a Note book for introduction to drug therapy b Preface Pharmacology is the science of drugs. It is the most essential of academic science as far as understanding the treatment of different diseases, their diagnosis and prophylaxis This book was designed to cover the essential knowledge required for medical students. Our main goal is to explain pharmacological basis of drugs , their actions, mechanisms and adverse effects. The book was written in a simple, clear and concised manner. We appreciate feedback from our students to c assure further improvement to this book The Authors. Introduction to drug therapy Code DRG 208 Overall Aims of Course Is to provide the students with basic knowledge about commonly used groups of drugs affecting different body systems and their implications in therapy of disease and health promotion, the safe use of drugs as regards adverse effects, contraindications and drug interactions, have enough skills & attitude towards selection and use of drugs on rational bases, and to adopt lifelong learning d Intended Learning Outcomes (ILOs) - Knowledge &comprehension 1- Identify the pharmacokinetic, pharmacodynamics properties of different drugs affecting body systems 2- Determine clinically relevant age, sex and genetic related variations that affect response to drugs 3- Explain mechanism of drug action and the efficacy of drugs in the management of diseases 4- Point out the indications, the relative advantages and disadvantages of pharmacotherapy modalities affecting autonomic nervous, skeletal muscles & ocular system 5- Summarize the adverse effects of drugs, & contraindications of the studied drugs - Intellectual skills 1- Select the proper drug for a certain disease in the context of case study 2- Interpret the use of selected drug in proper way including: dose- interval-duration-route of administration 3- illustrate management of adverse drug reactions.& detect earliest manifestations of side effects - Practical skills 1- Calculate accurately drug’s dosage, bioavailability, plasma hal f life and volume of distribution in different patient populations -.put in consideration – appropriate route of administration , age, sex & associated diseases 2- Perform experiment on isolated tissues to detect the effect of certain drugs &site of action 3- Choose the proper drugs to treat particular patient 4- Write a prescription for selected important diseases - Professional,& communication skills and attitude 1-Demonstrate the ability to work in group and use constructive feedback on his/her performance 2-Communicate effectively with, colleagues 3-Gather, organize and appraise information including the use of information technology where applicable e Contents 1-General pharmacology 1-25 2-Automonic nervous system 26-70 3-Skeletal muscle relaxants 71-76 4-Autacoids 77-88 5-Drugs affecting eye 89-94 1 GENERAL PHARMACOLOGY Pharmacology is the science of drug. Drug: is defined as a substance used for diagnosis, prevention and treatment of diseases. Sources of drugs: 1. Plant sources e.g., atropine from the leaves of belladonna. 2. Animal sources e.g., heparin, insulin... 3. Mineral sources e.g., MgSO 4 4. Microorganisms e.g., penicillin. 5. Synthetic e.g., sulphonamides. 6. Biotechnology e.g., human insulin, Tissue plasminogen activator (TPA). Every drug has three names: 1. Chemical name: describes the chemical structure of the drug e.g., Acetyl salicylic aicd. 2. Generic (non-proprietary) name: indicates the drug group e.g., Aspirin 3. Trade (proprietary) name: the commercial property of the drug company e.g., Aspocid, Asponasr. The Food and Drug Administration (FDA) It regulates both the efficacy and safety of drugs but not of food, nutritional supplements and herbal remedies. Drug therapy involve four main processes: 1. Pharmaceutical process: The active ingredient obtained from any source should be put in proper dosage forms to be absorbed and reached the blood. 2. Pharmacokinetics process: This process concerns with absorption, distribution, metabolism and excretion of drugs. 3. Pharmacodynamic process This process studies the effects of drugs (pharmacological actions and adverse effects of drugs) and their mechanism of action. 4. Pharmacotherapeutic process This process deals with the use of drugs. 