Pharmacology-I Textbook PDF

 A Text Book Of PHARMACOLOGY - I As Per PCI Regulations SECOND YEAR B. PHARM. Semester - IV Dr. S. B. Bhise Mrs. M. S. B...

 A Text Book Of PHARMACOLOGY - I As Per PCI Regulations SECOND YEAR B. PHARM. Semester - IV Dr. S. B. Bhise Mrs. M. S. Bhise Ex. Principal, Ex. Hon. Lecturer, Govt. College of Pharmacy Government College of Pharmacy, and Director of KARAD. LNBC Institute of Pharmacy Raigon, SATARA KLK Consultants Pune. Sowmya B.A. M. Pharm. Assistant Professor East West College of Pharmacy Bengaluru. N4360 Pharmacology - I ISBN 978-93-88293-84-6 First Edition : January 2019 © : Authors The text of this publication, or any part thereof, should not be reproduced or transmitted in any form or stored in any computer storage system or device for distribution including photocopy, recording, taping or information retrieval system or reproduced on any disc, tape, perforated media or other information storage device etc., without the written permission of Authors with whom the rights are reserved. Breach of this condition is liable for legal action. Every effort has been made to avoid errors or omissions in this publication. In spite of this, errors may have crept in. Any mistake, error or discrepancy so noted and shall be brought to our notice shall be taken care of in the next edition. It is notified that neither the publisher nor the authors or seller shall be responsible for any damage or loss of action to any one, of any kind, in any manner, therefrom. Published By: Polyplate NIRALI PRAKASHAN Abhyudaya Pragati, 1312, Shivaji Nagar Off J.M. Road, Pune – 411005 Tel - (020) 25512336/37/39, Fax - (020) 25511379 Email : [email protected] DISTRIBUTION CENTRES PUNE Nirali Prakashan : 119, Budhwar Peth, Jogeshwari Mandir Lane, Pune 411002, Maharashtra (For orders within Pune) Tel : (020) 2445 2044, 66022708, Fax : (020) 2445 1538; Mobile : 9657703145 Email : [email protected] Nirali Prakashan : S. 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Mob : 9850046155; Email : [email protected] NAGPUR Pratibha Book Distributors : Above Maratha Mandir, Shop No. 3, First Floor, Rani Jhanshi Square, Sitabuldi, Nagpur 440012, Maharashtra Tel : (0712) 254 7129; Email : [email protected] DELHI Nirali Prakashan : 4593/15, Basement, Agarwal Lane, Ansari Road, Daryaganj Near Times of India Building, New Delhi 110002 Mob : 08505972553 Email : [email protected] BENGALURU Nirali Prakashan : Maitri Ground Floor, Jaya Apartments, No. 99, 6th Cross, 6th Main, Malleswaram, Bengaluru 560003, Karnataka; Mob : 9449043034 Email: [email protected] Other Branches : Hyderabad, Chennai Note : Every possible effort has been made to avoid errors or omissions in this book. In spite this, errors may have crept in. Any type of error or mistake so noted, and shall be brought to our notice, shall be taken care of in the next edition. It is notified that neither the publisher, nor the author or book seller shall be responsible for any damage or loss of action to any one of any kind, in any manner, therefrom. The reader must cross check all the facts and contents with original Government notification or publications. [email protected] | www.pragationline.com Also find us on www.facebook.com/niralibooks Acknowledgement We are extremely thankful to Mrs. Roshan Shaikh and Mrs. Manasi Pingle for technical editing of the content of the book. Encouragement from Prof. S. B. Gokhale and support from Mr. Jignesh Furia is kindly acknowledged. We are thankful to Mr. Sameer Tuli for his able assistance. Nirali Prakashan and their employees are acknowledged for their active support in bringing out the book at an appropriate time. Dr. S. B. Bhise Mrs. M. S. Bhise Mrs. Sowmya B. A. Preface Clinical role of pharmacists have been identified during last 9 years after establishment of regulations for Pharm. D in 2008 followed by establishment of Pharmacy practice regulations in 2015 by Pharmacy Council of India. The practice of Pharmacy needs some time to get strong footing in our country. During such time, subject like Pharmacology-I need strong base by budding pharmacists. The subject of Pharmacology has a different context for pharmacists in comparison to doctors. While doctors give more importance to clinical effects, pharmacists are more concerned with mechanism of action, and effects of drugs on animals can have equal relevance in case of pharmacists. Trade names have equal relevance to both doctors and pharmacists. This approach has been reflected in the content. Strong background of physiology is needed for understanding of Pharmacology-I. Trade names of drugs have been included in the appendix. The list is not exhaustive but includes common tradenames. The content is as per new regulations of PCI and contains several additions as compared to syllabi of conventional universities. It is expected that the book will be welcomed by teachers and students of pharmacy. Still if there is any constructive criticism, it will be appreciated and considered while revising next edition of the book. We appeal to all the readers to forward their suggestions on the contents of the book. Dr. S. B. Bhise Mrs. M. S. Bhise Mrs. Sowmya B. A. Syllabus Unit I [08 Hours] 1. General Pharmacology (a) Introduction to Pharmacology: Definition, historical landmarks and scope of pharmacology, nature and source of drugs, essential drugs concept and routes of drug administration, Agonists, antagonists (competitive and non competitive), spare receptors, addiction, tolerance, dependence, tachyphylaxis, idiosyncrasy, allergy. (b) Pharmacokinetics: Membrane transport, absorption, distribution, metabolism and excretion of drugs. Enzyme induction, enzyme inhibition, kinetics of elimination Unit II [12 Hours] General Pharmacology (a) Pharmacodynamics: Principles and mechanisms of drug action. Receptor theories and classification of receptors, regulation of receptors. drug receptors interactions signal transduction mechanisms, G-protein–coupled receptors, ion channel receptor, trans-membrane enzyme linked receptors, trans-membrane JAK-STAT binding receptor and receptors that regulate transcription factors, dose response relationship, therapeutic index, combined effects of drugs and factors modifying drug action. (b) Adverse drug reactions. (c) Drug interactions (pharmacokinetic and pharmacodynamic) (d) Drug discovery and clinical evaluation of new drugs: Drug discovery phase, preclinical evaluation phase, clinical trial phase, phases of clinical trials and pharmacovigilance. Unit III [10 Hours] 2. Pharmacology of drugs acting on peripheral nervous system (a) Organization and function of ANS. (b) Neurohumoral transmission, co-transmission and classification of neurotransmitters. (c) Parasympathomimetics, Parasympatholytics, Sympathomimetics, sympatholytics. (d) Neuromuscular blocking agents and skeletal muscle relaxants (peripheral). (e) Local anesthetic agents. (f) Drugs used in myasthenia gravis and glaucoma Unit IV [08 Hours] 3. Pharmacology of drugs acting on central nervous system (a) Neurohumoral transmission in the C.N.S.special emphasis on importance of various neurotransmitters like with GABA, Glutamate, Glycine, serotonin, dopamine. (b) General anesthetics and pre-anesthetics. (c) Sedatives, hypnotics and centrally acting muscle relaxants. (d) Anti-epileptics (e) Alcohols and disulfiram Unit V [07 Hours] 4. Pharmacology of drugs acting on central nervous system (a) Psychopharmacological agents: Antipsychotics, antidepressants, anti-anxiety agents, anti-manics and hallucinogens. (b) Drugs used in Parkinsons disease and Alzheimer’s disease. (c) CNS stimulants and nootropics. (d) Opioid analgesics and antagonists (e) Drug addiction, drug abuse, tolerance and dependence. Contents 1. General Pharmacology - I 1.1 - 1.40 1.1 Introduction to Pharmacology 1.1 1.1.1 Definitions 1.1 1.1.2 Historical Landmarks and Scope of Pharmacology 1.10 1.1.2.1 Historical Landmarks 1.10 1.1.2.2 Scope of Pharmacology 1.12 1.1.3 Nature and Sources of Drugs 1.13 1.1.4 Essential Drugs Concept 1.14 1.1.5 Routes of Drug Administration 1.14 1.1.6 Agonists 1.20 1.1.7 Antagonists (Competitive - Non-competitive) 1.20 1.1.7.1 Competitive Antagonists 1.21 1.1.7.2 Non-competitive Antagonists 1.21 1.1.7.3 Uncompetitive Antagonists 1.21 1.1.8 Spare Receptors 1.22 1.1.9 Addiction 1.23 1.1.10 Tolerance 1.23 1.1.11 Dependence 1.24 1.1.12 Tachyphylaxis 1.24 1.1.13 Idiosyncrasy 1.24 1.1.14 Allergy 1.24 1.2 Pharmacokinetics 1.25 1.2.1 Membrane Transport 1.25 1.2.2 Absorption 1.28 1.2.3 Distribution 1.30 1.2.4 Metabolism 1.32 1.2.5 Excretion 1.33 1.2.6 Enzyme Induction 1.34 1.2.7 Enzyme Inhibition 1.36 1.2.8 Kinetics of Drug Elimination 1.37 Questions 1.39 2. General Pharmacology - II 2.1 - 2.36 2.1 Pharmacodynamics 2.1 2.1.1 Principles and Mechanisms of Drug Action 2.1 2.1.2 Receptor Theories 2.3 2.1.3 Classification of Receptors 2.3 2.1.4 Regulation of Receptors 2.4 2.1.5 Drug-Receptor Interaction 2.5  2.1.6 Signal Transduction Mechanisms 2.7 2.1.7 G-protein Coupled Receptors 2.9 2.1.8 Ion-channel Receptors 2.12 2.1.9 Trans-Membrane Linked Receptors 2.15 2.1.10 JAK-STAT Binding Receptor 2.16 2.1.11 Receptors Regulating Transcription Factors 2.18 2.1.12 Dose-Response Relationship (DRR) 2.20 2.1.13 Therapeutic Index (TI) 2.22 2.1.14 Combined