Pharmacodynamics

Mode of action of drugs

Lecture № 3
Module «Pharmacology»

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 Pharmacodynamics
investigation of processes in the body due to the influence of
pharmaceutical substances

Pharmacological effects – all processes in the body

induced by the influence of PS:
(alteration of functions of organs and systems, such as ↑BP,
↓BP, tachycardia, bradycardia, mydriasis)

Pharmacological effect – result of interaction between

PS and biological structures (cells, organelles, enzymes,
nucleic acids and other)

Mode of action of PS – the way a PS can achieve

pharmacological effect.

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 Influence of PS is
found on:

Molecular;
Cellular;
Organ;
Systemic;
Whole body

levels.

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 Targets for PS
Biological structure on cellular and molecular levels PS interacts
with is termed «target» (emetic center, heart)

«TARGETS»
FOR PHARMACEUTCIAL SUBSTANCES
1. Biomembrances and ionic channels
2. Receptors (outside and inside cells)
3. Enzyme systems
4. Intracellular metabolites
5. Intercellular substances
6. Infectious and parasitic agents
7. Toxins and venoms

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 Targets for PS
Biological structure on molecular level PS interacts with is
termed «receptor» (pharmacological receptor)
Receptors – functionally active macromolecules (proteins,
lipoproteins, nucleoproteins, glycoproteins) or their fragments :
regulating proteins; enzymes; carrier proteins; structural
proteins

Specificity – ability to interact with one PS and does not

interact with another PSs.
Interaction of PS with receptors is Drug-receptor
interactions

Non receptor mediated actions = interaction of PS with

other PSs or water molecules

Interaction – formation of bonds with receptors.

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 Types of bonds between PS and receptors

Covalent – irreversible, strong – bond between two atoms via joint

electron pair (antitumor drugs);
Non-covalent – bonds (interactions) without formation of joint electron
cloud, reversible and typical for PS:
1. Electrostatic forces – between groups with opposite sign charges;
А. Ionic interactions – between two ions; the strongest bonds among non-
covalent interactions; distance up to 50 nm;
Б. Ion-dipole interaction – distance up to 1,5 nm;
В. Dipole-dipole interaction – due to formation of induced dipoles in
electroneutral molecules; distances up to 0,5 nm, (hydrogen bond –Н atom binds
atoms O2, N, S, Cl and others, distance ≤ 0,3 nm;
2. Van der Waals forces – between any two atoms with the distance ≤ 0,2 нм; these are
weak forces;
3. Hydrophobic effect – interaction of non-polar molecules in aqueous media.

Generally, PS at the interaction site forms several bonds of different types.

Some substances that are almost completely inert may also possess pharmacological activity
(xenon).
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 Interaction of drugs with receptors

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 Quantitative characteristics of drug-receptor interaction

Affinity (lat. affinitas – relationship, close connection):

а) ability of PS to bind to receptor;
б) Strength of bonds between PS and receptor.

Kd (dissociation constant) – affinity measure for binding between PS and

receptor – numerically equals such PS concentration when 50% of receptors are
bound to PS, mol/L (М);

The higher Kd , the lower affinity; the lower Kd, the higher affinity.

If Kd of pharmaceutical substance А = 10-5М,

Kd of pharmaceutical substance B = 10-10М,
consequently, affinity of PS B > affinity of PS A.

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 Quantitative characteristics of drug-receptor interaction

Efficacy - maximum effect that a drug can produce regardless of dose

Potency
Potency is -an expression
amount of the
of a drug activity
that of a drug
is needed in terms
to produce of theeffect
a given concentration
or amount •ofe.g.,
theEC50
drugisrequired to produceor
the concentration a defined effectthat causes 50% of
dose of drug
maximum
Clinical efficacy effect
judges the therapeutic effectiveness of the drug in humans
•determined by affinity of drug for receptor and number of receptors available
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 Quantitative characteristics of drug-receptor interaction

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 Characteristics of pharmaceutical molecules
Origin:
1. Analogues of endogenous compounds (hormones, enzymes);
2. Xenobiotics (Greek «xenos» – alien).

