Pharmacodynamics Principles 2024 PDF

PHARMACODYNAMICS: PRINCIPLE OF DRUG ACTION DEPT. OF PHARMACOLOGY BENJAMIN S. CARSON COLLEGE OF HEALTH & MEDICAL SCIENCES BABCOCK UNIVERSITY  Outline At the end of this class you should be able to describe:...

PHARMACODYNAMICS: PRINCIPLE OF DRUG ACTION DEPT. OF PHARMACOLOGY BENJAMIN S. CARSON COLLEGE OF HEALTH & MEDICAL SCIENCES BABCOCK UNIVERSITY  Outline At the end of this class you should be able to describe: Principles of Drug Action Drug Receptor Interaction Mechanisms of Drug Receptor Interaction Types of Receptors Dose – Response Relationship Agonist and Antagonist Therapeutic Index  Introduction Pharmacodynamics deals with the study of the biochemical and physiological effects of drugs and their mechanisms of action. It is the study of drug effects. It attempts to elucidate the complete action-effect sequence and the dose-effect relationship. It also involves the modification of the action of one drug by another drug.  Introduction Cont’d Clinically, PHARMACODYNAMICS has to do with the following:  Dosage of drug  Receptors  Drug effects  Side events/adverse drug effects  Therapeutic effect and safety of drugs  drug interactions  Therapeutic basis of drugs  And many more  Mechanisms of action  Principles of Drug Action WHAT IS A DRUG? For the purpose of this lecture, A drug is chemical substance that when taking from outside the body is bring about physical or biochemical change in the cell environment. Drugs are also called xenobiotics, because they are taking from outside the body and can influence or modify the internal environment of the body Introduction Cont’d  Principles of Drug Action Drugs generally do not impart new function or new system on the body, but rather modify or alter already existing processes that is they modulate intrinsic physiological functions in the body Drugs usually work in one of four ways: 1. To replace or act as substitutes for missing chemicals 2. To increase or stimulate certain cellular activities 3. To depress or slow cellular activities 4. To interfere with the functioning of foreign cells, such as invading microorganisms or neoplasms (drugs that act in this way are called chemotherapeutic agents).  Principles of Drug Action Drugs generally do not impart new function or new system on the body, but rather modify or alter already existing processes that is they modulate intrinsic physiological functions in the body Drug effect can be classified into: 1. Stimulation: e.g effect of adrenaline on the heart, excessive cause problem. Picrotoxin, a CNS stimulant, produces convulsions followed by coma and respiratory depression. 2. Depression: e.g. barbiturates depress CNS, quinidine depresses heart. Some others may stimulant one organ and depress another e.g. ACh  Drug Action Cont’d 3. Irritation: nonselective, often noxious effect and is particularly applied to less specialized cells may lead to increase secretions or blood flow. But strong irritation results in inflammation, corrosion, necrosis and morphological damage. May result in diminution or loss of function e.g. alcohol, smoking, substance abuse. 4. Replacement: e.g. e.g. levodopa in Parkinsonism, insulin in diabetes mellitus, iron in anaemia. 5. Cytotoxic action: penicillin, chloroquine, zidovudine, cyclophosphamide, etc. It is commonly called chemotherapy.  Drug targets Cont’d Based on the drug target sites, the mechanisms of drug action can be classified broadly as a. Non-receptor mediated mechanisms b. Drug receptor interaction or Receptor mediated mechanisms Non-receptor mediated mechanisms The action of the drugs is due to it physical, chemical or biochemical properties of the drug. Examples such drugs include: Bulk laxatives (ispaghula) – physical mass Dimethicone, petroleum jelly – physical form, opacity Paraamino benzoic acid PABA – absorption of UV rays Activated charcoal – adsorptive property Mannitol, mag. sulphate – osmotic activity  Drug targets Cont’d 131 I and other radioisotopes – radioactivity Antacids – neutralization of gastric HCI Potassium Permanganate – oxidizing property Chelating agents (EDTA, dimercaprol) – chelation of heavy metals. Cholestyramine - sequestration of cholesterol in the gut Mesna - Scavenging of vasicotoxic reactive metabolites of cyclophosphamide Simethicone - adsorsb gases, used as antiflatulent MgSO4 – osmosis, use as purgative alkylating agents which react covalently with several critical biomolecules.  Drug targets in the body Drug Receptor Interaction: In general, drugs are molecules that interact with specific molecular components of an organism to cause biochemical and physiologic changes within that organism. Most drugs produce their effects by targeting biomolecules in the cells usually proteins, of which they 4 main types: Receptors Ion channels Enzymes Carrier proteins  Drug targets Cont’d ION CHANNELS Ion channels are pore-forming protein complexes that facilitate the flow of ions across the hydrophobic core of cell membranes. They are present in the plasma membrane and membranes of intracellular organelles of all cells, performing essential physiological functions including: Establishing and shaping the electrical signals which underlie muscle contraction/relaxation and neuronal signal transmission, neurotransmitter