Pharmacology Lecture Notes PDF 2004

LECTURE NOTES For Health Science Students Pharmacology Teferra Abula, Srinivasa A.Rao, Amare Mengistu, Solomomon Worku, Eshetu Legesse, Musie Aberra, Dawit University of Gonda...

LECTURE NOTES For Health Science Students Pharmacology Teferra Abula, Srinivasa A.Rao, Amare Mengistu, Solomomon Worku, Eshetu Legesse, Musie Aberra, Dawit University of Gondar In collaboration with the Ethiopia Public Health Training Initiative, The Carter Center, the Ethiopia Ministry of Health, and the Ethiopia Ministry of Education 2004  Funded under USAID Cooperative Agreement No. 663-A-00-00-0358-00. Produced in collaboration with the Ethiopia Public Health Training Initiative, The Carter Center, the Ethiopia Ministry of Health, and the Ethiopia Ministry of Education. Important Guidelines for Printing and Photocopying Limited permission is granted free of charge to print or photocopy all pages of this publication for educational, not-for-profit use by health care workers, students or faculty. All copies must retain all author credits and copyright notices included in the original document. Under no circumstances is it permissible to sell or distribute on a commercial basis, or to claim authorship of, copies of material reproduced from this publication. ©2004 by Teferra Abula, Srinivasa A.Rao, Amare Mengistu, Solomomon Worku, Eshetu Legesse, Musie Aberra, Dawit All rights reserved. Except as expressly provided above, no part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or by any information storage and retrieval system, without written permission of the author or authors. This material is intended for educational use only by practicing health care workers or students and faculty in a health care field. ACKNOWLEDGMENT The authors would like to thank the Carter Center for the initiation and financial support of the preparation of this material. Ato Getu Degu’s role in coordinating this work is greatly acknowledged. Finally, we thank the department heads and the faculty heads of the health institutions for their cooperation to participate in the preparation of the lecture note. i INTRODUCTION Pharmacology is a medical science that forms a backbone of the medical profession as drugs form the corner stone of therapy in human diseases. Therefore, it is of utmost importance to describe the pharmacological basis of therapeutics in order to maximize the benefits and minimize the risks of drugs to recipients. This lecture note on pharmacology is primarily a note for undergraduate health science students such as health officer, nursing, midwifery and laboratory technology students. However, other health professionals whose career involves drug therapy or related aspects should also find much of the material relevant. The goal is to empower the practitioner through an understanding of the fundamental scientific principles of pharmacology. The effects of prototypical drugs on physiological and pathophysiological processes are clearly explained to promote understanding. Other related drugs are touched briefly. The selection of the drugs is based on the national drugs list for Ethiopia and on the accumulated experience of teaching pharmacology to many health profession students. The chapters open with a list of objectives to guide the reader, and most end with questions which challenge the reader’s understanding of the concepts covered with in the chapter. Most sections have an introduction that provides an overview of the material to be covered. Readers are encouraged to refer the references mentioned for further information and we hope that this material will be a valuable companion in our pursuit of a fundamental understanding in a most fascinating area of clinical knowledge, pharmacology. The Authors April 2004: ii  Table of Contents Acknowledgment................................................................................................................... i Introduction.......................................................................................................................... ii Table of Contents.................................................................................................................. iii Abbreviation.......................................................................................................................... vi Chapter one: General pharmacology................................................................................... 1 Learning objectives..................................................................................... 1 Introduction................................................................................................. 1 Pharmacodynamics..................................................................................... 2 Pharmacokinetics........................................................................................ 5 Theoretical pharmacokinetics..................................................................... 17 Drug safety and effectiveness..................................................................... 19 Development and evaluation of new drugs................................................. 26 Exercise...................................................................................................... 29 Chapter two: Drugs acting on autonomic nervous system................................................. 30 Learning objectives..................................................................................... 30 Introduction................................................................................................. 30 Autonomic drugs......................................................................................... 35 Cholinergic drugs........................................................................................ 36 Anticholinergics........................................................................................... 40 Adrenergic drugs......................................................................................... 42 Adrenergic blockers.................................................................................... 47 Exercise..................................................................................................... 50 Chapter three: Cardiovascular-renal drugs.......................................................................... 51 Learning objectives..................................................................................... 51 Introduction................................................................................................. 51 Antihypertensive drugs............................................................................... 51 Drugs used in heart failure.......................................................................... 57 Pharmacotherapy of angina pectoris.......................................................... 60 Anti-arrhythmics.......................................................................................... 62 Diuretics...................................................................................................... 64 Drugs used in hypotensive states and shock............................................. 66 Exercise..................................................................................................... 68 Chapter four: Autacoids and their antagonists.................................................................... 69 Learning objectives..................................................................................... 69 Introduction................................................................................................ 69 Hisamine..................................................................................................... 69 iii  5-hydroxytryptamine.................................................................................... 72 Prostaglandins............................................................................................ 73 Exercise..................................................................................................... 75 Chapter five: Drugs Action on the Respiratory System.......................................................... 76 Learning objectives.......................................................................................... 76 Introduction..................................................................................................... 76 Pharmacotherapy of bronchial asthma............................................................ 77 Antitussives...................................................................................................... 82 Expectorants & Mucolytics............................................................................... 83 Decongestants................................................................................................. 83 Exercise.......................................................................................................... 85 Chapter six: Drugs used in Gastrointestinal Diseases............................................................ 86 Learning objective............................................................................................ 86 Introduction....................................................................................................... 86 Drugs used in acid-peptic diseases................................................................... 86 Purgatives.......................................................................................................... 90 Antidiarrhoeals................................................................................................... 91 Antiemetics........................................................................................................ 92 Drugs used to induce vomiting (emetics).......................................................... 94 Antihaemorrhoidal agents.................................................................................. 94 Drugs used in inflammatory bowel disease....................................................... 94 Chapter seven: Drugs used to treat the diseases of blood, inflammation and gout................ 95 Learning objectives........................................................................................ 95 Introduction..................................................................................................... 95 Agents used in anemias................................................................................. 95 Drugs used in disorders of blood coagulation................................................ 101 Nonsteroidal antiinfammatory agents............................................................. 