Effects of Drugs 2.22 2.1.15 Factors Modifying Drug Action 2.23 2.2 Adverse Drug Reactions (ADRs) 2.23 2.3 Drug Interactions (Pharmacokinetic and Pharmacodynamic) 2.24 2.3.1 Pharmacokinetic Drug Interactions 2.24 2.3.1.1 Absorption Interactions 2.24 2.3.1.2 Transport and Distribution Interactions 2.24 2.3.1.3 Metabolism Interactions 2.25 2.3.1.4 Excretion Interactions 2.26 2.3.2 Pharmacodynamic Drug Interactions 2.27 2.4 Drug Discovery and Clinical Evaluation of New Drugs 2.27 2.4.1 Drug Discovery 2.27 2.4.2 Pre-clinical Evaluation 2.28 2.4.3 Phases of Clinical Trial 2.29 2.4.3.1 Phase 0 2.29 2.4.3.2 Phase I 2.29 2.4.3.3 Phase II 2.30 2.4.3.4 Phase III 2.30 2.4.3.5 Phase IV 2.31 2.4.4 Pharmacovigilance 2.32 Questions 2.35 3. Pharmacology of Peripheral Nervous System 3.1 - 3.80 3.1 Introduction 3.1 3.2 Organisation and Functions of Autonomic Nervous System (ANS) 3.2 3.2.1 Organisation of ANS 3.2 3.2.1.1 Somatic Nervous System 3.2 3.2.1.2 Autonomic Nervous System (ANS) 3.3 3.2.2 Functions of ANS 3.6 3.3 Neuro-humoral Transmission, Co-transmission and Classification of Neuro- transmitters 3.9 3.3.1 Neuro-humoral Transmission and Co-transmission 3.9 3.3.2 Classification of Neurotransmitters 3.10  3.4 Parasympathomimetics, Parasympatholytics 3.10 3.4.1 Biosynthesis, Storage and Release of ACh 3.10 3.4.2 Parasympathomimetics 3.15 3.4.3 Parasympatholytics 3.20 3.5 Sympathomimetics and Sympatholytics 3.28 3.5.1 Endogenous Sympathomimetics 3.28 3.5.1.1 Endogenous 3.28 3.5.1.2 Synthetic Sympathomimetics 3.36 3.5.1.2.1 Directly Acting Sympathomimetics 3.36 3.5.1.2.2 Indirectly Acting Sympathomimetics 3.46 3.5.1.2.3 Mixed Action Sympathomimetics 3.49 3.5.2 Sympatholytics 3.50 3.5.2.1 α-Adrenergic Blockers 3.50 3.5.2.2 β-Adrenergic Blockers 3.54 3.6 Neuro-muscular Blocking Agents and Skeletal Muscle Relaxants (Peripheral) 3.62 3.6.1 Neuromuscular Blocking Agents 3.62 3.6.2 Peripheral Skeletal Muscle Relaxants 3.68 3.7 Local Anaesthetic Agents 3.69 3.8 Drugs used in Myasthenia Gravis and Glaucoma 3.75 3.8.1 Drugs for Myasthenia Gravis 3.75 3.8.2 Drugs for Glaucoma 3.76 Questions 3.78 4. Pharmacology of Central Nervous System - I 4.1 - 4.44 4.1 Organisation of CNS 4.1 4.2 Neuro-humoral Transmission in the CNS, Special Emphasis on Importance of Various Neurotransmitters like GABA, Glutamate, Glycine, Serotonin, Dopamine 4.3 4.2.1 Neurohumoral Transmission in the CNS 4.3 4.2.2 GABA 4.4 4.2.2.1 GABAA Receptors 4.4 4.2.2.2 GABAB Receptors 4.5 4.2.3 Glutamate 4.5 4.2.3.1 NMDA Receptors 4.6 4.2.3.2 AMPA and Kainate Receptors 4.7 4.2.4 Glycine 4.7 4.2.5 Serotonin (5-Hydroxytryptamine, 5-HT) 4.7 4.2.6 Dopamine (DA) 4.10  4.3 General Anaesthetics and Pre-anaesthetics 4.11 4.3.1 Stages of Anaesthesia 4.11 4.3.2 General Anaesthetics 4.12 4.3.2.1 Specific Inhalation Anaesthetics 4.13 4.3.2.2 Specific Intravenous Anaesthetics 4.16 4.3.2.3 Dissociative Anaesthetic - Ketamine 4.17 4.3.3 Pre-Anaesthetics 4.18 4.4 Sedatives, Hypnotics and Centrally Acting Muscle Relaxants 4.18 4.4.1 Sedatives and Hypnotics 4.18 4.4.2 Centrally Acting Skeletal Muscle Relaxants (Spasmolytics) 4.25 4.5 Anti-epileptics 4.27 4.5.1 Classification of Seizures 4.27 4.5.2 Mechanism of Action of Anti-Epileptic Drugs 4.29 4.5.3 Individual Drugs 4.30 4.6 Alcohol and Disulfiram 4.38 4.6.1 Alcohol (Ethyl Alcohol/Ethanol) 4.38 4.6.1.1 Pharmacological Effects (Acute) 4.38 4.6.1.2 Pharmacological Effects (Chronic) 4.40 4.6.1.3 Treatment of Acute and Chronic Alcoholism 4.41 4.6.2 Drug Interactions 4.42 4.6.3 Clinical Uses of Ethanol 4.42 4.6.4 Disulfiram 4.42 Questions 4.43 5. Pharmacology of Central Nervous System - II 5.1 - 5.40 5.1 Psycho-pharmacological Agents: Anti-psychotics, Anti-depressants, Anti-anxiety agents, Anti-maniacs and Hallucinogens 5.1 5.1.1 Antipsychotics 5.1 5.1.1.1 Classification of Antipsychotics 5.2 5.1.1.2 Mechanism of Action 5.2 5.1.1.3 Therapeutic Uses 5.2 5.1.1.4 Adverse Effects 5.3 5.1.1.5 Drug Interactions 5.4 5.1.2 Anti-Depressants 5.6 5.1.2.1 Classification 5.6 5.1.2.2 Mechanism of Action 5.6 5.1.2.3 Pharmacokinetics 5.7 5.1.2.4 Therapeutic Uses 5.8 5.1.2.5 Adverse Effects 5.8 5.1.2.6 Drug Interactions 5.9 5.1.3 Anti-anxiety Agents 5.11 5.1.4 Anti-maniacs 5.12 5.1.5 Hallucinogens 5.13 5.2 Drugs used in Parkinson’s Disease and Alzheimer’s Disease 5.16 5.2.1 Drugs for Parkinson’s Disease 5.16 5.2.1.1 Drugs which Increase Dopamine Levels 5.17 5.2.1.2 Drugs which Prevent Dopamine Degradation 5.19 5.2.1.3 Drugs which Stimulate Dopamine Receptors 5.19 5.2.1.4 Drugs which Restore DA-ACh Balance 5.20 5.2.2 Drugs for Alzheimer’s Disease (AD) 5.21 5.3 CNS Stimulants and Nootropics 5.22 5.3.1 CNS Stimulants 5.22 5.3.1.1 Methylxanthines 5.24 5.3.2 Nootropics 5.26 5.4 Opioid Analgesics and Antagonists 5.27 5.4.1 Pathophysiology of Pain 5.27 5.4.2 Endogenous Opioid Peptides 5.29 5.4.3 Opioid Receptors 5.29 5.4.4 Opioid Analgesics 5.29 5.4.5 Morphine Related Drugs (Opioids) 5.32 5.4.6 Opioid Antagonists 5.34 5.5 Drug Addiction, Drug Abuse, Tolerance and Dependence 5.36 5.5.1 Drug Addiction 5.37 5.5.2 Drug Abuse 5.37 5.5.3 Drug Tolerance 5.37 5.5.4 Drug Dependence 5.37 5.5.5 Treatment of Drug Dependence 5.38 Questions 5.38 Appendix A.1 - A.18 Unit... Unit... 1 GENERAL PHARMACOLOGY - I ♦ LEARNING OBJECTIVES ♦ After completing this chapter, student should be able to understand: History, Landmarks and Scope of Pharmacology Nature and Sources of Drugs Concept of Essential Drugs Basic Concepts of Agonists, Antagonists, Spare Receptors Special terms like Addiction, Tolerance, Dependence, Allergy etc. Concepts of Pharmacokinetics involving ADME Enzyme Induction, Inhibition and Kinetics 1.1 INTRODUCTION TO PHARMACOLOGY 1.1.1 Definitions Active ingredient (Active Substance, Compound, Active Pharmaceutical Ingredient) Ingredient that alone or in combination with one or more other ingredients is considered to fulfil the intended activity of a medicine. Acute care A type of health care in which a patient is treated for an acute (immediate and severe) episode of illness, for the subsequent treatment of injuries related to an accident or other trauma, or during recovery from surgery. Adherence The extent to which a person’s behaviour - taking medication, following a diet, and/or executing life-style changes, corresponds with agreed recommendations from a health care provider. Adverse reaction A response to a reaction which is noxoious and unintended and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease or for the restoration, correction or modification of physiological function. Batch (Lot) A specific quantity of material produced in a process or series of processes so that it is expected to be homogenous within specified limits. In the case of continuous production, a batch may correspond to a defined fraction of the production. The batch size can be defined either by a fixed quantity or by the amount produced in a fixed time interval. (1.1) Pharmacology - I (B.Pharm. Sem. IV) 1.2 General Pharmacology - I Bioavailability It is defined as, "the rate and extent to which the active substance or active moiety is absorbed from a pharmaceutical form and becomes available at the site of action". Bioequivalence Two medicines are bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and if their bioavailabilities after administration in the same molar dose are similar to such degree that their effects, with respect to both efficacy and safety, will be essentially the same. Biological marker (Biomarker) A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. Biological medicine It is a product, the active substance of which is a biological substance. Bio-similar It is defined as, "a biological medicine that is developed to be similar to an existing biological medicine (the “reference medicine”)". Biosimilar medicines can only be marketed following the patent expiry of reference medicine. Brand Name (Innovator’s Name/Proprietary Product Name/Medicine Speciality Product Name/Medicinal Product Speciality Name) It is the name given for marketing purposes to any ready-prepared medicine placed on the market under a special name and in a special pack. A brand name may be a protected trade mark. Bulk product It is defined, "as any product that has completed all processing stages up to, but not including, final packaging". Burden of disease It is a measurement of the gap between a population’s current health and the optimal state where all people attain full life expectancy without suffering major ill-health. Chronic care The ongoing provision of medical, functional, psychological, social, environmental and spiritual care services that enable people with serious and persistent health and/or mental conditions to optimize their functional independence and well-being, from the time of condition onset until problem resolution or death. Chronic condition (Chronic Disease) A disease which has one or more of the following characteristics: is permanent; leaves residual disability; is caused by no reversible pathological alteration; requires special training of the patient for rehabilitation; or may be expected to require a long period of supervision, observation or care. Pharmacology - I (B.Pharm. Sem. IV) 1.3 General Pharmacology - I Clinical pharmacology It is defined as, "the study of effects of the pharmaceuticals in