anti-viral).
12-Demeclocycline(Anti-bacterial tetracycline).
13-Lithium(Anti-manic + mood stabilizer).
14-Methoxyflurane(inhald general anaesthesia as halothane).
B- Diuretics causing Hpokalemia:

1 Thiazide diuretics (e.g hydrochlorothiazide)
2 Loop diuretics (e.g. frusamide , ethacrynic acid)
3 Carbonic anhydrase inhibitors (e.g. Acetazolamide , methazolamide)
C-Diuretics causing hyperkalemia = K+ sparing diuretics

1 Spironolactone
Aldosterone antagonists
2 Canrenone
3-Trimetaphane
Non-Aldosterone antagonists
4-Amiloride
D-Diuretics causing alkalosis :

1 Thiazide diuretics
2 Loop diuretics
E-Diuretics causing acidosis :

1 K+ sparing diuretics
2 Carbonic anhyrase inhibitors
Cause hyperchromic acidosis
3 Acidifying diuretics (NH4Cl)
F-Self – limiting diuretics :

They cause acidosis leading to reabsorption of Na+ in exchange for H+ or NH4+
1 Carbonic anhydrase inhibitors
2 Acidifying diuretics
G-Diuretics causing hypercalcemia :

1 Thiazide diuretics
2 Non-aldosterone antagonists
H-Diuretics causing hypocalcemia :

1 Loop diuretics
2 Spironolactone (Aldosterone antagonist)
6-Teratogenic drugs:
1-NSAIDs except paracetamol(Aspirin causes cardiac septal defect,but is the safest
NSAID).
2-Benzodiazepines.
3-Barbiturates.
4-Chlorpromazine(phenothiazine antipsychotic and anti emetic).
5-Lithium.
6-ACE-inhibitors e.g. Captopril.
7- AT1_(Angiotersin) receptor-antagonists e.g. Losartan.
8-Antihistaminics e.g. Cyclizine and Meclizine.
9-Oral anticoagulants e.g. Warfarin.
10-Thiazide and Loop diuretics.
11-Phenytoin. :
12-carbamazepine.
13- Sodium valproate: antiepileptic,causes spina bifida.

14-Nitrous oxide(inhaled gas general anesthetic).
15-Sodium nitroptusside(mixed vasodilators given I.V. infusion)
16-Aminoglycosides→fetal deafness.
17-Tetracyclines.
18-Sulphonamides→hyperbilirubinemia and kernicterus.
19-Quinolones→damage of growing cartilage and arrest of growth.
20-Griseofulvin(antifungal).
N.B. 1-Morphine is not teratogenic but cause "fetal Addiction".

2-Thalidomide was used as anxiolytic ∕ hypnotic and it caused"Amelia"= absent limbs
and "phocomelia"= short limbs (thalidomide catastroph)
7-Prodrugs -- Active drugs---Active

metabolite:
Prodrugs:
1 Inactive drugs converted in the body into active metabolites.
2 Activation usually occurs in the liver.
3 Chlorazepate is converted into active metabolite nordiazepam in the stomach
by gastric acid.
EXAMPLES:
1. Dipivefrin (used in glaucoma).
2. Phenoxybenzamine (α-blocker).
3. Hexoprenaline (selective β2 agonist used in bronchial asthma, it is a
non-catecholamine, converted to active metabolite by COMT).
4. Minoxidil (antihypertensive, converted into minoxidil sulphate).
5. Enalapril,Fosinopril,Ramipril (ACE inhibitors).
6. Proton pump inhibitors ,e.g; Omeprazole (in treatment of peptic ulcer).
7. Cortisone is converted into cortisol (=hydrocortisone).
8. Sulindac and Nabumetone (NSAID).
9. Ampicillin esters(=pro-ampicillins) as
Bacampicillin,Pivampicillin,Talampicillin, converted into ampicillin in
liver and GIT mucosa.
10. Chlorazepate (Benzodiazepine).
11. Propacetamol→Paracetamol, given by injection.
Active drugs converted into active metabolites:
1. Phenacetin→ Paracetamol= Acetaminophen (analgesic-antipyretic).

