Basic Principles of Pharmacology - Lecture Notes

Basic principles of Pharmacology What is Pharmacology? It is the science that deals with the study of drugs, including their origin, nature, chemistry, uses and beneficial and adverse effects. It includes the study of substances that bind to regulatory molecules and activate or inhibit normal body...

Basic principles of Pharmacology What is Pharmacology? It is the science that deals with the study of drugs, including their origin, nature, chemistry, uses and beneficial and adverse effects. It includes the study of substances that bind to regulatory molecules and activate or inhibit normal body processes. What is Drug? A substance, material or product used for the purpose of diagnosis, prevention, relief the symptoms or cure of disease. With the exception of gene-based drug, drug does not create a new function, but alters the existing function. Drug is poison if used irrationally. Poisons in small doses are the best medicines; and useful medicines in too large doses are poisonous”  Branches of Pharmacology Pharmacology can be divided into various branches. Its major branches are:- Pharmacokinetics (PK): what our body does to a drug. It is the study of drug Absorption, Distribution, Metabolism, and Elimination (ADME) Pharmacodynamics (PD): what a drug does to our body. It is the study of mechanism of action of a drug, drug-receptor interaction, post- receptor drug effect, dose-response relationship, the physical and chemical effects of drugs on our body, parasites and micro-organisms. Therapeutics/Pharmacotherapeutics: It is the application of pharmacological information together with the knowledge of disease, for the prevention and cure of disease. Chemotherapy: The study of treatment of diseases by chemicals that kill the cells, especially those of micro-organisms and neoplastic cells.  Branches of Pharmacology…cont’d Toxicology: is study the adverse effects of drugs on the body. It deals with the symptoms, mechanisms, treatment and detection of poisoning caused by different chemical substances. For toxicology, main criterion is the dose (A medicine in high dose can be a poison while a poison in low dose can be a medicine). What is the difference between adverse effects and side effects of drugs? Clinical Pharmacology: It is the use of drugs in the clinical routine. Main objectives of clinical pharmacology are: To maximize the effect of drug To minimize the adverse effects To generate optimum data for use of drugs To promote the usage of evidence-based medicine  Branches of Pharmacology…Cont’d Pharmacoeconomics: It is the study of economic factors regarding the cost of drug therapies, including their impact on healthcare system and society. Pharmacogenetics: study of individual gene-drug interactions, usually one or two genes that have dominant effect on a drug response (SIMPLE relationship) Pharmacogenomics: study of genomic influence on drug response, often using high-throughput data (sequencing, SNP chip, expression, proteomics - COMPLEX interactions. Pharmacoepidemiology: It deals with the study of effects of drugs on a large population. It includes trial studies on healthy and diseased individuals and collecting the opinion of physicians prescribing a drug. It deals with the comparison of different drugs of same or different uses Pharmacovigilance: Also known as Drug Safety, is the pharmacological science relating to the collection, detection, assessment, monitoring, and prevention of adverse effects with pharmaceutical products  Principles of Pharmacology….Cont’d CHARACTERISTICS OF DRUGS:  It has a physiological effect when introduced into the body.  It interacts with molecule or protein that plays a regulatory function in the living system to alter the organism’s function.  Examples of such components (sites of drug action) are:  enzymes,  ion channels,  neurotransmitter transport systems,  nucleic acids  Types of Drug Responses Therapeutic (desired) effects  Medication is administered in a dose intended to produce a desired clinical response.  Some require repeated dosing.  Capable of demonstrating cumulative action Adverse medication effects  Clinical changes that are not desired and cause harm or discomfort to the patient  Consider in relation to the patient’s condition  Patients with chronic medical conditions are more susceptible.  Patients may be unable to tolerate even mild adverse effects  May range in severity  Can be desirable in certain situations and harmful in others  Can be completely unexpected  Idiosyncratic medication reactions Types of drug responses…Cont’d Side effect  Unintended effect occurring at normal dose and related to the Pharmacological properties of the drug (not necessary harmful) (what are the differences between adverse effects and side effects of drugs?) Factors affecting drug response  Factors affecting drug response….Cont’d 1. AGE: Newborns or neonates ( birth to 4 weeks). Newborns are more sensitive to drug effects (drug dosage for newborn is decreased because:-  Gastric acid secretion are not adequate e.g.GIT absorption of ampicillin and amoxicillin is greater in neonates due to decreased gastric acidity.  