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Reading assignments: Katzung’s Basic & Clinical Pharmacology , 13th Edi ,Ch-1,p1-10; Lippincott Pharmacology,6th Edi,Ch-1,p1-6; Sanjib Das M.B.B.S.,M.D.,P.G.D.H.A. 1 Learning Objectives Discussing Pharm as a course for Step1 USMLE Define the different terms presented Identify sources of drugs, and recall their nomenclature Describe the different routes of drug administration and list their merits and demerits Describe the different phenomena of pharmacokinetics such as Absorption and Bioavailability 2 In current USMLE STEP 1 exams 2 types of questions are asked -straight recall -integrated (horizontal/vertical)-mostly 2nd or 3rd order Ref: www.nbme.org PHARMACOKINETICS GIT DRUGS CNS DRUGS PHARMACODYNAMICS ENDOCRINE CHEMOTHERAPY CVS & RELATED DRUGS Quiz1 5% BL1 25% TOXICOLOGY Quiz2 5% BL2 25% Tested in Shelf CLINICAL THERAPEUTIC PRESENTATION (10%) External Shelf Exam (30%) High yields topics are 1.General Principles of kinetics & dyanamics (approx.10) 2.ANS ( mostly. physio-path vignetted Qs.)(approx.10%) 3.CVS (approx.20%) 4.CNS (approx.20%) 5.Antimicrobial & Anticancer (approx.20%) 6.Endocrinal drugs (approx.8%) & Low yield topics are 7.Miscell:GI drugs, Blood,Autacoids etc. (more number questions are being asked these days) (approx.5%) Scanning lecture notes Text (while considering what lectures had emphasized) Key study objectives (Primary-know very well;Secondary-pretty well;Others-only familiarization) Notes & review section with emphasis with key objectives Qs. After every topic Analyze mistakes Review poorly understood areas Subject practice tests Prescribing the most appropriate drug for a Clinical Scenerio?think like a physician Introductory Information Integrative science Have to understand how the whole body works Pharmacokinetics How the body affects Drugs? Pharmacodynamics How Drugs affect the body? Adverse effects Deals with Risks to the patient! Pharmacotherapeutics How to use drugs clinically? Penicillin G: Beta-lactam ring Penicillinase sensitive Acid labile Tubular secretion Inhibits cell wall synthesis Highest Chemottherapy Index Hypersensitivity Used mainly for gram positive bacteria How others differ: Amoxicillin; acid stable; broad spectrum Oxacillin; acid stable; penicillinase resistant Nafcillin; biliary excretion; penicillinase resistant Template for drug information Pharmacokinetics-absorption -distribution -metabolism -excreton Pharmacodynamics-moa -indication -a/e LEARN EACH PROTOTYPIC DRUG INFORMATION USING THIS TEMPLATE MEMORIZE HOW THE OTHER DRUGS FROM THE SAME GROUP DIFFERS FROM PROTOTYPIC DRUG D-D Interaction -both kinetic & dynamic level Toxicity -both kinetic & dynamic level -‘Prototype’ -most commonly used drugs clinically -Drugs with atypical pharmacological attributes -existing category wise -common endings or common characteristics with in the name. -only a few pneumonic Pre-read before every lecture Good Luck!! 14 Greek words: Pharmacon: an active principle (a drug or poison) Logos: Knowing A science that deals with fate and the mechanism of action of drug in body. Pharmacology covers both aspects of basic and clinical sciences 15 Molecular pharmacology 2. Pharmacogenetics 3. Drug metabolism 4. Toxicology 1. Clinical Pharmacology (pharmacotherapeutics) 16 2. WHO (1966) defined drug as “any substance or product that is used or intended to be used physiological systems or pathological states can also be defined as any substance used for the purpose of of a disease in human, plants or animals. 17 Goodman&Gilman’s The Pharmacological Basis of Therapeutics, 12th Edition, PP:75 18 A drug molecule should be safe and effective (safety and efficacy) If drug is not safe it shows toxicity 19 SOURCE OF DRUGS 1-Natural resources (Including plants, animals, microorganisms, minerals) Plants –Morphine, Atropine, Epedrine, Vincristine, Vinblastin, Taxol, Caffein, Cocain Animals – Gelatin, Heparin, Insulin Human – GH, HCG Minerals – Iron, Al(OH)3, BaSO4 Microorganisms – Penicillin, Amphotricin B, Gentamycin, Doxorubicin, Vancomycin 2- Synthetic and semisynthetic –Aspirin, Acetaminophen, Oxycodone, 3- Genetic Engineering: - Alcohol, GH, Insulin, 20 Pharmacokinetics (PK) (The fate of drug in body or what body does to drug) Pharmacodynamics (PD) (The effect of drug on body or what drug does to body) Pharmacogenetics (PG): Different genotypes in a population have different receptors, different drug metabolizing enzymes or transporters