A primer on pharmacology Universidade do Algarve Faro 2017 by Ferdi Engels, Ph.D. 1 2 1 3 Utrecht university campus ‘de Uithof’ Dept. of Pharmaceutical Sciences Division of Pharmacology 4 2 Bachelor and master education Ferdi Engels, PhD ‐ Associate professor of pharmacology ‐ Director of Undergraduate School of Science PhD training Research expertise 5 for today 1. Understand the main concepts of pharmacokinetics Main concept 2. Be able to apply this new knowledge 6 3 Pharmacology is about drugs………. Drugs = chemicals that alter physiological processes in the body for treatment, prevention, or cure of diseases input output (administration of the drug) (biological response) ‐ dose ‐ no effect ‐ frequency of administration ‐ beneficial effects ‐ route of administration ‐ adverse / toxic effects onset, intensity, and duration of therapeutic effects 7 Pharmacology is about drugs………. Drugs = chemicals that alter physiological processes in the body for treatment, prevention, or cure of diseases What does the body do to the drug? pharmacokinetics What does the drug do to the body? pharmacodynamics 8 4 Thursday, June 15 Lecture on topic 1 Workshop on topic 1 Friday, June 16 Lecture on topic 2 Workshop on topic 2 Course Topic 1 Course Topic 2 9 Rosenbaum ‐ Basic pharmacokinetics and pharmacodynamics: an integrated textbook and computer simulations, 1st ed. (2011) input output (administration of the drug) (biological response) ‐ dose ‐ no effect ‐ frequency of administration ‐ beneficial effects ‐ route of administration ‐ adverse / toxic effects onset, intensity, and duration of therapeutic effects Examples of common daily doses and dosing intervals 10 Rosenbaum ‐ Basic pharmacokinetics and pharmacodynamics: an integrated textbook and computer simulations, 1st ed. (2011) 5 Pharmacokinetics derives from Greek words: pharmackon = drug kinetikos = moving Study of drug movement into, around, and out of the body or ADME = absorption, distribution, metabolism, and elimination Time course of drug concentrations in body compartments 11 Lippincott’s illustrated reviews: Pharmacology 5th ed (2012) Assumption: plasma concentration reflects drug concentration at site of action 12 Rosenbaum ‐ Basic pharmacokinetics and pharmacodynamics: an integrated textbook and computer simulations, 1st ed. (2011) 6 Why study pharmacokinetics? ‐ Natural variation in population yields average ADME characteristics ‐ ADME characteristics may be influenced by age, sex, disease, drug use, etc. ‐ Therapeutic range of drugs may vary Guys With Large Dongles Totally Make Perfect Internet Connections Gentamycin Methotrexate antibiotic oncolytic, DMARD Warfarin Phenytoin anticoagulant antiseizure Lithium Insulin bipolar disorder antidiabetic Digoxin Ciclosporin atrial fibrillation immunosuppressant Theophylline COPD, asthma 13 Why study pharmacokinetics? ‐ Natural variation in population yields average ADME characteristics ‐ ADME characteristics may be influenced by age, sex, disease, drug use, etc. ‐ Therapeutic range of drugs may vary unsafe MEC = minimum effective concentration MTC = maximum tolerated concentration Therapeutic range – between MEC and MTC uneffective 14 Rosenbaum ‐ Basic pharmacokinetics and pharmacodynamics: an integrated textbook and computer simulations, 1st ed. (2011) 7 Routes of drug administration 15 Meyer & Quenzer – Psychopharmacology: Drugs, the Brain and Behavior (2005) Oral vs. intravenous administration elimination phase absorption phase 16 8 ADME ‐ Drug absorption Drug absorption requires movement across membranes (except after intravenous application) most usual a= transcellular pathway b = paracellular pathway c = transcytosis and receptor‐ mediated endocytosis d = absorption into the lymphatic circulation via M‐cells of Peyer's patches antigen‐presenting cells 17 Goldberg & Gomez‐Orellana ‐ Nature Reviews Drug Discovery 2, 289‐295 (April 2003) ADME ‐ Drug absorption Rate of transmembrane diffusion determined by: ‐ concentration gradient ‐ permeability of barrier (membrane) Lipid diffusion therefore Lipophilic and uncharged drug molecules are absorbed fastest !! logP pKa 18 9 ADME ‐ Drug absorption Lipophilic drugs are absorbed faster []drug Partition coefficient P octan ol []drug water separatory funnel Log P instead of P (smaller range of values) 100 logPP 2 102 lipophilic 1 1 logPP 2 102 hydrophilic 100 19 ADME ‐ Drug absorption Uncharged drugs are absorbed faster Drug ionisation is dependent on pH and pKa The effect of pH on drug ionisation Acid dissociation constant pKa • quantitative measure of the strength of an acid in solution []HA [][] A H Ka []A pH pKa log Henderson‐Hasselbalch equation []HA • at pH = pKa, half of the acid is protonated 20 Waller et al ‐ Medical Pharmacology and Therapeutics (2005) 10 ADME ‐ Drug absorption example Stomach: pH ≈ 2 Intestines: pH ≈ 6‐7 exampleQ: Where is aspirin absorbed best? Q: Explain alkaline diuresis used with aspirin poisoning. Aspirin (a.k.a. acetylsalicylic acid) –pKa= 3.5 by IV sodium bicarbonate A: Uncharged in stomach, charged in intestines BUT buzzing moment What about its dissolution in acid environment? What about surface area for uptake? Le Chatelier’s principle []HAAH [][] When a change is imposed on a system Ka at equilibrium, the equilibrium will shift to counteract the change. 