104 Drugs used in gout......................................................................................... 108 Exercise.......................................................................................................... 112 Chapter eight: Drugs acting in the central nervous system................................................... 113 Learning objectives........................................................................................ 113 Introduction..................................................................................................... 113 General anesthetics....................................................................................... 114 Sedative and hypnotic drugs.......................................................................... 115 Drugs used in Parkinsonism.......................................................................... 116 Antipsychotic drugs........................................................................................ 117 Antidepressant agents.................................................................................... 121 Opioid analgesics........................................................................................... 122 CNS stimulants............................................................................................... 125 iv  Local anesthetics............................................................................................ 126 Exercise.......................................................................................................... 128 Chapter nine: Endocrine Drugs............................................................................................... 129 Learning objectives........................................................................................ 129 Introduction..................................................................................................... 129 Antidiabetic drugs........................................................................................... 129 Oxytocics........................................................................................................ 133 Female sex hormones and hormonal contraception...................................... 134 Adrenocortical hormones............................................................................... 138 Exercise.......................................................................................................... 143 Chapter ten: Chemotherapeutic Agents.............................................................................. 144 Learning objectives........................................................................................ 144 Introduction..................................................................................................... 144 Antibacterial drugs.......................................................................................... 146 Antifungal agents............................................................................................ 165 Antiviral agents............................................................................................... 169 Antineoplastic agents..................................................................................... 177 Treatment of protozoal infection.................................................................... 178 Treatment of helminthic infections................................................................. 188 Exercise.......................................................................................................... 195 Chapter eleven: Toxicology...................................................................................................... 196 Learning objectives....................................................................................... 196 Introduction................................................................................................... 196 General measures in poisoning.................................................................... 196 Exercise........................................................................................................ 199 Chapter twelve: Prescription writing and rational use of drugs............................................... 200 Learning objective......................................................................................... 200 Introduction................................................................................................... 200 Prescription writing...................................................................................... 200 Rational use of drugs.................................................................................... 201 Exercise........................................................................................................ 202 References.......................................................................................................................... 203 v  List of Abbrevations ACE= angiotensin converting enzyme ACH= Acetylcholine ACTH= Adrenocorticotropic hormone AIDS= Acquired Immuno deficiency syndorme ANS= Autonomic nervous system B.C.G vaccine= Bacille Calmette-Guerin Vaccine CAMP= Cyclic adenosine Monoposphate CHO= Carbohydrate CMS= Cytomegalovirus CNS= Central nervous system CSF= Cerebrospinal fluid CTZ= Chemoceptor trigger zone CVS= Cardiovascular system DKA = Diabetic ketoacidosis DNA= Deoxyribonucleic acid EBV= Epstein-barr virus FSH= Follicle Stimulating hormone GABA= Gamma amino butyric acid GIT= Gastrointestinal Tract HBV= Hepatitis B virus HDL= Hgh Density lipoproteins HHV= Human Herpes Virus HIV= Human Immunodeficiency viru HSV= Herpes simplex virus 5-HT= 5-Hydroxytryptamine IDDM= Insulin dependent Diabetes Mellitus IM= Intramusular INH= Isoniazid vi  CHAPTER ONE GENERAL PHARMACOLOGY Learning Objectives At the end of this chapter the student will be able to: 1. Define various terminologies used in Pharmacology. 2. Know about nature and sources of drugs. 3. Understand pharmacodynamics like mechanism of drug action, dose relation ship and pharmacokinetics like absorption, distribution, metabolism and excretion (ADME) of drugs. 4. Understand theoritical pharmacokinetics like half-life, order of kinetics, steady state plasma concentration. 5. Understand drug safety and effectiveness like factors affecting drug action and adverse drug reactions. 6. Understand new drug development and evaluation. I. Introduction to Pharmacology A. Definitions: 1. Pharmacology: Pharmacology is the study of interaction of drugs with living organisms. It also includes history, source, physicochemical properties, dosage forms, methods of administration, absorption, distribution mechanism of action, biotransformation, excretion, clinical uses and adverse effects of drugs. 2. Clinical Pharmacology: It evaluate the pharmacological action of drug preferred route of administration and safe dosage range in human by clinical trails. 3. Drugs: Drugs are chemicals that alter functions of living organisms. Drugs are generally given for the diagnosis, prevention, control or cure of disease. 4. Pharmacy: It is the science of identification, selection, preservation, standardisation, compounding and dispensing of medical substances. 1  5. Pharmacodynamics: The study of the biological and therapeutic effects of drugs (i.e, “what the drug does to the body”). 6. Pharmacokinetics: Study of the absorption, distribution metabolism and excretion (ADME) of drugs (“i.e what the body does to the drug”). 7. Pharmacotherapeutics: It deals with the proper selection and use of drugs for the prevention and treatment of disease. 8. Toxicology: It’s the science of poisons. Many drugs in larger doses may act as poisons. Poisons are substances that cause harmful, dangerous or fatal symptoms in living substances. 9. Chemotherapy: It’s the effect of drugs upon microorganisms, parasites and neoplastic cells living and multiplying in living organisms. 10. Pharmacopoeia: An official code containing a selected list of the established drugs and medical preparations with descriptions of their physical properties and tests for their identity, purity and potency e.g. Indian Pharmacopoeia (I.P), British Pharmacopoeia (B.P). B. Drugs are obtained from: 1. Minerals: Liquid paraffin, magnesium sulfate, magnesium trisilicate, kaolin, etc. 2. Animals: Insulin, thyroid extract, heparin and antitoxin sera, etc. 3. Plants: Morphine, digoxin, atropine, castor oil, etc. 4. Synthetic source: Aspirin, sulphonamides, paracetamol, zidovudine, etc. 5. Micro organisms: Penicillin, streptomycin and many other antibiotics. 6. Genetic engineering: Human insulin, human growth hormone etc. Out of all the above sources, majority of the drugs currently used in therapeutics are from synthetic source. II. Pharmacodynamics Involves how the drugs act on target cells to alter cellular function. A. Receptor and non-receptor mechanisms: Most of the drugs act by interacting with a cellular component called receptor. Some drugs act through simple physical or chemical reactions without interacting with any receptor. 2  Receptors are protein molecules present either on the cell surface or with in the cell e.g. adrenergic receptors, cholinoceptors, insulin receptors, etc. The endogenous neurotransmitters, hormones, autacoids and most of the drugs produce their effects by binding with their specific receptors. Aluminium hydroxide and magnesium trisilicate, which are used in the treatment of peptic ulcer disease act by non-receptor mechanism by neutralizing the gastric acid. Many drugs are similar to or have similar chemical groups to the naturally occurring chemical and have the ability to bind onto a receptor where one of two things can happen- either the receptor will respond or it will be blocked. A drug, which is able to fit onto a receptor, is said to have affinity for that receptor. Efficacy is the ability of a drug to produce an effect at a receptor. An agonist has both an affinity and efficacy whereas antagonist has affinity but not efficacy or intrinsic activity. When a drug is able to stimulate a receptor, it is known as an agonist and therefore mimics the endogenous transmitter. When the drug blocks a receptor, it is known as antagonist and therefore blocks the action of the endogenous transmitter (i.e. it will prevent the natural chemical from acting on the receptor). However, as most drug binding is reversible, there will be competition between the drug and the natural stimulus to the receptor. The forces that attract the drug to its receptor are termed chemical bonds and they are (a) hydrogen bond (b) ionic bond (c) covalent bond (d) Vander waals force. Covalent bond is the strongest bond and the drug-receptor complex is usually irreversible. K1 K3 DR Biological effect D+R K2 Where D = Drug, R= receptor DR= Drug receptor complex (affinity) K1 = association constant K2 = dissociation constant K3 = intrinsic activity When first messengers like neurotransmitters, hormones, autacoids and most of drugs bind with their specific receptors, the drug receptor complex is formed which subsequently causes the 3 synthesis and release of another intracellular regulatory molecule termed as second messengers e.g. cyclic AMP, calcium, cyclic GMP, inositol triphosphate (IP3), diacylglycerol and calmodulin which in turn produce subcellular or molecular mechanism of drug action. B. Site of drug action: - A drug may act: (i) Extracellularly e.g: osmotic diuretics, plasma expanders. (ii) On the cell surface e.g.: digitalis, penicillin, catecholamines (iii) Inside the cell e.g.: anti-cancer drugs, steroid hormones. C. Dose Response relationship The exact relationship between the dose and the response depends on the biological object under observation and the drug employed. When a logarithm of dose as abscissa and responses as ordinate are constructed graphically, the “S” shaped or sigmoid type curve is obtained. The lowest concentration of a drug that elicits a response is minimal dose, and the largest concentration after which further increase in concentration will not change the response is the maximal dose. 100 50 EC50 Log dose Fig 1.1: Log dose response relationship. 