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GENERAL
FARMACOLOGY
PhD, Ass. Aleksandrova A.V.
PHARMACODYNAMICS
is the study of the biochemical and physiological effects of drugs
and their mechanisms of action.
It describes:
- Effects
- The mechanism of action
- Drugs interactions
- Doses
- Dose-effect dependence
- Factors influencing a drug action
Pharmacological effect - it changes the functions of organs and
systems of the body caused by the drug substance.
(Increased heart rate, lower blood pressure, decrease in body
temperature)
PHARMACOLOGICAL EFFECTS:
* Stimulation- it is selective enhancement of the level of
activity of specialized cells
(adrenaline stimulates heart, pilocarpine – salivary glunds)
* Depression- it is selective diminution of activity of
specialized cells
(barbiturates depress CNS, quinidine depresses heart).
* Replacement- this refers to the use of natural metabolites,
hormones or their congeners in deficiency states
(levodopa in parkinsonism, insulin in diabetes mellitus,
iron in anemia).
PHARMACOLOGICAL EFFECTS:
* Irritation- this connotes a nonselective, often noxious effect and
is particularly applied to less specialized cells. Mild irritation
may stimulate associated function
(bitters increase salivary and gastric secretion).
But strong irritation results in inflammation, corrosion, necrosis
and morphological damage. This may result in diminution or loss
of function.
* Cytotoxic effect- for invading parasites or cancer cells
attenuating them without significantly affecting the host cells is
utilized for cure/palliation of infections and neoplasms
(chloroquine, mebendazole, cyclophosphamide).
Types of drugs action
Local
(in the site of administration)
Resorptive
(after the absorption into the blood)
Direct
Indirect
(in the organ with target (in other organs but due
cells)
to the action on the
target organ)
Non selective
(on all cells)
Reversible
(with restoration to the initial state
after the elimination of the drug)
Main effects
(for which the drug is used)
Reflexive
(by reflex)
Selective
(on celected cells and tissues)
Irreversible
(without restoration to the initial
state after the elimination of the
drug)
Side effects
(unwanted effects of a therapeutic
dose of the drug)
FACTORS MODIFYING DRUG ACTION
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Body size
Age
Sex
Species and race
Genetics
Route of administration
Environmental factors and time of administration
Psychological factor (placebo)
Pathological states (GIT, liver, kidney, heart desease)
Other drugs
Cumulation
Tolerance
THE MECHANISMS OF DRUG ACTION:
Receptor interaction
Action on ion channels
Action on enzymes
Effect on transport systems (transport protein)
Effect on the permeability of cell membranes
Effect on the function of genes
Direct chemical action
THE MECHANISMS OF DRUG ACTION
Mechanism of action
Characteristics
Example
Receptor interaction
Interacts with specific receptors
Cholinergic, adrenergic,
histaminic drugs.
Action on ion channels
Blockade or activation of sodium,
potassium, calcium and chloride
channels
Local anesthetics,
blockers of Ca2+
channels
Action on enzymes
Amplification or suppression of the
activity of different enzymes
ACE inhibitors
COX inhibitors
Effect on transport systems
(transport protein)
that carry substances across cell
membranes
Sympatholytics
Effect on the permeability
of cell membranes
Stabilization or violation of the
permeability of cell membranes
Steroidal, NSAI,
antiallergic drugs
Effect on the function of
genes
Increase or decrease gene expression,
as well as the replacement of the
mutant gene
Under basic research
Direct chemical action
Direct chemical interaction
Antidotes
Antacides
DRUG RECEPTOR
A macromolecular component of a cell
with which a drug interacts to produce
a response
LIGAND
Molecules that binds to a receptor
TYPES OF RECEPTORS
In accordance with the receptor-effector
linkage:
*Type 1- coupled to an ion channel (nicotinic,
GABA, glutamate-receptors),
*Type 2 – coupled to effector system via
G-protein (muscarinic, NA- receptor),
*Type 3 - directly linked to tyrosine kinase
(insulin, growth hormone),
*Type 4 – soluble cytosolic or intranuclear
proteins (receptors for steroid and thyroid
hormones, for vit A and D).
