Pharmacodynamics

1. Pharmacodynamics Dr. Asmah Nasser

2. Drug Dose Administration Disintegration of Drug Absorption/distribution metabolism/excretion Drug/Receptor Interaction Drug Effect or Response General Concepts Pharmaceutical Pharmacokinetics Pharmacodynamics Pharmacotherapeutics

3. Introduction Pharmacodynamics: Study of the biochemical and physiologic effects of drugs and their mechanisms of action.

4. Drug action • The main ways by which drugs act are via interaction with cell proteins, namely receptors, ion channels, enzymes and transport/carrier proteins. • In addition, drugs can work by themselves mechanically or chemically. • Its useful to know what are the basic principles of drug action.

5. Principles of Drug action • Stimulation: Enhancement of the level of a specific biological activity (usually already ongoing physiological process). E.g. adrenaline stimulates heart rate. • Depression: Diminution of the level of a specific biological activity (usually already ongoing physiological process). E.g. barbiturate depress the CNS. • Replacement: Replacement of the natural hormones or enzymes (any substance) which are deficient in our body. E.g. insulin for treating diabetes. • Cytotoxic action: Toxic effects on invading micro organisms or cancer cells.

6. How does all this happen? • A drug can produce all the said effects by virtue of any of the following action 1. Through enzymes: a drug can act by either stimulating or inhibiting an enzyme • Through receptors: this is when a drug produces its response by attaching itself to a protein called as receptor which in turn regulates the cell function. • Receptor action is the most commonest way of producing action.

7. Continuation... 2. Physical action: The physical property is responsible for drug action. E.g. radioisotope I131 and other radioisotopes. 3. Chemical action: The drug reacts extracellularly according to simple chemical equations. E.g. antacids neutralising the gastric acid. 4

8. A deeper look into the receptor • The best-characterized drug receptors are regulatory proteins, which mediate the actions of endogenous chemical signals such as neurotransmitters and hormones. • This class of receptors mediates the effects of many of the most useful therapeutic agents. • Word “Receptor” is used as a loose term

9. Other Receptors • Other classes of proteins that have been identified as drug receptors include • Enzymes, which may be inhibited (or, less commonly, activated) by binding a drug (eg, dihydrofolate reductase, the receptor for the antineoplastic drug methotrexate) • Transport proteins (eg, Na+/K+ ATPase, the membrane receptor for cardioactive digitalis glycosides) • Structural proteins (eg, tubulin)

10. Agonist & Antagonist Tricky • When a drug binds to a receptor the following can occur and based on this the drugs are classified. • Agonist: when a drug binds to the receptor and activates it to produce an effect • Antagonist: when a drug binds to a receptor and prevents the action of an agonist, but does not have an action on its own.

11. Other terms • Inverse agonist: when a drug activates a receptor to produce an effect in the opposite direction to that of the agonist • Partial agonist: when a drug binds to the receptor and activates it but produces a submaximal effect (by antagonising the full effect of the agonist)

12. Agonist & Inverse Agonist

13. Affinity & Intrinsic activity • Affinity: It is the ability of a drug to bind to the receptor (just bind) • Intrinsic activity: It is the ability of a drug to activate a receptor following receptor occupation.

14. Terms revisited

15. Agonist • Agonists are the chemicals that interact with a receptor, thereby initiate a chemical reaction in the cell and produces effect . • Example—ACh is agonist at muscarinic receptor in heart cell. • Will have both Affinity and maximal Intrinsic activity

16. Receptor Acetylcholine So, what is a receptor “agonist”? • Any drug that binds to a receptor and stimulates the functional activities • e.g.: Ach Some Effect A Cell

17. Antagonist • A drug that binds to the receptor and blocks the effect of an agonist for that receptor • Atropine is antagonist of ACh at Muscarinic receptors. • Will have only Affinity but no Intrinsic activity

18. So, what is a receptor “antagonist”? • Any drug that prevents the binding of an agonist • eg: Atropine (an anticholinergic drug) Atropine Dude, you’re in my way! Acetylcholine

19. Inverse agonist • Inverse Agonists are the chemicals that interact with a receptor, but produces opposite effect of the well recognized agonist for that receptor • Will have Affinity and negative Intrinsic activity • Example: Flumazenil is an inverse agonist of Benzodiazepine

20. Receptor Inverse agonist Inverse agonist • Any drug that binds to a receptor and produces an opposite effect as that of an agonist Effect opposite to that of the true agonist A Cell

21. Partial agonist • Partial agonist activates receptor to produce an effect. Less response than a full agonist . • Partial agonist blocks the agonist action. • Will have Affinity but sub maximal Intrinsic activity

22. Partial agonist • Produces a submaximal response Partial agonist Oh!!!, I should Have been here Submaximal effect True agonist

23. Types of Receptors • Are they specific? • usually, but not always • Are there subtypes? • sometimes … • example: • there are several types of epinephrine receptors

24. There can be several types of receptors: Epinephrine 1 Receptors in Heart 2 Receptors in Bronchioles

26. A Problem • Epinephrine is a non-specific drug: it is an agonist for BOTH 1 and 2 receptors • Why might this be a problem for someone with asthma and hypertension?