humans". Clinical trial (Clinical study) Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or the pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy. Combination product It is defined as, "a medicine that contains more than one active ingredient". Community care Services and support to help people with care needs to live as independently as possible in their communities. (Considered as synonym for the out-patient health care sector in contract to the hospital sector). Community pharmacy It is defined as, "health care facility dispensing medicines (prescription-only medicines/ POM and Over-the-Counter/OTC medicines), reimbursable and non-reimbursable medicines to out-patients". Co-morbid condition (co-morbidity) It is defined as, "conditions that exist at the same time as the primary condition in the same patient. Two or more conditions may interact in such a way as to prolong a stay in hospital or hinder successful rehabilitation". Complication A medical condition that arises during a course of treatment and is expected to increase the length of stay by at least one day for most patients. Cost-benefit analysis It compares the cost of a medicinal intervention to its benefit. Both costs and benefits must be measured in the same monetary units (e.g. Rupees, Euro or Dollars). Cost-effectiveness It is defined, "as value for money". A specific health care treatment is said to be ‘cost- effective’ if it gives greater health gain than could be achieved by using the resources in other ways. Counterfeit medicine It describes a product with a false representation of its identity and/or source. This applies to the product, its container or other packaging or labelling information. Counterfeiting can apply to both branded and generic medicines. Defined daily dose (DDD) The DDD is a unit of measurement defined as, "the assumed average maintenance dose per day for a pharmaceutical used for its main indication in the adult". Pharmacology - I (B.Pharm. Sem. IV) 1.4 General Pharmacology - I Disability-Adjusted Life Years (DALYs) It is defined as, "a measure of the burden of the disease on a defined population and the effectiveness of the intervention". DALYs are advocates as an alternative to Quality Adjusted Life Years (QALY) and claimed to be a valid indicator of population health. Disease A failure of the adaptive mechanisms of an organism to counteract adequately, normally or appropriately to stimuli and stresses to which the organism is subjected, resulting in a disturbance in the function or structure of some part of the organism. Dispensing To supply a clinically appropriate medicine to a patient or care giver, usually against a written prescription, for self-administration by another professional, and to advise on safe and effective use. Drug utilisation research It is defined as, "the research on marketing, distribution, prescription, and use of medicines in a society, with special emphasis on the resulting medical, social and economic consequences". Effectiveness It is the extent to which an intervention does more good than harm when provided under the usual circumstances of health care practice. Efficacy It is the extent to which an intervention does more good than harm under ideal circumstances. Emergency Sudden unexpected onset of illness or injury which requires the immediate care and attention of a qualified physician, and which, if not treated immediately, would jeopardise or impair the health of the individual. Essential medicines These are the medicines that satisfy the priority healthcare needs of the population. They are selected with due regard to public health relevance, evidence on efficacy and safety, and comparative cost effectiveness. Excepient A substance, other than the active ingredient, which has been appropriately evaluated for safety and is included in a medicine delivery system to: o Aid in the processing of the medicine delivery system during its manufacture; o Protect, support or enhance stability, bioavailability, or patient acceptability; o Assist in product identification; or o Enhance any other attribute of the overall safety and effectiveness of the medicine during storage or use. Pharmacology - I (B.Pharm. Sem. IV) 1.5 General Pharmacology - I Fixed dose combination (FDC) product It is defined as, "a combination of two or more active substances in a fixed ratio of doses". It may be administered as single entity products given concurrently or as a finished pharmaceutical product. Generic (Generic medicine) A pharmaceutical product (medicine) which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicine, and whose bioequivalence with the reference medicine has been demonstrated by appropriate bioavailability studies. Generic substitution Practice of substituting a medicine, whether marketed under a trade name or a generic name (branded or unbranded generic), with a less expensive medicine (e.g. branded or unbranded generic), often containing the same active ingredient(s). Good clinical practice (GCP) A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and the reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected. Good distribution practices (GDP) This is that part of quality assurance which ensures that the quality of a pharmaceutical product is maintained through adequate control throughout the numerous activities which occur during the distribution process. Good manufacturing practices (GMP) This is that part of quality assurance which ensures that pharmaceutical products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorisation. Haemovigilance It is defined as, "a set of organised surveillance procedures relating to serious adverse or unexpected events or reactions in donors or recipients of blood products, and the epidemiological follow-up of donors". Health It is defined as, "a state of complete physical, social and mental well-being, and not merely the absence of disease or infirmity". Herbal medicine It is defined as, "any medicine, exclusively containing as active ingredients, one or more herbal substances or one or more herbal preparations, or one or more such herbal substances in combination with one or more such herbal preparations". Herbal substances They are defined as, "whole, fragmented or cut plants, plant parts, algae, fungi, lichen in an unprocessed, usually dried form, but sometimes fresh". Certain exudates that are not being subjected to a specific treatment are also considered to be herbal substances. Pharmacology - I (B.Pharm. Sem. IV) 1.6 General Pharmacology - I Herbal preparations They are defined as, "preparations obtained by subjecting herbal substances to treatments such as extraction, distillation, expression, fractionation, purification, concentration or fermentation". These include comminuted or powdered herbal substances, tinctures, extracts, essential oils, express juices and processed exudates. Home care It comprises medical and paramedical services delivered to patients at home. Homeopathic medicines Any medicine prepared from substances called homeopathic stocks in accordance with a homeopathic manufacturing procedure described by the European Pharmacopoeia or, in the absence thereof, by the Pharmacopoeias currently used officially in the Member States. Hospice (Hospice care) It is defined as, "a facility or a programme providing care for the terminally ill". Hospital pharmacists Health care professionals who provide services to patients and health care professionals in hospitals are called as hospital pharmacists. Hospital pharmacy It is the health care service, which comprises the art, practise, and profession of choosing, preparing, storing, compounding and dispensing pharmaceuticals and medical devices, advising health care professionals and patients on their safe, effective and efficient use. Illness A person’s own perceptions, experience and evaluation of a disease or condition, or how he or she feels is called as illness; e.g. an individual may feel pain, discomfort, weakness, depression or anxiety, but a disease may or may not be present. Infusion Administration, from a syringe or other rigid or collapsible container e.g. plastic bag, of a volume of sterile solution of an injectable medicine directly into a tissue, organ, vein or artery, at a constant rate, under gravity or by means of an electronic or mechanical pump or other means of rate control, over a defined period usually of at least 10 minutes is called as infusion. In-patient care An in-patient is a patient who is formally admitted (or hospitalised) to an institution for treatment and/or care and stays for a minimum of one night in the hospital or other institution providing in-patient care. In-patient care is delivered in hospitals, or in nursing and residential care facilities or in other establishments. International Non-proprietary Name (INN, Generic name) The shortened scientific name based on the active ingredient is called as INN. WHO is responsible for assigning INNs to pharmaceutical substances. INN is a unique name that is globally recognised and is public property. Pharmacology - I (B.Pharm. Sem. IV) 1.7 General Pharmacology - I Internet pharmacy (Online pharmacy) It is an umbrella term for retailers of prescription-only medicines (POM) and Over-the- Counter (OTC) medicines who sell their