2. Benzodiazepines except LOT-Nitrazepam-Clonazepam.
3. Morphine→Morphine-6-glucuronide.
4. TCA's e.g; Imipramine→Desipramine, Amitriptyline→Nortriptyline.
5. Spironolactone→Canrenone (Aldosterone-antagonist K-sparing diuretic).
8-Iatrogenic diseases: Examples of

Iatrogenic (Drug-induced) Diseases :
Drugs Disease
- NSAIDS ( except paraacetamol ) 1- peptic ulcer
- Glucocorticoids
- NSAIDS ( except paraacetamol ) 2- Bronchial Asthma
- Morphine
- Non-selective B-blockers (propranolol)
- Muscarinic agonists,e.g:Methacholine,Carbachol,Neostigmine
- Glucocorticoids 3- Hypertension
- oral contraceptives
- Alpha1-agonists (adrenaline-noradrenaline,phenylephrine-
ephedrine,phenylpropranolamine)
- B1-agonist (adrenaline-isoprenaline) 4- Angina pectoris
- Thyroid hormones
- Methyl xanthines
- Arteriodilators (hydralazine,minoxidil,nifedipine....)
due to reflex tachycardia
- Atropine – Hyoscine 5- Glaucoma
- Atropine substitutes
- Atropine- like drugs
- ganglion blockers
- vasodilators (e.g:nitrates)
- Glucocorticoids
- Hydralazine (arteriodilator used as anti hypertensive) 6- Systemic Lupus
- Procainamide (class I.A anti arrhythmic) Erythematosus (SLE)
- Isoniazid (anti T.B)
( They cause iatrogenic SLE especially in slow acetylators)
- D2-blockers (e.g:phenothiazines as Chlorpromazine,butyrophenones 7- Parkinsonism
as haloperidol,metoclopramide)
- Reserpine
- Alpha-methyl dopa
- Glucocorticoides (given systemically for long duration) 8- Cushing Syndrome
- Digitalis 9- AV block (Heart

- verapamil block)
- B-blockers
- Methacholine
- Salicylates (tinnitus I the most important manifestation of 10- Tinnitus Vertigo

salicylism)
- Ototoxic drugs,e.g:loop diuretics, aminoglycosides,vancomycin
- Metronidazole – Minocycline
- Indomethacin and phenylbutazone
9-Drugs used for diagnostic tests:
Drug Diagnosis of
1-Phentolamine Sustained type of pheochromocytoma
(non-selective α-blocker) (Phentolamine cause severe hypotension in
these patients). “Regtive test”
2-Clonidine (central α2-agonist ) Sustained type of pheochromocytoma =

clonidine suppression test (Clonidine can’t
supress release of catecholamines from the
tumor)
3-Methacholine (M-agonist) Paroxysmal type of pheochromocytoma =

4-Histamine (Autacoid) provocative test (they cause hypertension in
patients with pheochromocytoma instead of
hypotension in other patients)
5-Ergotamine (ergot alkaloid- Prinzmetal (variant or vasospastic) angina.
oxytocic-weak α1-agonist) (Ergotamine causes marked coronary V.C. in
these patients)
6-Adrenaline (sympathomimetic- Acute hemorrhagic pancreatitis (Lewi’s test).
catecholamine-β and α agonist) (Adrenaline causes active mydriasis in this
case)
7-Methacholine (M-agonist) Bronchial asthma = provocative test
(Methacholine causes marked bronchospasm
and inc. bronchial secretion in these patients)
8-Edrophonuim I.V. Myathenia gravis
9-Neostigmine I.M. + Atropine
(Edrophonium and neostigmine
are reversible anti -
cholinesterases)
10-Edrophonium I.V. Differentiation between myasthenic and
cholinergic crisis in patients of myathenia
gravis.
11-Ampicillin Infections mononucleasis (Ampicillin causes

maculopopular rash). “See chemotherapy”
10-Acute toxicity of the drues:

