Presentation is loading. Please wait.

Presentation is loading. Please wait.

Dr. Laila M. Matalqah Ph.D. Pharmacology Pharmacodynamics 2 General Pharmacology M212.

Similar presentations


Presentation on theme: "Dr. Laila M. Matalqah Ph.D. Pharmacology Pharmacodynamics 2 General Pharmacology M212."— Presentation transcript:

1 Dr. Laila M. Matalqah Ph.D. Pharmacology Pharmacodynamics 2 General Pharmacology M212

2 Drug Effectiveness Dose-response (DR) curve Represent 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)

3 Two important properties of drugs can be determined by graded DRC: 1- Potency : a measure of the amount of drug necessary to produce an effect of a given magnitude. 2- Efficacy (intrinsic activity) of the drug, the ability to elicit a response when it interacts with a receptor.

4 1. Potency (Affinity) A measure of the amount of drug necessary to produce an effect (response) of a given magnitude The lower the dose, the more potent the drug To determine potency we used: The concentration producing an effect that is 50 % of the maximum is used to determine potency - commonly designated as the EC 50. EC 50, or ED 50 = parameters of affinity of a drug EC 50 or ED 50 = the concentration or dose needed to produce a 50% maximal response;  the lower EC 50 or ED 50, the higher affinity

5 Potency –D-R curve shifts left with greater potency –The potency of an agonist is inversely related to its EC 50 value

6 ED 50 = effective dose in 50% of population 100 50 0 DRUG DOSE 0X ED50 % subjects

7

8 EFFICACY (intrinsic activity) Efficacy: is the ability of a drug to elicit a response when it interacts with a receptor The maximal response produced by a drug (E max ), depends on: the number of drug-receptor complexes and the efficiency with which the activated receptor produces a cellular action. A drug with greater efficacy is more therapeutically beneficial than one that is more potent.

9 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

10

11 Average Response Magnitude LO DRUG DOSE 0X HI A B C Comparisons

12 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

13 Sensitization Increased response to same dose with repeated 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

14 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

15 Log-concentration-effect curve (graded DRC) ( results are displayed as CRC/DRC) effect conc 10 -8 10 -7 10 -6 10 -5 10 -4 potency (affinity) 50% EC 50 efficacy (intrinsic act.) slope of the curve

16 Agonist: A drug binds to a receptor and produces a biologic response that mimics the response to the endogenous ligand  agonist. Types of agonists: 1.Full agonists - induce a maximal response when all receptors are occupied E.g., phenylephrine is an agonist at α 1 -adrenoceptors because it produces effects that resemble the action of norepinephrine. Agonist may have many effects that can be measured, including actions on intracellular molecules, cells, tissues, and intact organisms. A full agonist has a strong affinity for its receptor and good efficacy. Efficacy = 100% Agonists

17 2. Partial agonists : It cannot produce as high (max.) response as full agonist even in the case that all the receptors are occupied! Efficacy (intrinsic activity) > than zero but < than efficacy of a full agonist. The partial agonist may be more, less, or equally potent. Potency is an independent factor In the presence of a full agonist, a partial agonist acts like a competitive inhibitor. The potential of partial agonists to act both agonistically and antagonistically may be used therapeutically. Agonists

18 3.Inverse agonist it stabilizes receptor in its inactive form (R*) inverse agonists reverse the constitutive activity of receptors and exert the opposite pharmacological effect of receptor agonists. Inverse agonist effects are opposite to those of agonist; e.g – famotidine (H2-receptor blocker), metoprolol ( β- receptor blocker) ) Agonists

19

20 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

21 Response Hi Lo Time AB A. 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 warfarin 1 +1 = 2 1. Synergism

22 Response Hi Lo Time AB A + B B. Potentiation 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, levodopa and carbidopa 1 +1 > 2

23 Response Hi Lo Time AB A + B 2. Antagonism The effect of two chemicals taken together is less than the sum of their separate effect at the same doses 1 +1 < 2

24 Drug Antagonism Antagonism: The effect of one drug is diminished or abolished in the presence of another drug. Antagonists: drugs that decrease or oppose the actions of another drug or endogenous ligand. An antagonist has no effect if an agonist is not present. 1.Physical antagonism 2.Chemical antagonism 3.Physiological antagonism 4.Pharmacokinetics antagonism 5.Pharmacodynamic (receptor) antagonism