G-protein coupled receptors (GPCRs)
G-PROTEINS HAVE 3 MAIN TARGETS OF ITS ACTION:
- ADENYLATE CYCLASE,
- PHOSPHOLIPASE “C ”
- ION CHANNEL.
The effects may be either activating or inhibiting
depending on G-protein type.
G-PROTEIN COUPLED RECEPTORS (GPCRS)
- Activation of adenylate cyclase results in formation
of cyclic adenosine monophosphate (cAMP),
- activation of phospholipase “C” results in cleavage
of phospholipids into diacylglycerol (DAG) and
inositol (1,4,5)-triphosphate (iP3).
All three substances (cAMP, DAG and iP3) play the
role of “second messengers “, exerting regulatory
effects on many functions of cells
TARGETS FOR G-PROTEINS
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Adenyl cyclase : cAMP formation
Phospholipase C : IP3 and DAG formation
Ion channels : Ca2+ and K+ channels
cGMP
Affinity (from Lat. Affinis - related) – it is
ability of the drug to combine with receptor,
resulting in the formation of a complex
"substance-receptor."
Intrinsic activity - the ability of a substance
to activate the receptor consequent to receptor
occupation.
Agonists - occupy receptors, produce a conformational
change which leads to receptor activation and thus
efficacy (adrenalin, histamin).
Antagonists - occupy receptors, produce no
conformational change and prevent the action of
agonists (Naloxone).
Partial agonists - have affinity and submaximal intrinsic
activity (Nalorphine).
Agonist-antagonist – is the drug which stimulates one
subtype of the receptor, but blocks another one
(Pentazocine).
TYPES OF DRUGS DOSES
The DOSE is the ammount of drug administered into the body
The dose may be:
Single
(for single administration)
Daily
Total
(for the day of treatment)
(for the course of treatment)
Threshold
(minimal dose which begins to act)
Therapeutic (minimal, average, maximal)
the dose which has therapeutic action
Toxic (minimal, average, maximal)
the dose which causes toxic action
Mortal
the dose which causes the death of animals in experiment
Striking
(a large dose at the start of treatment)
Supporting dose
(an individual dose for supporting a
therapeutic effect during long-term
treatment)
DRUGS INTERACTION
IS THE ACTION OF ONE DRUG ON
ANOTHER ONE.
Drug interactions:
It is usual for patients to receive a number of drugs at the same
time.
It is a phenomenon which occurs when the effects of one drug are
modified by the prior or concurrent administration of another
drug(s). A drug interaction may result in beneficial or harmful
effects and may be classified into:
a) Pharmaceutical drug interactions
b) Pharmacokinetic drug interactions
C) Pharmacodynamic interactions
a) Pharmaceutical drug interactions:
Serious loss of potency can occur from
incompatibility between an infusion fluid and a
drug that is added to it.
For example diazepam if added to infusion
fluid there will be a precipitate formation →
loss of therapeutic effect.
b) Pharmacokinetic drug interactions:
1) Interaction
during absorption: Drugs may interact in the
gastrointestinal tract resulting in either decreased or increased
absorption.
Example: Tetracycline + Calcium → Decreased absorption of
tetracycline.
2) Interaction
during distribution: A drug which is extensively
bound to plasma protein can be displaced from its binding sites by
another drug or displacement from other tissue binding sites.
Example: Sulfonamide can be displaced by salicylates from
plasma proteins and it leads to sulfonamide toxicity. Quinidine
displaces digoxin from binding sites in tissues and plasma and leads to
digoxin toxicity.
3) Interactions during biotransformation: This can be explained
by two mechanisms:
- Enzyme induction.
- Enzyme inhibition.
Enzyme induction: By this the biotransformation of drugs is
accelerated and is a cause of therapeutic failure. If the drug A is
metabolized by the microsomal enzymes, then concurrent
administration with a microsomal inducer (drug B) will result in
enhanced metabolism of drug A.
(Ex:Warfarin (anticoagulant) + Barbiturate (enzyme inducer) → decreased anticoagulation).
Enzyme inducers: Rifampicine, phenytoin, sulfonamides, etc.
Enzyme inhibition: By this the biotransformation of drugs is delayed
and is a cause of increased intensity, duration of action and some
times toxicity.
