GENERAL FARMACOLOGY

1. GENERAL FARMACOLOGY PhD, Ass. Aleksandrova A.V.

2. 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)

3. 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).

4. Pharmacological effects: * Irritation- this connotes a nonselective, often noxious effectand 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).

5. Types of drugs action

6. Factors modifying drug action • 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

7. 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

8. The mechanisms of drug action

9. DRUG RECEPTOR A macromolecular component of a cell with which a drug interacts to produce a response LIGAND Molecules that binds to a receptor

10. 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).

11. G-proteins have 3 main targets of its action:- adenylatecyclase, - phospholipase “C ” - ion channel. G-protein coupled receptors (GPCRs) The effects may be either activating or inhibiting depending on G-protein type.

12. 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

13. Targets for G-proteins • Adenyl cyclase: cAMP formation • Phospholipase C : IP3 and DAG formation • Ion channels :Ca2+ and K+ channels • cGMP

14. 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.

15. 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).

16. Types of drugs doses The DOSE is the ammount of drug administered into the body The dose may be:

17. DRUGS INTERACTIONis the action of one drug on another one.

18. 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 interactionsC) Pharmacodynamic interactions

19. 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.

20. 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 tosulfonamide toxicity. Quinidine displaces digoxin from binding sites in tissues and plasma and leads to digoxin toxicity.

21. 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.

22. 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 ofpenicillin (Both drugs excreted through tubular secretion) c) Pharmacodynamic interactions:- Drug Synergism- Drug Antagonism

23. EFFECTS OF REPEATED DOSES OF DRUGS • Cumulation • Tolerance • Tachyphylaxis • Drug dependence • Withdrawal syndrome (abstinence)

24. Cumulationit is accumulation of the drug or its effect Material Functional The increase in blood and / or tissue concentrations of a substance after each new introduction in comparison with the previous concentration Enhancing effect of a substance when its applied repeatedly but without increasing of its concentration in the blood and / or tissues For example: hypnotic drugs from the group of barbiturates, cardiac glycosides For example, ethyl alcohol, MAO inhibitors

25. 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)

26. DRUG DEPENDENCEits irresistible aspiration to take the drug for euphoria or improvement of condition. There are two types of drug dependence: *Physical dependence *Psychological dependence

27. *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)

28. 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!

29. 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.

30. 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).

31. 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

32. Antagonists - occupy receptors, produce no conformational change and prevent the action of agonists.

33. ANTAGONISM Physical Chemical Physiological Based on the physical property of the drugs The functional effects of drug substances Direct   (stimulants and blockers of β adrenoseptors) Competitive (morphine and naloxone) Indirect (Aceclidine and papaverine) For example: Activated charcoal and alkaloids, cardiac glycosides, heavy metals (absorption) For example: Acids and alkalis (neutralization) The two drugs react chemically and form an active product

34. Competitive or reversible antagonism: In this the agonist and antagonist compete for the same receptors and the extent to which the antagonist opposes the pharmacologicalaction of the agonist. Competitive antagonism can be overcome by increasing theconcentration of the agonist at the receptor site. (Example: Acetylcholine and atropine antagonism at muscarinic receptors).

35. 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).

36. EQUILIBRIUMantagonism: 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.

37. Importance of drug antagonism 1. Correcting adverse effects of drugs2. Treating drug poisoning.Morphine with naloxone, organophosphate compounds with atropine.3. Predicting drug combinations which would reduce drug efficacy.

38. SIDE EFFECTSare non-useful effects of drugs in therapeutic doses • Allergic reactions as immune reactions of hypersensitivity (anaphylaxis caused by penicillin)These allergic reactionsare 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).

39. 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)

40. SIDE EFFECTS • Photosensitivity it is cutaneous reaction resul- • ting 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)

41. SIDE EFFECTS • Embryotoxic, fetotoxic and • teratogenouseffects as a negative • influence on the embrio and the fetus during pregnancy (hypoplesia of tooth enamel caused by tetracyclin) • Canserogenous and mutagenousaction as the ability to provoke the development of malignant tumors (secondary malignancy caused by leukopoiesis inhibitors).

42. Types of pharmacotherapy ☺ Preventive ☺ Etiotropic ☺ Replacement ☺ Symptomatic ☺ Pathogenetic

43. 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.

44. Replacement Insufficient function involved in the pathological process of organs and systems requires substitution treatment.For example, atrophic gastritis, diabetes mellitus.

45. 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.

46. Thank you for your attention