resulting to different susceptibility to drugs 21 Movement (Kinetic) of drug in the body= fate of drug in the body What body does to drug= what happens to a drug in body 22 Greek words pharmacon+ dynamis (power) - action of the drug inside the body - what the drug does to the body or how the drug handles the body physiological and biochemical effects of drugs, their mechanism of action at macromolecular/ subcellular / organ levels 23 Use this slide to organize your understanding of Pharmacokinetics & Dyamics Intramuscular >>>>>>>>>>>>>>>>>>>>>>>> (Topical or subcutaneous) Skin >>>>>>>>>> NBME reservoir Efficacy Toxicity Figure out step by step fate & D-R Interactions following administration of a drug by Oral ,Inhalational and IV route. 25 NBME 26 3 kinds of names (a) Chemical name Accepted as IUPAC name (International Unit of Pure and Applied Chemistry nomenclature) NBME (b) Non-proprietary name (Generic) Accepted by a competent scientific body such as the United States Adopted Name (USAN) Council (c) Proprietary name (Brand): Name assigned by the manufacturer(s) One drug may have multiple brand names 27 Chemical (IUPAC) name: (2S)-1-[(2S)-2-methyl-3-sulfanylpropanoyl] pyrrolidine-2-carboxylic acid Generic name: >>> used on examinations: Diazepam Look for common endings Propranolol Doxazosin Captopril Brand Name: Capoten (Bristol -Myers Squibb) NBME 28 Brand names are not tested in usmle exams – but still you need to know for few most Prescribed Drugs in USA because----- 29 The 10 Most Prescribed Drugs in USA Brand names are not tested in NBME exams Hydrocodone (combined with acetaminophen) -- 131.2 million prescriptions Generic Zocor (simvastatin), a cholesterol-lowering statin drug -- 94.1 million prescriptions Lisinopril (brand names include Prinivil and Zestril), a blood pressure drug -- 87.4 million prescriptions Generic Synthroid (levothyroxine sodium), synthetic thyroid hormone -- 70.5 million prescriptions Generic Norvasc (amlodipine besylate), an angina/blood pressure drug -- 57.2 million prescriptions Generic Prilosec (omeprazole), an antacid drug -- 53.4 million prescriptions (does not include over-the-counter sales) Azithromycin (brand names include Z-Pak and Zithromax), an antibiotic -- 52.6 million prescriptions Amoxicillin (various brand names), an antibiotic -- 52.3 million prescriptions Generic Glucophage (metformin), a diabetes drug -- 48.3 million prescriptions Hydrochlorothiazide (various brand names), a water pill used to lower blood pressure -47.8 million prescriptions. 30 THE NATURE OF DRUGS Size and molecular weight (MW): Drugs in common use vary in size from MW 7(lithium) to over NBME MW 50,000 (thrombolytic enzymes). The majority of drugs, however, have molecular weights between 100 and 1000. Drug-receptor bonds: NBME Drugs bind to receptors with a variety of chemical bonds. These include very strong covalent bonds (which usually result in irreversible action), somewhat weaker electrostatic bonds (eg, between a cation and an anion), and much weaker interactions (eg, hydrogen, van der Waals, and hydrophobic bonds). http://www.google.com/imgres?imgurl=http://thedrevilshow.com/wp-content/uploads/2013/11/routes-of-drug-delivery.jpg&imgrefurl =http://thedrevilshow.com/?p%3D1051&h=480&w=882&tbnid=yjomFZLHdXMKmM:&zoom=1&docid=Kme_4MEzkzrGjM&ei =d7Y-U5anFKiU0QGp64HQAg&tbm=isch&client=firefox-a 32 Routes of Administration 34 Merits: Most common, convenient, Noninvasive (No need for surgical procedure) self-medication possible economical Demerits: cannot be used for uncooperative / vomiting patients. certain drugs are not absorbed or destroyed by the gastric juices cannot be given in emergencies Drugs are more likely to undergo first-pass metabolism 35 Low Bioavailability by oral route-why? Destroyed in gut (1) Dose Not absorbed (2) Destroyed by gut wall (3) NBME Destroyed by liver (4) to systemic circulation (3)+(4) are called Pre-systemic metabolism (1st Pass Metabolism) What is the difference between 1st Pass Metabolism & real metabolism? NBME No first pass metabolism Fast onset of action compared to oral route Example ○ NG ○ Lorazepam (Ativan) (3)+(4) are called Pre-systemic metabolism (1st Pass Metabolism) 37 Roach’s Introductory Clinical Pharmacology, 9th Edition 38 NBME Merits Immediate action, so useful in emergencies Avoids gastric juices / first pass metabolism Can be used in unconscious patients Irritant drugs 39 Demerits Painful Risk of thrombophlebitis Expertise required Aseptic condition needs to be maintained, hence costly Attains high concentration in plasma & tissues If administered very rapidly – can cause organ toxicity 40 Basic methods for delivering iv therapy Making the right choice! 