(Ex.: Warfarin + Metronidazole (enzyme inhibitor) → Haemorrhage).
Enzyme inhibitors: Disulfiram, isoniazid, allopurinol, cimetidine, etc.
4) Interactions during excretion: Some drugs interacts with
others at the site of excretion in kidneys.
(Ex.:Penicillin (antibiotic) + Probenecid (antigout drug) → Increases
the duration of action of penicillin (Both drugs excreted through
tubular secretion)
c) Pharmacodynamic interactions:
- Drug
Synergism
- Drug Antagonism
EFFECTS OF REPEATED
DOSES OF DRUGS
• Cumulation
• Tolerance
• Tachyphylaxis
• Drug dependence
• Withdrawal syndrome
(abstinence)
CUMULATION
IT IS ACCUMULATION OF THE DRUG OR ITS
EFFECT
Material
The increase in blood and / or tissue
concentrations of a substance after each
new introduction in comparison with
the previous concentration
For example: hypnotic drugs
from the group of barbiturates,
cardiac glycosides
Functional
Enhancing effect of a substance
when its applied repeatedly but
without increasing of its
concentration in the blood and / or
tissues
For example, ethyl alcohol, MAO
inhibitors
Tolerance (habituation) - is a decrease of drug‘s
action after its repeated administration in the same
dose.
(tolerance to hypnotic, alcohol, nitroglycerine).
Tachyphylaxis
reducing the effect of the
drug when it is frequent use
for short period (rapid
form of tolerance).
(tachyphylaxis to ephedrine)
DRUG DEPENDENCE
its irresistible aspiration to take the drug for
euphoria or improvement of condition.
There are two types of drug dependence:
*Physical dependence
*Psychological dependence
*Physical dependence – if the patients want to take
the drug for altering general state and mood.
(ethyl alcohol, barbiturates and narcotic
analgesics may cause physical dependence).
*Psychological dependence – if the patient wants
to take the drug for altering the mood (for
euphoria).
(psyhomotor stimulants can cause this type of
drug dependence)
Withdrawal syndrome (abstinence)
The physical and mental discomfort when the
drug is not used.
For example: increase in blood pressure after the abolition of
antihypertensive agent; acute attack of angina after the
abolition of antianginal drugs.
To prevent withdrawal syndrome drugs should
be discontinued gradually!
EMOTIONAL FACTORS.
Placebo response.
Placebo: It is a Latin word meaning” I shall please”
and it is a tablet looking exactly like the active
treatment but containing no active component. It
refers originally to substances merely to please the
patient when no specific treatment was available.
COMBINED ACTION OF DRUGS
is the action of two or more co-administered drugs on the
organism.
DRUG SYNERGISM ( the strengthening of effect) : When the therapeutic
effect of two drugs are greater than the effect of individual drugs, it is said to
be drug synergism.
It is of two types.
1. ADDITIVE effect: When the total pharmacological action of two or more
drugs administered together is equivalent to the summation of their individual
pharmacological actions is called additive effect.
A + B = AB
(Example: vasoconstrictor and hypertensive effects of norepinephrine and
phenylephrine, which stimulate α- adrenergic receptors of peripheral vessels.
Combination of ephedrine and aminophyllin in the treatment of bronchial
asthma).
2. POTENTIATION
Potentiation effect: When the net effect of two drugs used
together is greater than the sum of individual effects, the
drugs are said to have potentiation effect.
AB > A + B
(Example: chlorpromazine (antipsychotic drug) potentiates the effect of drugs
for general anaesthesia).
Practical purpose
Achieving pharmacological effect by reducing the dose of drug
substance
Antagonists - occupy receptors, produce
no conformational change and prevent the
action of agonists.
ANTAGONISM
Chemical
The two drugs react
chemically and form
an active product
For example:
Acids and alkalis
(neutralization)
Physical
Based on the physical
property of the drugs
For example:
Activated charcoal
and alkaloids,
cardiac glycosides,
heavy metals
(absorption)
Physiological
The functional effects of
drug substances
Direct
(stimulants and blockers
of β adrenoseptors)
Competitive (morphine
and naloxone)
Indirect (Aceclidine and
papaverine)
Competitive or reversible antagonism:
In this the agonist and antagonist compete for
the same receptors and the extent to which the
antagonist opposes the pharmacological
action of the agonist. Competitive antagonism can be
overcome by increasing the
concentration of the agonist at the receptor site.