27. A Solution • More specific agonists have been developed: • eg: terbutaline is a more specific 2agonist that is used for treating people with asthma

28. Major Concepts • Drugs often work by binding to a “receptor” • Receptors are found in the cell membrane, in the cytoplasm, and in the nucleus • Anything that binds to a receptor is a “ligand”

29. Drug-Receptor interaction • In most cases, a drug (D) binds to a receptor (R) in a reversible bimolecular reaction • Antagonists can bind to the receptor and occupy its binding site and, therefore, participate only in the first equilibrium. • Agonists, on the other hand, have the appropriate structural features to force the bound receptor into an active conformation (DR*). • This conformational change leads to a series of events causing a cellular response.

30. Assessment of Receptor Occupation Measure of Affinity • kd is a relative measure of affinity of a drug for its receptor. • It varies inversely with the affinity of the drug for its receptor • High-affinity drugs have lower kd values and occupy a greater number of drug receptors than drugs with lower affinities.

31. Drug-receptor interaction • Generally the intensity of response increases with dose • The drug receptor interaction obeys the law of mass action Emax X [D] KD+[D] E=

32. Law of mass action • E is observed effect at dose [D] of a drug • Emax is the maximal response • KD is the dissociation constant of a drug receptor complex • KD is usually equal to the dose of a drug at which half maximal response is produced

33. Classification of receptors • G-protein coupled receptors • Ion channels • Enzymatic receptors • Intracellular receptors (regulates gene expression)

34. Ion channels • The cell surface enclose ion channels specific for Ca2+, K+, or Na+ • These ion channels are controlled by the receptors • E.g. Gs opens Ca2+ channels in the myocardium and skeletal muscle and Gi opens the K+ channels in heart • Some receptors also modulate the ion channels without the intervention of coupling proteins or 2nd messengers • E.g. benzodiazepines modulating Cl- channels in the brain

35. Ion channels

36. Dose-response relationship

37. Dose Vs Response • Increases in response until it reaches maximum, Later it remains constant despite increase in dose .. Plateau effect

38. DOSE RESPONSE CURVE After this point increase in dose doesn’t increase the response % of Response DOSE of drug

39. Log dose response curve • The dose response curve is a rectangular hyperbola • If the doses are plotted on a logarithmic scale, the curve becomes sigmoid • A linear relationship between log of dose and the response can be seen

40. Efficacy and Potency • Efficacy is the maximal response produced by a drug • It depends on the number of drug-receptor complexes formed • Potency is a measure of how much drug is required to elicit a given response • The lower the dose required to elicit given response, the more potent the drug is

41. ED50 • It is the dose of the drug at which it gives 50% of the maximal response • A drug with low ED50 is more potent than a drug with larger ED50

42. Potency of Drug A >Drug B > Drug C A B C 100% 75% 50% % of response 25% 0% 10mg 20mg 30mg 40mg 50mg 200mg Log drug concentration

43. Efficacy and Potency C

44. Potency • Dose of a drug that required to produce 50% of maximal effect (ED 50) • Relative PositionsoftheDRCon x-axis • More left the DRC, more potent the drug Efficacy • Maximum effect of the drug • Height of the curve onx-axis indicates the efficacy of the drug • Taller the DRC ,more efficacious the drug

45. Probing question • A 55-year-old woman with congestive heart failure is to be treated with a diuretic drug. Drugs X and Y have the same mechanism of diuretic action. Drug X in a dose of 5 mg produces the same magnitude of diuresis as 500 mg of drug Y. This suggests that • Drug Y is less efficacious than drug X • Drug X is about 100 times more potent than drug Y • Toxicity of drug X is less than that of drug Y • Drug X is a safer drug than drug Y • Drug X will have a shorter duration of action than drug Y because less of drug X is present for a given effect

46. Slope of DRC • The slope of midportion of the DRC varies from drug to drug • A steep slope indicates small increase in dose produces a large change in response

47. Hydralazine.. steep Fall in BP Thiazides.. Flat Drug Dose

48. SLOPE STEEP DRC • Moderate increase in dose leads to more increase in response • Dose needs individualization for different patients • Unwanted and Uncommon FLAT DRC • Moderate increase in dose leads to little increase in response • Dose needsno individualization for different patients • Desired andCommon

49. Quantal dose response curves • The quantal dose-effect curve is often characterized by stating the median effective dose (ED50), the dose at which 50% of individuals exhibit the specified quantal effect. • Similarly, the dose required to produce a particular toxic effect in 50% of animals is called the median toxic dose (TD50) If the toxic effect is death of the animal, a median lethal dose (LD50) may be experimentally defined • Quantal dose-effect curves are used to generate information regarding the margin of safety (Therapeutic index)

50. Quantal DRC