1. Graded dose effect: As the dose administered to a single subject or tissue increases, the pharmacological response also increases in graded fashion up to ceiling effect. - It is used for characterization of the action of drugs. The concentration that is required to produce 50 % of the maximum effect is termed as EC50 or ED50. 4 2. Quantal dose effect: It is all or none response, the sensitive objects give response to small doses of a drug while some will be resistant and need very large doses. The quantal dose- effect curve is often characterized by stating the median effective dose and the median lethal dose. Median lethal dose or LD50: This is the dose (mg/kg), which would be expected to kill one half of a population of the same species and strain. Median effective dose or ED50: This is the dose (mg/kg), which produces a desired response in 50 per cent of test population. Therapeutic index: It is an approximate assessment of the safety of the drug. It is the ratio of the median lethal dose and the median effective dose. Also called as therapeutic window or safety. LD50 Herapeutic index (T. I) = ED50 The larger the therapeutic index, the safer is the drug. Penicillin has a very high therapeutic index, while it is much smaller for the digitalis preparation. D. Structural activity relationship The activity of a drug is intimately related to its chemical structure. Knowledge about the chemical structure of a drug is useful for: (i) Synthesis of new compounds with more specific actions and fewer adverse reactions (ii) Synthesis of competitive antagonist and (iii) Understanding the mechanism of drug action. Slight modification of structure of the compound can change the effect completely. III. Pharmacokinetics Pharmacokinetics deals with the absorption, distribution, metabolism and excretion drugs in the body. A. Biotransport of drug: It is translocation of a solute from one side of the biological barrier to the other. 1. Structure of biological membrane: The outer surface of the cell covered by a very thin structure known as plasma membrane. It is composed of lipid and protein molecules. The 5  membrane proteins have many functions like (a) contributing structure to the membrane (b) acting as enzyme (c) acting as carrier for transport of substances (d) acting as receptors. The plasma membrane is a semipermeable membrane allowing certain chemical substances to pass freely e.g. it allows water, glucose, etc. but it won’t allow sucrose until it is converted into glucose and fructose. 2. Passage of drug across membrane. i) Simple diffusion (a) Passive transfer ii) Filtration i) Facilitated diffusion (b) Specialized transport ii) Active transport iii) Endocytosis. (a) i) Simple diffusion: Movement of a solute through a biological barrier from the phase of higher concentration to phase of lower concentration. No need of energy e.g. highly lipid soluble drugs. ii) Filtration: Is the process by which water soluble drug of relatively low molecular weight crosses the plasma membrane through pores as a result of hydrodynamic pressure gradient across the membrane e.g. urea and ethylene glycol. (b) i) Facilitated diffusion: It means the passage of drug across the biological membrane along the concentration gradient by the protein carrier mediated system also called as carrier mediated diffusion. It depends on number of carrier e.g. tetracycline, pyrimidine. ii) Active transport: The process by which drugs pass across the biological membrane most often against their concentration gradient with the help of carriers along with the expenditure of energy e.g. alpha methyl dopa, levodopa, 5-fluoro-uracil, 5 bromouracil. iii) Endocytosis: It is the process by which the large molecules are engulfed by the cell membrane and releases them intracellularly e.g. protein, toxins (botulinum, diphtheria) 6  Differences amongst different transport systems Characteristics Simple diffusion Facilitated Active transport Incidence Commonest Less common Least common Process Slow Quick Very Quick Movement Along concentration Along concentration Against concentration gradient gradient gradient Carrier Not needed Needed Needed Energy Not required Not required Required B. Drug absorption: Absorption is the process by which the drug enters in to the systemic circulation from the site of administration through biological barrier. In case of intravenous or intra-arterial administration the drug bypasses absorption processes and it enters into the circulation directly. 1. Routes of drug administration: a) From the alimentary tract: (i) Buccal cavity: e.g. nitrates (ii) Stomach: e.g. aspirin, alcohol (iii) Intestine: e.g. most of non ionized and ionized drugs. (iv) Rectum: e.g. rectal suppositories, bisacodyl laxatives. Advantages of oral route: This route is safe, convenient and economical. Disadvantages of oral route: Onset of drug action is slow, irritant drugs cannot be administered and it is not useful in vomiting and severe diarrhea, gastric acid and digestive enzymes may destroy some drugs, and water soluble drugs are absorbed poorly. b) From the parenteral route: (i) Intradermal: This is given into the layers of the skin e.g. B.C.G. vaccine (ii) Subcutaneous: Non-irritant substances are given into subcutaneous tissue e.g. insulin (iii) Intramuscular: Soluble substances, mild irritants, suspensions and colloids can be injected by this route. These injections can be given to deltoid or gluteal muscle. This route is one of the more common routes e.g. multivitamins, streptomycin, etc. 7  Advantages: rate of absorption is uniform, onset of action is faster than oral and it can be given in diarrhoea or vomiting. Disadvantages: Pain at local site of injection, the volume of injection should not exceed 10 ml. (iv) Intravenous: Drugs directly given into a vein, produce rapid action, no need of absorption as they enter directly into blood, can be given as bolus e.g. furosemide, morphine, dopamine or as continous infusion e.g. fluids during shock or dehydration. Advantages: It can be given in large volumes, production of desired blood concentration can be obtained with a well designed dose. Disadvantages: Drug effect cannot be halted if once the drug is injected, expertise is needed to give injection. (v) Intrathecal: Injected into subarachnoid space of spinal cord e.g. spinal anaesthetics. (vi) Intraperitonial: Injections given into the abdominal cavity e.g. infant saline, glucose. (vii) Intra-articular: Injected directly into a joint e.g. hydrocortisone. c) Transcutaneous route: i) Iontophoresis: Galvanic current is used for bringing about the penetration of drugs into the deeper tissue e.g. salicylates. ii) Inunctions: Absorbed when rubbed in to the skin e.g. nitroglycerin ointment in angina pectoris. iii) Jet injection: With help of high velocity jet produced through a micro fine orifice; No need of needle and therefore painless. e.g. mass inoculation programmes. iv) Adhesive units: A transdermal therapeutic system produce prolonged systemic effect e.g. scopolamine for motion sickness. d) Topical/ local route: The absorption through skin is a passive process. The absorption occurs more easily through the cell lining e.g. dusting powder, paste, lotion, drops, ointment, suppository for vagina and rectum. e) Inhalation: Drugs may be administered as dry powders, and nebulized particles when sprayed as fine droplets get deposited over the mucous membrane producing local effects and may be 8 absorbed for systemic effects e.g. salbutamol spray used in bronchial asthma and volatile general anaesthetics. 2. Bioavailability: It is the rate and amount of drug that is absorbed from a given dosage form and reaches the systemic circulation following non-vascular administration. When the drug is given IV, the bioavailability is 100%. It is important to know the manner in which a drug is absorbed. The route of administration largely determines the latent period between administration and onset of action. Drugs given by mouth may be inactive for the following reasons: a) Enzymatic degradation of polypeptides within the lumen of the gastrointestinal tract e.g. insulin, ACTH. b) Poor absorption through gastrointestinal tract e.g. aminoglycoside antibiotic. c) Inactivation by liver e.g. testosterone during first passage through the liver before it reaches systemic circulation. 3. Factors affecting drug absorption and bioavailability: a) Physico-chemical properties of drug b) Nature of the dosage form c) Physiological factors d) Pharmacogenetic factors e) Disease states. a) Physico-chemical properties of drug: i) Physical state: Liquids are absorbed better than solids and crystalloids absorbed better than colloids. ii) Lipid or water solubility: Drugs in aqueous solution mix more readily than those in oily solution. However at the cell surface, the lipid soluble drugs penetrate into the cell more rapidly than the water soluble drugs. iii) Ionization: Most of the drugs are organic compounds. Unlike inorganic compounds, the organic drugs are not completely ionized in the fluid. Unionized component is predominantly lipid soluble and is absorbed rapidly and an ionized is often water soluble component which is absorbed poorly. Most of the drugs are weak acids or weak bases. It may be assumed for all practical purposes, that the mucosal lining of the G.I.T is impermeable to the ionized form of a weak organic acid or a weak organic base. These drugs exist in two forms. 