products via World Wide Web. Life expectancy A statistical abstraction based on existing age-specific death rates is termed as life expectancy. Medical device A medical device is any instrument, apparatus, appliance, software, material or other article, whether used alone or in combination, including the software intended by its manufacturer to be used specifically for diagnostic and/or therapeutic purposes and necessary for its proper application, intended by its manufacturer to be used for human beings for the purpose of: o Diagnosis, prevention, monitoring, treatment or alleviation of disease, diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap; o Investigation, replacement or modification of the anatomy or of a physiological process; o Control of conception, and which does not achieve its principle intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means. Medication error Any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professional, patient, or consumer, is termed as medication error. Medicine (Pharmaceutical, Pharmaceutical product, Medication, Medicinal product) (a) Any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or (b) Any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis is termed as medicine. Mortality rate An estimate of the proportion of a population that dies during a specified period is called as mortality rate. Out-patient An out-patient is a person who goes to a health care facility for a consultation/ treatment, and who leaves the facility within several hours of the start of the consultation without being admitted to the facility as a patient. Out-patient care (Ambulatory care, Community care) It comprises of medical and para-medical services delivered to out-patients. Pharmacology - I (B.Pharm. Sem. IV) 1.8 General Pharmacology - I Palliative care The active total care offered to a person and that person’s family when it is recognised that the illness is no longer curable, in order to concentrate on the person’s quality of life and the alleviation of distressing symptoms is called as palliative care. Patent It is a set of exclusive rights granted by a state (National Government) to an inventor or their assignee for a limited period of time in exchange for public disclosure for its invention. Pharmaceutical alternatives Medicines are pharmaceutical alternatives if they contain the same active moiety but differ in chemical form (salt, ester etc.) of that moiety in the dosage form or strength. Pharmaceutical care It is the responsible provision of medicine therapy for the purpose of achieving definite outcomes that improve a patient’s quality of life. These outcomes are: o Cure of a disease o Elimination or reduction of a patients’ symptomatology o Arresting or slowing of a disease process; or o Preventing a disease or symptomatology. Pharmaceutical equivalence Medicines are pharmaceutically equivalent if they contain the same amount of the same active substance(s) in the same dosage forms that meet the same or comparable standards. Pharmacovigilance It is the process and science of monitoring the safety of medicines and taking action to reduce risks and increased benefits from medicines. It comprises of: o Collecting and managing data on safety of medicines, o Looking at the data to detect signals (any new or changing safety issue), evaluating the data and making decisions with regard to safety issues, o Acting to protect public health (including regulatory action); communicating with stakeholders, o Audit, both the outcomes of action taken and of the key processes involved. Polypharmacy The administration of many medicines at the same time or the administration of excessive number of medicines is called as polypharmacy. Quality-Adjusted Life Years (QALYs) It is a measure of health outcome which looks at both length of life and quality of life. QALYs are calculated by estimating the years of life remaining for a patient following a particular care pathway and weighing each year with a quality of life score (on a zero to one scale). One QALY = one year of life in perfect health, or two years at 50% health, and so on. Pharmacology - I (B.Pharm. Sem. IV) 1.9 General Pharmacology - I Rational use of medicines It requires that, patients receive medications appropriate to their clinical needs, in doses that meet their own individual requirements, for an adequate period of time, and at the lowest cost to them and their community. Reference product (Reference medicine) A medicine which has been granted a marketing authorisation by a country or by the regulatory authority on the basis of submitted quality, pre-clinical and clinical data, to which the application for marketing authorisation for a generic or a bio-similar product refers. Risk The probability that an event will occur, e.g., that an individual will become ill or die within a stated period of time or by a certain age. Risk-benefit balance An evaluation of the positive therapeutic effects of the medicine in relation to its risks (any risk relating to the quality, safety or efficacy of the medicinal product as regards patients’ health or public health and any risk of undesirable effects on the environment) is called risk-benefit balance. Self-medication It is the treatment of common health problems with medicines especially designed and labelled for use without medical supervision and approved as safe and effective for such use. Therapeutic benefit (Therapeutic value) The effect conveyed on a patient following administration of a pharmaceutical which restores, corrects or modifies a physiological function(s) for that patient is called as therapeutic benefit. Therapeutic equivalence Two pharmaceutical products are considered to be therapeutically equivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and after administration in the same molar dose, their effects, with respect to both efficacy and safety, are essentially the same when administered to patients by the same route under the conditions specified in the labelling. Therapeutic group A group of medicines according to their indications of use are called as a therapeutic group. Tertiary care Services provided by highly specialised providers (e.g. neurosurgeons, thoracic surgeons, intensive care units), usually in in-patient facility is called as tertiary care. Vulnerable groups Groups within a society facing higher risks of poverty and social exclusion compared to the general population are called as vulnerable groups; e.g. people with disabilities, isolated elderly people, children, migrants, ex-prisoners and drug addicts. Pharmacology - I (B.Pharm. Sem. IV) 1.10 General Pharmacology - I 1.1.2 Historical Landmarks and Scope of Pharmacology The science of pharmacology has evolved over the period of time. Knowledge about various events during evolution of drugs constitutes historical landmarks of pharmacology. Along with knowing the history, the scope of pharmacology is also advancing with time. Both the topics are of interest to students of Pharmacology. 1.1.2.1 Historical Landmarks The knowledge of primitive pharmacology developed from human experiences with use of plants. Some plants were safe while others were toxic. Based on this knowledge, a catalogue of good and bad evolved and was passed down through oral traditions. Over the period of time, the knowledge was transformed to include natural sources which appeared to cure some diseases. The oldest recorded event cites about events in 16th Century bc when beer, turpentine, myrrh, juniper berries and poppy and other therapies were described to treat disease. Similar historical records exist for most ancient civilizations including the Sumerian, Indian and Chinese. In India, Ayurveda has older traditions even before 16th century BCE. Sumerians around 3400 BCE cultivated the opium poppy in lower Mesopotamia and recorded its action in clay tablets. It was referred to as the “joy plant” and its reputation lead to its spread across neighbouring civilizations like Egypt. Around 460 BCE Hippocrates, a famous Greek physician and teacher of medicine, described opium as having narcotic properties and described use of opium in treating internal diseases. In 330 BCE, Alexander the great, introduced opium to Persia and India and by the year 400 it reached China. In the 10th century, the noted Islamic physician Avicenna of Persia described opium as the “most powerful stupefacients”. About the year 1200, the Indian medical treatises The Shodal Gadanigraph and Sharangdhar- Samahita describe the use of opium for diahorrhoea and sexual debility. In the 1300’s opium disappeared from European historical record till 1527; during which Paracelsus prescribed opium as a pain killer. The modern era began in 1680 when the English apothecary, Thomas Sydenham introduced Sydenham’s Laudanum which mentioned about many opium proprietary brands useful for various ailments. In 1803, the German Friedrich Serturner dissolved opium in acid and then neutralised it with ammonia resulting in formation of morphine which exhibited long-lasting and predictable effects. By 1827, morphine became a commercial product. In 1874, an English researcher, Wright synthesised heroin which went into commercial production in Germany by 1898. The molecular basis of opioid action was revealed