Pharmacodynamics

Describes general principles of Pharmacodynamics including agonists antagonists synergism

1. Pharmacodynamics Mechanism of action 1 PATKI

2. Mechanism Study of the biochemical and physiological effects of a drug and their mode of action. Stimulation –Adrenaline Depression –Barbiturates Irritation – Bitters, Replacement- hormones Cytotoxic –Anti cancer 2 PATKI

3. Mechanism Physical action – Osmotic , Adsorption Chemical action- Neutralization-Antacids, Chelation Enzymatic action- Stimulation- Decarboxylase by Pyridoxine Inhibtion - ACE, Competative inhibition- Physostigmine – Choline estarases . Non competative Acetazolamide - Carbonic anhydrase Aspirin- Cyclooxygenase 3 PATKI

4. MECHANISM Through transporters - Desipramine and cocaine block neuronal norepinephrine transport. - Fluoxetine - inhibits reuptake of 5HT by amine transporter. - Furosemide - inhibits the NA K 2cl cotransporters loop of Henle . PATKI 4

5. Receptors Affinity Efficacy Intrinsic activity- ability to trigger pharmacological response after receptor drug complex formation. Agonist –Affinity +Efficacy- Adrenaline Antagonist- Affinity- Atropine Partial agonist- Affinity but less intrinsic – Pentazocine Inverse agonists- Affinity, but efficacy is opposite. Beta carbolines act as inverse agonist at Benzodiazepine 5 PATKI

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7. Receptor mechanism Macromolecular protein which is capable of binding with the specific functional group of drugs or endogenous substances. D + R----DR –RESPONSE 7 PATKI

8. Receptors-Functions 1. Recognition and binding of the ligand 2, Propagation of message Two domains- 1. Ligand binding domain 2. Effecter domain 8 PATKI

9. RECEPTOR Membrane bound receptors- Muscarinic receptor Second messengers- Cyclic AMP, Cyclic GMP, Inositol triphosphate Calcium and Calmulin . PATKI 9

10. Receptor Regulation Desensitisation : Receptor mediated responses to drugs and hormones desensitise with time after reaching initial high level. The responses diminishes even in continuing presence of agonist. Eg : β adrenoceptors . Down-regulation: Prolonged exposure to higher conc of agonist cause reduction in number of receptors available for activation leading to diminished effect. Agonists produce down regulation . Up- regulation : Prolonged occupation of receptors by a blocker(antagonist) leads to an increase in the number of receptors with subsequent receptor sensitivity. Antagonists 10 PATKI

11. Clinical consequences of up and down regulation of receptors Constant use of β adrenergic agonists in bronchial asthma results in reduced therapeutic response due to down regulation of β 2 receptors. Prolonged use of β adrenergic antagonists like propranolol results in upregulation of β adrenergic receptors leading to increased sensitivity.hence the drug should be tapered slowly after long term use,otherwise leads to angina . 11 PATKI

12. DOSE DOSE : It is the required amount of drug (in weight, volume, moles or international units), that is necessary to provide a desired effect. Therapeutic dose: Clinical practice Effective dose: Experimental purposes (in animals) The therapeutic dose varies from person to person and from one clinical situation to the other and hence is indicated by a range. eg : Aspirin- 300-1000mg. ( min.dose – max.dose ). 12 PATKI

13. Single Dose Piperzine (oral, 4-5g)---eradicate round worm Ceftriaxone (im, 250mg)---gonorrohea Daily Dose -Quantity of drug administered in 24hr -All at once or in equally divided doses -Dose interval is decided on the basis of t1/2, aVd eg: Erythromycin 1g/day in 4 equally divided doses. Total Dose -Maximum quantity of drug that is needed during the complete course of the therapy. 13 PATKI

14. Loading Dose: -Large dose of the drug to be given initially to provide the effective plasma concentration rapidly ( Css ), usually twice the therapeutic dose. Digoxin Maintenance Dose: It is therapeutic dose administered after the loading dose, to maintain . Digoxin It is usually half the loading dose. 14 PATKI

15. DOSE RESPONSE CURVE 15 PATKI

16. Log dose response curve (LDR) 16 PATKI

17. Drug potency & efficacy The position of DRC on the dose axis is the index of drug potency. Refers to the amount of the drug needed to produce a response. A DRC positioned rightward indicates lower potency. Eg : 10 mg of morphine= 100mg of pethidine as analgesic. Morphine is 10 times more potent than pethidine . 17 PATKI

18. Drug potency & efficacy 18 PATKI

19. EFFICACY The upper limit of DRC is the index of drug efficacy. Refers to the maximal response elicited by the drug. Eg: morphine produces a degree of analgesia not obtainable with any dose of aspirin. Efficacy is more important factor in selection of drug. 19 PATKI