9  Acidic drugs: rapidly absorbed from the stomach e.g. salicylates and barbiturates. Basic drugs: Not absorbed until they reach to the alkaline environment i.e. small intestine when administered orally e.g. pethidine and ephedrine. b) Dosage forms: i) Particle size: Small particle size is important for drug absorption. Drugs given in a dispersed or emulsified state are absorbed better e.g. vitamin D and vitamin A. ii) Disintegration time and dissolution rate. Disintegration time: The rate of break up of the tablet or capsule into the drug granules. Dissolution rate: The rate at which the drug goes into solution. iii) Formulation: Usually substances like lactose, sucrose, starch and calcium phosphate are used as inert diluents in formulating powders or tablets. Fillers may not be totally inert but may affect the absorption as well as stability of the medicament. Thus a faulty formulation can render a useful drug totally useless therapeutically. c) Physiological factors: i) Gastrointestinal transit time: Rapid absorption occurs when the drug is given on empty stomach. However certain irritant drugs like salicylates and iron preparations are deliberately administred after food to minimize the gastrointestinal irritation. But some times the presence of food in the G.I tract aids the absorption of certain drugs e.g. griseofulvin, propranolol and riboflavin. ii) Presence of other agents: Vitamin C enhances the absorption of iron from the G.I.T. Calcium present in milk and in antacids forms insoluble complexes with the tetracycline antibiotics and reduces their absorption. iii) Area of the absorbing surface and local circulation: Drugs can be absorbed better from the small intestine than from the stomach because of the larger surface area of the former. Increased vascular supply can increase the absorption. iv) Enterohepatic cycling: Some drugs move in between intestines and liver before they reach the site of action. This increases the bioavailability e.g. phenolphthalein. v) Metabolism of drug/first pass effect: Rapid degradation of a drug by the liver during the first pass (propranolol) or by the gut wall (isoprenaline) also affects the bioavailability. Thus a drug though absorbed well when given orally may not be effective because of its extensive first pass metabolism. 10 d) Pharmacogenetic factors: Individual variations occur due to the genetically mediated reason in drug absorption and response. e) Disease states: Absorption and first pass metabolism may be affected in conditions like malabsorption, thyrotoxicosis, achlorhydria and liver cirrhosis. 4. Bioavailability curves Single dose bioavailability test involves an analysis of plasma or serum concentration of the drug at various time intervals after its oral administration and plotting a serum concentration time curve. AUC after oral dose Bioavailability (F) = AUC after I.V. dose AUC= Area under curve – which provides information about the amount of drug absorbed. 9.0- Formulation A 6.0- MTC Formulation B 3.0- MEC Formulation C 0- Time hours Fig 1.2 : The plasma drug level curves following administration of three formulations (A, B and C) of the same basic drug. MTC: Minimum toxic concentration MEC: Minimum effective concentration Formulation A = would produce quick onset and short duration of action, produce toxic effects. Formation B = Effect would last much longer and nontoxic Formulation C = gives inadequate plasma level so therapeutically ineffective. 11 C) Distribution of drugs 1. Definition: Penetration of a drug to the sites of action through the walls of blood vessels from the administered site after absorption is called drug distribution. Drugs distribute through various body fluid compartments such as (a) plasma (b) interstitial fluid compartment (c) trans-cellular compartment. Apparent Volume of distribution (VD): The volume into which the total amount of a drug in the body would have to be uniformly distributed to provide the concentration of the drug actually measured in the plasma. It is an apparent rather than real volume. Factors determining the rate of distribution of drugs: 1. Protein binding of drug: A variable and other significant portion of absorbed drug may become reversibly bound to plasma proteins. The active concentration of the drug is that part which is not bound, because it is only this fraction which is free to leave the plasma and site of action. (a) Free drug leave plasma to site of action (b) binding of drugs to plasma proteins assists absorption (c) protein binding acts as a temporary store of a drug and tends to prevent large fluctuations in concentration of unbound drug in the body fluids (d) protein binding reduces diffusion of drug into the cell and there by delays its metabolic degradation e.g. high protein bound drug like phenylbutazone is long acting. Low protein bound drug like thiopental sodium is short acting. 2. Plasma concentration of drug (PC): It represents the drug that is bound to the plasma proteins (albumins and globulins) and the drug in free form. It is the free form of drug that is distributed to the tissues and fluids and takes part in producing pharmacological effects. The concentration of free drug in plasma does not always remain in the same level e.g. i) After I.V. administration plasma concentration falls sharply ii) After oral administration plasma concentration rises and falls gradually. iii) After sublingual administration plasma concentration rise sharply and falls gradually. 12  I.V Sublingual Oral Plasma Concentration 0 Time Fig 1.3: Plasma concentration of drug after different routes of administration. 3. Clearance: Volume of plasma cleared off the drug by metabolism and excretion per unit time. Protein binding reduces the amount of drug available for filtration at the glomeruli and hence delays the excretion, thus the protein binding reduces the clearance. 4. Physiological barriers to distribution: There are some specialized barriers in the body due to which the drug will not be distributed uniformly in all the tissues. These barriers are: a) Blood brain barrier (BBB) through which thiopental sodium is easily crossed but not dopamine. b) Placental barrier: which allows non-ionized drugs with high lipid/water partition coefficient by a process of simple diffusion to the foetus e.g. alcohol, morphine. 5. Affinity of drugs to certain organs: The concentration of a drug in certain tissues after a single dose may persist even when its plasma concentration is reduced to low. Thus the hepatic concentration of mepacrine is more than 200 times that of plasma level. Their concentration may reach a very high level on chronic administration. Iodine is similarly concentrated in the thyroid tissue. D. Metabolism of drugs: Drugs are chemical substances, which interact with living organisms and produce some pharmacological effects and then, they should be eliminated from the body unchanged or by changing to some easily excretable molecules. The process by which the body brings about changes in drug molecule is referred as drug metabolism or biotransformation. Enzymes responsible for metabolism of drugs: a) Microsomal enzymes: Present in the smooth endoplasmic reticulum of the liver, kidney and GIT e.g. glucuronyl transferase, dehydrogenase , hydroxylase and cytochrome P450 13  b) Non-microsomal enzymes: Present in the cytoplasm, mitochondria of different organs. e.g. esterases, amidase, hydrolase. Types of biotransformation: The chemical reactions involved in biotransformation are classified as phase-I and phase – II (conjugation) reactions. In phase-I reaction the drug is converted to more polar metabolite. If this metabolite is sufficiently polar, then it will be excreted in urine. Some metabolites may not be excreted and further metabolised by phase –II reactions. Phase-I: Oxidation, reduction and hydrolysis. Phase-II: Glucuronidation, sulfate conjugation, acetylation, glycine conjugation and methylation reactions. Phase - I reactions a) Oxidation: Microsomal oxidation involves the introduction of an oxygen and/or the removal of a hydrogen atom or hydroxylation, dealkylation or demethylation of drug molecule e.g. conversion of salicylic acid into gentisic acid. b) Reduction: The reduction reaction will take place by the enzyme reductase which catalyze the reduction of azo (-N=N-) and nitro (-NO2) compounds e.g. prontosil converted to sulfonamide. c) Hydrolysis: Drug metabolism by hydrolysis is restricted to esters and amines (by esterases and amidases) are found in plasma and other tissues like liver. It means splitting of drug molecule after adding water e.g. pethidine undergoes hydrolysis to form pethidinic acid. Other drugs which undergo hydrolysis are atropine and acetylcholine. Phase - II reactions (conjugation reactions): This is synthetic process by which a drug or its metabolite is combined with an endogenous substance resulting in various conjugates such as glucoronide, ethereal sulfate, methylated compound and amino acid conjugates. Glucuronide conjugation: It is the most common and most important conjugation reaction of drugs. Drugs which contain a) Hydroxyl, amino or carboxyl group undergo this process e.g. phenobarbitone. b) Sulfate conjugation: Sulfotransferase present in liver, intestinal mucosa and kidney, which transfers sulfate group to the drug molecules e.g. phenols, catechols, etc. 14  c) Acetyl conjugation: The enzyme acetyl transferase, which is responsible for acetylation, is present in the kupffer cells of liver. Acetic acid is conjugated to drugs via its activation by CoA to form acetyl CoA. This acetyl group is then transferred to-NH2 group of drug e.g. dapsone, isoniazid. d) Glycine conjugation: Glycine conjugation is characteristic for certain aromatic acids e.g. salicylic acid, isonicotinic acid, p-amino salicylic acid. These drugs are also metabolized by other path ways. e) Methylation: Adrenaline is methylated to metanephrine by catechol-o-methyl transferase. Here the source of methyl group is s – adenosyl methionine. E. Excretion of drugs Excretion of drugs means the transportation of unaltered or altered form of drug out of the body. The major processes of excretion include renal excretion, hepatobiliary excretion and pulmonary excretion. The minor routes of excretion are saliva, sweat, tears, breast milk, vaginal fluid, nails and hair. The rate of excretion influences the duration of action of drug. The drug that is excreted slowly, the concentration of drug in the body is maintained and the effects of the drug will continue for longer period. Different routes of drug excretion a) Renal excretion: A major part of excretion of chemicals is metabolically unchanged or changed. The excretion of drug by the kidney involves. i) Glomerular filtration ii) Active tubular secretion iii) Passive tubular