Signs and symptoms of acute toxicity
Drugs causing toxicity
(overdose)
Hallucinations (shizophrania-like) – convulsions – 1-Amphetamine
hypertension – active mydriasis – coma and 2-Cocaine
finally inhibition of R.C.
Mania – hallucinations – convulsions - Ergot alkaloids (Ergotism) due to
hypertension followed by hypotension – overdose of ergotamine or eating
hyperpyrexia – bradycardia – nausea & rye grains infected by ergot
vomitting – coma and finally inhibition of R.C. fungus.
Bradycardia – hypotension – bronchospasm and Organophosphorus compund
increased bronchial secretion – excessive secretion – poisoning.
diarrhea – urination – miosis – skeletal muscle twitches
followed by paralysis – convulsions – followed by
coma and inhibition of R.C.
Mania – hallucinations – convulsions – hypotension – Atropine

tachycardia – passive mydriasis – dry hot skin (fkush &
fever) – constipation – urine retention – finally coma
and inhibition of R.C.
Apnea (due to paralysis of respiratory muscles) Competitive neuro - muscular

– hypotension – tachycardia – bronchospasm blockers as curare
Coma + inhibition of R.C. + pin point pupil Morphine (see CNS)
1 The cause of death in acute toxicity is due to depression of R.C., i.e central
respiratory failure.
2 Competitive neuro-muscular blockers cause peripheral respiratory failure but
not central because they don’t cross B.B.B
3 Organophosphorus compund poisoning cause both central and peripheral
respiratory failure.
4 General rules for treatment of acute drug toxicity :
1. Stomach wash = gastirc lavage (if the drug is ingested**)
2. Care for respiration (endotrachial intubation – artificail respiration)
3. Antidote (if there is a specific antidote , e.g. atropine for
organophosphorus poisoning , neostigmine for curare toxicity ,
physostigmine for atropine poisoning)
4. Symptomatic treatment (e.g. anticonvulsant as diazepam)
5. Increase (promote) renal excretion of the drug (by changing pH of urine :
Acidification of urine in toxicity of basic drugs as amphetamine and
ephedrine using ammonium chloride or ascorbic acid , Alkalinization of
urine in toxicity of acidic drugs as salicylates (aspirin) using NaHCO3. The
drug should be completely or partially execreted in urine unchanged)
** In acute morphine toxicity stomach wash is performed although morphine is
given by I.V. injection!! (see CNS)
N.B : The size of the pupil is a useful diagnostic sign.
* Theraputic uses of choline esters:
Choline esters include: Theraputic uses:

1-Acetylcholine (natural) None (must be given I.V. – very short duration –
non-selective M-agonist)
2-Methacholine 1.Provocative test in diagnosis of bronchial asthma
2.P.V.D.
3.P.A.T
4.Provocative test in diagnosis of paroxysmal type
of pheochromocytoma
3-Carbachol 1.Glucoma (eye drops)
4-Bethanechol 2.Non-obstructive post-operative paralytic ilieus
3.Non-obstructive post-operative (or post-partum)
urine retention
5-Succinylcholine 1.Adjuvant to general anaesthesia
(Depolarizing neuro – 2.Endotrachial intubation
muscular blocker)
N.B. : - All except Acetylcholine are synthetic.

- All are quaternaty ammonium compunds.
- All except succinylcholine are parasympathomimetic.
11-Causes & Examples of Cross allergy :
1-Similarity in the chemical structure of different drugs e.g.