by Snyder and Pert who located the molecular site of action for opium in 1972. These opioid receptors were found in neural tissues and mediate the pain reducing effect. Later Hughes and Kosterlitz discovered that humans produce endogenous morphine-like compounds, called as enkephalins, which act on opioid receptors. Besides opium there are few more milestones in historical development of pharmacology. In early 19th century, physiologists performed many pharmacological studies. Pharmacology - I (B.Pharm. Sem. IV) 1.11 General Pharmacology - I Magendie studied the action of Nux Vomica (a strychnine-containing plant drug) on dogs and showed that the spinal cord was the site of convulsant action. His work was presented to the Parris academy in 1809. Later in 1842, Bernard discovered that the arrow poison curare acts at the neuro-muscular junction to interrupt the stimulation of muscle by nerve impulses. Till 1846, the science of effect of drugs developed under physiology only. It was only in 1847, Buchheim was appointed as professor of pharmacology at University of Dorpat in Estonia (then a part of Russia). Initially there were no funds and professor Buchheim built a laboratory on his own expense in the basement of his home. His studies were mostly descriptive. His student Schmiedeberg (1838-1921) is recognised as founder of modern pharmacology. He obtained his medical doctorate in 1866 with a thesis on the measurement of chloroform in blood. He worked at Dorpat till 1869. In 1872, he became professor of pharmacology at the University of Starssburg, receiving generous Government support for developing an institute of pharmacology. He studied the pharmacology of chloroform and chloral hydrate. In 1869, he showed that muscarine evoked the same effect on heart as electrical stimulation of the vagus nerve. In 1885, he introduced urethane as a hypnotic. He was largely responsible for the pre-eminence of German pharmaceutical industry up to Second World War. In USA, the first chair in pharmacology was established in the University of Michigan in 1890 under Abel who was trained under Schmiedeberg. In 1893, Abel went to Johns Hopkins University in Baltimore. His contributions include isolation of epinephrine from adrenal gland extracts (1897-98), isolation of histamine from pituitary extract (1919), and preparation of pure crystalline insulin (1926). His student Hunt discovered acetyl choline in adrenal extracts in 1906. Pharmacology largely depends on experiments conducted in laboratory animals; however there are isolated cases where human beings have been used to study the effect of drugs. Serturner, the German pharmacist who isolated the first alkaloid from opium in 1805, administered a dose of 100 mg to himself and his three friends. All of them experienced the symptoms of severe opium poisoning for several days. Another interesting story where human beings were used for testing drugs occurred in 1940s. Biological assays (bioassays) of digitalis performed in frogs, pigeons and cats were highly unsatisfactory. In 1942, a group of cardiologists published “a method for bioassay of digitalis in humans”. The assay was based on changes in ECG of patients. Of 97 patients in whom ECG was tried, only 18 proved to be satisfactory assay subjects. Animals are primarily used to detect toxicity of substances,. Most frequently pharmaco- logical studies are conducted in mammals. Mice are preferred because of their small size, ease of breeding and short generation time. Rats, guinea pigs, rabbits and dogs are also used; each has special characteristics that make it optimal for certain type of tests. The efforts of animal activists have restricted use of animals for experimental study on drugs. In India, permission from the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) is necessary for conducting any animal experiments. It is suggested that animals should be used only for research and development and not for education/demonstration. Every pharmacy college is supposed to take permission from CPCSEA, with one of their representative in the committee. Pharmacology - I (B.Pharm. Sem. IV) 1.12 General Pharmacology - I Early in the development of pharmacological techniques, it was found that an isolated organ or tissue remained functional for several hours in a bath containing a physiologic solution of salts through which oxygen was bubbled. Magnus (1802-1870) first applied this method to a strip of small intestine. Later Heymans (1904) worked with mammalian heart and Bernard experimented with isolated nerve-muscle preparation. In 1924, Allen and Doisy used ovarictomized rats to test the action of estrogenic hormone. With advancement of knowledge of human biochemistry and molecular biology, pharmacological actions are often studied on actions of enzymes and receptors. The drug Captopril was developed by Ondetti and co-workers at Squib in 1970s to inhibit the enzyme - Angiotensin Converting Enzyme (ACE). Subsequently, it was proved that inhibitors of ACE work as anti-hypertensive drugs. Knowledge of cell receptors is yet another milestone. Adrenalin is the neurotransmitter for sympathetic nervous system. Adrenalin acts on α- and β- receptors. Propranolol was the first β-adrenergic receptor blocking agent. From 1964, β-blockers have been used for treating hypertension and cardiac arrhythmia. Synthetic organic chemistry was born in 1828, when Wohler synthesised urea from inorganic substances. Several substances, existing in the body or their derivatives were synthesised in laboratories as an extension of developments in organic chemistry. With the knowledge of receptors, a complimentary substance can be synthesised in laboratories. With the help of Structure – Activity Relationship (SAR) derivatives of main active moiety can be synthesised. In recent years, developments in medicinal chemistry have greatly contributed to development of various synthetic drugs. 1.1.2.2 Scope of Pharmacology The science of Pharmacology has interfaces with Anatomy and Physiology, Organic and Inorganic Chemistry, Microbiology and Pathophysiology. Pharmacology is related to action and uses of drugs. In development of new drugs, pharmacology has greatest contribution. It has two main components: pharmacodynamics and pharmacokinetics. Pharmacodynamics deals with what drug does to the human/animal body. It involves study of action of drugs on receptors, its mechanism of action, indications for clinical use, contra-indications and adverse reactions caused by drugs. Pharmacokinetics deals with what body does towards drugs. It has four main components: Absorption, Distribution, Metabolism and Excretion (ADME). Out of these four components, absorption, distribution and excretion are dependent on transport through membranes without any chemical change in the entity. In metabolism, there is chemical change in the moiety because of action of enzymes in the body. Cytochromal enzymes in the liver are the main metabolising enzymes in the liver. A drug may have n number of metabolites. Every metabolite can have different action in the body. Thus, what we observe as action(s) of drugs is the net effect of main drug moiety and its metabolites. Several factors can alter ADME of drugs. It is the main reason why we get different kinds of actions for the same drug in different individuals. Clinical pharmacology and therapeutics primarily deals with actions of drug in human beings. It incorporates indications, therapeutic uses, contra-indications, posology, bio- availability, prescription writing and drug nomenclature. The science of clinical toxicology is Pharmacology - I (B.Pharm. Sem. IV) 1.13 General Pharmacology - I an extension of clinical pharmacology. Forensic toxicology addresses to medico-legal aspects of use of drugs. Pharmacovigilance is gaining vital importance in last few decades. It involves study of adverse reactions of drugs and their safety. Based on observations on pharmacovigilance, some drugs have been withdrawn from the market due to severe adverse reactions. 