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21. Combined effect of drugs When two or more drugs are given simultaneously they may exhibit synergism or antagonism. Synergism – when the action of one drug is increased by the other. a. additive – The effect of the two drugs is in the same direction and simply adds up. Effect of drugs A+B = effect of drug A + effect of drug B. Eg . Aspirin paracetamol Inhibition of PGs Analgesia + Analgesia + Analgesia ++ 21 PATKI

22. b. Supra additive – Effect of combination is greater than the individual effects of the components. Effect of drug A+B > effect of drug A + effect of drug B. Eg . Levodopa + carbidopa for Rx of parkinsonism. 22 PATKI

23. Effect of other drugs: Synergism : Additive: effect of drugs A+B = effect of drugs A+ effect of drug B. Potentiation : effect of drug A+B > effect of drug A+ effect of drug B. Sulpha + Trimethrprim OC 23 PATKI

24. Antagonism When one drug decreases or abolishes the action of another. Effect of drugs A+B < effect of drug A + effect of drug B. Physical antagonism: Based on physical property Eg. Charcoal adsorbs alkaloids – alkaloid poisoning. b. Chemical antagonism - the two drugs react chemically and form an inactive product. Eg. KMNO 4 oxidizes alkaloids – used for gastric lavage in poisoning. Chelating agents: Metal poisonings 24 PATKI

25. c. Physiological antagonism – the two drugs act on different sites but have opposite effects on the same physiological system. Eg . Histamine and adrenaline on BP. (Anaphylaxis. ) Glucagon and insulin on blood sugar level. D. Receptor antagonism – one drug (antagonist) blocks the receptor action of the other (agonist) 25 PATKI

26. Two types Competitive Non competitive Antagonist binds with the same receptor as the agonist Binds to an other site of receptor Antagonist resembles chemically with the agonist Does not resemble Same maximal response can be attained by increasing the dose of agonist Maximal response is suppressed Intensity of response depends on conc of both agonist and antagonist Max. response depends only on the conc of antagonist Eg. Ach – atropine, morphine – Naloxone Eg . Diazepam – bicuculine 26 PATKI

27. Factors modifying the dosage and response Body size: Individual dose =B.W(kg)/70 X average adult dose. Exception – obese/ edema individuals For anticancer drugs. Individual dose = BSA(m 2 )/1.7 X average adult dose. Age: GFR reaches adult rates by 5 th month age Hepatic metabolizing function inadequate in infants. Clark’s formula = weight in kg/70 X adult dose Young’s formula = child dose = age/age+12 X adult dose. Dilling’s formula = child dose = age/20 X adult dose. Children more sensitive to CNS depressants (BBB less marked), More tolerate atropine. Elderly – renal function progressively ↓. (so ↓ dose of streptomycin) & ↓ metabolism. 27 PATKI

28. Sex: Females – smaller body size & hence less dose. Special care in prescribing drugs during menstruation, pregnancy & lactation. Species & race: Rabbits more tolerate atropine. Rats & mice resistant to digitalis. Blacks requires more dosage of atropine for mydriasis 28 PATKI TERATOGENECITY PHOCOMELIA THALIDOMIDE

29. Diet and environment: Milk products ↓ absorption of tetracyclines. Food ↓ bioavailability of rifampicin. Cigarette smoking (polycyclic hydrocarbons) – microsomal enzyme induction - ↑ metabolism of drugs. Route of administration: I.V route (less dose) than oral route. Emotional factor: Personality of physician. Placebos (inert drugs) – lactose tablets. Pharmacogenetics: Acetylation (INH) Atypical Pseudo cholinesterase (succinyl choline apnoea) G6PD deficiency (hemolysis with Primaquine, vit. K3, sulfonamides, salicylates). Malignant hyper thermia with halothane. 29 PATKI

30. Pathological states: Cirrhosis liver Kidney disease Congestive heart failure Hypothyroidism Cumulation: If rate of absorption more than rate of elimination Digitalis glycosides, emetine, heavy metals. Tolerance: Requirement of higher dose to produce response on chronic administration Natural tachyphylaxis acquired (acute tolerance) pseudo true (Dispositional) (Functional) 30 PATKI

31. Natural: Black people (negroes) – to mydriatic effect of ephedrine Tachyphylaxis – ephedrine (acute tolerance) tyramine Acquired tolerance – barbiturates, morphine, alcohol. Effect of other drugs. Synergism: when the action of one drug facilitated or increased by the other, they are said to be synergistic. Additive: effect of drugs A+B = effect of drugs A+ effect of drug B. Ex. Aspirin + paracetamol as analgesic/ antipyretic. Potentiation : effect of drug A+B > effect of drug A+ effect of drug B. Ex. a. Enalapril + diuretic in hypertension b. levodopa + carbidopa in parkinsonism. 31 PATKI