_Penicillins & Cephalosporins
_Sulphonamides & thiazide diuretics, loop diuretics, Carbonic
anhydrase inhibitors ,& Sulphonylureas.
2- Similarity in the mechanism of action e.g.
_ Aspirin & other NSAIDS (except paracetamol ):Bronchial asthma
12-Drugs that should never be stopped
SUDDENLY (abruptly)
1. β-blockers : sudden withdrawal causes rebound tachycardia , arrhythmia ,

angina & even acute myocardial infarction
2. Clonidine (and other selective a2-agonists ) : sudden withdrawal causes
“rebound hypertension” which is treated by giving clonidine again or by a1-
blocker ± β-blocker or labetolol but never use non-selective β-blocker alone
3. Noradrenaline IV infusion : sudden withdrawal cause “rebound hypotention“
4. Corticosteroids : sudden withdrawal after chronic use causes “Acute
Addisonian crisis“
13-Drugs and pheochromocytoma

Drugs used in treatment of pheochromocytoma (If inoperable):
1 α1-Blockers , especially phenoxybenzamine because it is a non-competitive
irreversible blocker and is the most potent α-Blocker.
2 Labetalol (β1 + α1 Blocker).
3 β-Blockers may be added to α-Blocker but never use non-selective β-
Blockers (as proranolol) Alone as they cause more hypertension due to
unopposed α-effect.
N.B. α-blockers may be also used pre-operative and intra-operative to avoid
elevation of B.P during excision of pheochromocytoma.
Drugs used in diagnosis of pheochromocytoma:

1. α-Blockers as phentolamine (Regitine test) Marked in B.P in sustained
pheochromocytoma.
2. Clonidine (Clonidine suppresion test) can’t release of catecholamines in
sustained pheochromocytoma.
3. Methacholine and Histamine release of catecholamines of B.P
(instead of hypertension in other patients).
This is a “Provocative test” which is obsolete.
Drugs contraindicated in pheochromocytoma :

1. Guanethidine (inhibit uptake 1 of noradrenaline sustained action of
noradrenaline on post-synaptic α1-receptors on B.Vs more in B.P )
2. Non-selective β-Blockers if used alone (see before)
3. α1-Agonists
14-Drugs and body characters:
A-Drugs causing alopecia:
1. Anticancer drugs.
2. Heparin (anticoagulant).
3. Colchicine (treatment and prophylaxis of acute gouty arthritis).
4. Sodium Valproate (broad spectrum antiepileptic).
5. Oxazolidinediones (antiepileptics in petit-mal epilepsy).
6. Interferons (in treatment of Hepatitis C virus "HCV").
B-Drugs used in treatment of alopecia:
1. Minoxidil sulphate
2. Pilocarpine
C-Drugs causing hirsutism:
1. Androgens.
2. Progesterone (in contraceptive pills).
3. Phenytoin (antiepileptic).
N.B: Minoxidil causes "Hypertrichosis".
D-Drugs causing Gynecomastia :

1 Digitalis (due to steroid structure)
2 Spironolactone (due to steroid structure)
3 Reserpine
Due to decrease dopamine in CNS increase prolactin
4 α-methyl dopa
5 Ketoconazole (antifungal , decrease synthesis of androgens)
6 Cimetidine (H2-blocker , used in treatment of peptic ulcer , causes anti-
androgenic action)
7 Estrogen (given to males for treatment of cancer prostate)
15-Drug groups:
1 -zoline group:
2 Naphazoline
3 Tetrahydrozoline α1-Agonists , used locally as nasal decongestants
4 Xylometazoline
5 Tolazoline α-blocker , causes nasal congestion
-lol group:
6 β-Blockers (Propranolol-Nadolol-Atenolol-Esmolol-…………)
(Butoxamine is selective β2-Blocker)
 -zosin group = selective α1-blockers
2 Prazosin
3 Terazosin
4 Doxazosin
(Tamsulosin = selective α1A-blocker used in prostatic hyperplasia)
 -nidine group = α2-Agonists