1.1.3 Nature and Sources of Drugs Several drug candidates have been derived from various naturally occurring medicinal sources. They can be broadly divided in to four major categories: Plant sources Animal sources Microbial sources Marine sources. In addition to the above mentioned natural sources, two other sources need specific mention. A drug may be derived either as a semi-synthetic product from any of the naturally occurring resources or it may be of totally synthetic origin. Having knowledge about the receptor and Quantitative Structure-Activity Relationship (QSAR), one may predict possible structure of a drug. Subsequently, a drug with optimum biological action can be synthesised, tested and evaluated for possible clinical activity. The use of plants as medicines has a long history. Opium has been the first known drug from plant sources. Plants continue to be a significant part of traditional medicine and herbal medicine. Several important drugs like Taxol, Camptothecin, Morphine and Quinine have been isolated from plant sources. Animals have been sources for some drugs. Insulin and heparin are two common names of drugs of animal origin. Till last few decades insulin was obtained from pancreas of animals. Now insulin is available by genetic engineering from microbial sources. Heparin is obtained from lungs of animals. Epibatidine, obtained from the skin of an Ecuadorian poison frog, is ten times more potent than morphine. Teprotide, extracted from a Brazilian snake viper, has led to the development of Cilazapril and Comptopril, which are effective against hypertension. Microorganisms as a source of potential drug candidates were not explored till the discovery of penicillin in 1929. Subsequently several antibiotics have been obtained either from microbial sources or from their semi-synthetic derivatives. Marine organisms have also been sources for new drugs. The first active compounds to be isolated from marine species were Spongouridine and Spongothymidine from the Carribean sponge Cryptotheca crypta in 1950s. These compounds are nucleotides and show a great potential as anticancer and antiviral agents. Discodermolide, isolated from the marine sponge, Discodermia gissoluta has a strong antitumour activity and has mode of action similar to that of Paclitaxol. Few antibiotics also originate from ocean. Several derivatives of antibiotics, β-blockers, anti-protozoal drugs, anti-malarial drugs are of totally synthetic origin. The examples of the categories of drugs are illustrative only. In recent years most of the new drugs are of synthetic origin based on the knowledge about the receptor. Pharmacology - I (B.Pharm. Sem. IV) 1.14 General Pharmacology - I 1.1.4 Essential Drugs Concept Although a large number of medicines are available in the market, all of them may not be necessary for majority of population. Based on this observation, World Health Organisation (WHO) proposed a concept of ‘essential medicines’ in 1977. According to this concept, essential medicines are those that satisfy the priority health care needs of the population. They are selected with due regard to public health relevance, evidence on safety and efficacy, and comparative cost-effectiveness. Essential medicines are intended to be available within the context of functioning health systems at all times in adequate times, in the appropriate dosage forms, with assured quality and adequate information, and at a price the individual and the community can afford. The implementation of the concept of essential medicines is intended to be flexible and adaptable to many different situations; exactly which medicines are regarded as essential remains responsibility of that country. In the first, 1977 version of list of essential medicines, 208 medicines were identified to address the global burden of disease at that time. The list is revised by a committee of independent experts after every two years to reflect new health challenges, pharmaceutical developments and changing resistance patterns by microorganisms. In 2007, 30th anniversary of WHO was celebrated. By then 156 of 193 WHO member states have official essential medicine lists, of which 127 countries have been updating it in past 5-10 years. The list of essential medicines published in 2007 contains 340 medicines including drugs for malaria, HIV/AIDS, tuberculosis, reproductive health, chronic diseases like cancer and diabetes. The list of essential medicines published in October 2007 contained for the first time “Essential Medicines for children”. The list of essential medicines for children is also updated every two years. In the year 2015, 19th model list of essential medicines and 5th revised list of essential medicines for children has been published by WHO. The 20th revision of essential medicines and the 6th revision of essential medicines for children is in the process. Government of India has published a list of essential medicines. Few states have implemented it. In the year 2013, eighth edition of essential medicines list for the National Capital Territory of Delhi has been published. Few other states like Rajasthan, Kerala, Karnataka and Madhya Pradesh have essential lists prepared by an expert committee and the concept is implemented in these states. 1.1.5 Routes of Drug Administration Route of administration refers to the starting point for the drug’s introduction in to the body up to the place where it acts upon the target organ or system. The route of administration for the drug depends on a number of factors like nature of the drug, its pharmacokinetics, and the nature and urgency of the medical condition. The main routes of administration are: local and systemic. The local route is further sub-classified into topical like administration to eye, ear, nose etc. The systemic route is further divided as enteral and parenteral. Enteral route consists of oral, rectal and sub-lingual. Parenteral route consists of inhalation, and various injections like sub-cutaneous, intra-muscular and vascular types. Definitions of all routes of administration are presented below: Pharmacology - I (B.Pharm. Sem. IV) 1.15 General Pharmacology - I Enteral It means through gastro-intestinal tract. It includes oral, sublingual and rectal routes. Parenteral It means through routes other than enteral. It includes all types of injections, inhalations. Local It includes administration of a drug at the site where the desired action is intended. It includes topical administration in oral cavity, gastro-intestinal tract, rectum/anal canal, eye, ear, nose, bronchi, skin, intra-arterial, injection in deep tissues e.g. joints. Systemic It includes drugs administered to enter the blood to produce systemic effects. Oral It means drugs taken by mouth e.g. tablets, capsules, syrups, mixtures etc. Intravenous It includes drugs injected directly in to blood stream through a vein. It may be administered as: bolus, slow intravenous injection or an intravenous infusion. Intrathecal It includes drugs injected in to the sun-arachnoid space e.g. spinal anaesthetics like lignocaine. Intra-articular It includes drugs injected directly in to the joint space e.g. hydrocortisone injection for rheumatoid arthritis. Subcutaneous It includes drugs injected in to the sub-cutaneous tissues of the thigh, abdomen and arm e.g. adrenalin, insulin etc. Intradermal It includes drugs injected in to the dermis layer of the skin e.g. tuberculin and allergy tests. Intramuscular It includes drugs injected in to large muscles such as deltoid, gluteus maximus and vastus lateralis. A volume of 5-10 ml can be given at a time e.g. paracetamol, diclofenac. Intraosseous It includes injecting a drug directly in to the marrow of a bone. Transdermal (patch) It includes administration of a drug in the form of a patch or ointment that delivers the drug into the circulation for systemic effect. Rectal It includes administration of drugs in the form of suppository or enema in to the rectum. Sublingual In this case, the preparation is kept under the tongue. The drug is absorbed through the buccal membrane and enters the systemic circulation bypassing the liver e.g. nitroglycerine for acute angina attack. Inhalation It includes volatile gases and liquids which are given by inhalation for systemic effects e.g. general anaesthetics. Endotracheal It includes a catheter inserted in to the trachea for primary purpose of establishing and maintaining an airway to ensure adequate exchange of oxygen and carbon dioxide. Pharmacology - I (B.Pharm. Sem. IV) 1.16 General Pharmacology - I The broad classification is presented in Fig. 1.1. Otic Ocular Parenteral: IV, IM, SC Inhalation Oral Sublingual Buccal Transdermal patch Topical Epidural Rectal Fig. 1.1: Routes of administration Fig. 1.2 indicates pictorial presentation of various injectable routes. Subcutaneous Intramuscular Intravenous Epidermis Dermis Subcutaneous tissue Muscle with vein Fig. 1.2: Injectable routes of drug administration Pharmacology - I (B.Pharm. Sem. IV) 1.17 General Pharmacology - I Brief characteristics of different routes of administration are presented in table 1.1. Table 1.1: Absorption pattern, advantages and disadvantages of most common routes of administration Sr. Name of Absorption Advantages Disadvantages No. route pattern 1. Oral Variable; Safest and most Limited affected by common, convenient, absorption of many factors. and economical some drugs. Food may affect absorption. Patient compliance is necessary. Drugs may be metabolised before systemic absorption. 2. Intravenous Absorption not Can have Unsuitable for oily required. immediate substances. effects. Bolus injection Ideal if dosed in may result in large volumes. adverse effects. Suitable for Most substances irritating must be slowly substances and injected. complex Strict aseptic mixtures. techniques Valuable in needed. emergency situations. Dosage titration permissible. Ideal for high molecular weight proteins and peptides. 3. Subcutaneous Depends on Suitable for slow- Pain or necrosis if drug diluents; release drugs. drug is irritating. Aqueous Ideal for some Unsuitable for solution: prompt; poorly soluble drugs adminis- Depot suspensions. tered in large preparations: volumes. Slow and sustained contd. … Pharmacology - I (B.Pharm. Sem. IV) 1.18 General Pharmacology - I 4. Intramuscular Depends on Suitable if drug Affects certain lab drug diluents; volume is tests (creatine Aqueous moderate. kinase). solution: prompt; Suitable for oily Can be painful. Depot vehicles and Can cause preparations: some irritating intramuscular Slow and substances. haemorrhage. sustained Preferable to Avoided during intravenous if anticoagulant patient can self- therapy. administer. 