(Example: Acetylcholine and atropine antagonism at
muscarinic receptors).
Non competitive antagonism:
In this type of the antagonism an
antagonist inactivates the receptor (R) so that
the effective complex with the agonist cannot
be formed, irrespective of the agonist
concentration.
(Example: Acetylcholine and papaverine on
smooth muscle. Acetylcholine and
decamethonium on neuromuscular junction).
EQUILIBRIUM antagonism:
Certain antagonists bind to the receptor with
strong (covalent) bonds or dissociate from it slowly
(due to very high affinity) so that agonist molecules
are unable to reduce receptor occupancy of the
antagonist molecules – law of mass action cannot
apply – an irreversible or NONEQUILIBRIUM
ANTAGONISM is produced.
Example: Phenoxybenzamine is a nonequilibrium
antagonist of adrenaline at the α-adrenergic
receptors.
IMPORTANCE OF DRUG ANTAGONISM
1. Correcting adverse effects of drugs
2. Treating drug poisoning.
Morphine with naloxone, organophosphate
compounds with atropine.
3. Predicting drug combinations which would
reduce drug efficacy.
SIDE EFFECTS
ARE NON-USEFUL EFFECTS OF
DRUGS IN THERAPEUTIC DOSES
• Allergic reactions as immune reactions of
hypersensitivity (anaphylaxis caused by penicillin)
These allergic reactions are 4 types.
Type-I reactions or anaphylactic reactions (Immediate
hypersensitive reaction).
Type-II reactions or cytotoxic reactions.
Type-III reactions or immune complex mediated
reactions.
Type-IV reactions or cell mediated reactions (Delayed
hypersensitive reactions).
SIDE EFFECTS
• Direct toxic effects (nefrotoxicity,
ototoxicity and neurotoxicity of streptomycin)
• Idiosyncrasy as an abnormal reaction
occurred after the first drug administration and caused by
generic factors
(hemolysis of erythrocytes after the use of quinine in
patients deficient on glucose-6-phosphate dehydrogenase)
SIDE EFFECTS
• Photosensitivity it is cutaneous reaction resulting from drug induced sensitization of the skin
to UV radiation.
The reactions are of two types:
a) Phototoxic (drug or it metabolite accumulates in the skin,
absorbs light and undergoes a photochemical reaction followed by
a photobiological reaction resulting in local tissue damage
(sunburn-like) – erythema, edema). (Tetracyclines and tar
products)
b) Photoallergic (drug or its metabolite induces a cell mediated
immune response which on exposure to light of longer wave
lengths (320-400 nm.UA-A) produces a papular or eczematous
contact dermatitis like picture that may persist long after
exposure. (Sulfonamides, sulfonylureas, griseofulvin, chloroquine,
chloropromazine, carbamazepine)
SIDE EFFECTS
• Embryotoxic, fetotoxic and
teratogenous effects as a negative
influence on the embrio and the fetus
during pregnancy (hypoplesia of tooth
enamel caused by tetracyclin)
• Canserogenous and mutagenous action as
the ability to provoke the development of
malignant tumors (secondary malignancy
caused by leukopoiesis inhibitors).
TYPES OF PHARMACOTHERAPY
☺ Preventive
☺ Etiotropic
☺ Replacement
☺ Symptomatic
☺ Pathogenetic
Preventive therapy
Aims to prevent certain diseases or relapse and
prevention of complications of medical
treatment.
Example: the appointment of antimalarials
Etiotropic
The elimination of the causes of a
pathological condition.
Example: assignment of antibacterial
agents.
REPLACEMENT
Insufficient function involved in the pathological process of
organs and systems requires substitution treatment.
For example, atrophic gastritis, diabetes mellitus.
Symptomatic
The elimination of symptoms can alleviate the
patient's condition and course of the disease, but can
not eliminate the cause. This type of treatment is
palliative and can not be regarded as basic.
Pathogenetic
The use of drugs affecting various parts of the mechanism of the
disease
Example: enalapril in hypertension.
Thank you for your attention