release, cognition, hormone secretion, sensory transduction and maintaining electrolyte balance and blood pressure  Drug targets Cont’d Most Na+, K+, Ca2+ and some Cl- channels are gated by voltage, whereas others (such as some K+ and Cl- channels, transient receptor potential (TRP) channels, ryanodine receptors and IP3 receptors) are relatively voltage-insensitive and are gated by second messengers and other intracellular and/or extracellular mediators. Examples include:  Drug targets Cont’d Examples include: nicotinic acetylcholine (nAch), Serotonin 5-HT3, ionotropic glutamate (NMDA, AMPA and kainate receptors) and The inhibitory, anion-selective, GABAA and glycine The epithelial sodium channels (ENaC) mediate sodium reabsorption principally in the aldosterone-sensitive distal part of the nephron and the collecting duct of the kidney  Drug targets Cont’d ENZYMES Enzymes are proteins which act as catalysts to facilitate the conversion of substrates into products. Many drugs are targeted by enzymes which are catalytic compounds involve in almost all biological processes and reactions. Drugs may alter enzyme function leading to enzyme stimulation, induction or inhibition. The majority of drugs which act on enzymes act as inhibitors and most of these are competitive, in that they compete for binding with the enzyme's substrate. They can be non-competitive, or causing an allosteric conformational change or they can be irreversible Drug targets Cont’d  Drug targets Cont’d CARRIER MOLECULES/TRANSPORTERS Several substrates are translocated across membranes by binding to specific transporters (carriers) which either facilitate diffusion in the direction of the concentration gradient or pump the metabolite/ion against the concentration gradient This are molecules that transport several substrates such as of ions and small organic molecules across cell membranes due to molecules being too polar or in direction against concentration gradient using energy. Drug targets Cont’d  Drug targets Cont’d Examples of carrier mediated transport Monoamine reuptake transporters Desipramine and cocaine block neuronal reuptake of noradrenaline by interacting with norepinephrine transporter (NET).  RECEPTORS These are regulatory macromolecules and have sites on them which bind and interact with the drug and control a lot of effector molecules such as ion channels, enzymes structural proteins. Receptors are typically glycoproteins located in cell membranes that specifically recognize and bind to ligands. Effect or Response  Introduction to Receptors Receptors are macromolecules that mediate biological change following ligand binding The richest sources of therapeutically relevant pharmacologic receptors are proteins that transduce extracellular signals into intracellular responses. Most receptors are proteins They have an amino acid sequence They are regular sub-structures They are three dimensional Sometimes they are multi-protein complexes  Introduction to Receptors Most receptors have endogenous molecules that bind to them Opportunity of this is used in rational drug design Thus exogenous molecules can be designed to have agonist or antagonist action at the receptor site  Types of receptors Drugs usually act on receptors. There are basically 4 families of receptors: ligand-gated ion channels G protein – coupled receptors Enzyme – linked receptors or kinase-linked and related receptors Intracellular receptors Types of receptors  Receptors Cont’d Ligand – Gated Ion Channels They are also known as ionotropic receptors and are transmembrane ligand-gated ion channels with extracellular domain of the channel containing a ligand binding site. They are typically receptors on which fast neurotransmitters act including neurotransmission, and cardiac or muscle contraction. The channel briefly for a few milliseconds when activated allowing ion influx into the cell e.g. nicotinic acetylcholine, GABAA receptor, glycine, and glutamate receptors of the NMDA.  Receptors Cont’d G Protein – Coupled Receptors (Gpcrs) Also known as metabotropic receptors and are made up of 7 α-helical membrane spanning hydrophobic amino acid (AA) segments which run into 3 extracellular and 3 intracellular loops. The extracellular domain of this receptor contains the ligand-binding area, and the intracellular domain interacts (when activated) with a G protein or effector molecule. Made up three protein subunits α, β and γ. The α subunit binds guanosine triphosphate (GTP), and the β and γ subunits anchor the G protein in the cell membrane.  G Protein – Coupled Receptors Courtesy: Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy 3ed.  Receptors Cont’d Enzyme-linked receptors This family of receptors consists of a protein that form dimers or multisubunit complexes. They comprise an extracellular ligand-binding domain linked to an intracellular domain by a single transmembrane helix. When activated by an agonist, they increased cytosolic enzyme activity and the response lasts on the order of minutes to hours. There are two major subgroups of Enzyme-linked receptors, a. Those that have intrinsic enzymatic activity with intracellular domain of either a protein kinase or guanylyl cyclase. b. Those that lack intrinsic enzymatic activity, but bind a JAK- STAT kinase on activation  Receptors Cont’d Insulin receptor  Receptors Cont’d Intracellular receptors This family of receptors are entirely intracellular, therefore, the ligand has to diffuse into the cell to interact with the receptor (lipid soluble ligands). This receptors regulate gene transcription and expression. The primary targets of this ligand – receptor complexes are transcription factors in the cell nucleus. Examples include receptors for steroid hormones, thyroid hormone, tubulin target of antineoplastic agents, dihydrofolate reductase and other agents such as retinoic acid and vitamin D.  