5. Transdermal Slow and Bypasses the Some patients are sustained. first-pass effect. allergic, causing Convenient and irritation. painless. Drug must be Ideal for lipophilic highly lipophilic and poorly May cause. bioavailable delayed delivery drugs. to the site. Ideal for drugs Limited to drugs which are quickly which can be eliminated. taken in small daily doses. 6. Rectal Erratic and Partially bypasses Drugs may irritate variable. first-pass effect. the rectal mucosa. Bypasses Not a well- destruction by accepted route. stomach acid. Ideal if drug causes vomiting. Ideal in patients who are vomiting or comatose. 7. Inhalation Systemic Absorption is Most addictive absorption may rapid; can have route (drug can occur; it is immediate enter the brain undesirable. effects. quickly). Ideal for gases. Patient may have Effective for difficulty in patients with regulating dose. respiratory Some patients problems. may have Dose can be difficulty in using titrated. inhalers. Localised effect to target lungs: lower doses can be used. Fewer systemic side effects. contd. … Pharmacology - I (B.Pharm. Sem. IV) 1.19 General Pharmacology - I 8. Sublingual Depends on the Bypasses first- Limited to certain drug: few drugs pass effect. types of drugs. have rapid direct Bypasses Limited to drugs systemic destruction by which can be absorption. Most stomach acid. taken in small drugs are Drug stability is doses. absorbed maintained May lose part of incompletely because pH of the drug dose if and erratically. saliva is relatively swallowed. neutral. May cause immediate pharmacological effects. Duration in which the effect can initiate also depends on route of administration. Table 1.2 provides information in this context. Table 1.2: Effect of route of administration on initiation of effect of drugs Sr. No. Route of administration Time until effect 1. Intravenous 30-60 seconds 2. Intraosseous 30-60 seconds 3. Endotracheal 2-3 minutes 4. Inhalation 2-3 minutes 5. Sublingual 3-5 minutes 6. Intramuscular 10-20 minutes 7. Subcutaneous 15-30 minutes 8. Rectal 5-30 minutes 9. Oral 39-90 minutes 10. Transdermal (topical) Variable (minutes to hours) Drug and patient related factors determine the selection of routes for drug administration. The factors are: Characteristics of drugs. Emergency/routine use. Site of action of the drug - local or systemic. Condition of the patient (unconscious, vomiting, diarrhoea). Age of the patient. Effect of gastric pH, digestive enzymes and first-pass metabolism. Patient’s/doctor’s choice. Pharmacology - I (B.Pharm. Sem. IV) 1.20 General Pharmacology - I 1.1.6 Agonists An agonist is a chemical which binds to a receptor and activates the receptor to produce a biological response. Receptors can be activated by either endogenous agonists (like hormones or neurotransmitters) or exogenous agonists (like drugs). Agonists can be divided into following sub-categories: Full agonists They bind to and activate a receptor with the maximum response that an agonist can elicit at the receptor e.g. isoproterenol mimics the action of adrenaline at β-adrenoceptors. Co-agonists A co-agonist works with other co-agonists to produce the desired effect together; e.g. NMDA receptor activation requires binding of glutamate, glycine and D-serine co-agonists. Selective agonists A selective agonist is selective for a specific type of receptor only; e.g. buspirone is a selective agonist for serotonin 5-HT1A. Partial agonists Partial agonists like buprinorpine also bind and activate a given receptor but have only partial efficacy at the receptor relative to a full agonist, even at maximal receptor occupancy. Inverse agonists An inverse agonist is an agent which binds to the same receptor binding-site as an agonist and inhibits the constitutive activity of the receptor. Inverse agonists exert the opposite pharmacological effect to that of an agonist. This is unlike an antagonist; e.g. Cannabinoid inverse agonists rimonabant. Super agonists It is a term used to identify a compound which is capable of producing a greater response than the endogenous agonists for the target receptor. Irreversible agonists An irreversible agonist is a type of agonist which binds permanently to a receptor through formation of covalent bonds. 1.1.7 Antagonists (Competitive and Non-competitive) An antagonist is a type of receptor ligand or drug which blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. They are sometimes called as blockers e.g. α-blockers, β-blockers, calcium channel blockers etc. Antagonists have affinity but no efficacy for their cognate receptors. The concept of affinity and efficacy is presented below. Affinity The affinity of an antagonist for its binding site is its ability to bind to a receptor. It determines the duration of inhibition of agonist activity. It can be measured experimentally. Pharmacology - I (B.Pharm. Sem. IV) 1.21 General Pharmacology - I Efficacy and Potency By definition, antagonists display no efficacy to activate the receptors to which they bind. Antagonists do not maintain the ability to activate a receptor. However, once bound they will inhibit the function of agonists, inverse agonists and partial agonists. Thus, antagonists can have variable affinity but no efficacy. Antagonists are of different types: Competitive, Non-competitive and Uncompetitive. 1.1.7.1 Competitive Antagonists Competitive antagonists bind to receptors at the same binding site (active site) as the endogenous ligand or agonist, but without activating the receptor. Agonists and antagonists compete for the same binding site on the receptor. Once bound, an antagonist will block binding of agonist. Sufficient concentration of an antagonist will displace the agonist from the binding sites, resulting in a lower frequency of receptor activation. The level of activity of the receptor will depend on relative affinity of each molecule for the site and their relative concentrations. Competitive antagonists are used to prevent the activity of drugs and to reverse the effects of drugs that have already been consumed. Naloxone is an antagonist of morphine/heroine and is used to reverse effects of opioid overdose. Competitive antagonists are sub-classified as reversible (surmountable) or irreversible (insurmountable) competitive antagonists, depending on how they interact with their receptor protein targets. In case of irreversible antagonism, the bond with receptor is probably of covalent nature. 1.1.7.2 Non-competitive Antagonists A non-competitive antagonist is a type of unsurmountable antagonist that may act in one of two ways: by binding to the active site of receptor or by binding to an allosteric site of the receptor. If it binds to the allosteric site, it is called as allosteric antagonist. In both the cases, end-results are functionally similar. Unlike competitive antagonists, which affect the amount of agonists necessary to achieve a maximal response but do not affect the magnitude of that maximal response, non-competitive antagonists reduce the magnitude of the maximum response that can be attained by any amount of agonists. This property makes the title as “non-competitive” because their effects cannot be negated, no matter how much agonist is present. Cyclothiazide is known to be a reversible non-competitive antagonist of mGluR1 receptor. 1.1.7.3 Uncompetitive Antagonists Uncompetitive antagonists differ from non-competitive antagonists in that, they require receptor activation by an agonist before they can bind to a separate allosteric binding site. This type of antagonism produces a kinetic profile in which the same amount of antagonist blocks higher concentrations of agonists better than lower concentrations of agonists. Memantine, used for treating Alzheimer’s disease, is an uncompetitive antagonist of the NMDA receptor. Pharmacology - I (B.Pharm. Sem. IV) 1.22 General Pharmacology - I Dose-response Curve Dose-response relationships, or exposure-response relationship can be conveniently used to know the type of antagonism. Dose-response relationship describes the change in effect of an organism caused by differing levels of exposure (or doses) to a stress or (usually a drug) after a certain exposure time. Biologic effect is usually placed on Y-axis in terms of percentage. Drug concentration is depicted on X-axis in terms of units of dose. Dose-response curve is usually S-shaped as depicted in Fig. 1.3. The dose corres-ponding to 50% of the response is termed as EC50, (effective concentration for 50% effect). In case of a competitive antagonist, the dose-response curve shows a parallel right shift with increase in value of EC50. Unlike this, in case of non-competitive or uncompetitive antagonists, shift to the right is not parallel and there is only a slight change in the value of EC50. Drug with non- Drug with competitive competitive antagonist antagonist Biologic effect EC50 EC50 for drug for drug alone or in the presence in the presence of a competitive of a non-competitive antagonist antagonist EC50 = Drug dose that shows 50% of maximal response. Fig. 1.3: Effect of drug antagonists 1.1.8 