41 Continuous Infusion 42 Intermittent Infusion 43 Direct Injections 44 45 Mild irritant drugs can be given Absorption is quick Volume injected is max. 10 ml No first-pass metabolism 46 Roach’s Introductory Clinical Pharmacology, 9th Edition 47 Absorption is slow and constant -produce sustained effect Max 2 ml can be injected Self-administration possible – e.g., Insulin Absorption is slow Drug volume should be small (e.g. BCG vaccination, drug sensitivity testing) 48 e.g. Steroids in Rheumatoid arthritis http://www.rheumatologynetwork.com 49 Used where drugs (lipid insoluble/ highly polar) do not cross blood brain barrier but required action in brain or spinal space. strict aseptic precautions should be taken. pedagogyeducation.com 50 Examples: 1. 2. 3. 4. Amphotericin B in cryptococcal meningitis Spinal anesthesia Opioid analgesics EPIDURAL 51 Application of drugs to skin or to the mucus membrane like eye, ear, mouth, airways, rectum and vagina 52 Relatively little first pass metabolism due to the high vascularity of rectum Used in patients with vomiting /or where drug induces vomiting Larger amount and drugs with unpleasant taste can be administered Examples: Diclofenac, Acetaminophen http://nursing-knowhows.blogspot.com 53 Absorption to blood circulation Protection of Skin, No absorption Color Atlas of Pharmacology, Editted by: Heinz Lüllmann, Thieme, 2005 54 NBME TRANSDERMAL DELIVERY Administration of drugs to skin for systemic effects Provides uniform plasma concentration Follows zero order absorption Less inter-individual variations No first pass metabolism Convenient – better compliance e.g, Estradiol, Nitroglycerin, Scopolamine In Transdermal patch delivery polymers control the release of drugs 55 56 Delivery of drug to respiratory tract Alveolar epithelium offers good surface area for lipid soluble drugs Very rapid onset of action due to large surface area and more vascularity Drugs administered in gases or aerosol form Rapid action No/less systemic toxicity dose required is less e.g., inhalational anesthetics (Nitrous oxide, ether, halothane), Albuterol, Steroids – Beclomethasone in Asthma 57 Demerits training for use (skill required); so difficult in children and geriatric patients Expensive Can not be given to unconscious patients 58 It can be used for either local or systemic administration of drugs Example of local effects: Decongestive effect (Oxymethazoline) Example of systemic effects: Antimigraine drugs (Rizatriptan), insulin or flu vaccine 59 The nasal cavity is covered by a thin mucosa which is well vascularised. Therefore, a drug molecule can be transferred quickly across the single epithelial cell layer directly to the systemic blood circulation without first-pass hepatic and intestinal metabolism. The effect is often reached within 5 min for small drug molecules Drugs with poor absorption or extensive first pass metabolism can be given in this way Small dosage of administration is most important pitfall in using these drugs 60 61 Dose (Dosage): The amount of Drug given to a patient (e.g. 200 mg of Ketoconazole or 10 units of Insulin) Dosage form: The physical form of a drug given to a patient (e.g. Tablet, Capsule or Ampoule) 62 Oral Dosage forms: Tablet, Capsule, Suspension, Emulsion, Sachet (powder, granules), Syrup,….. Topical dosage forms: Creams, Ointments, Lotions, gels, Suppositories, Aerosols, Foams, Douch, pastes,….. Parenteral Dosage forms: Injectables (Ampoule, Vial, Infusions,…..) 63 64 Greek words Pharmacon (drug)+ kinesis (movement) - movement and alteration of the drug inside the body - what body does to the drug or how body handles the drug (ADME) - Absorption (A), - Distribution (D), - Metabolism or Biotransformation (M) - Excretion (E) 65 - Passage of drugs from the site of administration to the systemic circulation (plasma , serum or blood) - Intravenous (IV) administration does not involve absorption, and there is no loss of drug Processes of absorption NBME 1. Simple or Passive diffusion 2. Carrier-mediated facilitated diffusion 3. Active transport 4. Pinocytosis 66 NBME The rate of Absorption of drug from site of absorption to central compartment (Blood) is proportional to drug concentration gradient across the barrier, the surface area of the absorption