reabsorption. The function of glomerular filtration and active tubular secretion is to remove drug out of the body, while tubular reabsorption tends to retain the drug. i) Glomerular filtration: It is a process, which depends on (1) the concentration of drug in the plasma (2) molecular size, shape and charge of drug (3) glomerular filtration rate. Only the drug which is not bound with the plasma proteins can pass through glomerulus. All the drugs which have low molecular weight can pass through glomerulus e.g. digoxin, ethambutol, etc. 15  In congestive cardiac failure, the glomerular filtration rate is reduced due to decrease in renal blood flow. ii) Active tubular secretion: The cells of the proximal convoluted tubule actively transport drugs from the plasma into the lumen of the tubule e.g. acetazolamide, benzyl penicillin, dopamine, pethidine, thiazides, histamine. iii) Tubular reabsorption: The reabsorption of drug from the lumen of the distal convoluted tubules into plasma occurs either by simple diffusion or by active transport. When the urine is acidic, the degree of ionization of basic drug increase and their reabsorption decreases. Conversely, when the urine is more alkaline, the degree of ionization of acidic drug increases and the reabsorption decreases. b) Hepatobiliary excretion: the conjugated drugs are excreted by hepatocytes in the bile. Molecular weight more than 300 daltons and polar drugs are excreted in the bile. Excretion of drugs through bile provides a back up pathway when renal function is impaired. After excretion of drug through bile into intestine, certain amount of drug is reabsorbed into portal vein leading to an enterohepatic cycling which can prolong the action of drug e.g. chloramphenicol, oral estrogen are secreted into bile and largely reabsorbed and have long duration of action. Tetracylines which are excreted by biliary tract can be used for treatment of biliary tract infection. c) Gastrointestinal excretion: When a drug is administered orally, a part of the drug is not absorbed and excreted in the faeces. The drugs which do not undergo enterohepatic cycle after excretion into the bile are subsequently passed with stool e.g. aluminium hydroxide changes the stool into white colour, ferrous sulfate changes the stool into black and rifampicin into orange red. d) Pulmonary excretion: Drugs that are readily vaporized, such as many inhalation anaesthetics and alcohols are excreted through lungs. The rate of drug excretion through lung depends on the volume of air exchange, depth of respiration, rate of pulmonary blood flow and the drug concentration gradient. e) Sweat: A number of drugs are excreted into the sweat either by simple diffusion or active secretion e.g. rifampicin, metalloids like arsenic and other heavy metals. f) Mammary excretion: Many drugs mostly weak basic drugs are accumulated into the milk. Therefore lactating mothers should be cautious about the intake of these drugs because they may enter into baby through breast milk and produce harmful effects in the baby e.g. 16  ampicillin, aspirin, chlordiazepoxide, coffee, diazepam, furosemide, morphine, streptomycin etc. Clearance of a drug: It is the volume of plasma cleared of the drug by metabolism (hepatic) and excretion (renal) and other organs. Total clearance will be calculated by Ct = Ch + Cr + C others Ct = total clearance Ch = hepatic clearance Cr = Renal clearance IV. Theoretical Pharmacokinetics Information about the time course of drug absorption, distribution and elimination (pharmacokinetics) can be expressed in mathematical terms and has contributed to our understanding and planning of drug regimens. Pharmacokinetic principles aid in the selection and adjustment of drug-dose schedules. Half life: Half life (t1/2) of a drug is the time taken for the concentration of drug in the blood or plasma to decline to half of original value or the amount of drug in the body to be reduced by 50%. It has two phases i.e half-life of distribution and half-life of elimination. A half-life value can be readily determined for most drugs by administering a dose of the drug to a subject, taking blood samples at various time intervals and then assaying the samples., For example if a blood level of drug A is 8.6 mg/ml at 10 minutes and 4.3 mg/ml at 60 minutes, so the half – life of that drug is 50 minutes. In most of the cases the rate of disappearance of a drug from the body is reflected in the rate of lowering of its plasma concentration following a single intravenous dose, the plasma concentration of the drug is focused to fall exponentially. With drugs whose elimination is exponential, the biological half – life is independent of the dose, the route of administration and the plasma concentration. It depends on VD as well as on the metabolism and renal excretion of the drug. 17  Concentration mg/L Intravenous Oral 0 4 8 Time in hrs Fig 1.4: Exponential curves of plasma concentration following oral and intravenous drug administration. Order of kinetics Drugs are used for the treatment of diseases but the modes of administration of drugs are different. For example atenolol is administered once daily where as paracetamol needs 3-4 times administration daily. Morphine is more effective in intramuscular route, and insulin is in subcutaneous route. The mode of administration is designed on the basis of absorption, distribution, metabolism and excretion (ADME) of drugs. Drugs usually follow two processes for their phamacokinetic behaviour in the body. These are first order and zero order process. First order: This is the most common process for many drugs. The rate at which absorption, distribution, metabolism and excretion occur are proportional to the concentration of drugs i.e. constant fraction of this drug in the body disappears in each equal interval of time. Zero order kinetic: It is independent of the amount of drug present at the particular sites of drug absorption or elimination. Few drugs follow this process e.g. ethanol, phenytoin. Here constant amount of the drug is eliminated in each equal interval of time. On repeated administration of drug after certain stage it goes on accumulating in the body and leads to toxic reactions. Steady state plasma concentration: When a drug dose is given repeatedly over a given period, a steady state is eventually reached, at which point the amount of drug absorbed is in equilibrium with that eliminated from the body. 18 Steady state is achieved after 4 to 5 half –lives for most of the drugs which follow first order kinetics. For example a drug with half life of 6 hours will be expected to be at steady state after more than 24 hours of administration. The pattern of drug accumulation during repeated administration of drug at intervals equal to its elimination half-life. Fig 1.5: Steady state plasma concentration of a drug after repeated administrations. For some drugs, the effects are difficult to measure, toxicity and lack of efficacy are both potential dangers, and/or the therapeutic window is narrow. In these circumstances doses must be adjusted carefully to a desired steady- state concentration by giving loading and maintenance doses. Loading dose: The loading dose is one or a series of doses that may be given at the onset of therapy with the aim of achieving the target concentration rapidly. Maintenance dose: To maintain the chosen steady-state or target concentration, the rate of drug administration is adjusted such that the rate of input equals to rate of loss. V. Drug safety and effectiveness A. Factors modifying the dosage and action of drugs : Individuals differ both in the degree and the character of the response that a drug may elicit and therefore the optimum dose of a drug which produces the desired therapeutic effect varies from person to person. The important factors which influence the effect of a drug are: 19 1. Drug intolerance: It is a quantitative deviation from the anticipated response to a given dose of a drug. Thus drug intolerance is inability of the individual to tolerate a drug. It is also called as hypersusceptibility. 2. Sex difference: Special care should be exercised when drugs are administrated during menstruation, pregnancy and lactation. a) Menstruation: Drugs producing pelvic congestion should be avoided during menstruation e.g. drastic purgatives. b) Pregnancy: During pregnancy, the use of all drugs except those essential to maintain pregnancy should be used with caution. Drugs which may stimulate the uterine smooth muscle, are contraindicated during pregnancy. Further, many drugs administered to mother are capable of crossing the placenta and affecting the foetus. Most of drugs can produce teratogenicity when they are used in pregnancy. Teratogenicity means congenital malformation i) Drugs known to produce teratogenicity e.g thalidomide, cyclophosphamide, methotexate, tetracyclines, phenytoin, carbamazepine and progestogens. ii) drugs may be teratogenic e.g Warfarin, lithium, quinine, primaquine, trimethoprim, rifampicin, anaesthetic agents. c) Breast feeding: Nearly all agents received by mother are likely to be found in her milk and could theoretically harm the infant. Most of the lipid soluble drugs get into breast milk. Therefore the drugs, which are excreted in the milk and harm the infant health should be, avoided by breast-feeding mothers e.g. sulphonamides, tetracyclines, nalidixic acid, isoniazid, diazepam, lithium, Indomethacin, aspirin, etc. 3. Body Weight: The average dose is mentioned either in terms of mg per kg body weight or as the total single dose for an adult weighing between 50-100kg. However, dose expressed in this fashion may not apply in cases of excessively obese individuals or those suffering from edema, or dehydration nutritional factors can sometimes alter drug metabolizing capacity and this should be kept in mind in malnourished patients. 4. Age: The pharmacokinetics of many drugs changes with age. Thus gastric emptying is prolonged and the gastric pH fluctuates in neonates and infant, further the liver capacity to metabolize drugs is low, renal function is less developed and the proportion of body water is higher in the newborn and the neonates. Hence children may not react to all drugs in the same fashion as young adults. With a few exceptions, drugs are more active and more toxic in the new born than the adults. 