Physical state of PS:

1. At room t° - 1. solid; 2. fluid; 3. gaseous.

Sizes:
From very tiny (Li, MW=7) up to enormous (Alteplase, MW=59 050)
The major part: from 100 to 1000 Da
100 – lowest MW that can provide selectivity of binding processes;
1000 – largest size (upper limit) that can provide movement of PS throughout the
body

Shape:
Provide physical interaction with receptor
The best option – shape of PS is complementary to receptor’s shape

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 Chirality phenomenon. Enantioselectivity of PS
About 50-50% of PS are chiral molecules i.e. they are enantiomer pair.
Racemic mixture (racemate) – mixture of two compounds,
which structural formulas correlate as a subject
and its mirror reflection

Distance between atoms in enantiomers is the same,

thus their physico-chemical properties (solubility,
melting point, molecular weight) are the same.
Chemical synthesis results in formation of the same amounts
of both enantiomers; in nature – more often only one.
In solution enantiomers linearly refract a light polarizing beam
in opposite directions:
Dextorotaion and levorotaion form:
d-form (or [+]-form and l (or [-]-form);
R/S – nomenclature; D/L – nomenclature.

Enantioselectivity is different;
Potency and efficacy are different;
Metabolism rate is different;
Duration of action is different.

Legislative solution – manufacturing must

produce chiral PS in form of their
active enantiomers

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 Chirality phenomenon. Enantioselectivity of PS
About 50-50% of PS are chiral molecules i.e. they are enantiomer pair.
Racemic mixture (racemate) – mixture of two compounds,
which structural formulas correlate as a subject
and its mirror reflection

Distance between atoms in enantiomers is the same,

thus their physico-chemical properties (solubility,
melting point, molecular weight) are the same.
Chemical synthesis results in formation of the same amounts
of both enantiomers; in nature – more often only one.
In solution enantiomers linearly refract a light polarizing beam
in opposite directions:
Dextorotaion and levorotaion form:
d-form (or [+]-form and l (or [-]-form);
R/S – nomenclature; D/L – nomenclature.

Enantioselectivity is different;
Potency and efficacy are different;
Metabolism rate is different;
Duration of action is different.

Legislative solution – manufacturing must

produce chiral PS in form of their
active enantiomers

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 Types of interactions between PS and receptor
Type I: Type II:
PS binds to receptor and activates it → PS binds to receptor and prevents other
molecules (PS-agonist or endogenous
pharmacological effect.
substrates) to bind with receptor →
induction of pharmacological effects
opposite to the agonist effect.

PS – agonist (Greek. agon – strugle, PS – agonist (Greek. anti,

agonistes – competitor) antagonisma – competition).
possesses inner activity

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 Interaction of PS-agonist with receptor

The main factor: excessive quantity of receptors:

Endogenous ligand interacts with 10-25% receptors resulting in

physiological effect

Agonist activates up to 80-100% receptors

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 Interaction of PS-antagonist with receptors

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 Mathematical evaluation of PS-receptor interaction

Reaction induced by low doses of PS increases directly the dose increase;

then with the following increase the responding reaction becomes lower;
then we achieve the dose when effect no more increases (maximum respond).
Relationship between effect and PS concentration (perfect under in vitro conditions)
is described by hyperbola in accordance with the following equation
(concentration – effect) :

E = Emax ∙ C / C + EC50, where

E – effect, noted at concentration С;

Emax – highest effect of PS;
EC50 – PS concentration providing the effect that is 50% of the highest one.

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 Types of antagonism:
If antagonist occupies the same binding sites on receptors as agonist
does then they both are able to displace each other from the binding
sites. This is competitive antagonism.
PS – competitive antagonist (reversible).

