Introduction to Pharmacology[1].ppt

Introduction to Pharmacology Prof. Nassiri Director, Institute of International Health Michigan State University Medical Mission Trip May 9-16, Dominican Republic What is Pharmacology? From the Greek pharmakon (drug), legein (to speak) Broadly defined as the study of how chemical agents affect living processes. Hormones Neurotransmitters Growth factors Local autocrine factors Drugs (Pharmaceuticals) Toxic agents in the environment The medicinal/ organic chemist may create the candidate compound (sometimes referred to as a new chemical entity, NCE), it is the pharmacologist who is responsible for testing it for pharmacological activity. Ultimately will lead to the discovery of novel drug targets for therapeutic intervention in diseases where distal steps in signal transduction have gone awry. Pharmacology studies the effects of drugs and how they exert their effects. Acetylsalicylic acid (ASA) can reduce inflammation, pain and fever inhibit the action of a human cell membrane enzyme known as cyclooxygenase, which is responsible for the synthesis of a number of inflammatory mediators. Penicillin cures certain bacterial infections disrupt the synthesis of cell walls in susceptible bacterial strains by inhibiting a key enzyme. Some Pharmacology Definitions and Areas of Study disorders; the emphasis is on clinical management Pharmacoepidemiology - study of the effect of drugs on populations; questions dealing with the influence of genetics are particularly important Pharmacoeconomics - study of the costeffectiveness of drug treatments; the cost of medications is of worldwide concern, particularly among certain groups such as the elderly and AIDS patients Pharmacotherapeutics - use of drugs to treat Pharmacokinetics Study the fate of drugs once ingested and the variability of drug response in varying patient populations How the body absorbs, distributes, metabolizes, and excretes drugs Calculation of various rates brings a quantitative component to assessing drug action Pharmacodynamics Study the mechanisms by which drugs work Also study endogenous agents Pharmacokinetics Principles Movement of drugs in the body Absorption Distribution Elimination Dosage regimens Pharmacodynamic Principles Receptor type Drug-receptor interactions Graded dose-response relationships Quantal dose-response relationships Drug-drug antagonism Binding Studies Association to receptor Dissociation from receptor Forces of binding Covalent Electrostatic Hydrophobic Clearance Adsorption t1/2 Steps in Manufacture of Drugs Scientific Research to discover/synthesize new compounds, or improve existing compounds (R & D) Computer simulation Combinatorial chemistry Develop safe and effective applications of promising compounds Screen compounds in bacterial cultures or animal subjects Clinical trials on humans Clinical Trials Kidneys and liver are two most important organs In Phase I trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects. In Phase II trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety. In Phase III trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely. In Phase IV trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use. Purpose of Drug Therapy “… to prevent, control or cure various disease states.” To achieve this, the right drug dose must be delivered to the tissues Important to know… Speed of onset of drug action Intensity of drug effect Duration of drug action A Graphical Example: Drug Concentration Lethal Dose Peak Onset Duration ⎬ Therapeutic Range SubTherapeutic Time in Hours How Do We Study Pharmacology? General Concepts Drug Dose Administration Pharmaceutical Pharmacokinetics Pharmacodynamics Pharmacotherapeutics Disintegration of Drug Absorption/distribution metabolism/excretion Drug/Receptor Interaction Drug Effect or Response Routes of Drug Delivery Parenteral (IV) Oral Transdermal Parenteral (SC, IM) Rectal Inhaled Topical What Happens After Drug Administration? Drug at site of administration 1. Absorption Drug in plasma 2. Distribution Drug/metabolites 3. Metabolism in tissues Drug/metabolites in urine, feces, bile 4. Elimination Modified from Mycek et al. (1997) Movement of Drug in the Body Passive diffusion Occurs across lipid membranes Requires some degree of lipid solubility Lipid solubility is determined in part by the electrical charge on the molecule. Majority of drugs are weak acid or weak bases. The charge is determined