1 Clonidine (anti hypertensive)
2 Apraclonidine
Used in glucoma
3 Brimonidine
4 Tizanidine (central skeletal muscle relaxant)
 -zepine group = selective M1-blocker (useful in treatment of peptic ulcer)
5 Pireuzepine
6 Telenzepine
 -stigmine = carbamates , reversible anticholine-esterases :
7 Physostigmine
8 Rivastigmine (in Alzheimer)
9 Neostigmine
In myasthenia gravis
4 Pyridostigmine
5 -tripan group : used in acute migraine headache , agonists on 5HT1D
6 Sumatripan
7 Rizotripan
8 Zolmitripan
9 Ranitripan
 -tropium group = Atropine substitutes in bronchia asthma
10 Ipratropium
11 Oxytropium
12 Tiotropium
* -tropine group = Atropine substitutes
1 Benzotropine (in Parkinsonism)
2 Homatropine
Mydriatics
3 Eucatropine
 -curium and curonium group = Competitive neuro-muscular blockers
4 Atracurium
5 Cis-atracurium
6 Mivacurium
7 Pancuronium
8 Vecuronium
9 Alcuronium
10 -tidine group = H2-Blockers used in peptic ulcer
11 Cimitidine (+ HME inhibitor + Gynecomastia and infertility)
12 Famotidine
13 Ranitidine
14 Nizatidine
 -setron group = 5HT3-Antagonists used as anti-emetics in cancer chemotherapy
and radiotherapy
15 Ordansetron
16 Granisetron
17 Tropisetron
 -lukast group = Leukotriene receptor anatgonist used in prophylaxis of bronchial
asthma
18 Montelukast
19 Zafirlukast
 -zolamide group = Carbonic Anhydrase Inhibitors
20 Acetazolamide
21 Methazolamide See diuretics
22 Ethoxzolamide
23 Dorzolamide (eye drops in glaucoma)
 -dipine group = Dihydropyridine calcium channel blockers (cause
arteriodilatation more than cardiac dep.)
24 Nifedipine
25 Amlodipine
26 Nimodipine
27 Felodipine
28 Nicardipine
29 Isradipine
 -pril group = ACE Inhibitors
30 Captopril
31 Lisinopril
32 Enalapril
 -sartan group = ARBs (Angiotensin-Receptor Blockers)

1 Losartan
2 Valsartan
3 Candesartan
4 Telmesartan
 -caine group = Na+ channel blockers acting as local anaesthetics
5 Procaine
6 Tetracaine
7 Lidocaine (which is also antiarrhythmic)
Take care :
Butyryl choline esterase = Pseudocholine esterase
Scopolamine = Hyoscine
 Suxamethonium = Succinyl choline
Isoproterenol = Isoprenaline
Epinephrine = Adrenaline
Norepinephrine = Noradrenaline
G-protein coupled receptors
Gs Stimulation of adenyl cyclase (A.C.) enzyme increase cAMP

1- All β-receptors (β1 , β2 , β3)
2- H2-receptors (in heart , parietal cells of stomach, B.Vs)
Gq Stimulation of phospholipase C (PLC) increase Diacyl glycerol

(DAG) and inositol triphosphate (IP3) increase Ca2+ spasmogenic
Except in endothelium of B.Vs release of nitric oxide increase
cGMP V.D.
1 α1-receptors
2 M1-receptors
3 M3-receptors
4 H1-receptors (in smooth muscle fibres as bronchi-B.Vs-skin)
5 5HT2-receptors (in CNS-smooth muscle fibres as bronchi-platelets)
6 AT1-receptors (AT II acts on AT1-receptors V.C , increase aldosterone
, increase sympathetic activity and trophic changes in heart and B.Vs)
Gi Inhibit adenyl cyclase decrease cAMP

1 α2receptors (presynaptic-CNS-inhibit renin secretion)
2 M2-receptors (Heart-presynaptic)
3 5HT1-receptors (in CNS)
4 H3-receptors (presynaptic-CNS)
* Therapeutic uses of Ergot Alkaloids :

1. Acute attack of Migraine headache :
Ergotamine , Dihydroergotamine , cafergot
2. Prophylaxis of migraine headache : Methysergide (anti-serotonin)
3. Prevention & treatment of post-partum hemorrhage
4. Involution of the uterus after delivery Ergomrtrine &
5. Diagnosis of prinzmetal angina Methylergometrine
6. Senile cerebrovascular insufficiency: Dihydroergotoxine
7. PVD : Dihydroergotoxine
8. Parkinsonism Bromocriptine
9. Hyperprolactinemia in males and females (D2-agonist that crosses BBB)