2 P harmacokinetics It means what the body does to the drug and includes: absorption distribution, metabolism and excretion. Pharmacokinetics is important to design proper dosage schedule (doses, route and frequency of administration) and to determine bioavailability. The biodisposition of a drug involves its permeation across cellular membrane barriers. - Permeation of Drugs Across Cell Membrane The cell membranes is formed of bimolecular lipid sheet, interrupted by protein macromolecules (receptors, carriers....), water filled pores and ions channels. Modes of drug transport across cell membrane I. Simple Diffusion: The drugs here pass with concentration gradient (concentration of drugs and electric of ions) through the cell membranes. No energy and No carrier are needed. Simple diffusion depends on: 1. The smaller in size and molecular weight pass faster 2. The higher gradient pass faster. 3. Slight water solubility is needed. Drug administration (IV, PO, etc.) Absorption into plasma Sit es of action Receptors Tissue storage Drug metabolism (liver, lung, blood, etc.) Drug excretion (renal, biliary, exhalation, etc.) Plasma distribution to tissues bound drug Free drug 3 4. Lipid solubility: is measured by lipid/water partition coefficient. The higher is the better absorbed. 5. Ionization which depend on pH of the medium and pKa of drug a) PKa of drug = Dissociation constant of drug which is the pH at which 50% of the drug is ionized and 50% non ionized. Importance of PKa 1. Affect absorption, distribution and excretion. 2. Alkalinization of urine → renal clearance of drugs with low PKa. 3. Acidification of urine → renal clearance of drugs with high PKa b) High lipid soluble (low ionization) better passage. c) The drugs mostly either weak acid or weak base For weak acid drugs are more unionized in acid and more ionized in alkaline media. - Aspirin and Barbiturates (weak acid drugs) - Better absorbed in stomach (acid medium) / unit surface area. - Acidification of urine decrease their excretion while, alkalinization of urine increase their excretion. For weak base drugs are more unionized in alkaline, and more ionized in acid media. - Ephedrine and Amphetamine (weak base drugs). - Better absorbed in intestine (alkaline medium). Alkaliniation of urine (decrease) their excretion while, acidification (increase) their excretion. II. Filtration - The drugs must be: water soluble and small size to pass through capillary endothelium and glomeruli. This depends on hydrostatic and osmotic pressure. - No energy and No carriers are needed. III. Facilitated Diffusion : Is similar to simple diffusion but requires a carrier e.g., Glucose uptake IV. Active transport: Drug pass against concentration gradient , so needs carrier, and energy e.g., Renal excretion of penicillin and Na + / K + pump. V. Pinocytosis: Passage of large molecules inside the cells e.g., Absorption of vit B12 and intrinsic factor by terminal ileum need energy N.B. The degree of Ionization of drug is determined by Henderson Hasselbalch equation. 4 A bsorption It is the passage of drugs fro the site of administration into systemic circulation. - Factors Affecting Drug Absorption A. Factors Related to the Drug 1. Lipid water partition coefficient: Absorption is proportional to lipid solubility. e.g., Barium chloride is lipid insoluble therefore not absorbed orally. 2. Degree of ionization: The more the drug is ionized the lesser the absorption because ionized drug are less lipophilic. 3. Valency: Ferrous salts are better absorbed orally than Ferric salts. 4. Nature of the drug: Inorganic iron is better absorbed than organic iron. 5. Pharmaceutical form: Solutions > Suspension > Tablet. ** Drugs Which are destroyed by gastric juice or those irritant on stomach are administered in enteric coated form e.g., Sodium salicylate OR Drugs may be given in sustained release form to prolong their duration. B. Factors Related to the Patient 1. Route of administration: I.V > inhalation > I.M. > S.C. > Oral > Skin. 2. Absorbing surface: a) Area and vascularity of absorbing surface: absorption is directly proportional to both area and vascularity. Rubbing of injection site increase vascularity and absorption. b) State of Absorbing Surface: e.g., Atrophic gastritis and malasorption syndrome decrease rate of absorption of drugs. 3. Rate of general circulation: In shock, peripheral circulation is reduced and absorption decrease, so avoid subcutaneous injection. 4 Specific factors: e.g., Intrinsic factor of the stomach is essential for vitamin B 12 absorption. 