General Pharmacology (Pharmacodynamic III) Principles of Pharmacology (PP IV)
Dr. Ahmad Al-ZohyriDept. of Pharmacology Baghdad College of Medicine
References:Basic & clinical pharmacology by KatzungLippincott’s illustrated reviews by Finkel, Cubeddu & ClarkClinical pharmacology by Laurence4. Describe what is meant by the terms ‘efficacy’ and ‘affinity’ in describing agonist potency and how these relate to the concepts of ‘spare receptors’ and ‘partial agonists’.
Dose-response relationships AGONIST DRUG: "An agent that can bind to a receptor producing a biological response". The magnitude of the drug effect depends on the drug's concentration at the receptor site (determined by the dose of drug administrated and by factors characterized of the drug kinetic profile. i.e. the rate of absorption, distribution and metabolism.
Learning Objectives At the end of pharmacodynamic lectures you should be able to
1. Describe the relationship between drug dose and response, and between log (drug dose) and response2. Define ‘competitive’ and ‘non-competitive’ antagonism, and indicate, on appropriate graphs, how these may be distinguished3. Describe the different types of receptor-effectors coupling with reference to: a) ion channels; b) second messengers; c) protein kinases; and d) intracellular receptorsCharacteristics: 1) A drug that interacts with a receptor. 2) Causes a response. 3) It has affinity for the receptor. 4) It has efficacy (intrinsic activity). 5) It has "fast" rate of association and dissociation from the receptor.
Agonist drugs are known to activate receptors because they resemble the natural transmitters or hormones. Their importance depends on their capacity to resist degradation inside the body and to act for longer than the natural substances they mimic. For example: Bronchodilation produced by "salbutamol" lasts longer than that induced by "adrenaline".
POTENCY: A measure of the amount of drug necessary to produce an effect of a given magnitude. The concentration producing an effect that is 50% of the maximum is used to determine potency; it commonly designated as the "EC50" as the diagram below shows;
AFFINITY AND INTRINSIC ACTIVITY (EFFICACY): The magnitude of the response is the function of number of receptors occupied. AFFINITY"Is the tendency of a drug to form a combination with the receptor".The response is not only the function of concentration of drug-receptor complex but it also depends on the intrinsic activity or "efficacy". EFFICACY"Is the capacity to stimulate for a given receptor occupancy”
Log dose-response curves showing the difference between potency and efficacy. Panel A: drug A is much more potent than drug B but both have the same maximum response. Panel B: drug A is not only more potent but also has a greater efficacy (higher Peak Effect) than drug B.
ANTAGONISTS: "Are drugs that decrease the activity of another drug or endogenous ligand". Characteristics: 1) A compound or a drug that interacts with receptors preventing the action of agonist. 2) Produces very small or no response. 3) It has affinity for receptors. 4) It has NO efficacy. 5) Slow rate of association and dissociation Antagonists are similar to some extent to the natural agonists to be recognized by receptors and to occupy these receptors without activating them, thereby preventing (blocking) the natural agonist from exerting its effect.
2)CHEMICAL ANTAGONISM: A mechanism at which one drug antagonize the actions of a 2nd drug by binding to it and causes its inactivation. For example: "Protamine" a protein positively charged at physiological pH, can be used to counter the effects of "Heparin ", an anticoagulant negatively charged. 3) PHYSIOLOGICAL (FUNCTIONAL) ANTAGONISM: A mechanism at which one compound or drug opposes the physiological action of another drug. For example: "Glucocorticoid Hormones" increase blood sugar while "insulin" decrease it.
MEDIAN TOXIC DOSE (TD 50): "Is the dose required to produce a particular toxic effect in 50% of experimented animals".MEDIAN LETHAL DOSE (LD 50): "Is the dose required to cause death to 50% of experimented animals", THERAPEUTIC EFFICACY: "Is the capacity of a drug to produce an effect and refers to the maximum of such effect". This means if drug A can produce a therapeutic effect that can’t be obtained by drug B however much of drug B is given then drug A has the higher therapeutic efficacy.
“THE GREATER THE INDEX, THE MORE SAFE IS THE DRUG” (TI) is a measure of the drugs' safety, because Larger Value of (TI) indicates a wide margin between doses that are effective and doses that are toxic.
TOLERANCE:A condition when developed, it becomes necessary to increase the dose of a drug to obtain an effect which is previously obtained by a smaller dose. Tolerance is either: NATURAL: It’s not induced by the drug but it happens due to "inherited factors" (Pharmacogenetic).