Essentials of Drug Action PDF

ESSENTIALS OF DRUG ACTION VPM 61 - Basic Veterinary Pharmacology Philip John S. Sajol Assistant Professor I Department of Anatomy, Physiology, and Pharmacology College of Veterinary Medicine Essentials of Drug Action Pharmacodynamics focuses on the action and e ects of drugs within the body...

ESSENTIALS OF DRUG ACTION VPM 61 - Basic Veterinary Pharmacology Philip John S. Sajol Assistant Professor I Department of Anatomy, Physiology, and Pharmacology College of Veterinary Medicine Essentials of Drug Action Pharmacodynamics focuses on the action and e ects of drugs within the body concerned with what and how the drug can produce an e ect terminologies used to de ne the pharmacodynamic properties of a drug include: 1) receptor; 2) ligand; 3) drug activity; 4) a nity; 5) e cacy / intrinsic activity; and 6) potency fi ff ffi ffi ff Essentials of Drug Action Receptors macromolecular component of body tissues with which a drug interacts to initiate its pharmacologic e ects proteins: muscarinic receptors on cells of the heart, smooth muscle, or exocrine glands enzymes: acetylcholinesterase (AChE) other cellular constituents: nucleic acids, ion channels tubulin ff Essentials of Drug Action Receptors Essentials of Drug Action Receptors Properties of receptors saturability: a nite number of receptors are present in a cell speci city: the binding of the drug with receptors is made possible by their complementary structures similar to a lock and key reversibility: the drug that binds to a receptor can dissociate in its non- metabolized form fi fi Essentials of Drug Action Ligands any drug or substance with speci c a nity to a receptor receptors bind ligands (drugs) and transduce signals (signal transduction) drug binding to receptor uses similar chemical bonds as that used for enzyme- substrate interaction fi ffi  Essentials of Drug Action Properties of Drugs Intrinsic activity also known as e cacy, it is the property of the drug that permits it to initiate post- receptor processes, which lead to a response A nity the tendency of the drug to combine with a particular kind of receptor ffi ffi Essentials of Drug Action Properties of Drugs Essentials of Drug Action Classi cation of Ligands (Drugs) Agonists ligands (drugs) with both a nity and intrinsic activity (e.g epinephrine, acetylcholine) full agonists: produces full cell/tissue response partial agonist: provokes a response, but the maximum response is less than the maximum response of a full agonist, due to a higher a nity for the receptor but a lesser activity than a full agonist inverse agonist: drugs that bind to the receptor, suppressing the signaling activity (e.g propanolol and antihistamines) fi ffi ffi Essentials of Drug Action Classi cation of Ligands (Drugs) fi Essentials of Drug Action Classi cation of Ligands (Drugs) Antagonists have a nity for receptor site but with no intrinsic activity, and block or reduce the e ects of agonists ffi fi ff Essentials of Drug Action Classi cation of Ligands (Drugs) Antagonists antagonist e ect is seen as a DEFICIENCY of the normal physiological e ects of the blocked hormone, transmitter or substrate fi ff ff Essentials of Drug Action Classi cation of Ligands (Drugs) Antagonists competitive antagonist: reversible on removal, where the degree of antagonism depends on the quantity of the antagonist relative to the quantity of the agonist noncompetitive antagonist: irreversible, removes the receptor or response potential from the system, where the agonist has no in uence upon the degree of antagonism or reversibility fi fl Essentials of Drug Action Antagonism Competitive Antagonism occurs on the same receptor protein such that two drugs, an agonist and an antagonist, compete and bind to the same receptor protein Essentials of Drug Action Antagonism Physiologic Antagonism occurs as the result of activating receptors with opposite physiological e ects ff Essentials of Drug Action Antagonism Chemical Antagonism occurs as the result of a drug combining with two or more molecules via the formation of chemical bonds often does not require animal tissue to be demonstrated, commonly used to treat heavy metal intoxication e.g dimercaprol chelates Hg and As, penicillamine chelates Cu, Pb, and Hg Essentials of Drug Action Signal Transduction Ligand-gated ion channels regulates ow of ions through the cellular plasma membrane channels rapid response e.g Ach at nicotinic receptors fl Essentials of Drug Action Signal Transduction Kinase-linked receptors signal transduction occurs through activation of an enzyme associated with the intracellular domain of a receptor e.g tyrosine kinase Essentials of Drug Action Signal Transduction GTP-binding proteins couple the binding of the ligand on the cell surface receptor to intracellular second messengers catecholamines cause displacement of GDP from G protein and its replacement by GTP Essentials of Drug Action Signal Transduction Intracellular