by the pH of the medium according to the HendersonHasselbalch equation: Log (protonated form/unprotonated form) = pKa - pH Movement of Drug in the Body Passive diffusion Log (protonated form/unprotonated form) = pKa - pH Protonated form of a weak acid Uncharged, more lipid soluble form Unprotonated form of a weak base Uncharged, more lipid-soluble form Movement of Drug in the Body Active transport Requires special carrier molecules Drugs should be structurally related to endogenous molecules such as amino acids or sugars Some very large or very polar drugs (vitamin B12, Iron) are complexed with proteins and actively transported into cells by endocytosis. Very small molecules (lithium, alcohols, gases) diffuse rapidly. Drug Absorption First-pass effect Bioavailability First-pass effect Refers to the elimination that occurs when a drug is first absorbed from the intestine and passes through the liver via the portal circulation. Because the liver is the primary drugmetabolizing organ of the body, drugs are easily metabolized have a large first-pass effect and low bioavailability. Drug Absorption Bioavailability (F ) Describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes (such as orally), its bioavailability decreases (due to incomplete absorption and first-pass metabolism). Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be considered when calculating dosages for non-intravenous routes of administration. Definition: An Important Concept: BIOAVAILABIITY Serum Concentration Fraction of a drug that reaches systemic circulation after a particular route of administration Injected Dose Affected by: 1st pass metabolism (eg: Lidocaine, propranolol) Solubility Instability (eg: Penicillin G, insulin) Oral Dose Time An Important Concept: BIOAVAILABIITY Factors Affecting Drug Absorption Transport Active vs. passive ATP pH Physical factors Blood flow Surface area Contact time ADP + Pi ABH+ Drug Distribution Blood flow to the tissue Size of the organ Solubility of the drug Binding Volume of distribution Drug Distribution Blood flow to the tissue Tissues with high blood flow (viscera, brain, muscle) receive significant amount of drug on a short time. Organs with low perfusion (fat, bone) receive the drug more slowly. Size of the organ Very large organs (eg., skeletal muscle) can take up large quantities of drug if allowed to reach steady state. Drug Distribution Binding Drugs that bind to macromolecules in a tissue may be restricted in distribution. For example, drugs that bind avidly to plasma albumin (eg. Warfarin) may be effectively restricted to the vascular compartment. Volume of distribution (Vd) Vd of a drug is a proportionality constant defined as: Vd = amount of drug in the body/plasma concentration Volume of Drug Distribution Drugs may distribute into any or all of the following compartments: Plasma Interstitial Fluid Intracellular Fluid Plasma (4 litres) Interstitial Fluid (10 litres) Intracellular Fluid (28 litres) What Factors Affect Distribution? Blood flow Brain vs. fat Endothelial cells in liver capillary Capillary permeability Differences in capillary structure Binding to proteins Role of albumin Endothelial cells in brain capillary Glial cell More “So What?” Serum Concentration It takes time for a drug to distribute in the body Drug distribution is affected by elimination 1.5 Drug is not eliminated 1.0 0.5 Distribution Phase 0 0 Drug is eliminated Elimination Phase Time Albumin Affects Distribution Drugs bind Albumin differentially to albumin 2 drug classifications: Class I: dose less than available binding sites (eg: most drugs) Class II: dose greater than binding sites (eg: sulfonamide) Drug X The problem: One drug may outcompete the other Sulfonamide Drug Metabolism First pass Metabolism of drugs may occur as they cross the intestine or transit the liver eg: Nitroglycerin Other drugs may be destroyed before absorption eg: Penicillin Such reactions decrease delivery to the target tissues Drug Metabolism (cont’d) Two Phases: I and II Phase I: conversion to lipophilic compounds Phase II: conjugation Drug Phase I Oxidation Reduction Hydrolysis Phase I involves the cytochrome P-450 system Ultimate effect is to facilitate elimination Activation/Inactivation Glucuronidation Phase II Conjugation Products Example of First Pass Effect Drug Elimination Most important route is the kidney May also involve bile, intestine, lung, breast milk What clinical scenarios