In the presence of agonist and antagonist in the system their resulting

effect depends on their affinity to receptor and their concentration.
If their concentrations are equal than the resulting effects is the one of
the PS with high affinity.
If affinities of these PS are equal then resulting effect is the one of PS
with higher concentration.
Competitive antagonism supposes that effect of agonist fully restores
after increase of its concentration.
In the presence of constant agonist concentration, an increase of competitive
antagonist concentration gradually reduces reactions induced by agonist
until full inhibition of this effect.
Vice versa, an increase of agonist concentration can completely overpass
inhibiting effect of competitive antagonist. i.e. Emax (highest effect) for agonist
is the same for any fixed concentration of competitive antagonist, but the
curve concentration-effect moves right.
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 Type of antagonism:

If antagonist occupies the receptor binding sites which are not

serving as binding sites for agonist but regulating receptor activity
(allosteric sites)

then antagonist does not displace agonist but alters receptor

conformation (shape) as though receptors looses its capacity to
interact with agonist

This is non-competitive antagonism;

PS – non-competitive antagonist
(irreversible).

Increase of agonist concentration

does not fully restore its effects
as they are provided by covalent bonds.

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 Type of antagonism:

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 Type of antagonism:

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 Drug – receptor interaction

PS may at the same time stimulate one receptor type (subtype)

and block another receptor type (subtype).
This PS – agonist-antagonist.

All receptors are supposed to be equivalent and equally available

Pharmacological effect is directly depending on the number of occupied

receptors

Maximal (highest) effect – all receptors are occupied

Duration of action: PS exerts effect until receptors are occupied. This

influence discontinues after dissociation of PS from receptor

Effect of PS may continue after dissociation of PS from receptor if part of

participating molecules are still in active state
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 Drug – receptor interaction

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 Drug – receptor interaction

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 Drug – receptor interaction

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 Physiological antagonism of PS effects

Physiological antagonism may be found in the body which is

based on function of different regulating systems

For example,
Glucocorticoid hormones increase blood glucose level,
whereas insulin exert physiological opposite influence,
because they affect different receptor-effector systems.

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 Types of receptors
and signal transfer via plasmatic membrane

I. Intracellular proteins –
cytosol and nuclear proteins.

PS is diluted in plasmatic membrane lipids

→transport into cell→
Interaction with cytosol receptor
→conformational receptor alteration
→transport of PS-receptor complex into
nucleus via nuclear membrane
→binding to specific DNA part close to gene
which expression is to be regulated
→activation (inhibition) of gene
transcription →activation
(inhibition) of protein (enzyme) synthesis
→alteration of biochemical processes
→pharmacological effect.
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 Types of receptors
I. Intracellular receptors

Period between time of PS interaction with intracellular receptor

and resulting effect – from 30 min to few hours
(time required for new protein synthesis).

After PS administration discontinued its effect lasts for several

hours and days; as beneficial as toxic effects disappear gradually;
Here is no correlation between plasma PS concentration and PS-
induced effects

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 Types of receptors

II. Membrane receptors

(2 domains – extracellular and intracellular):
1) Receptors linked to enzymes–
intracellular domain=enzyme
(PS binds to extracellular domain
of transmembrane protein and
activate allosterically enzyme
activity of its cytoplasm domain
(protein kinase; tyrosine kinase)→
phosphorilation of extracellular
proteins;
Guanylate cyclase→cGMP;
serine kinase);
Examples: insulin,
Other trophic hormones.
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 Types of receptors

2) Receptors coupled with ion channels (ligand-gated ion channels)

Receptors penetrates membrane and forms ion channel;
PS binds to extracellular domain→
channel opens→membrane permeability
changes (period from binding till reaction
is several milliseconds).

Acetylcholine →binding to choline receptor →

Na-channel opens→Na goes inside cell →
membrane depolarization→muscle contraction.