FIGURE 1-8. Lipophilic molecule binding to an intracellular transcription factor. A. Courtesy: Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy 3ed.  Receptors Cont’d Functions of Receptors To propagate regulatory signals from outside to within the effector cell when the molecular species carrying the signal cannot itself penetrate the cell membrane. Amplify the signal. Integrate various extracellular and intracellular regulatory signals. And help adapt to short term and long term changes in the regulatory melieu and maintain homeostasis.  Drug (D) - Receptor (R) Interaction D + R= (DR) → Response Kd = ([D] * [R]) / [DR] = k2/k1 Kd = dissociation constant k1 = association rate constant k2 = dissociation rate constant  Dose–response Relationships The magnitude of the drug effect depends on the drug concentration at the receptor site. There are two forms of dose – response relationships: a. Graded dose–response relations b. Quantal dose–response (all or none) relationships When the response is plotted against the log dose, the sigmoid DRC is obtained.  Dose–response Relationships Fig. 1: Dose-response and log dose-response  Dose–response Relationships Graded dose–response Points to Note The value of Kd can be used to determine the affinity of a drug for its receptor. The higher the Kd value, the weaker the interaction and the lower the affinity, and vice versa. The magnitude of the response is proportional to the amount of receptors bound or occupied. The Emax occurs when all receptors are bound, and Binding of the drug to the receptor exhibits no cooperativity and is not dependent on the binding of other molecules.  Dose–response Relationships Fig. 2: DRC Showing Potency & Efficacy  Agonists Affinity: is the ability of a drug to bind to receptor. It shows The capacity of a drug to form the complex with its receptor (DR complex). It is usually depicted by the proximity of the dose – response curve (DRC) to the y-axis (if the curves are parallel); the nearer they axis, the greater the affinity. Affinity can be compared only when two drugs bind to the same receptor. Acetylcholine (ACh): One drug with different affinities for two different receptors (adapted from Clark, 1933)  Agonists Intrinsic Activity: The intrinsic activity of a drug determines its ability to fully or partially activate the receptors. Drugs may be categorized according to their intrinsic activity and resulting Emax values. Ligand: Any molecule which attaches selectively to particular receptors or sites  Agonists Potency: is a measure of the amount of drug necessary to produce an effect of a given magnitude. It shows how relative doses of two or more agonists produce the same magnitude of effect. shown by the proximity of the respective curves to the y-axis in (if the curves do not cross). It is measured using the concentration of drug producing 50% of the maximum effect (EC50)  Agonists Efficacy: is the magnitude of response a drug produces when an agonist binds to a receptor. It is a measure of how well a drug produces a response. A maximum effect is achieved when the maximum height is reached on the curve by the highest practical concentration of the agonist. Efficacy is dependent on the number of drug–receptor complexes formed and the intrinsic activity of the drug.  Agonists AGONIST Agonist drugs mimic the action of the original endogenous ligand for the receptor, it activates a receptor to produce an effect similar to that of the physiologic signal molecule. The magnitude of response is dependent on the number of receptors occupied And has both high affinity as well as high intrinsic activity, therefore can trigger the maximal biological response. Figure B: Agonist Action on a receptop  Types of Agonists There are 3 types of agonist, full, partial and inverse agonists. Full agonist: is a drug that binds to a receptor and produces a maximal biologic response, they have maximal efficacy. Has an intrinsic activity of one. Partial agonist: Partial agonists have intrinsic activities greater than zero but less than one. Even if all the receptors are occupied, partial agonists cannot produce the same Emax as a full agonist.  