5. Presence of other drugs: e.g., Adrenaline induces vasoconstriction so delay absorption of local anaesthetic drugs and calcium decrease oral absorption of Tetracyclines. 6. pH within the gut: a) Absorption of weak acidic drugs starts in stomach. b) Weak base drugs are absorbed from intestine. 7) Gastric empty: Decreased gastric emptying will increase the rate of absorption of slowly dissoluted drug. * Metoclopramide increases gastric emptying → decrease Digoxin absorption and increases. * Paracetamol absorption (opposite Atropine effect). 5 - First pass effect (pre-systemic metabolism) = inhibits bioavailability Where drugs must pass through gut mucosa and liver before reaching systemic circulation. a) Hepatic first pass effect : Some drugs are inactivated in liver before reaching system circulation e.g., Testosterone, Lidocaine and Nitroglycerin.. b) Gut first pass effect: e.g., Benzyl penicillin (destroyed by gastric juice) and Insulin (destroyed by gastric enzyme). OR not absorbed orally e.g., Streptomycin (high PKa and ionized). c) Pulmonary metabolism: Nicotine (aerosol inhalation). Sublingual Parental and Rectal routes bypass first pass effect. N.B.: To overcome hepatic first pass do not use oral route or increase the dose (Morphine and Propranolol). 6 D istribution A) Patterns of Distribution 1. Single compartment (intravascular): Substances with relatively high molecular weight e.g., Dextran and Heparin are retained in the plasma as they can not pass through vascular endothelium. 2. Two compartments: (Intravascular and interstitial). Drugs that pass capillary wall but can not pass across cell membranes are localized in the extracellular fluid e.g., Quaternary Ammonium compounds, Mannitol and NaCl. 3. Multicompartment (Extracellular and Intracellular): Drug is distributed allover the body plasma, extracellualr and intracellular fluids. It is usually has a low molecular weight and is lipid soluble e.g., Alcohol. 4. Tissue Reservoirs: Special affinity for specific tissue g.., Calcium precipitated in bones, Iodide in thyroid gland-Tetracycline in bone and teeth. 5. Blood brain barriers (BBB) a) Endothelial cells of brain capillaries are characterized by presence of tight intercellular pores, thus the drug molecules to pass through must be lipid soluble and non-ionized. b) Inflammation increases the permeability of penicillin and aminoglycosides (can pass in meningitis). In tuberculous , rifampcin,pyrazinamide are effective as they can pass ,while,streptomycin can not. c) Quarternary NH 4 compound can not pass while secondary and tertiary can pass. 6. Placental barrier a) Placenta behaves as cell membrane but the excretory and enzymatic mechanisms in foetus are underdeveloped, so level of the drug will be high and prolonged. b) Drugs passing through placenta can cause congenial malformations especially in first trimester (teratogenic) e.g.,Thalidomide *Oral anticoagulants--------------------- fatal hemorrhage in newbon *Oral hypoglycemia.--------------------- neonatal hypoglycemia *Antithyroid drugs----------------------- neonatal goiter&hypothyroidism.. ,* During labour : Morphine ---------- neonatal asphyxia. B. Binding of drugs to plasma proteins Bound fraction chiefly to albumin . It is inactive and is not metabolized or excreted and acts as reservoir . Binding to plasma proteins is reversible and is not selective and drugs highly bound to plasma proteins are in general expected to persist in body longer than those less bound. 7 The bound drug is act as reservoir which containuously releases the free part .This prolong the t ½ of the drug. Free fraction of drug is active, diffusible and available for biotransformation and excretion. Hypoalbuminemia raise the free fraction of some drugs, e.g., Diphenylhydantoin. Competition for binding between drugs(Drug interactions) When a patient taking a drugA, such as warfarin, is given a drug,B such as a sulfonamide (Warfarin is highly bound to albumin, and only a small fraction is free). When sulfonamide is administered, it displaces warfarin from albumin, leading to a rapid increase in the concentration of free warfarin in plasma causing bleeding. Nonsteroidal anti-inflammatory drugs e.g., Phenylbutazone, Salicylates can displace oral anticoagulant from plasma protein → bleeding. Sulphonamides can displace bilirubin from plasma protein → Hyperbilirubinemia. In infants, due to defective conjugation → bilirubin will pass to brain → kernicterus. 