Spare Receptors Spare receptors are defined as those receptors without combining with which maximal response can be obtained. In order to understand this concept, understanding of receptor occupancy theory is essential. Receptor Occupancy Theory Consider dose response curves A, B and C for an agonist along with various antagonists. (Fig. 1.4) In this graph, X-axis indicates log agonist (M) indicating that log molar concentration of agonist is plotted. Y-axis indicates percentage of maximal effect. In Fig. 1.4, maximal responses, as shown in dose-response curves B and C have been obtained with incremental change in concentrations of agonists in presence of antagonists, as needed for 50% of effects. Further, the maximal response (100%) has not changed as indicated in dose response curve B and C, even in presence of antagonist which has occupied certain fraction of receptors. In other words, maximal response in case of dose-response curve A was obtained without binding to all receptors. These receptors, without binding with which maximal response was obtained, are termed as spare receptors. Pharmacology - I (B.Pharm. Sem. IV) 1.23 General Pharmacology - I 120 100 % of maximal effect A 80 B Increasing C concentration of 60 D irreversible inhibitor 0.5 Effectmax 40 E- 20 0 -11 -10 -9 -8 -7 -6 -5 -4 EC50 (A) EC50 (B) EC50 (C) EC50 (D, E) = KD Log agonist (M) Fig. 1.4: Pharmacodynamics 1.1.9 Addiction Addiction is a brain disorder characterised by compulsive engagement in rewarding stimuli despite adverse consequences. It is related to addictive behaviour which is both rewarding and reinforcing. Rewarding stimuli are interpreted by brain as intrinsically positive and desirable or as something to be approached. Reinforcing stimuli increase the probability of repeating behaviours paired with them. Addiction is caused by addictive drug, consumption of which compels addictive behaviour. 1.1.10 Tolerance Drug tolerance is defined as, "the diminishing effect of drug resulting from repeated administration at a given dose". Drug tolerance is a pharmacological concept describing subjects’ reduced reaction to a drug following its repeated use. Increasing its dosage may re-amplify the drug’s effects, however this may accelerate tolerance, further reducing the drug’s effects. Drug tolerance is indicative of drug use but is not necessarily associated with drug dependence or addiction. The process of tolerance development is reversible and can involve both physiological factors and psychological factors. It is divided in to three types: pharmacodynamic, pharmacokinetic (metabolic) and behavioural. Pharmacodynamic tolerance begins when the cellular response to a substance is reduced with repeated use. A common cause is high concentration of a substance constantly binding with a receptor, desensitizing it through constant interaction. Usually, it occurs after sustained exposure to a drug. Pharmacokinetic tolerance occurs because of a decreased quantity of the substance reaching the site it affects, this may be caused by increase in induction of enzymes required for degradation of drug e.g. CYP450 enzymes. Alcohol is a common example. In addition to enzyme induction, several other mechanisms contribute to tolerance. Behavioural tolerance occurs with the use of some psycho-active drugs, where tolerance to a behavioural effect of a drug occurs with repeated use of the drug. Amphetamine causes behavioural tolerance. Pharmacology - I (B.Pharm. Sem. IV) 1.24 General Pharmacology - I 1.1.11 Dependence It is defined as, "an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g. drug intake)". Withdrawal syndrome is identified as a set of symptoms that occur upon cessation of repeated drug use. Dependence is of two types: physical and psychological. Physical dependence involves persistent physical-somatic withdrawal symptoms (e.g. fatigue and delirium tremens). Psychological dependence involves emotional-motivational withdrawal symptoms (e.g. dysphoria and anhedonia). 1.1.12 Tachyphylaxis Tachyphylaxis is a sub-category of drug tolerance referring to cases of sudden, short- term onset of tolerance following the administration of drug. It is a rapid and short term onset of drug tolerance. It can occur after an initial dose or after a series of small doses. Increasing the dose of the drug may be able to restore the original response. Tachyphylaxis is characterised by the rate sensitivity: the response of the system depends on the rate with which a stimulus is presented. To be specific, a high-intensity prolonged stimulus or often- repeated stimulus may bring about a diminished response also known as desensitization. Opioids, nicotine, nitroglycerine and metoclopramide are examples of some drugs which are known to cause tachyphylaxis. 1.1.13 Idiosyncrasy Idiosyncratic drug reactions occur rarely and unpredictably amongst the population. They frequently occur with exposure to new drugs. They are listed as rare adverse drug reactions. They do not appear to be concentration dependent. A minimal amount of drug will cause an immune response but only after second administration; since development of antibodies need time and first dose is mandatory. The proposed mechanism of most idiosyncratic drug reactions is immune-mediated toxicity. The classical example is allergy caused by penicillin. A drug may cause an immune response if it binds to a larger molecule. In few cases a metabolite rather than the parent drug may bind to proteins. Thus a drug/its metabolite, injury or infection may sensitize a person and can cause idiosyncratic reactions. These reactions are studied under toxicology. 1.1.14 Allergy Allergic reaction to a drug will not occur on the first exposure to a substance. The first exposure allows the body to create antibodies and memory lymphocyte cells for the antigen. Subsequently antibodies or lymphocytes interact with the antigen causing what we understand as allergic reactions. Following signs and symptoms are observed with allergy: Hives Itching Rash Fever Facial swelling Pharmacology - I (B.Pharm. Sem. IV) 1.25 General Pharmacology - I Shortness of breath due to the short term constriction of lung airways or long-term damage to lung tissues. Anaphylaxis, a life threatening drug reaction causing low blood pressure. Cardiac symptoms such as chest pain, shortness of breath, fatigue, chest palpitation, light headedness, syncope and eosinophilic myocarditis. Following drugs are known to cause allergy: Antibiotics: Penicillin, Sulphonamides, Tetracyclines Analgesic: Codine, NSAIDs Anti-epileptic: Phenytoin, Carbamazepine The list is given for illustration only. It is not an exhaustive list. Risk Factors Risk factors for drug allergies can be attributed to the drug itself or the characteristics of the patient. Drug-specific risk factors include dose, route of administration, duration of treatment, repetitive exposure to the drug. The patient related factors include concurrent illness, age, sex, specific genetic polymorphism and inherent predisposition to react to multiple unrelated drugs. A drug allergy is more likely with large doses and extended exposure. Mechanisms Drug allergies are related to drug hypersensitivity. Drug hypersensitivity reactions are the mediators of a drug allergy. There are two mechanisms for drug allergy: IgE mediated or non-IgE mediated. In IgE-mediated reactions drug allergens bind to IgE antibodies, which are attached to mast cells and basophils, resulting in IgE cross-linking, cell activation and release of performed and newly formed mediators. In case of non-IgE mediated reactions, probably other immunoglobulins are involved. 1.2 PHARMACOKINETICS 1.2.1 Membrane Transport Membrane transport refers to the collection of mechanisms which regulate passage of solutes like ions and small molecules through biological membrane, which are lipid bilayers containing proteins embedded in them. Regulation of passage through the membrane is due to selective membrane permeability - a characteristic of biological membranes which allows them to separate substances of distinct chemical nature. Alternatively, it can be stated that biological membranes are permeable to certain substances but not to others. The movements of most solutes through the membrane are mediated by membrane transport proteins which are specialised to varying degrees in the transport of specific molecules. There are different types of cells; hence specific transport proteins exist for each cell type during a specific physiological state. The differential expression of proteins is regulated through the differential transcription of the genes coding for these proteins. In addition, production of these proteins can be activated by cellular signalling pathways, at the biochemical level, or even by cytoplasmic vesicles. Pharmacology - I (B.Pharm. Sem. IV) 1.26 General Pharmacology - I Transport Types: There are two types of transports in biological tissues viz Passive transport and Active transport. 1. Passive transport It is a movement of ions and other atomic/molecular substances across cell membrane without the input of metabolic energy. The concentration gradient of the transported substances acts as a source of energy. The rate of passive transport depends on the permeability of cell membrane,