Types of Agonists Inverse agonists: as the name implies, inverse agonist function opposite to a full agonist. Inverse agonists have full affinity for the receptor, reverse the activity of receptors, and exert the opposite pharmacological effect of agonists. Their intrinsic activity ranges between 0 to -1 Examples Benzodiapines on GABA, Histamine receptors, beta- blockers carvedilol and bucindolol Theoretical concentration-effect curves for a full and partial agonist of a given receptor Types of Agonists  Types of Agonists Table 1: Summary of Drug – Receptor Activities Ligand Affinity Intrinsic Activity Efficacy Full Agonist Yes +1 Maximum Partial Agonist Yes > 0 < +1 (+ 0.5) Minimal Inverse Agonist Yes 0 to -1 Reverse Antagonist Yes 0 Zero  Antagonists A drug is called an antagonist when binding to the receptor is not associated with a response. The drug has an effect by preventing an agonist from binding to the receptor, but doesn’t have any effect of its own. Have only affinity but no intrinsic activity There is a difference between antagonist and ANTAGONISM  Antagonists Antagonism is when one drug diminishes or blocks the activity of another drug. There several kinds of antagonism: Physical Antagonism: this based on the physical property of the drugs, e.g. charcoal adsorbs alkaloids and can prevent their absorption-used in alkaloidal poisonings. Chemical Antagonism: This is when two drugs react chemically and form an inactive product, e.g. KMnO+ oxidizes alkaloids used for gastric lavage in poisoning, Chelating agents (BAL, Cal. disod. edetate) complex toxic metals (As, Pb).  Antagonists Physiological Antagonism: it is also known as functional antagonism. This is The two drugs act on different receptors or by different mechanisms, but have opposite overt effects on the same physiological function e.g. Histamine and adrenaline on bronchial muscles and BP. Pharmacokinetic Antagonism: Pharmacokinetic antagonism describes the situation in which the 'antagonist' effectively reduces the concentration of the active drug at its site of action. could be either through increased metabolic degradation of active drug, e.g. increased warfarin metabolism due to enzymatic induction by  Antagonists Receptor Antagonism: One drug (antagonist) blocks the receptor action of the other (agonist). Antagonists bind to a receptor with high affinity but possess zero intrinsic activity. Antagonism may occur either by blocking the drug’s ability to bind to the receptor or by blocking its ability to activate the receptor.  Types of Receptor Antagonism Competitive antagonism (equilibrium type): this is when both the antagonist and the agonist bind to the same site on the receptor in a reversible manner e.g. Acetylcholine and atropine Higher concentration of the agonist progressively overcomes the block. Summary of effects on the DRC include: Cause a parallel shift to the right in the D-R curve for agonists Can be reversed by increasing the dose of the agonist drug Decreases potency of the agonist Figure D: Competitve Antagonism Courtesy: Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy 3ed.  Types of Receptor Antagonism Non - competitive antagonism: this is also known as allosteric antagonism. The antagonist is chemically unrelated to the agonist and binds to a site (“allosteric site”) other than the agonist-binding site and prevents the receptor from being activated by the agonist. Increasing concentrations of the antagonist progressively flatten the agonist DRC Figure A & E: Receptor Antagonism, non competive  Types of Receptor Antagonism Irreversible antagonists/non equilibrium antagonism: Irreversible antagonists bind covalently to the active site of the receptor preventing the binding of an agonist. Summary of non-competitive antagonists’ pharmacological effect: Cause a nonparallel shift to the right Can be only partially reversed by increasing the dose of the agonist or not at all (spare receptors) Causes a decrease in the efficacy of the agonist Courtesy: Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy 3ed. Courtesy: Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy 3ed.  Summary of Antagonist Physical Antagonist Pharmacokinetic Antagonist Courtesy: Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy 3ed.  Dose–response Relationships Fig. 4: D-R Curves of Antagonists and Potentiators  Quantal DRC Quantal dose–response This is also known as the All – or none response relationship. It is dose–response relationship is that is between the dose of the drug and the proportion of a population that responds to it. They have similar shapes as log dose–response curves, and the ED50 is the drug dose that causes a therapeutic response in half of the population. Spare Receptors  Therapeutic index The therapeutic index (TI): It is also know as therapeutic window and is the range of doses (concentrations) of a drug that elicits a therapeutic response, without unacceptable effects (toxicity), in a population of patients. It is the ratio of the dose that produces toxicity in half the population (TD50) to the dose that produces a clinically desired or effective response (ED50) in half the population. Therapeutic index (TI) = TD5O or LD50 ED50 ED50 Where TD50 or LD50 = is the dose od drug that causes a toxic response in 50% of the population ED50 = is the dose of drug that is therapeutically effective in 50% of the population.  The therapeutic index Fig. 6: Quantal D-R Curves of Therapeutic and Toxic Effects of a Drug  Further Reading & Resources Essentials of Medical Pharmacology 8th Edition by KD Tripathi Katzung BG, Masters SB, Trevor AJ (2012). Basic & Clinical Pharmacology 12th ed. The McGraw-Hill Companies, Inc. Brunton LL, Chabner BA & Knollman BC (2011). Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. David E. Golan, and CO. https://www.pharmacologyeducation.org/ Assignment