GABA →А-receptors (linked to Cl-channels) →

Cl-channels open → Cl goes inside cells→
Membrane hyperpolarization →activation of
Inhibiting processes in CNS;

Examples:
Acetyl choline, GABA, glycine, aspartate, glutamate

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 Types of receptors
3) G-protein coupled receptors:
System with three components: Receptor –
G-protein (GTP-binding protein) –
enzyme(s) or ion channel(s).
Gs-proteins→adenylate cyclase stimulation→
↑cAMP →(+) chronotropic effects;
Gi-proteins→ adenylate cyclase inhibition →
(-) chronotropic effects.
Gq-proteins →phospholipase С activation→
Hydrolysis of phosphatidylinositol 4,5-bisphosphate
→formation of inositol 1,4,5-trisphosphate→
Interaction with Ca-channels
sarcoplasmic reticulum→
release of Ca2+ into cytoplasma→
accelerated formation of Ca2+-calmodulin complex
→activation of kinase of myosin light chains→
phosphorylation of myosin light chains →
amplification of actin to myosin interaction
→smooth muscle contraction (vessels).
G-protein coupled receptors, structurally similar;
they make a group of serpentine receptors».
Examples: ACTH, norepinephrine, adrenaline, dophamine, 31
LH, TSH, PSH, glucagon.
 Types of receptors

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 Intracellular messengers (mediators): cAMP

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 Intracellular messengers (mediators)
cAMP→stimulation of protein kinase (phosphate transfer from ATP to
substrate enzyme-proteins):
glycogen degradation in hepatocytes (glycogen phosphorylase);
triglyceride degradation in fat cells (lipase);
smooth muscle relaxation (phosphorylation of myosin light chain kinase).

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 Intracellular messengers (mediators)
Ca2+ and phosphoinositides:

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 Intracellular messengers (mediators)
Ca2+ and phosphoinositides: PS+R →phospholipase С activation →
hydrolysis of phosphatidylinositol 4,5-bisphosphate (phospholipids of
plasmatic membrane) into diacylglycerol and inositol 1,4,5-
trisphosphate.

Diacylglycerol →activation of Ca2+-sensitive protein kinase С;

inositol 1,4,5-trisphosphate → diffuses into cytoplasm and helps Ca2+

release from intracellular storages→
Ca2+ release into cytoplasm→increased level of intracellular Ca2+ →acceleration
of the Ca2+-calmodulin complex formation → regulation of activity of other
enzymes.

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 Intracellular messengers (mediators)
cGMP →stimulation of cGMP-dependent protein kinase →relaxation of smooth
muscles in vessels

NO (nitrogen oxide) in cell binds to guanylate cyclase → guanylate cyclase

activation → increase of intracellular cGMP level → protein kinase stimulation
→ relaxation of smooth muscles in vessels.

Some vasodilating PS acts via NO formation.

Pharmacological effects due to activation of secondary messengers:

• Increase/reduction of gland secretion;
• Relaxation of smooth muscles;
• Stimulation/inhibition of protein synthesis;
• Relaxation of striated muscles;
• on organ and system level: strengthening of functions (cardiac contraction
force) or reduction (nap, sleep).

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 Non-receptor interactions
(non-receptor targets for PS)
Ion channels – voltage-gated channels (regulated by action potential), i.e. open due to
depolarization of cell membrane - Na+,
K+, Ca2+ and other. PSs block (more often) or activate channels.

• Slow Ca2+ channel blockers (verapamil)→inhibition of Ca2+ ion flow inside cells.

• Na+-channel blockers (antiarrhythmic, local anesthetics, anticonvulsant drugs) →inhibition of

Na+ getting inside cell→ inhibition of cell membrane depolarization.

• K+-channel activators →contribute K+ ion outflow from cells→ membrane hyperpolarization

→ reduction of smooth muscle toning in vessels →↓blood pressure

• K+-channel blockers →prevent K+ ion outflow from cells→increase duration of action

potential → prolong effective refractory period of heart.

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 Non-receptor interactions
(non-receptor targets for PS)

• Enzymes:
PS inhibit enzymes (cyclooxygenase→ inhibition of prostaglandin synthesis)
• Carrier systems (carrier proteins): Na+, K+- ATPase of cardiomyocyte membranes.
• Infectious and viral pathogens;
• Toxins and venoms (reaction antidote + toxin (unithiol binds heavy metal ions;
• HCl neutralization in stomach;
• Effects of general anesthetics (PS dissolves in membrane lipids);
• Laxative effect of saline drugs (effect of hypertensive solution);
• Diuretic action of osmotic diuretics;
• Dissociation of oxidative phosphorylation (Т3, Т4);
• Inhibition of protein biosynthesis.