8 B iotransformation - Metabolism: It is the metabolic conversaion of drug molecules from lipid soluble, non ionized and active drugs to water soluble, ionized and inactive to be easily excreted. Biotransformation reactions occur in two phases: Phase I (Non Synthetic Reactions): Definition: It means modification of drug molecule via oxidation, reduction and hydrolysis. Phase I reactions may result in: 1. Inactivation of drugs, e.g., Most of drugs. 2. Conversion of active drug (phenacetin) → active metabolite (Paracetamol). 3. Conversion of inactive drug (cortisone) → active (cortisol). 4. Conversion into toxic compound e.g., Methanol → Formaldehyde. Phase II (Synthetic and Conjugation) Definition It means conjugation with endogenous compounds via the activity of transferases. They result usually in drug inactivation but glucuronide metabolite of Morphine is active (Morphine-6- glucuronide). N.B.: Reversal of order of the phases may occur with some drugs i.e., isoniazid is first acetylated (phase II) and then hydrolyzed to isonicotinic acid (phase I). Conjugation of compound with: - Glucuronic acid: Chloramphenicol, Morphine. - Acetic acid: Sulphonamides, Hydralazine and Isoniazid. - Glycine: Salicylates - Methyl group: Catecolamiens and Histamine Site of Metabolism : Occurred mainly in the Liver and also, in lung, kidney, GIT., skin and plasma. Metabolism is mainly controlled by cellular enzymes which may be: a) Microsomal Enzymes: 1) Found in endoplasmic reticulum of the liver. 2) They catalyze most of oxidative reactions by cytochrome P-450, 3) Responsible for reduction, oxidation, hydrolysis and glucuronide conjugation only. 4) Lipid soluble drugs. b) Non Microsomal Enzymes: 1) Found in cytoplasm, mitochondria of all organs. 9 2) They are concerned with oxidation, reduction, hydrolysis and conjugation except with glucuronic acid. 3) Water soluble drugs - Factors Affecting Hepatic Microsomal Activity 1) Drugs: A. Enzyme Activators (Inducers) They increase rate of enzyme synthesis Phenobarbitone, Rifampicin, Diphenylhydatoin, Androgens ,Griseofulvin and smoking. Enzyme induction results in: - Decrease activity of some drugs as oral anticoagulants, oral contraceptives and corticosteroids due to increase metabolism. - Tolerance to B arbiturates (due to ↑ their own metabolism). B. Enzyme inhibitors as Cimetidine, Chloramphenicol, Oestrogen, Progesteron Sodium Valproate, Tolbutamide and Grapefruit so, increase the effect of drugs (exaggeration) 2) Age i.e. in premature Neonate can not conjugate with glucuronic acid e.g., Chloramphenicol → Grey baby syndrome; also, in elderly. 3) Sex: Androgn, stimulate drug metabolism, while female hormones are inhibitors. 4) Starvation: Decrease enzyme activity. 5) Patholgoical conditions: Liver disease and cancer 6) Genetic factors: eg Succinyle choline apnea. 10 E xcretion Drugs are eliminated through one or more of the following routes in the form of free or metabolized product. 1. Renal (main site) Glomerular filtration: The drug should be unbound, non volatile, low molecular weight, water soluble and pass along concentration gradient e.g., Mannitol. Active tubular secretion: Such as Pencillin, Probenecid. Passive tubular reabsorption: Drugs should be unionized, lipid soluble and is affected by pH of urine. 2. Alimentary Tract: a) Salivary glands : e.g., Iodides, Rifampicin and Aspirin b) Stomach: e.g., Morphine so, stomach wash must done in Morphine toxicity. c) Large Intestine: e.g., Tetracycline, Streptomycin. d) Liver Bile: - Ampicillin and Rifampicin are excreted in active form and used in cholecystitis and in typhoid carriers. - Morphine and phenolphthalein in conjugated form, pass through enterohepatic circulation. 3. Skin e.g., Rifampicin (red color), vitamin B 1 4. Lungs e.g., Gases and volatile anesthetics 5. Milk: The drugs that pass in milk are contraindicated during breast feeding: 1-CNS drugs: Morphine, Amphetamine, alcohol,&nicotine. 2-Antibiotics: Chloramphenicol, tetracyclines&sulfonamides. 3-Hormones: Oral contraceptive ,corticosteroids &bromocriptine. 4- Others: Oral anticoagulants, antithyroid and laxatives. Lactating mothers should take drugs immediately after nursing And\or 3 — 4hrs before the next feeding. 