25 Drug Antagonism 1. Physical antagonism  Example: Charcoal adsorb drugs like alkaloids 2. Chemical antagonism Interaction of two substance based on their chemical properties  a loss of all effects of a drug (e.g., chelators bind the metal ions to form an inactive complex, Examples:  protamine sulfate (weak base)- ionically binds to heparin)(weak acid).  Heparin + Tetracyclin

26 3. Physiological antagonism  when two drugs act on separate physiological systems and produce opposite actions. Many drugs may interact with various types of the receptors producing opposite effect Examples - Bronchoconstriction after histamine - mediated by H 1 receptors - vs. bronchodilation after Epinephrine mediated by  2 receptors. -Glucagon and insulin Drug Antagonism

27 4. Pharmacokinetic antagonism "Antagonist" reduces the concentration of active drug at its site of action in various ways: e.g., an increase of the biotransformation (metabolism) of the Anticoagulants (e.g, warfarin) during the use of phenobarbitone (enzyme induction), Or increase in the excretion Or decrease in absorption : antacid and ketoconazole

28 /5. pharmacodynamic Antagonism by receptor block Antagonists in this sense are drugs that bind to receptors but do not activate them and thereby it decrease the effect of an agonist A) competitive (reversible) antagonism: Competitive antagonists bind reversibly with receptors at the same site as the agonist but induce no action – they block the receptor for agonist The response can be returned to normal by increasing the dose of agonist as this increases the probability of agonist-receptor collisions at the expense of antagonist receptor collisions. The ability of higher doses of agonist to overcome the effects of the antagonist  a parallel shift of the dose-response curve to the right Drug Antagonism

29 Competitive Antagonism Shifts The Agonist D-R Curve (Potency) Drug Concentration (log scale) % Max Response AG + ANT AG alone EC 50

30 A) competitive (reversible) antagonism: The maximum response is not depressed e.g., Propranolol competes with the endogenous ligand, norepinephrine, at β -receptor e.g., Morphine and Naloxone Drug Antagonism

31 B) Non-competitive antagonism: There is a decrease in the maximum response present without a DRC shift by two mechanisms:  Antagonist binds with the same site as the agonist but dissociates very slowly, or not at all, from the receptors (due to the covalent bond)  no change (or nearly no change) in the antagonist occupancy when the agonist is applied. Irreversible competitive antagonism occurs with drugs that form covalent bonds with receptors  Antagonist binds to receptor at the site different from the agonist binding site "allosteric site“ either prevents binding of the agonist or prevents the agonist from activating the receptor Drug Antagonism

32 Noncompetitive Antagonism Decreases Agonist Efficacy Log Drug Concentration % Max response AG alone AG + NC ANT AG + higher dose NC ANT

33

34 Therapeutic index The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals: Where: TD 50 = the drug dose that produces a toxic effect in half the population ED 50 = the drug dose that produces a therapeutic or desired response in half the population.

35 Therapeutic index therapeutic index is a measure of a drug's safety, a larger value indicates a wide margin between doses that are effective and doses that are toxic. Warfarin (example of a drug with a small therapeutic index) Penicillin (example of a drug with a large therapeutic index):

36

37 Summary

38 AGONIST - Has affinity for receptor and efficacy. AGONIST - Has affinity for receptor and efficacy. ANTAGONIST - Has affinity but no efficacy. ANTAGONIST - Has affinity but no efficacy. Competitive Antagonist Competitive Antagonist Noncompetitive Antagonist Noncompetitive Antagonist Partial Agonist or Partial Antagonist – Partial Agonist or Partial Antagonist – Has affinity but lower efficacy than full agonist. Has affinity but lower efficacy than full agonist. Agonists and Antagonists

39 Drug Antagonism Pharmacologic Chemical Pharmacokinetic Physiologic Protamin and heparin Propranolol & norepinephrine Phenobarbital & warfarin Epinephrine & histamine

40 THE END of pharmacodynamics


Download ppt "Dr. Laila M. Matalqah Ph.D. Pharmacology Pharmacodynamics 2 General Pharmacology M212."

Similar presentations


Ads by Google