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 Role of PS chemical structure for its action
Relationships between structure and pharmacological effects:
•-COOH, NH2-groups→molecule ionization→absorption

Digitoxin Digoxin Strophanthin

•Homologues orders of PS
Ammonium tetramethyl =1 un. acetyl choline, 1,4 un., 60 un., 86 un., 430 un., 58 un., 1

Similarity of PS and natural metabolites: AC and carbachol

15.02.24 Adrenaline Mesatone Ephedrine 40

 Role of PS chemical structure for its action
No relationships between structure and pharmacological action

uracil – metacyl (methyluracil) - fluorouracil

•Steroid compounds – cholesterol derivatives: sex hormones, cardiac glycosides, diuretics, antibiotics

Testosterone Estradiol Aldosterone

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 Role of PS chemical structure for its action
• Prostanoic acid derivatives – PGF - ↑BP, PGЕ - ↓AD

Tubocurarine

Reason of no relationship:
•Structural formula does not reflect real conformation and properties of PS.
•Physico-chemical properties of PS when interacting with receptors is not known.
•Comparison of PS with different mode of actions: for example, Mg2+→blocks AC release from
synaptic vesicles; curare poison→blocks AC receptors: both PSs→muscle relaxation.
•Comparison of inactive PS (pro-drugs) with active metabolites.
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 Influence of ambient factors on PS effects
Food – food quality, lack of food, lack of nutritional components:
Diet regime for various diseases; protein deficit→hypovitaminosis ;
Carbohydrate excess→increased rick of peptic ulcer due to aspirin intake;
Cheese, sour cream taken with antidepressant → BP↑

Temperature – affect rate of PS absorption, summer = increased tone of autonomic nervous

system →atropine intake may result in death (due to inhibited perspiration)

Atmosphere pressure – affect efficiency of cardiovascular drugs

Isolation – excitability, aggression – psychostimulants become toxic, sedative drugs become less
effective.
Biological rhythms (daily, seasonal) – chronopharmacology (part of chronobiology) –
Investigating dependence of drug effects on time of administration. Biorhythms: circadian
(daily), hourly, weekly, monthly.
Biological rhythms characteristics: acrophase – period in a cycle during which the cycle crests or peaks,
batiphase – the moment in cycle in which the minimum value is produced; amplitude – deviation of
function from mean; mesor – mean (e.g. mean daily) value of the function studied.
Main terms of chronopharmacology: chronopharmacokinetics – alteration of absorption,
distribution, biotransformation and excretion of PS; chronesthesia – rhythmic alteration of the body
sensitivity to PS; chronergia – rhythmic alteration of pharmacological effects of PS.

Examples: hypnotics are more effective at night, penicillins are metabolized slower during night,
ginseng is not effective in summer.

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 Influence of intrinsic factors on PS effects

Gender (influence of male and female sex hormones): hexenal IP to rats

→female rats sleep 3 times longer than males (testosterone activates
microsomal enzymes in liver)→accelerated hexenal metabolism.

Age (aging pharmacology)

Peculiarities of childhood:
Many genes are not active yet→lack of some enzymes; low activity of enzymes;
Undeveloped CNS; weak humoral and cellular immunity; imperfect barrier mechanisms
(generalization of infection); fast PS absorption; low albumin level; imperfect
microsomal enzymes →slow biotransformation;
excretory function of kidneys is not developed yet.