11 S ome Pharmacokinetics Principles - Plasma half life of a drug (t ½ ) Rate of attainment of steady state concentration of a drug the plamsma (Lippincott’s illustrated reviews). - It is the time needed for concentration of drug to decrease in plasma to its half. It depends on drug clearance (distribution, metabolism and excretion). It is a measure for drug elimination and frequency. T ½ = o693 V d \CL s (systemic clearance) - Half life (t½) is important to indicate time required to reach steady state concentration (Css) which is reached after 4-5 half lives after repeated administration of drugs at regular interval and when rate of elimination of the drug equal rate of administration. It is constant in first order kinetic and is increased in zero order kinetic. - Most of drugs more than 95% will disappear after 4-5 t ½ after stopping drug administration. 100% 1/2 t 50% 1/2 t 25% 1/2 t ...... etc. Clinical Importance of t½: 1. It indicates time required to reach steady state concentration (Css) 2. It determines the dosage interval (frequency). 12 - First Order Kinetics Most drugs follow first order kinetics. 1. It is a linear type of kinetic and t 1/2 is constant. 2. Kinetics of drug are proportional to its time concentration. 3. Area under curve (AUC) is proportional to drug concentration e.g., Aspirin and Phenytoin in (small dose). 4. A Constant fraction of the drug is eliminated per unit time i.e., 80 mg h 4 40 mg h 4 20 mg h 4 10 mg. -Zero order kinetics 1. It is a non linear kinetic and t 1/2 will increase with dose Phenytoin, Salicylates and Ethylalcohol (large dose). 2. Limited capacity of drug's kinetics due to saturation of enzyme or carrier. 3. AUC is not proportional to drug concentration. 4. A constant amount of drug is eliminated per unit time i.e., 80 mg h 4 70mg h 4 60mg h 4 50 mg h 4 40 mg ...etc. - Apparent volume of distribution (Vd) Total amount of drug in body (mg) Apparent volume of distribution (Vd) = ––––––––––––––––––––––––––––––– Concentration in plasma, (mg/ml) V d is increased by increased tissue binding, decreased plasma binding and increased lipid solubility. Importance of Vd: 1. It is an estimate of the extent of extra vascular tissue uptake of drugs a) Small Vd e.g., frusemide indicates very low tissue uptake b) Large Vd e.g., digoxin indicates extensive tissue distribution 2. In case of toxicity: a) Dialysis is not useful for drugs with large Vd b) Dialysis is useful for drugs with low Vd (most of the drug in circulation). 3. Vd is important to calculate size of loading dose: LD = Vd x Css 4. Vd is directly proportionate to half life and inversely proportionate to the elimination rate of the drug. Time Lo g conc. Time Lo g conc. 13 - Clearance of a drug (CLs) It is the factor that predicts the rate of elimination in relation to drug concentration in blood or plasma. Rate of elimination Systemic clearance = ––––––––––––––––––––––––– Concentration in plasma Total body clearance (CL total ) = CL hepatic + CL renal + CL pulmonary + CL others ) - Bioavailability 1. It is the fraction of unchanged drug reaching systemic circulation following administration by any route. 2. It is used to indicate the rate at which administered dose reaches the general circulation. 3. After IV administration bioavailability will be 100%. Factors that influence bioavilability: 1. First-pass metabolism: A- Hepatic first pass effect : Nitroglycerin B- Intestinal first pass effect : Estrogen C- Pulmonary first pass effect: Nicotine 2. Solubility of the drug: 3. Chemical instability 4. Nature of the drug formulation TIME Drug AUC OR AL Plasma concentration Plasma concentration TIME AUC I.V Drug 14 - Bioavailability of a Route Area under the curve (AUC) of the route x 100 It is estimated by: ––––––––––––––––––––––––––––––––––––––– Area under the curve (AUC) IV N.B.: Bioequivalence: Means that two related drugs with a significant difference in bioavailability. - Prolongation of Duration of Action of Drugs A) Delay absorption: 1. Reduction of vascularity e.g., Adrenaline with local anesthetics. 2. Reduction of solubility, e.g., Procaine penicillin. 3. Mixing with oil, e.g., Vasopressin Tannate in oil. 4. Implantation of drug sc e.g., DOCA in Addison's disease. 5. Using sustained release form. B. Delay metabolism by enzyme inhibitors., e.g. Cimetidine and Grapefruit. C. Delay excretion, e.g., Probenecid inhibits tubular secretion of Penicillin. D. Increasing binding to plasma protein, e.g., Sulphadimethoxine.