20 The paediatric doses are expressed in terms of body weight (mg/kg per dose or day) or in terms of body surface area (mg/m2per day). The body surface area can be calculated from the height and weight of the child. Like children, old people also present problems in dosage adjustment and this may vary widely with different people. The metabolism of drugs may diminish in the elderly and the renal function declines with age. Elderly are sensitive to the drugs like hypnotics, tranquilizers, phenylbutazone, diazepam, pethidine, etc. i) Dose adjustment on the basis of age (young’s formula) Age in years____ x adult dose Age in years + 12 ii) Dose adjustment on the basis of body weight (Clark s formula) (1 Kg=2.2 pounds) Weight of child in pound x Adult dose 150 e.g. A 3 year old child having body weight of 30 pound requires to administer drug X. The adult dose is 100mg. So a) Using age of the child the dose will be 3 x 10 = 3 x100 = 20mg 3+12 15 b) Using body weight of the child it will be 30 x 100 = 1 x 100 = 20mg 150 5 5. Disease state: Some antimicrobial agents penetrate the cerebrospinal fluid well across the normal meninges while other antimicrobials penetrate well only when the meninges are inflammed (meningitis) e.g. sulphonamides, metronidazole, chloramphenicol, isoniazid and rifampicin penetrate well through the normal meninges and other antimicrobial agents like benzyl penicillin, ampicillin, tetracycline, streptomycin, gentamicin and cephalosporin penetrate only when the meninges are inflammed. Acute or chronic liver diseases markedly modify the rate and extent of biotransformation of drugs. The t1/2 of chlordiazepoxide and diazepam in patients with liver cirrhosis is greatly increased with corresponding prolongation of their effects. Cardiac disease by limiting blood flow to the liver may impair disposition of those drugs whose biotransformation is flow limited e.g. imipramine, isoniazid, lignocaine, morphine and propranolol. 21 Similarly renal and pulmonary diseases may modify the biotransformation of drugs like insulin or isoprenaline. Excretion of drug is impaired in chronic renal disease. 6. Pharmacogenetics: The science pharmacogenetics is concerned with the genetically- mediated variations in drug responses. Some examples of genetically mediated variations are: Acetylation and hydroxylation of drugs: The rate of acetylation of INH, dapsone, hydralazine procainamide and some sulfonamides is controlled by an autosomal recessive gene and the dosage of these drugs depends up on the acetylator status of individuals. 7) Drug interactions: It is usual for patients to receive a number of drugs at the same time. It is a phenomenon which occurs when the effects of one drug are modified by the prior or concurrent administration of another drug(s). A drug interaction may result in beneficial or harmful effects and may be classified into: a) Pharmaceutical drug interactions: Serious loss of potency can occur from incompatibility between an infusion fluid and a drug that is added to it. For example diazepam if added to infusion fluid there will be a precipitate formation → loss of therapeutic effect. b) Pharmacokinetic drug interactions: 1) Interaction during absorption: Drugs may interact in the gastrointestinal tract resulting in either decreased or increased absorption. e.g. Tetracycline + Calcium → Decreased absorption of tetracycline. 2) Interaction during distribution: A drug which is extensively bound to plasma protein can be displaced from its binding sites by another drug or displacement from other tissue binding sites. e.g. (i) Sulfonamide can be displaced by salicylates from plasma proteins and it leads to sulfonamide toxicity. (ii) Quinidine displaces digoxin from binding sites in tissues and plasma and leads to digoxin toxicity. 22 3) Interactions during biotransformation: This can be explained by two mechanisms: (i) Enzyme induction. (ii) Enzyme inhibition. (i) Enzyme induction: By this the biotransformation of drugs is accelerated and is a cause of therapeutic failure. If the drug A is metabolized by the microsomal enzymes, then concurrent administration with a microsomal inducer (drug B) will result in enhanced metabolism of drug A. e.g. Warfarin (anticoagulant) + Barbiturate (enzyme inducer) → decreased anticoagulation. Enzyme inducers: Rifampicine, phenytoin, sulfonamides, etc. (ii) Enzyme inhibition: By this the biotransformation of drugs is delayed and is a cause of increased intensity, duration of action and some times toxicity. e.g. Warfarin + Metronidazole (enzyme inhibitor) → Haemorrhage. Enzyme inhibitors: Disulfiram, isoniazid, allopurinol, cimetidine, etc. e) Interactions during excretion: Some drugs interacts with others at the site of excretion i.e. in kidneys. e.g. Penicillin (antibiotic) + Probenecid (antigout drug) → Increases the duration of action of penicillin (Both drugs excreted through tubular secretion). C. Pharmacodynamic interactions: (i) Drug Synergism: When the therapeutic effect of two drugs are greater than the effect of individual drugs, it is said to be drug synergism.It is of two types. (a) Additive effect: When the total pharmacological action of two or more drugs administered together is equivalent to the summation of their individual pharmacological actions is called additive effect. i.e A + B = AB e.g. Combination of ephedrine and aminophyllin in the treatment of bronchial asthma. (b) Potentiation effect: When the net effect of two drugs used together is greater than the sum of individual effects, the drugs are said to have potentiation effect. i.e AB > A + B e.g. Trimethoprim+sulfamethoxazole 23 (iii) Drug Antagonism: The phenomenon of opposing actions of two drugs on the same physiological system is called drug antagonism. a) Chemical antagonism: In this the biological activity of a drug can be reduced or abolished by a chemical reaction with another agent. e.g. Antagonism between acids and alkalis. b) Competitive or reversible antagonism: In this the agonist and antagonist compete for the same receptors and the extent to which the antagonist opposes the pharmacological action of the agonist. Competitive antagonism can be overcome by increasing the concentration of the agonist at the receptor site. e.g. Acetylcholine and atropine antagonism at muscarinic receptors. c) Non competitive antagonism: In this type of the antagonism an antagonist inactivates the receptor (R) so that the effective complex with the agonist cannot be formed, irrespective of the agonist concentration. e.g. Acetylcholine and papaverine on smooth muscle. Acetyl choline and decamethonium on neuromuscular junction. d) Physiological antagonism: When the physiological effect of a drug is antagonized by another drug by acting on two different types of receptors e.g. Acetyl choline causes constriction where as adrenaline causes dilatation of pupil. Importance of drug antagonism (i) Correcting adverse effects of drugs (ii) Treating drug poisoning. e.g. Morphine with naloxone, organophosphate compounds with atropine. (iii) Predicting drug combinations which would reduce drug efficacy. 8) Repeated administration and drug cumulation: If a drug is excreted slowly, its administration may build up a sufficiently high concentration in the body to produce toxicity. e.g. digitalis, emetine. To avoid cumulation. a) One must know if a drug is eliminated slowly or rapidly, b) Stop the drug administration at the appearance of the first warning symptoms c) Carefully select the form in which the drug is to be administered. 24 d) Check liver and kidney function before and during drug administration, as even an otherwise non-cumulative drug would produce cumulation in the presence of hepatic and renal damage. 9) Drug tolerance: When an unusually large dose of a drug is required to elicit an effect ordinarily produced by the normal therapeutic dose of the drug, the phenomenon is termed as drug tolerance. Tachyphylaxis: Rapid development of tolerance on repeated administration is called tachyphylaxis e.g. Ephedrine, amphetamine and nitroglycerine which produce tachyphylaxis on repeated administration. 10) Emotional factors. eg. Placebo response. Placebo: It is a Latin word meaning” I shall please” and it is a tablet looking exactly like the active treatment but containing no active component. It refers originally to substances merely to please the patient when no specific treatment was available. B. Adverse drug reactions: The drugs that produce useful therapeutic effect may also produce unwanted or toxic effects. It has been estimated that about 0.5% of patients who die in hospitals do so as a result of their treatment rather than the condition for which they were treated. Serious systemic drug toxicity may result from overdoses. If is always an exaggeration of its pharmacological actions and some times it is predictable. e.g. Hypotension following antihypertensive drugs. Hypoglycaemia following insulin. An adverse drug reaction is defined as any response to a drug that is noxious and unintended and that occurs at doses used in man for prophylaxis, diagnosis or therapy (WHO). The adverse effects are 1)Side effects 2)untoward effects 3)allergic reactions 4)idiosyncratic reactions and 5)teratogenic effects. 1) Side effects: Side effects are infact pharmacological effects produced with therapeutic dose of the drug. e.g: Dryness of mouth with atropine which is troublesome in peptic ulcer patients and useful when used as a preanaesthetic medication. 25 2) Untoward effects: Untoward effects develop with therapeutic dose of a drug. They are undesirable and if very severe, may necessitate the cessation of treatment. e.g: Diarrhoea with ampicillin and potassium loss with diuretics. 3) Allergic reactions: Most of the drugs and sera used in therapeutics are capable of causing allergic or hypersensitive reactions. These reactions may be mild or very severe like anaphylaxis. When an individual has been sensitized to an antigen (allergen) further contact with that antigen can some times lead to tissue damaging reactions. These allergic reactions are 4 types. Type-I reactions or anaphylactic reactions (Immediate hypersensitive reaction). Type-II reactions or cytotoxic reactions. Type-III reactions or immune complex mediated reactions. Type-IV reactions or cell mediated reactions (Delayed hypersensitive reactions). 4) Idiosyncratic reactions: The term idiosyncrasy means one’s peculiar response to drugs. With the increasing knowledge of pharmacogenetics, many idiosyncratic reactions have been found to be genetically determined. e.g: Drugs like primaquine, sulfonamides and dapsone may cause haemolysis in patients with glucose -6 phosphate dehydrogenase defeciency. 