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 Influence of intrinsic factors on PS effects

Methods of dose calculation for kids:

1. body weight; 2. body surface square; 3. depending on age:
before 1 year – 1/24, 1 year – 1/12, 2 years – 1/8, 4 years – 1/6, 6 years – ¼,
7 years – 1/3, 14 years – ½ adult dose.
4. Based on dose factor (for children with excessive body weight or lack of body
weight):
Single adult dose/kg body weight х dose factor х child body weight(kg):
Dose factor: – 0-1 year – 1,8; 1-6 years – 1,6; 6-10 years – 1,4, 10-14 year – 1,2.

There are special tables for poisons and high potent drugs.

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 Influence of intrinsic factors on PS effects

Features of senile and senior age:

• Reduced absorption;
• Low dynamics of intestine;
• Slow distribution (slowed bloodstream, low blood albumin level), slowed
metabolism (liver atrophy); slowed excretion (reduced number of nephrons,
reduced glomerular filtration).

Doses are lowered to 1/3 – ½ of regular doses.

Receptor sensitivity increased or decreased→unusual reaction→constant dose

adjustment.

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 Influence of intrinsic factors on PS effects
Body weight – dose increase or decrease required (mg/kg).
Pathologic processes – alter body reaction on PS (taken to account that PS works in the
presence of pathologic process and pathologic process itself affects reaction on PS).
Exhaustion, dehydration – increased reaction on PS (1.5-2.0-fold dose decrease).
Anacid gastritis → K+ resorption decreases in 5 times compared to normal values.
↓рН → PS weak acids (phenobarbital) are deionized (become less polar) → easier transport
through biomembranes → better absorption from blood into tissues → effect strengthening.
Hence, barbiturate poisoning requires blood alkalization.
Kidney disorders → slowed excretion (in 5-10 times) → toxic effect.
Liver disorders → biotransformation defects → toxic effects.
Tuberculosis, alcoholism → гlow blood albumin level → toxic effect.
Endocrine diseases → thyroxin inhibits microsomal oxidation, myxedema (thyroid hypofunction)
→ dramatic reduction of PS effects.

Genetic factors – determine sensitivity of the body to PS (pharmacogenetics).

Gene mutation → alteration of biotransformation enzyme activity. Fermentopathies → increased / reduced activity
→ strengthened /weaken PS metabolism→ strengthened /weaken PS effects (PS toxicity). Atypical reactions on
PS – idiosyncrasy. For example, congenital deficiency glucose-6-phosphate dehydrogenase of erythrocytes makes
quinine (antimalarial PS) transforms into quinone → hemolysis of erythrocytes (hemolytic anemia).

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 Combination drug therapy
Pharmacotherapy – treatment of disease with drugs:
1. Monotherapy – treatment with one medication.
2. Polytherapy – treatment with several medication (for 1 patient):

Combination therapy – polytherapy of one disease

(etiotropic + pathogenetic + symptomatic).
Complex therapy – polytherapy of two or more diseases

Polypharmacy
Polytherapy – unreasonable
1-5 medication polytherapy.
results in side effects in 4%
16-20 medication - in 54%.
Doctor is to prescribe no more than 3-5 PS.
For treatment of major part of diseases 200 drugs is enough
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 Four classes of interactions
Class Description Example Measures
А Not significant Ranitidine+ Therapy
interaction Phenobarbital correction is
В Interaction is not - nor required
described

С Therapy effects Warfarin + Therapy

altered Phenobarbital correction+
monitoring
D Therapy Propranolol + Inaccessible
ineffective. Verapamil
Risk of severe (full AV block)
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 Drug Incompatibility
with other medication

PHARMACEUTICAL PHARMACOLOGICAL
(outside human body) (inside human body)

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 Pharmacological drug incompatibility
with other medications

PHARMACOKINETIC PHARMACODYNAMIC

Synergism Antagonism
Absorption
Distribution
New effects
Biotransformation

Excretion
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 Pharmacokinetic drug
incompatibility
at absorption from GI

1. Effect of PS on Ph value in GI
(increased рН rises degree of ionization of weak acids
and slows down their absorption)
Example of incompatibility:
Antacids and direct anticoagulant, NSAID, cardiac
glycosides, sulfanilamides, nitrofurans

