PHARMACODYNAMICS

1. PHARMACODYNAMICS

2. what are DRUGS ? • A drug is a chemical substance or a product that is used or intended to be used to modify/explore the physiological system/ pathological state , for the benefit of the recipient.

3. *Pharmacokinetics :deals with actions of the biologic system on the drug. *Pharmacodynamics: deals with the effects of drugs on biologic systems .

5. MECHANISMS OF DRUG ACTION • Physical action • Physical mass- bulk laxatives • Osmotic property- mannitol • Radioactivity- I131 • Radio opacity- barium sulfate

6. Chemical action • Acidity or alkalanity- aluminium hydroxide, sodium bicarbonate • Chelation- penicillamine, BAL

7. Through enzymatic mechanisms • Enzyme stimulation • Enzyme inhibition

8. Through receptors

9. Receptors • Sensing elements in the system of chemical communication that co-ordinate the function of all the different cells in the body

10. Function of receptors • To propagate regulatory signal from outside & within effective cell • To amplify the signal • To integrate various extra cellular & intracellular regulatory signalling • To adapt to short & long term changes in regulatory system • To maintain homeostasis

11. Affinity - the ability of a drug to get bound to a receptor • Efficacy or intrinsic activity -the ability of the drug to elicit a pharmacological response after its interaction with its receptor

12. Agonist – a drug which initiates a pharmacological action after combining with the receptors • Antagonists – drugs which bind to the receptor but not capable of eliciting a pharmacological response produce receptor blockade

14. Partial agonists – A drug with affinity for the receptor but sub maximal intrinsic activity • Inverse agonists – drugs bind to the receptor and produce action opposite to those produced by a pure agonists

15. RECEPTOR TYPES OR FAMILIES • Channel linked or ionotropic • G-protein coupled • Enzymatic or kinase linked • Receptors regulating gene expression

16. Channel linked or ionotropic

17. G-protein coupled Receptor

18. G-protein coupled Receptor • Adenyl cyclase:cAMP pathway • Phospholipase C: IP3-DAG pathway • Channel regulation

20. Enzymatic or kinase linkedreceptor

21. Receptors regulating gene expression • Intracellular soluble proteins • Steroidal hormones, thyroxine, vit D, vit A

23. Drug potency amount of drug needed to produce a certain response Drug efficacy maximal response that can be elicited by the drug ِ

24. A B Effect Dose Potency Therapeutic Effect Why? A! Which drug is more potent?

25. Effect Dose Dose Response Relationships B A Therapeutic Effect A Which drug has the lower threshold dose? Which has the greater maximum effect? B

26. Therapeutic Index (TI) = Margin of Safety: • LD50 = lethal dose to 50% of the population in animal experiments. • ED50= the effective dose in 50% of animals. • The higher the TI, the safer the drug e.g. barbiturate (TI=10) • The lower the TI, the greater the possibility of toxicity e.g. digitalis (TI=3), so death may occur if only 3mg has been administered because the usual therapeutic dose of cardiac glycoside is one mg.

27. COMBINED EFFECTS OF DRUGS • SYNERGISM: When the action of one drug is increased by the other, they are said to be synergistic Additive Potentiation

28. COMBINED EFFECTS OF DRUGS • Additive Action • 1 + 1= 2 • Paracetamol + Diclofenac

29. COMBINED EFFECTS OF DRUGS • Potentiation / Supra-additive • 1 + 1= 3 • Levodopa + Carbidopa

30. COMBINED EFFECTS OF DRUGS • ANTAGONISM 1+1= 0 Physical Chemical Physiological/functional Receptor

31. Receptor Interactions Lock and key mechanism Agonist Receptor Agonist-Receptor Interaction

32. Receptor Interactions Induced Fit Receptor Perfect Fit!

33. Receptor Interactions Competitive Inhibition Antagonist Receptor Antagonist-Receptor Complex DENIED!

34. Receptor Interactions Non-competitive Inhibition Antagonist Agonist Receptor DENIED! ‘Inhibited’-Receptor

35. FACTORS MODIFYING DRUG ACTION • Body size • Age • Sex • Species and race • Genetics • Route of administration • Emotional factors • Diet and environment

36. FACTORS MODIFYING DRUG ACTION • Pathological states • Other drugs • Cumulation • Tolerance

37. FACTORS MODIFYING DRUG ACTION • Differences in body weight: the adult dose is calculated to produce specific effect in population between ages 18-65 and weighing about 70 kg, so very thin or obese individuals have to receive special doses to give the same response.

38. Age: the immature liver or kidney of the chid may delay drug metabolism and excretion. • On the other hand delayed distribution, metabolism and excretion are common in elderly because of disease condition or normal deterioration of body system.

39. Calculation of dose for children: • Clark's formula for infants (<1 year): • Young's formula: • Dilling's formula:

40. Sex: males need higher doses than females owing to the higher bulky muscles and androgen which is an enzyme inducer. Drugs should be administered cautiously during pregnancy and lactation (see latter) Route of administration: MgSO4 IV Oral Topical CNS depresion purgation ↓edema

41. Disease states: long duration of action or toxic effect of a drug may be related to liver or kidney disease and long period of time for absorption and distribution related to heart disease.

42. Psychological factors: • the hopes, fears and expectation of the individual often affect the drug action. • Patients may even improve with placebo (tablet or capsule containing sucrose or lactose). • This may be due to release of endogenous substances like endorphins and enkephalins in the brain and other body parts

43. Timing of dosage: • A single dose of antacid or ranitidine taken at bedtime is more effective than two or three doses taken during the day. • Absorption is better on empty stomach. • Irritant drugs should be given after meals. • CNS stimulants never be given at bed time.

44. Cumulation:. A drug is designated as cumulative when its elimination and/or detoxification are slow e.g. digitalis, diazepam, amiodarone and large doses of aspirin or phenytoin. The toxicity could be avoided by decreasing the dose

45. Tolerance It is a decrease or failed response to the usual therapeuticdose of a drug. Types of Tolerance: • Congenital tolerance: existing from birth examples: • Negroes are tolerant to the mydriatic action of ephedrine. • Eskimos are highly tolerant to fat diet (not develop acidosis). • Biological variation i.e. individual tolerance within any population. This may be related to genetic factors. • Rabbits are tolerant to large doses of atropine , probably due to the presence of atropine esterase in the liver (species tolerance).

46. Acquired tolerance: an acquired resistance to the usual dose of a drug repeatedly administered and more drugs are needed to produce the same effect. • It is reversible when the drug is stopped for a period of time. Causes: • It may be due to increased metabolism of the drug. • or decreased sensitivity and number of receptors (down regulation). • Addiction is a phenomenon which often, accompanies the development of tolerance. Examples: cocaine, heroine, morphine, alcohol, nicotine, barbiturates, nitrates and xanthines.

47. Tachyphylaxis: • It is an acute form of acquired tolerance • Occurring within few minutes. • Usually occurs if a drug is given repeatedly, at short intervals & generally by i.v route. • Tachyphylaxis probably occurs due to a transient saturation of the cell receptors with the drug. • Increasing the dose cannot produce the same effect. Examples: • Disappearance of the hypertensive effect of ephedrine repeatedly administered i.v in an anesthetized dog. • Disappearance of the hypertensive effect of tyramine which releases and displaces noradrenaline from the adrenergic neurons.

48. Cross-tolerance: tolerance to a drug may extend to the related drugs. Example: nicotine/lobeline, morphine / pethidine, and between members of barbiturates. • Bacterial resistance: it is a sort of tolerance to the action of antimicrobial drugs