and the thickness of barrier (Fick’s first law). Based on Fick’s first law the diffusion goes from high concentration to low concentration Flux (molecule per unit time) dc / dt (c1 c2 ) Surface area Diffusion coefficient thickness 67 Non-permeable membrane 68 Semi-permeable membrane 69 Semi-permeable membrane Equilibrium 70 NBME 71 NBME 72 NBME - Majority of drugs are absorbed by this phenomenon - Transfer of drugs from the region of higher concentration to the region of lower concentration (along the concentration gradient) - No energy, no carrier required Not saturable and not inhibited - lipid soluble drugs readily move through the lipid bilayer by this process - - Driving force: concentration gradient 73 74 NBME Movement occurs along the concentration gradient - Carrier needed; but no energy required - highly selective (specific), competitive and saturable - - Examples: absorption of Vit B12 from the gut, uptake of Glucose through the membrane of red blood cells Mostly water soluble molecules pass through this process 75 NBME 76 NBME - Movement is against the concentration gradient Carrier and energy (both) are required Highly selective (specific), competitive and saturable examples: Glucose absorption from gut lumen into intestinal epithelial cells, Levodopa absorption 77 NBME Primary Active Transport Secondary Active transport 78 NBME Directly using of metabolic energy to transport molecules across the membrane by coupling of carrier to ATP (e.g. Na+-K+ ATPase) 79 NBME The sodium ions and ATP bind to the protein. Then the hydrolysis of ATP causes the protein to change conformation and transport the sodium ions to the other side of the cell membrane. As the potassium ions are bound to the protein on the outside of the cell, the sodium ions are released and the potassium ions are moved to the inside of the cell 80 NBME 81 NBME The transport across a biological membrane of one solute (s1) against its concentration gradient is energetically driven by the transport of another solute (s2) in accordance with its concentration gradient. 82 NBME Secondary active transporters are classified as either symporters or antiporters. Symporters, also termed cotransporters, transport S2 and S1 in the same direction, whereas antiporters, also term exchangers, move their substrates in opposite directions 83 NBME The driving force for this type of transport therefore is stored in the electrochemical potential created by the concentration difference of S2 across the plasma membrane, Depending on the transport direction of the solute. 84 85 A mode of endocytosis used for extracellular fluids Small particles coming into the cells by forming an invagination The formed vesicles will fuse with lysosymes and the enzymes release their contents The hydrolysis needs energy through ATP but at the end due the usage of energy from engulfed liquids (lipids) a surplus amount of energy will produce It is non specific and if it is specific it is called Receptor Mediated Endocytosis It has small role in drug transport however some medical proteins are use this method for their transport 86 87 Qs Visualize the interrelationships between various processes/steps of Pharmacokinetics & Pharmacodynamics following administration of a drug by oral route. Relationships betweenPharmacokinetics , Pharmacodynamics & Pharmacogenetics Drug Nomenclature Merits & demerits of various routes of drug administration with an emphasis on oral,s/l, intravenous,im,s/c & TDD routes Why s/l routes of cyclobenzamine is preferred over oral in the treatment of fibromyalgia? What is the diff.between dose & dosage Know various processes of drug absorption through various routes. What are the basic differences between Simple or Passive diffusion,Carrier-mediated facilitated diffusion & Active transport 88 PowerPoint Slides Several of the PowerPoint slides are Copyright © 2002-04, the American Society for Pharmacology and Experimental Therapeutics (ASPET). All rights reserved. Some of slides in this session are from the above mentioned format and are free for use by members of ASPET. Some others are from various sources like text book, recommended books, slides of Drs. Anooshirvan Shayeganpour (professor, SABA school of Medicine),S.Kacker (professor, Clinical Pharmacology & Therapeutics, MUA)& S. Akbar (ex. professor, Pharmacology ,MUA) Core concepts of various USMLE High yield review series like Kaplan ,BRS etc. are thoroughly explored & integrated whenever necessary