5) Teratogenic effect: Some drugs given in the first three months of pregnancy may cause congenital abnormalities and are said to be teratogenic. The best known example is thalidomide which results in early easily recognizable abnormalities such as absent or grossly abnormal limbs. Other drugs with teratogenic potential are androgens, steroids, anti convulsants, anti neoplastic drugs, cortisone, lithium, pencillamine, tricyclic antidepressants and warfarin. V) Development and evaluation of new drugs: The ultimate aim of pharmacological studies in animals is to find out a therapeutic agent suitable for clinical evaluation in man. No doubt, animal studies provide analogies and serve as useful models. The administration of biologically active agent to human beings is associated with an element of risk, which cannot be predicted by even the most careful and exhaustive animal experiments. Scientists all over the world are in a continuous effort to develop new drugs although drug development is an extremely technical and enormously expensive operation. Among the 26 contributors to new drug development, pharmacologists are more concerned in evaluating “new chemical entities” (NCE). Synthesis and evaluation of thousands of NCEs are usually necessary for new drugs to be introduced in the market. Research and development of new drugs have been done under strict government regulations which have greatly increased over the past couple of decades. Drug development comprises of two steps. a) Preclinical development and b) Clinical development A) Preclinical development: Synthesis of new chemical entities is done as per research policy decision which is based on: (i) Random synthesis (ii) Structure activity relationship (SAR) (iii) Biochemical and pharmacological insight and (iv) Chance finding. The aim of the preclinical development phase for a potential new medicine is to explore the drug’s efficacy and safety before it is administrated to patients. In this preclinical phase, varying drug doses are tested on animals and/or in vitro systems. If active compounds are found, then studies on animals are done which include pharmacodynamics, pharmacokinetics, toxicology and special toxicological studies (mutagenicity and carcinogenicity) have to be done. In this study single dose is used for acute toxicity and repeated doses for sub chronic and chronic toxicity studies. Most of the preclinical tests have to be conducted in accordance with the standards prescribed. B) Clinical development: About one in 1000 NCEs reach this stage. The steps to be studied in this stage include: a) Pharmaceutical study b) Pharmacological study c) Clinical trial. a) Pharmaceutical study covers stability of formulation and compatibility of the NCEs with other tablet or infusion ingredients. 27 b) Pharmacological study includes further chronic toxicological study in animal, initially animal metabolic and pharmacokinetic study. When studies in animals predict that a NCE may be useful medicine i.e. effective and safe in relation to its benefits, then the time has come to put it to the test in man i.e. clinical trial. c) Studies on human or Clinical Trial: Clinical trial is a means by which the efficacy of drug is tested on human being. It may also give some idea about the risk involved. It is divided into 4 phases. With each phase, the safety and efficacy of the compound are tested progressively. Phase - I: This is the first exposure of the new drug on man which is usually conducted in healthy volunteers and which is designed to test the tolerable dose, duration of action. This phase is usually carried out in only one centre on 20 to 50 subjects. Phase - II: This phase comprises small scale trials on patients used to determine dose level and establish that the treatment offers some benefit. It usually involves 100-500 patients and is usually conducted in several centres. Phase - III: Full scale evaluation of treatment comparing it with standard treatment is done in this phase. It involves randomised control trials on 250 to 2000 patients and is done in multiple centres. Information from all studies are received by the “Committee of safety of medicines” (CSM). If the drug is satisfied by the CSM, the product license is issued then the drug is marketed. Phase - IV: It is also called as phase of post marketing surveillance. Reports about efficacy and toxicity are received from the medical practitioners and reviewed by the committee of review of medicines. Renewal or cancellation of the product license depends on the comment of the review committee. 28 Exercise 1) What are different routes of drug administration and write about advantages and disadvantages of parenteral route of administration. 2) Define bio-availability and describe the factors affecting drug absorption. 3) Define the following: a) Half-life of a drug b) Steady state plasma concentration c) Adverse drug reactions 4) Write about the factors modifying drug action. 5) Write about different types of drug interactions. 29  CHAPTER TWO DRUGS ACTING ON THE AUTONOMIC NERVOUS SYSTEM Objectives After reading this chapter the students is expected to: Correctly identify the different classes of drugs affecting the autonomic nervous system(autonomic drugs) Discuss the effects and therapeutic uses of various drugs Identify side effects and contraindications of commonly used autonomic drugs. Prescribe autonomic drugs in clinical practice rationally. INTRODUCTION The nervous system controls all the major functions of the body. It is divided into central and peripheral nervous systems. The peripheral nervous system includes the somatic and autonomic nervous systems which control voluntary and involuntary functions respectively. The ANS controls the vegetative functions of the body. These include functions like circulation, respiration, digestion and the maintenance of body temperature. The ANS is subdivided into two major sub-divisions; this classification is based on both anatomic and physiologic grounds; the two subdivisions are sympathetic (thoracolumbar) and parasympathetic (craniosacral). Autonomic nerves are actually composed of two neuron systems, termed preganglionic and postganglionic, based on anatomical location relative to the ganglia. A preganglionic neuron has its cell body in the spinal cord or brain. The sympathetic nervous system arises from the thoracic and lumbar areas of the spinal cord and the preganglionic fibers for the parasympathetic nervous system arise from the cranial and sacral nerves. The postganglionic neurons send their axons directly to the effector organs (peripheral involuntary visceral organs). Autonomic innervation, irrespective of whether it belongs to the parasympathetic or the sympathetic nervous system, consists of a myelinated preganglionic fiber which forms a synapse with the cell body of a non-myelinated second neuron termed post-ganglionic fiber. The synapse is defined as a structure formed by the close apposition of a neuron either with another neuron or with effector cells. 30 In terms of function, the parasympathetic nervous system is concerned primarily with conservation and restoration of function. In contrast, the sympathetic nervous system is concerned with the expenditure of energy, i.e., it has almost opposite functions with parasympathetic nerve stimulation and it is usually associated with arousal or in emergency situations, i.e., prepares the body for fight-or-flight responses. To understand autonomic nervous system pharmacology, it is very important to know how the system works and clearly identify the mechanisms behind the functions, i.e., nerve transmission. 31 There are two important neurotransmitters in the autonomic nervous system. These are acetylcholine and noradrenaline (norepinephrine) Acetylcholine is a neurotransmitter which is released after stimulation of the parasympathetic nervous system to act on effector organs (cells) to elicit their response, but it also acts as a neurotransmitter: At the ganglia of both sympathetic and parasympathetic nervous system, At postganlionic sympathetic nerve endings to blood vessels of skeletal muscles and sweat glands(eccrine), At the neuromuscular junction of skeletal muscles (somatic motor fibers to skeletal muscle), Between some neurons in the CNS, and At preganglionic nerve endings to the adrenal medulla. The process of neurotransmission involves passage of an impulse across a synapse. Acetylcholine is synthesized inside the cytoplasm of nerve fibers from acetyl coenzyme A and choline through the catalytic action of the enzyme choline acetyltransferase. Once synthesized, it is transported form the cytoplasm into the vesicles to be stored; when action potential reaches the terminal and the latter undergoes stimulation, acetylcholine is released to the synaptic cleft. After release from the presynaptic terminal the molecule binds to and activates an acetylcholine receptor (cholinergic receptor) located on effector cell. Finally, it is hydrolyzed into choline and acetate by acetyl cholinesterase enzyme and thereby the action of the transmitter is terminated. Cholinergic receptors are classified into muscarinic and nicotinic cholinergic receptors. The response of most autonomic effector cells in peripheral visceral organs is typically muscarinic, whereas the responses in parasympathetic and sympathetic ganglia, as well as responses of skeletal muscle are nicotinic. The effect of parasympathetic nervous system activity in an organ may be produced either by stimulation of a parasympathetic nerve fibers supplying the organ or by the application of acetylcholine or other parasympathomimetics to the effector cells. This is known as cholinergic activity. Noradrenaline is the neurotransmitter released by post ganglionic sympathetic nerves to elicit its effect on effectors cells. The post-ganglionic sympathetic fibers are called noradrenergic or adrenergic. Sympathetic nerve activity may be demonstrated by sympathetic nerve stimulation or by application of noradrenaline or adrenaline or other sympathomimetics, i.e. ‘adrenergic 32 activity’, except in the case of sweat glands and blood vessels to skeletal muscles where acetylcholine is released as a neurotransmitter. Adrenergic neuron terminals synthesize noradrenaline, store it in vesicles and release it to effector cells upon stimulation of the nerve. The transmitter is synthesized from precursor tyrosine (amino acid) through several processes which are potential sites of drug action. After release to receptor sites noradrenaline produces its effects. Termination of noradrenergic transmission results from several processes such as reuptake into the nerve terminal (reuptake1), diffusion away from the synaptic cleft and subsequent reuptake into the perisynaptic glia or smooth muscle (reuptake2) or degradation by enzymes. Reuptake into the nerve terminal is the most important mechanism for termination of the effects of noradrenaline. Receptors that respond to adrenergic nerve transmitter are termed adrenergic receptors. These receptors are subdivided into alpha and beta adrenoreceptor types on the basis of both agonist and antagonist selectivity. The receptors have subclasses depending on drug selectivity. These are alpha 1 and 2 and beta 1, 2 and 3. Table 2.1: Distribution of adrenoceptor subtypes and their actions Type Tissue Actions Alpha1 Most vascular smooth muscles Contraction Pupillary dilator muscle Mydriasis Heart Increase force of contraction Alpha2 Adrenergic nerve terminals Inhibition of transmitter release Platelets Aggregation Beta1 Heart Increased rate and force of contraction Beta2 Respiratory, uterine, and Relaxation vascular smooth muscle Human liver Glycogenolysis Beta3 Fat cells Lipolysis 33 There are five key features of neurotransmitter function representing potential targets of pharmacologic therapy. These are synthesis, storage, release, activation of receptors and termination of the action of the transmitter. 