21 ADME ‐ Drug absorption kabs = Absorption rate constant http://www.boomer.org/c/p4/c03/c0318.html 22 11 ADME ‐ Drug absorption First‐pass effect: 1 g vs. 2 g dose Barr –Drug Inform. Bull. 3: 27‐45 (1969) Incomplete drug absorption through: . Incomplete release from the dosage form . Degradation in the GI lumen . Poor permeation across GI epithelial barrier . Active efflux into GI lumen . Biliary excretion . Metabolism 23 http://tmedweb.tulane.edu/pharmwiki/doku.php/bioavailability_the_first_pass_effect ADME ‐ Drug absorption AUC F (tablet )*100 AUCiv Extent to which a drug reaches F = Bioavailability the systemic circulation Example: Diclofenac Fiv = ?100% Ftabl = 50% 24 http://tmedweb.tulane.edu/pharmwiki/doku.php/bioavailability_the_first_pass_effect 12 ADME ‐ Drug distribution Blood • about 5.5 liter (8% of body weight) • composed of blood cells and plasma Plasma • about 55% of blood volume • about 90% water • further contains proteins, glucose, minerals, amino acids, hormones, CO2, waste albumin Serum • plasma without fibrinogen and other clotting factors 25 ADME ‐ Drug distribution Drugs may bind to plasma proteins according to the law of mass action: k1 [][]DP [ DP ] k1 free drug+= bound drug plasma concentration Cp clinically important easy (and cheap) to measure 26 13 ADME ‐ Drug distribution Central compartment Peripheral compartment 27 Raffa et al – Netter’s illustrated pharmacology (2005) ADME ‐ Drug distribution Plasma concentration after: 70 kg male 500 mg paracetamol plasma 3.5 L 143 mg/L extracellular fluid 14 L 36 mg/L body water 42 L 12 mg/L https://www.easycalculation.com/medical/plasma‐volume‐calculator.php 28 14 ADME ‐ Drug distribution Distribution of drug between plasma V = Volume of distribution d and tissues total amount of the drug inthebody() mg D Vd drug blood plasma concentration(/) mg L C0 29 logP = 4.63 www.drugbank.ca ADME ‐ Drug distribution 42,658 fold preference for octanol 115 L/kg = 8000 L for a 70 kg male Apparent volume of distribution Plasma volume 0.05 L/kg Extracellular fluid volume 0.2 L/kg Total body water 0.6 L/kg 30 from: Brown & Tomlin, Pharmacokinetic principles. In: Tomlin, Pharmacology & Pharmacokinetics (2010) 15 https://youtu.be/0IWMlf7b1M4 31 ADME ‐ Drug metabolism • Mainly in the liver • To make drugs more hydrophilic (for better elimination by kidney) • To inactivate drugs 32 Brown & Tomlin, Pharmacokinetic principles. In: Tomlin, Pharmacology & Pharmacokinetics (2010) 16 ADME ‐ Drug metabolism fast vs. poor metabolizers “DNA passport for everyone” “Asians, start low dose East Africans, increase dose quickly” 33 Brown & Tomlin, Pharmacokinetic principles. In: Tomlin, Pharmacology & Pharmacokinetics (2010) ADME ‐ Drug metabolism http://genomemag.com/whats‐your‐metabolizer‐rate 17 ADME ‐ Drug elimination Drug excretion can occur through: • exhalation • bile ‐‐> faeces • sweat, saliva • kidney 35 ADME ‐ Drug elimination Looking at it from 2 angles…. Cl = Clearance Volume of plasma completely cleared of drug in a unit of time kel = Elimination rate constant http://tmedweb.tulane.edu/pharmwiki/doku.php/pharmacokinetics Fraction of drug eliminated per unit time (hour‐1) Cl kel V d 36 18 ADME –The whole stuff Q: how to calculate plasma drug concentration at any given time? ktel CCet 0 lnCCkttel ln 0 y = b + ax intravenous administration i.e. first order elimination kinetics & 1‐compartment model distribution is fast cf. with absorption and elimination 37 ADME –The whole stuff Drug rapidly equilibrates with tissue compartment Drug equilibrates with tissue compartment much slower 38 19 ADME –The whole stuff Time taken for a drug concentration t = Elimination half‐life ½ to be reduced by a half ktel CCet 0 ktel 1 2 0.5CCe00 0.693 t 1 2 kel 39 ADME –The whole stuff intravenous administration oral administration 40 20 ADME – Multiple dose drug administration Loading dose 41 Adams et al – Pharmacology for nurses. A pathophysiological approach, 2nd ed (2008) Summary –5 pharmacokinetic parameters kabs FVd Cl t½ Absorption Distribution Metabolism Elimination 42 21 Further reading (there are so many good pharmacology books……) • Hitner, Nagel – Pharmacology. An introduction. 6th ed (2011) • Adams, Holland, Bostwick – Pharmacology for nurses. A pathophysiological approach, 3rd ed (2010) • Goodman And Gilman‘s The pharmacological basis of therapeutics, 12th ed (2010) 43 Further reading • Rang and Dale’s Pharmacology. 7th ed (2011) • Pea – Pharmacokinetics in everyday clinical practice. 1st ed (2012) • www.rxkinetics.com/pktutorial/1_1.html • http://pharmacologycorner.com/ • http://handwrittentutorials.com/ • Lecture handouts: www.staff.science.uu.nl/~engel110/Faro2017 44 22.