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2. PS effects of GI motility
(major part of PS is absorbed in proximal part of small
intestine, thus rate of stomach content evacuation
determines time of effect commencing and its intensity)
Examples of incompatibility:
М-choline blockers and narcotic drugs decelerate evacuation and
increase toxicity of iron medications, cardiac glycosides and
NSAID
Metoclopramide accelerates GI peristalsis, and this leads to faster
effects of ethanol, acetaminophen, tetracyclines and
bensodiazepines.
But slow absorbing PS (cardiac glycosides, cimetidine, etc.) do not
have enough time for absorption and this will reduce therapeutic
efficiency.
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3. Influence of PS on membrane transport systems in
GI (enzyme activity and membrane state of intestinal
epithelium) Some PS damage cells of mucous lining
Examples on incompatibility:
Aminoglycosides, polymyxins, tetracyclines – reduce absorption of
iron, cyanocobalamin and folic acid
So, aminoglycoside intake 3-times reduces digoxin blood level.
Diphenin – slows down absorption of folic acid with consecutive
megaloblastic anemia.

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 Pharmacokinetic drug
incompatibility
with other medications

at stage of distribution

Binding with proteins Transport Transport

and blood cells through tissue into center
barriers of inflammation
and receptors
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 Drug incompatibility
with other medications

at stage of protein binding

Major part of PS - organic compounds with high affinity
to blood proteins (mainly - albumins, having four binding
sites).
That’s why they can displace other PS that are organic
substances and bound to proteins, but having lower
degree of affinity, or they can be displaced by PS with
higher affinity.

_ + _ + + Drug (cation)
2 _ _
3
1 + + 4 Albumin (polyanion)
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Displacement effects is short :
Increase of drug concentration in free form affects
active sites as well as alters drug distribution and
elimination.
С’

Finally the new equilibrium is achieved, when

concentration of the drug free form reaches the
same level as it was before displacement.

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Long increase of concentration (and clinical
signs) are possible:
• If key sites of distribution and elimination
are saturated.
• if therapeutic index of the drug being
displaced is low
С’

t
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 Drug incompatibility
with other medications

transport through tissue barriers

Accelerated transport Slowed transport

Methylxanthines Anti-bradykinin medications

Neutral charge (parmidin)

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 Drug incompatibility
with other medications

transport into tissues – into

inflammation focus or to receptors

Accelerated transport Slowed transport

Lipophilicity, small Large molecule size
size and flat form + charge
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 Drug incompatibility
with other medications

biotransformation

I phase II phase
Metabolism Conjugation
(lowered pharmacological (increased hydrophilicity
activity – water solubility

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 Drug incompatibility
with other medications

conjugation

Conjugation needed Conjugation not needed

Organic acids: Nimesulide

1. Sulfating
2. Glucuronation }80% (NO2 hydrolysis at 4th position)
3. Hydroxylation NO2 – inhibitor COX-2 gene
+ glutathione !!! expression on 1st chromosome
– hepatocyte necrosis!!!
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 Drug incompatibility
with other medications

Elimination
Major part of NSAID (in particular indomethacin)
reduce (via COX-1 suppression):
• rate of glomerular filtration,
• velocity of urine formation,
• free water clearance,
• electrolyte excretion.
and disturb elimination pharmaceutical substances, that
are excreted through kidneys

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 Combination PS effects
1. Synergism (Greek. syn – together, erg – work) –
joint action of PSs, when effects of two PSs
is stronger, then this of one PS alone:

• Sub-additive synergism – resulting effect is lower than sum;

• Additive synergism – resulting effect is equal to sum(2 PS affect the
same receptors – direct synergism);
• Potentiation – resulting effect is higher than sum (2 PS affect different
types of receptors or possess different mode of action – indirect
synergism).
Meaning for clinics: administration of 2 PS makes possible to reach
desirable effects using lower doses with lower risk of side effects.