Liver microsomal enzymes (glucuronyl transferase) are deficient (administration of Chloramphenicol may lead to Grey baby syndrome because of inadequate glucouronidation of chloramphenicol resulting in drug accumulation)  Plasma protein binding is less (Higher level of free drug).  GFR & tubular secretions are not adequate.  There is immaturity of blood brain barriers in neonates (sulfonamides may lead to hyperbilirubinemia and kernicterus B. Infants (1 month-1 Year) {Similar to neonates} Infant and child are highly sensitive to large number of drugs (they requires fraction of adults doses) because of the following reasons:-  Drug metabolizing enzyme system is inefficient (Glucuronidation takes 3 months to develop).  Their barriers are not fully developed (BBB, blood aqueous barrier), thus are more sensitive to CNS stimulants.  Infants have an immature renal tubular transport system. Penicillin, streptomycin and amino glycosides are not administered. After one year of age, elimination by kidneys is increased.  Hepatic metabolizing capacity is also under developed. Chloramphenicol may cause grey baby syndrome. C. Children’s (Between 2 and 11 years old) Children metabolize certain drugs more rapidly than adults. Metabolism rates increases between 1 year and 12 years (depends on age and drug). After age 12 metabolism rates decline with age to a normal adult level. Geriatric age group (> 60 yrs) Elderly often require lesser doses than adults because they are prone to suffer from adverse drug reactions. Elderly patients may require dose adjustment because of the age-dependent changes in function and composition of the body: 1. A loss of water content and an increased of fat content in the body (affect the volume of distribution) 2. Reduced intestinal motility & mesenteric blood flow (affect oral bioavailability of drugs). 3. Reduced renal & hepatic functions 4. Altered mental functions Drugs with lower therapeutic index (e.g. diazepam, theophylline) may have much larger half lives (2 hrs in normal 90 hrs in old). Kidney functions are also impaired. Drugs like Digoxin, lithium and amino glycosides have decreased excretion. Plasma protein binding is decreased leading to greater amounts of free active drugs. Increased sensitivity to CNS depressants like diazepam, morphine also occurs  Factors affecting drug response….Cont’d 2. Pregnancy: In pregnancy, the following are to be considered: Change in cardiac output Change in GFR and renal elimination of drugs. Change in Volume of distribution Change in metabolic rate of some drugs 3. Plasma Protein Binding Malnutrition causes decreased amino acids, decreased proteins leading to decreased binding sites for drugs. 4. Food Drugs are better absorbed in empty stomach. To prevent gastric irritation most drugs are taken after or between foods, which affects the outcomes. Antimotion drugs are taken on empty stomach. Helminthes (for evacuation of worms) are also taken on empty stomach.  Factors affecting drug response….Cont’d 4. Pathological Factors: Diseases cause individual variation in drug response A. Liver Disease  In liver diseases, prolong duration of action occurs because of increased half life.  Plasma protein binding for warfarin, tolbutamide is decreased leading to adverse effects  If hepatic blood flow is reduced, clearance of morphine- propranolol may be affected.  Impaired liver microsomal enzymes may lead to toxic levels of Diazepam, rifampicin and theophylline B. Renal Disease GFR, tabular function and plasma albumin may be affected leading to abnormal effects of digoxin, lithium, gentamycin and penicillin C. Malnutrition Plasma protein binding of drugs is reduced along with the amount of microsomal enzymes, leading to increased portion of free, unbound drug e.g. Warfarin Factors affecting drug response…Cont’d Effect of Disease….cont'd Certain drugs are only effective in disease conditions:-  Antipyretics drug such aspirin and paracetamol do not reduce temperature in case of healthy individuals.  Iron is better absorbed in iron deficiency anemia. As the anemia improves, it has less response. 5. Dosage form of drug  Drugs in solid forms disintegrate slowly.  Onset of action is rapid when drug is given in liquid form  Factors affecting drug response….Cont’d 6. Genetic Factors *Pharmacogenetics is the study of the relationship between genetic factors and drug response. Genetic factors can influence the dose and the response to a drug in many ways. It affects the drug response in individuals at 2 levels.  At the level of receptors (at the pharmacodynamic level).  At the level of drugs absorption, metabolism (the most common), and elimination (Pharmacokinetic level). Genetic factors affecting drug metabolizing enzymes are the most common reason for variation in drug response Idiosyncrasy Idiosyncrasy is used to describe abnormal drug response on administration of first dose due to genetic disorder. Factors affecting drug response….Cont’d Genetic Polymorphism What is genetic Polymorphism? The existence in a population of two or more phenotypes with respect to the effect of a drug. Examples: Acetyl transferase (non-microsomal) affects Isoniazid, sulphonamides, etc. Slow acetylator phenotype may show peripheral neuropathy. Rapid acetylator phenotype may show hepatitis. Pseudocholinesterase deficiency: Succinyl choline is a skeletal muscle relaxant. Succinylcholine apnea may occur due to paralysis of respiratory muscles. Oxidation Polymorphism In case of Debrisoquine (antihypertensive drug) 1.Extensive metabolizers (EM) need larger dose. 2.Poor metabolizers (PM) – need smaller dose. Deficiency of Glucose-6 phosphate dehydrogenase (G-6-PD) (Favism) G-6-PD Deficiency in RBCs leads to haemolytic anaemia upon exposure to some oxidizing gents like 1.Antimalarial drug, primaquine 2.Long acting sulphonamides 3.Fava beans ( favism).  