34 Fig 2.3: Proposed site of action of drugs on the synthesis, action, and fate of norepinephrine at sympathetic neuroeffector junctions AUTONOMIC DRUGS There are several drugs affecting the autonomic nervous system which, for a better understanding of specific drugs, are classified into groups. 1. Drugs acting on the sympathetic nervous system a) Sympathomimetics or adrenergic drugs: are drugs that mimic the effects of sympathetic nerve stimulation. b) Sympatholytics: are drugs that inhibit the activity of sympathetic nerve or that of sympathomimetics. 2. Drugs acting on the parasympathetic nervous system a) Parasympathomimetics or cholinergic drugs: are drugs which mimic acetylcholine or the effects of parasympathetic nerve stimulation. b) Parasympatholytics: are drugs that inhibit parasympathetic nervous system activity or that of cholinergic drugs. 35 CHOLINERGIC DRUGS Cholinergic drugs are also called parasympathomimetics because their effect mimics the effect of parasympathetic nerve stimulation. Administration of these drugs will result in an increase in the parasympathetic activities in the systems innervated by cholinergic nerves. There are two groups of cholinergic drugs: 1. Direct-acting: bind to and activate muscarinic or nicotinic receptors (mostly both) and include the following subgroups: a. Esters of choline: methacholine, carbachol, betanechol b. Cholinergic alkaloids: pilocarpine, muscarine, arecoline, nicotine 2. Indirect-acting: inhibit the action of acetylcholinesterase enzyme a. Reversible: neostigmine, physostigmine, edrophonium b. Irreversible: Organophosphate compounds; echothiophate The actions of acetylcholine may be divided into two main groups: - 1. Nicotinic actions- those produced by stimulation of all autonomic ganglia and the neuromuscular junction 2. Muscarinic actions- those produced at postganglionic cholinergic nerve endings ESTERS OF CHOLINE ACETYLCHOLINE is the prototypical cholinergic agent. It functions as a neurotransmitter at all cholinergic sites in the body; because of its unique pharmacokinetic properties, it has never been used in medical therapeutics; the discussion which follows is for academic exercise. Pharmacokinetics Acetylcholine is poorly absorbed from the gastric mucosa; therefore it is ineffective if given orally. The recommended way of administration is parenteral. In the blood it is rapidly hydrolyzed by the enzyme cholinesterase into acetic acid and choline; this makes its duration of action very short and unreliable for therapeutic purposes. Pharmacodynamics As mentioned earlier it has two types of actions: nicotinic and muscarinic; the muscarinic actions are of main interest and are discussed below. ƒ Cardiovascular system HeartÆ slow heart rate 36 Blood vesselsÆ vasodilator Blood pressureÆ falls because of the effect on the heart and blood revels i) Gastrointestinal tract It stimulates the tone and motility of the Gl tract but the sphincters will be relaxed ii) Urinary tract It stimulates the detrusor muscle and relaxes the internal urethral sphincter resulting in evacuation of bladder iii) Bronchioles It increase bronchial secretion and brings about bronchoconstriction iv) Eye- It has two effects- miosis and accommodation for near objects because of stimulation of the constrictor pupillae and ciliary muscles respectively. v) Exocrine glands- it stimulates salivary, gastric, bronchial, lachrymal and sweat gland secretions. SYNTHETIC CHOLINE ESTERS. These are synthetic derivatives of choline and include metacholine, carbachol and betanechol. These drugs have the following advantages over acetylcholine: They have longer duration of action, They are effective orally as well as parenterally, and They are relatively more selective in their actions. CARBACHOL Pharmacokinetics It is completely absorbed from the gastro intestinal tract and is stable towards hydrolysis by cholinesterase enzyme; therefore it can be given both orally and parenteraly with almost similar dosage. Pharmacodynamics It has similar actions to those of acetylcholine with pronounced effects on the gastro intestinal tract and the urinary bladder Indications Glaucoma Retention of urine (postoperative) 37  Paralytic ileus BETANECHOL This drug is similar to carbachol in all parameters, i.e., pharmacokinetics, pharmacodynamics and clinical indications; it has a better advantage over carbachol because it has fewer side effects as a result as lack of nicotinic actions. Contra indications to the use of choline esters 1. Bronchial asthma because they may induce bronchial constriction and increase bronchial secretions 2. Hyperthyroidism because of the danger of inducing atrial fibrillation 3. Peptic ulcer disease because of the increase in gastric acid secretion 4. Coronary insufficiency because the hypertension produced will further compromise coronary blood flow 5. Mechanical intestinal and urinary outlet obstruction CHOLINERGIC ALKALOIDS 1. Those with chiefly nicotinic actions include nicotine, lobeline etc. 2. Those with chiefly muscarinic actions include muscarine, pilocarpine, etc. PILOCARPINE Pharmacokinetics This drug is readily absorbed from the gastrointestinal tract and it is not hydrolyzed by cholinesterase enzyme. It is excreted partly destroyed and partly unchanged in the urine. Pharmacodynamics The drug directly stimulates the muscarinic receptors to bring about all the muscarinic effects of acetylcholine. Indications Glaucoma ANTICHOLINESTERASE DRUGS The commonly used cholinesterase inhibitors fall into three chemical groups: 1. Simple alcohols bearing quaternary amines, e.g., edrophonium 2. Carbamate and related quaternary or tertiary amines, e.g., neostigmine, physostigmine 3. Organic derivatives of phosphates, e.g., isofluorophate, echothiophate 38 PHYSOSTIGMINE Pharmacokinetics This drug is completely absorbed from the gastrointestinal and is highly distributed throughout the body; it can pass the blood brain barrier. Pharmacodynamics Inhibits the enzyme cholinesterase; therefore, it increases and prolongs the effect of endogenous acetylcholine at the different sites.It has no direct effect on cholinergic receptors. Indications Glaucoma Atropine over dosage NEOSTIGMINE Pharmacokinetics This drug is poorly absorbed from the gastro intestinal tract and is poorly distributed throughout the body; it cannot pass the blood brain barrier. Pharmacodynamics Just like physostigmine, it inhibits cholinesterase enzyme; but unlike physostigmine, it has a direct nicotinic action on skeletal muscles. Indications Myasthenia gravis Paralytic Ileus Reversal of effect of muscle relaxants, e.g. tubocurarine Post operative urine retention Organophosphates such as echothiophate, isofluorophate, etc. combine with cholinesterase irreversibly and thus hydrolysis is very slow. They may be used in glaucoma. Other organophosphates like parathion and malathion are used as insecticides. Poisoning with organophosphates is an important cause of morbidity and mortality all over the world. It usually results from: Occupational exposure as in persons engaged in spraying insecticides, Accidental exposure, and 39  Ingestion of any of these compounds with suicidal intent. ANTICHOLINERGICS Anticholinergics block the effects of acetylcholine and other cholinergic drugs at cholinergic receptors of effector cells. Anticholinergics fall into two major families: 1. Antinicotinics which include ganglion blockers such as hexamethonium, trimethaphan, etc., and neuromuscular blockers such as gallamine, tubocurarine, pancuronium, etc. 2. Antimuscarinics include tertiary amines such as atropine, scopolamine, tropicamide, etc, andquaternary amines such as propantheline, ipratropium, benztropine, etc. ATROPINE Atropine is found in the plant Atropa belladonna and it is the prototype of muscarinic antagonists. Pharmacokinetics Atropine is absorbed completely from all sites of administration except from the skin wall, where absorption is for limited extent; it has good distribution. About 60% of the drug is excreted unchanged in urine. Pharmacodynamics Atropine antagonizes the effect of acetylcholine by competing for the muscarinic receptors peripherally and in the CNS; therefore the effects of atropine are opposite to the acetylcholine effects. Organ-system Effects: CNS: - lower doses produce sedation - higher doses produce excitation, agitation and hallucination Eyes: - relaxation of constrictor pupillae (mydriasis) - relaxation or weakening of ciliary muscle (cycloplegia-loss of the ability to accommodate) CVS: - blocks vagal parasympathetic stimulation (tachycardia) - vasoconstriction Respiratory: - bronchodilatation and reduction of secretion GIT: - decreased motility and secretions GUS: - Relaxes smooth muscle of ureter and bladder wall; voiding is slowed. Sweat Glands: - suppresses sweating 40 Clinical Indications Pre anesthetic medication -to reduce the amount of secretion and to prevent excessive vagal tone due to anesthesia. As antispasmodic in cases of intestinal, biliary, and renal colic Heart block Hyperhidrosis Organophosphate poisonings Side effects Dryness of the mouth, tachycardia and blurred vision Retention of urine Contraindications Glaucoma Bladder outlet obstruction. HYOSCINE (SCOPOLAMINE) This drug has the same effect as atropine except for some differences which includes:- - It has shorter duration of action - It is more depressant to the CNS. - All other properties are similar to atropine. It has certain advantage over atropine. These include: 3. Better for preanesthetic medication because of strong antisecretory and antiemetic action and also brings about amnesia 4. Can be used for short- travel motion sickness SYNTHETIC ATROPINE DERIVATIVES There are a number of synthetic atropine derivatives, which are used in the treatment of various conditions, their actions are similar to that of atropine but have fewer side effects. These groups of drugs include 1. Mydriatic atropine substitutes, this group of drugs have shorter duration of action than atropine and are used locally in the eye; drugs included: Homatropine, Eucatropine etc. 2. Antiseccretory antispasmodic atropine substitutes: - Effective more localized to the Gl. Drugs include: propantheline and hyoscine