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 Combination PS effects
2. Antagonism – interaction between PS resulting in reduced
or disappeared effects of one or both PSs.
Types:
а) pharmaceutical – occurs at different stages of production, storage or administration of
PS (in one syringe) with formation of inactive or toxic compounds, impaired solubility
(sedimentation), stratification of emulsions, melting of powders (eutectic mixtures).
б) physical – physical interaction of PSs (adsorption on activated carbons);
в) chemical – chemical interaction with formation of inactive complexes (cuprenil and
copper medications);
г) functional (pharmacological):
direct – PSs affect the same receptors (acetyl choline and blocker of acetyl
choline receptors);
indirect – PSs affect different receptors (or functional elements) (acetyl choline
→ binding to acetyl choline receptors → bronchospasm; adrenaline → binding to
noradrenaline receptors → bronchial dilatation);
can be unilateral (strychnine and ether – antagonists; ether reduce strychnine effects
(convulsions), but strychnine does not reduce ether effects).

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 Pharmacodynamic drug
interaction
5
3
Synergism:
2 1- sub-additive effect
2- summation
q 3-potentiation
4 4- ANTAGONISM

5- Synergy-antagosnism

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 Drug interaction

Practical meaning:

• Prescribing several medications it must be checked that here is

no antagonism.

• Reduced therapeutic effects, distortion of effects, lack of effect,

occurrence of undesirable effects – unreasonable combination
(drug incompatibility).

• Increased therapeutic effects, reduce or prevented negative

reactions → rational combination.

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 Body reactions on repeated drug intake
1. Effect weakening (habituation, tolerance – latin. tolerantia – capacity to stand to, patience)
– increase of body sustainability to drug associated with reduced therapeutic activity
(toxic effects). This may be due to:
• Limited absorption (inflammation, mucous lining GI, scars);
• Induction of microsomal oxidizing;
• Receptor desensitization. Developing in several days to several months.
Tachyphylaxis – rapidly diminishing response to successive doses of a drug, rendering it less
effective in several minutes and up to days.
Mithridatism – gradually developing habituation to medications and poisons occurring due to
long intake of increasing doses from very small to the large ones.

2. Effect enhancing – accumulation – increase of drug amount in the body and its effects:
• Material cumulation amounts of PS getting into body is higher than eliminated; may be
necessary for therapeutic effect (cardiac glycosides), may be caused by liver or kidney
disorders → toxic effects.
• Functional cumulation – enhanced effects of PS administered repeatedly without increase
of its blood or tissue concentration.

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 Drug addiction
predilection– aim of taking medication is not corresponding with its indication
base – need in mood alteration, pleasant relaxation,, facilitation, increase of working capacity,, an
effort to relieve pain, the desire for intoxication and easy ecstasy.

Predilection leads to addiction – condition associated with forced desire to take a medication
(or chemical compound) for a long period or periodically for experience of psychic effect again
or to avoid worsening of general state due to the lack of medication (cancellation).

Primary reason is a property of such medication and other compounds to induce pleasant and/or
unusual feeling leading to psychological dependence.

May medications and chemical compounds induce formation of physical dependence, i.e.
condition which is characterized by severe disturbance of somatic status when intake of he drug
or compound is discontinued. This condition is termed withdrawal syndrome.

Intake of medication or chemical compounds makes relief of the general conditions and continuing
intake reduce withdrawal syndrome.

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 Drug addition

Drug abuse – consumption of medication or other compounds that is harmful for

health. The number of psychotic substances causing addition includes narcotic
substances.

Narcotic compound (narcotic) – first of all, this is first of all, a legal term
indicating that some authority organization (in Russia – Russian ministry of
health) refers this compound and narcotic and included it into the official list of
narcotic compounds.

As medical term, narcotic – this is psychoactive compound causing dependence

leading to consumption of this substance in large doses that are harmful for
health and may lead to undesirable social consequences.
drug addiction – this is morbid mental stat characterized by predilection to narcotic
substances (usually, illegal) or narcotic dependence.

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 Drug side effects

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 Drug side effects

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 Drug influence of fetus and newborn

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15.02.24 74
 EL
EL FINAL
FINAL

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