Factors affecting drug response….Contd 7. Route of Administration Some drugs are incompletely absorbed after oral intake, when given intravenously; their dose has to be reduced (e.g. morphine and magnesium sulphate). MgSO4 when given orally is osmotic purgative, but its 20% solution IV used to control the convulsions in eclampsia of pregnancy. Amonoglycosides like streptomycin when given intravenously cause neuromuscular blockage, which is not observed after intramuscular injection. 8. Time of Administration Some antihypertensive and antihyperlipidemic drugs are more effective when administered at bedtime rather than at day time Hypnotics (producing sleep) act better when administered at night and smaller doses are required. 9. Effect of Climate Metabolism is low in hot and humid climate. Purgatives act better in summer while diuretics act better in winters. Oxidation of drugs is low at higher altitudes.  Factors affecting drug response….Contd Racial Differences: Castor oil, a purgative, is ineffective in Chinese. The Medriatic effect ephedrine in is absent in Negroes. Tolerance What is drug tolerance? Resistance to normal therapeutic dose of drug, producing lesser response to normal therapeutic dose is known as tolerance. Tolerance is acquired character and developed due to repeated use of drug. Examples include morphine, person is initially responsive, if continued, the effect is reduced. Thus one has to increase the dose of drug to overcome tolerance. Factors affecting drug response…Contd Cross Tolerance: Drugs with similar chemical structures or similar functions or effects can show cross tolerance. A person tolerant to drugs similar in their chemical structures is known as cross tolerance(e.g. morphine, pathedine, and codeine). Complete cross tolerance is observed in cases like diazepam and flurezepam Incomplete cross tolerance occurs with the drugs sharing the same pharmacological properties. Examples include barbiturates and general anesthetics, site of action is CNS, incomplete cross tolerance may be observed although they are not resembling chemically, but having same pharmacological properties. Factors affecting drug response…Contd Tolerance…Cont’d Tachyphylaxis (also known as acute tolerance) What is tachyphylaxis? Repeated administration of a drug at short intervals of time leads to a sudden (acute) tolerance due to depletion of neurotransmitters or endogenous receptors.  Tachyphylaxis developed with indirectly acting drugs.  Example includes ephedrine, which acts by releasing noradrenalin from adrenergic stores. After repeated administration, these stores are exhausted and pharmacological action is not restored even on increasing the dose.  Factors affecting drug response…Cont’d Drug interactions When two or more drugs are taken simultaneously by a patient, their effects can be modified. Independent effects (No interaction) The particular effects of two or more drugs can be independent one of the other while being complementary. For example, the action of an antibiotic can be independent of that of an analgesic prescribed simultaneously. The analgesic does not modify the antibiotic action and vise versa. Interactions:- The effect of a drug is modified by another drug. The interactions between drugs are observed when the drugs are taken simultaneously or with a short time interval. The consequences of this interaction can be described as additive, synergism, potentiation or antagonism.  Drug-drug interaction….Cont’d Additive effect: The effect of each drug is not affected by the other one. Thus, the effects of the two drugs equal to the summation of the effects of the two drugs when given separately. The response is not more than their total algebraic sum (represented as 1+1=2).. Aspirin + paracetamol as analgesic/ antipyretic Ephedrine + theophylline as bronchodilator Nitrous oxide + ether as general anesthetic  Factors affecting drug response…Contd Drug-drug interaction…….Cont’d Synergism The effects of 2 drugs are more than the sum of the individual drug effect (represented as 1+1=3). Examples of synergism: Acetylcholine + physostigmine (Physostigmine inhibits the action of esterase prolonging the effect of acetylcholine). Sulfonamide (effective against some microorganisms) when combined with trimethoprim is effective against a wider range of microorganisms. Potentiating: The effect of one drug is greatly increased by the intake of another drug which does not have effect (represented as 1+0=2). Example: Clavulanate-potentiated amoxycillin Antagonism:When two drugs, administered simultaneously, oppose the action of each other on the same physiological system (represented by 1+1