6 Pharma DR Ahmed Abdelrahman

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

6 Pharma DR Ahmed Abdelrahman

Uploaded by

Copyright:

Available Formats

GENERAL PHARMACOLOGY 2011/2012

 Drugs "modify" an existing cell function either by stimulation (activation) or inhibition

 Names (Nomenclature) of drugs:

Points to discuss about drugs (Scheme):

2 Dr.Ahmed Abdelrahman www.medadteam.org

3 Dr.Ahmed Abdelrahman www.medadteam.org

V- Indications = Therapeutic uses:

VI- Adverse effects:

VIII- Drug Interactions:

IX- Routes of Administration (see later).

4 Dr.Ahmed Abdelrahman www.medadteam.org

5 Dr.Ahmed Abdelrahman www.medadteam.org

Method Characteristics Factors and forces affecting

6 Dr.Ahmed Abdelrahman www.medadteam.org

3-Active 1) The drug passes through the lipid

7 Dr.Ahmed Abdelrahman www.medadteam.org

Drug Ionization (Effect of pH on oral absorption and renal excretion):

8 Dr.Ahmed Abdelrahman www.medadteam.org

Factors affecting (modifying) drug absorption:

a) Factors related to the drug:

9 Dr.Ahmed Abdelrahman www.medadteam.org

10 Dr.Ahmed Abdelrahman www.medadteam.org

How to avoid first pass effect ?:

11 Dr.Ahmed Abdelrahman www.medadteam.org

12 Dr.Ahmed Abdelrahman www.medadteam.org

PLASMA INTERSTITIAL INTRACELLULAR

13 Dr.Ahmed Abdelrahman www.medadteam.org

B) Binding of Drugs to Plasma Proteins:

Free Form Bound Form

 In conditions causing "hypoalbuminemia" as in old age, liver diseases, malnutrition or

14 Dr.Ahmed Abdelrahman www.medadteam.org

C) Passage across Barriers:

2) Passage across placental barrier to fetus:

D) Apparent volume of distribution (Vd):

15 Dr.Ahmed Abdelrahman www.medadteam.org

16 Dr.Ahmed Abdelrahman www.medadteam.org

Phases of Biotransformation Reactions:

17 Dr.Ahmed Abdelrahman www.medadteam.org

2) They catalyze the following biotransformation 2) They catalyze the following

18 Dr.Ahmed Abdelrahman www.medadteam.org

Factors Affecting Hepatic Microsomal Enzyme activity:

1) The Effect of Drugs:

Importance of HME induction:

Importance of HME inhibitors:

19 Dr.Ahmed Abdelrahman www.medadteam.org

5) Genetic factors (Pharmacogenetics):

20 Dr.Ahmed Abdelrahman www.medadteam.org

21 Dr.Ahmed Abdelrahman www.medadteam.org

3-Respiratory System: inhaled general anaesthetics, whether gases as nitrous oxide, or

22 Dr.Ahmed Abdelrahman www.medadteam.org

Give Reason (Explain):

23 Dr.Ahmed Abdelrahman www.medadteam.org

Routes of Drug Administration:

There are 4 main routes of drug administration:

Route The drug Advantages Disadvantages

b)Sublingual 1-Stable. 1-Rapid onset of

24 Dr.Ahmed Abdelrahman www.medadteam.org

c)Rectal: In the form of Can be used if oral 1-Psychologically inconvenient

2-Injection: All drugs should be

25 Dr.Ahmed Abdelrahman www.medadteam.org

3-Inhalation Gases-Volatile liquids- 1-Useful for systemic Irritation of bronchi by some

B-Mucous 1-Used for local Undesirable systemic actions

26 Dr.Ahmed Abdelrahman www.medadteam.org