32. Antagonism: when one drug ↓ the action of other, they are said to be antagonistic. Physical: charcoal adsorbs alkaloids and prevent its absorption. Chemical: KMno4 & alkaloids, chelating agents & metals. Physiological: histamine & adrenaline. Through receptors: a. competitive (reversible) ex. Ach & atropine, morphine & naloxone . b. non competitive (irreversible ) : noradrenalin & phenoxy benzamine on  - receptors. 32 PATKI

33. Antagonism Competitive antagonism Antagonist binds with same receptor as agonist. Parallel shift of dose response curve to right and maximum response can be attained with ↑ agonist dosage Non competitive antagonism Antagonist binds with same receptor as agonist/or other site Shift of dose response curve to right but maximal response ↓ even after ↑ dosage of agonist. 33 PATKI

34. Drug Effectiveness Dose-response (DR) curve Depicts the relation between drug dose and magnitude of drug effect Drugs can have more than one effect Drugs vary in effectiveness Different sites of action Different affinities for receptors The effectiveness of a drug is considered relative to its safety (therapeutic index)

35. ED 50 = effective dose in 50% of population 100 50 DRUG DOSE X ED50 % subjects

36. Therapeutic Index Effective dose (ED 50) = dose at which 50% population shows response Lethal dose (LD 50) =dose at which 50% population dies TI = LD 50 /ED 50 , an indication of safety of a drug (higher is better) ED 50 LD 50

37. Potency Relative strength of response for a given dose Effective concentration (EC 50 ) is the concentration of an agonist needed to elicit half of the maximum biological response of the agonist The potency of an agonist is inversely related to its EC 50 value D-R curve shifts left with greater potency

38. Efficacy Maximum possible effect relative to other agents Indicated by peak of D-R curve Full agonist = 100% efficacy Partial agonist = 50% efficacy Antagonist = 0% efficacy Inverse agonist = -100% efficacy

39. Average Response Magnitude LO DRUG DOSE X HI A B C Comparisons

40. Tolerance (desensitization) Decreased response to same dose with repeated ( constant) exposure or more drug needed to achieve same effect Right-ward shift of D-R curve Sometimes occurs in an acute dose (e.g. alcohol) Can develop across drugs (cross-tolerance) Caused by compensatory mechanisms that oppose the effects of the drug

41. Sensitization Increased response to same dose with repeated ( binge-like ) exposure or less drug needed to achieve same effect Left-ward shift in D-R curve Sometimes occurs in an acute dose (e.g. amphetamine) Can develop across drugs (cross-sensitization) It is possible to develop tolerance to some side effects AND sensitization to other side effects of the same drug

42. Mechanisms of Tolerance and Sensitization Pharmacokinetic changes in drug availability at site of action (decreased bioavailability) Decreased absorption Increased binding to depot sites Pharmacodynamic changes in drug-receptor interaction G-protein uncoupling Down regulation of receptors

43. Other Mechanisms of Tolerance and Sensitization Psychological As the user becomes familiar with the drug’s effects, s/he learns tricks to hide or counteract the effects. Set (expectations) and setting (environment) Motivational Habituation Classical and instrumental conditioning (automatic physiological change in response to cues) Metabolic The user is able to break down and/or excrete the drug more quickly due to repeated exposure. Increased excretion

44. Pharmacokinetic and pharmacodynamic With pharmacokinetic drug interactions, one drug affects the absorption, distribution, metabolism, or excretion of another. With pharmacodynamic drug interactions, two drugs have interactive effects in the brain. Either type of drug interaction can result in adverse effects in some individuals. In terms of efficacy, there can be several types of interactions between medications: cumulative, additive, synergistic, and antagonistic. Drug-drug Interactions

45. Response Hi Lo Time Cumulative Effects Drug A Drug B The condition in which repeated administration of a drug may produce effects that are more pronounced than those produced by the first dose.

46. Response Hi Lo Time A B Additive Effects A + B The effect of two chemicals is equal to the sum of the effect of the two chemicals taken separately, eg., aspirin and motrin.

47. Response Hi Lo Time A B A + B Synergistic Effects The effect of two chemicals taken together is greater than the sum of their separate effect at the same doses, e.g., alcohol and other drugs

48. Response Hi Lo Time A B A + B Antagonistic Effects The effect of two chemicals taken together is less than the sum of their separate effect at the same doses

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