receptors activated receptor proteins form dimer and move to the promoter region of the DNA, altering transcription processes e.g steroid hormones and thyroid hormones  Essentials of Drug Action Potency refers to the dose of a drug that must be administered to produce a particular e ect of a given intensity in uenced by a nity and by pharmacokinetic processes not necessarily correlated with e cacy or safety the most potent drug in a series is not necessarily clinically superior ff fl ffi ffi Essentials of Drug Action Drug Action vs Drug E ect Drug action where and how the e ect is produced (MOA) Drug e ect what is produced by the drug, consequence of the drug-receptor interaction e.g Aspirin blocks the synthesis of prostaglandins which mediates the raising of the body thermostat by the hypothalamus (DA), reducing fever (DE) ff ff ff Essentials of Drug Action Categories of Drug Action Stimulation or Depression: acts to increase or decrease activity of physiological function Replacement: in therapy for de ciencies e.g diabetes mellitus Inhibition or killing organisms: e.g antibiotics, antifungals, antiparasitics Irritation: e.g antiparasitics, anthelminthics fi Essentials of Drug Action Categories of Drug Action Physiologic E ect: retains the normal function of the biologic system Pharmacologic E ect: aka side e ects resulting from the lack of speci c action while binding to other tissues e.g antihistamines as Tx for allergy can depress the CNS and produce drowsiness and dizziness ff ff ff fi Essentials of Drug Action Categories of Drug Action Drug Toxicity: predictable adverse e ect of the drug related to the dose administered (range between therapeutic and toxic dose is known as drug safety) Allergic Reactions: unpredictable adverse e ects due to the response of the patient’s immune system Idiosyncratic Reactions: due to genetic di erences of patient occurring at the 1st exposure of the drug ff ff ff  Essentials of Drug Action Drug E ects Enhancement Additive E ects: if two drugs with the same e ect produces an e ect equal in magnitude to the sum of individual e ects (1+1=2) Synergism: if two drugs with the same e ect produces an e ect greater in magnitude than sum of individual e ects (1+1=3) Potentiation: occurs if a drug lacking an e ect of its own increases the e ects of a second active drug (0+1=3) ff ff ff ff ff ff ff ff ff ff Essentials of Drug Action Dose-Response Relationships parameter that characterizes drug activity describes the nature of drug action, potency of the drug, and presence of competitive or non-competitive antagonism two types: graded dose response and quantal dose-response relationship Essentials of Drug Action Dose-Response Relationships Graded dose-response relationship refers to the rate of change in the intensity of response proportional to the rate of change of drug concentration higher dose, greater response Essentials of Drug Action Dose-Response Relationships Graded dose-response relationship: characteristic variables Potency: refers to the dose needed to produce an e ect (smaller dose, greater potency) Slope of the curve: indicates the range of dosage to which the drug acts ff  Essentials of Drug Action Dose-Response Relationships Graded dose-response relationship: characteristic variables Variability in response: depends on physiological, pathological, or drug induced problem in the patient Maximal e ect: peak response possible for the e ector ff ff Essentials of Drug Action Dose-Response Relationships Quantal dose-response relationship all-or-none response, measures the frequency in which a dose of a drug produces a pharmacological e ect in a population assumes that an individual responds to their maximum capability or none at all the graph assumes a Gaussian or normal distribution curve used in clinical trials before a drug is marketed for use ff Essentials of Drug Action Dose-Response Relationships Quantal dose-response relationship: parameters that can be derived Standard deviation: determines the spread of the population around the mean Therapeutic index: ratio of LD50 to ED50 (TI=LD50/ED50), higher TI means the more safe is the drug Essentials of Drug Action Dose-Response Relationships Quantal dose-response relationship: parameters that can be derived Standard safety margin assume 10 mg/kg of a drug is e ective in 99% of the animal population and that a dose of 100 mg/kg will cause toxicity in 1% of the same population the dose which is e ective in 99% of the population must be increased by 900% to produce a toxic e ect in 1% of the population ff ff ff References Martin, RJ and Hsu, WH (2008). Principles of Drug Absorption, Drug Disposition, and Drug Action. Handbook of Veterinary Pharmacology. Wiley- Blackwell. USA. pp. 1-28. Brunton, et. al. (2008).PHARMACOKINETICS AND PHARMACODYNAMICS The Dynamics of Drug Absorption, Distribution, Action, and Elimination. Goodman and Gilman’s Manual of Pharmacology and Therapeutics. McGraw- Hill. USA. pp. 1-26.