may affect drug elimination? Drug Elimination Metabolites of drugs must eventually be excreted, but termination of action is of greater importance. The vast majority drugs follow first-order elimination kinetics The rate of elimination is proportionate to plasma concentration. Drug Elimination Only three clinically important drugs follow zeroorder elimination kinetics Ethanol Phenytoin (high dose) Aspirin (high dose) The rate of elimination is fixed and independent of plasma concentration. Drug Elimination The elimination of drugs that follow firstorder kinetics can be characterized by a proportionality constant, clearance, Cl. Clearance is defined as: Cl = rate of elimination/plasma concentration Drug Elimination For elimination half-life (t1/2) of drugs that follow first-order kinetics is defined as the time required (after distribution is complete) for the amount of drug in any compartment to fall by 50%. Half-life can be derived from graphs of plasma concentration versus tine, ot it can also be obtained by calculation: T1/2 = 0.693 x Vd/Cl After 4 half lives, elimination is 94% complete. Concept of “Half-Life” Time required to metobolize 1/2 of the original dose of the drug Use of this terms helps in determining how long a drug will remain in the body Elimination of a drug is usually linked to renal filtration, secretion and reabsorption. Example: Intravenous Infusions Plasma concentration rises until elimination = input Faster infusions get more drugs on board, but does not change the time to achieve a steady state Plasma Concentration Fast Infusion Slow Infusion Time Time at which steady state is achieved Example: Intravenous Injection Peak plasma concentration of the drug is achieved at time = 0 There is no steady state concentration. Why? 100 mg injected Plasma Concentration 50 mg injected Time Example: Oral Dose A single oral dose will give you a single peak plasma concentration The drug concentration then continuously declines Repeated doses result in oscillations in plasma concentration Plasma Concentration Time Aerosolized Agents: 7 Categories Adrenergic Agents Anticholinergic Agents Mucoactive agents Corticosteroids Antiasthmatics Antiinfectives Exogenous Surfactants Adrenergic Agents Action - stimulation of sympathetically mediated bronchorelaxation of smooth muscle Examples: Epinephrine; Isoetharine; Isoproterenol; Metaproterenol; Albuterol; Pibuterol; Bitolterol; Salmeterol Anti-cholinergic Agents Blockage of vagally-induced bronchospasm This results in bronchorelaxation Example: Iptratroprium bromide Mucoactive Agents Improve viscosity of mucus and enhance clearance of secretions Examples: Acetylcysteine, Dornase alpha Corticosteroids Reduce and control inflammatory response associated with asthma and other lung diseases Examples: Dexamethasone; Beclamethasone; Triamcinolone; Flunisolide Anti-asthmatic Agents Prevention of the inflammatory response seen in asthma by inhibition of chemical mediators necessary for inflammation to occur Corticosteroids Prednisolone, Betamethasone, etc. Beta-2 agonists (bronchodilators) Samleterol, Bambuterol, etc. Anti-asthmatic Agents Prevention of the inflammatory response seen in asthma by inhibition of chemical mediators necessary for inflammation to occur Anti-leukotrienes Montelukast, Zafirleukast Xanthines Theophylline Anti-infective Agents To inhibit or kill selected bacterial, protozoal, fungal or viral organisms Examples: Pentamidine, Ribavirin Exogenous Surfactants Used by instillation in the tracheas of premature newborns suffering from respiratory distress syndrome Examples: Beractant, Colfosceril palmitate Drug dosage forms Oral Injectable (parenteral) Subcutaneous Intramuscular Intravenous Spinal Topical Inhalational Concept of Critical Threshold Defined as the minimum level of drug concentration needed for the desired therapeutic effect to be present. Other Dose-related Terms Maximal Effect: greatest response that can be produced by a drug, above which no further response can be created (sometimes called “peak effect” Onset: how long before a drug is able to exert a therapeutic effect Duration: how long a drug effect lasts Agonists and Antagonists An agonist causes a particular effect by binding to the correct “receptor” What is an “antagonist”? An agent that blocks are reverses the actions of another medication. Concept of Potency Comparison of different drugs at the same dose to determine which is stronger.