A primer on pharmacology
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1 A primer on pharmacology Universidade do Algarve Faro 2017 by Ferdi Engels, Ph.D
2 3 Utrecht university campus de Uithof Dept. of Pharmaceutical Sciences Division of Pharmacology 4 2
3 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 2. Be able to apply this new knowledge Main concept 6 3
4 Pharmacology is about drugs. Drugs = chemicals that alter physiological processes in the body for treatment, prevention, or cure of diseases input (administration of the drug) dose frequency of administration route of administration output (biological response) no effect beneficial effects 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
5 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 Rosenbaum Basic pharmacokinetics and pharmacodynamics: an integrated textbook and computer simulations, 1 st ed. (2011) 9 input (administration of the drug) dose frequency of administration route of administration output (biological response) no effect beneficial effects adverse / toxic effects onset, intensity, and duration of therapeutic effects Examples of common daily doses and dosing intervals Rosenbaum Basic pharmacokinetics and pharmacodynamics: an integrated textbook and computer simulations, 1 st ed. (2011) 10 5
6 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 Lippincott s illustrated reviews: Pharmacology 5 th ed (2012) 11 Assumption: plasma concentration reflects drug concentration at site of action Rosenbaum Basic pharmacokinetics and pharmacodynamics: an integrated textbook and computer simulations, 1 st ed. (2011) 12 6
7 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 antibiotic Warfarin anticoagulant Lithium bipolar disorder Digoxin atrial fibrillation Theophylline COPD, asthma Methotrexate oncolytic, DMARD Phenytoin antiseizure Insulin antidiabetic Ciclosporin immunosuppressant 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 uneffective MEC = minimum effective concentration MTC = maximum tolerated concentration Therapeutic range between MEC and MTC Rosenbaum Basic pharmacokinetics and pharmacodynamics: an integrated textbook and computer simulations, 1 st ed. (2011) 14 7
8 Routes of drug administration Meyer & Quenzer Psychopharmacology: Drugs, the Brain and Behavior (2005) 15 Oral vs. intravenous administration elimination phase absorption phase 16 8
9 ADME Drug absorption Drug absorption requires movement across membranes (except after intravenous application) most usual a= transcellular pathway b = paracellular pathway c = transcytosis and receptormediated endocytosis d = absorption into the lymphatic circulation via M cells of Peyer's patches antigen presenting cells Goldberg & Gomez Orellana Nature Reviews Drug Discovery 2, (April 2003) 17 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
10 ADME Drug absorption Lipophilic drugs are absorbed faster Partition coefficient P [ drug] [ drug] oc tan ol water Log P instead of P (smaller range of values) separatory funnel log P 2 P 10 1 lipophilic log P 2 P hydrophilic 19 ADME Drug absorption Uncharged drugs are absorbed faster Drug ionisation is dependent on ph and pka Acid dissociation constant pka quantitative measure of the strength of an acid in solution [ HA] [ A ] [ H ] K a The effect of ph on drug ionisation ph [ A ] pka log [ HA ] Henderson Hasselbalch equation at ph = pka, half of the acid is protonated Waller et al Medical Pharmacology and Therapeutics (2005) 20 10
11 ADME Drug absorption example Stomach: ph 2 Intestines: ph 6 7 example Q: Where is aspirin absorbed best? Q: Explain alkaline diuresis used with aspirin poisoning. by IV sodium bicarbonate Aspirin (a.k.a. acetylsalicylic acid) pka= 3.5 A: Uncharged in stomach, charged in intestines BUT What about its dissolution in acid environment? What about surface area for uptake? [ HA] [ A ] [ H ] K a buzzing moment Le Chatelier s principle When a change is imposed on a system at equilibrium, the equilibrium will shift to counteract the change. 21 ADME Drug absorption k abs = Absorption rate constant
12 ADME Drug absorption First pass effect: 1 g vs. 2 g dose 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 Barr Drug Inform. Bull. 3: (1969) 23 ADME Drug absorption AUC F ( tablet )*100 AUC iv F = Bioavailability Extent to which a drug reaches the systemic circulation Example: Diclofenac F iv =?100% F tabl = 50%
13 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, CO 2, 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: [ 1 D ] [ P ] k [ DP ] k 1 free drug + bound drug = plasma concentration C p clinically important easy (and cheap) to measure 26 13
14 ADME Drug distribution Central compartment Peripheral compartment Raffa et al Netter s illustrated pharmacology (2005) 27 ADME Drug distribution 70 kg male plasma 3.5 L extracellular fluid 14 L body water 42 L volume calculator.php Plasma concentration after: 500 mg paracetamol 143 mg/l 36 mg/l 12 mg/l 28 14
15 ADME Drug distribution V d = Volume of distribution Distribution of drug between plasma and tissues V d total amount of the drug in thebody ( mg) D drug blood plasma concentration ( mg / L) C 0 29 ADME Drug distribution logp = ,658 fold preference for octanol 115 L/kg = 8000 L for a 70 kg male Apparent volume of distribution from: Brown & Tomlin, Pharmacokinetic principles. In: Tomlin, Pharmacology & Pharmacokinetics (2010) Plasma volume 0.05 L/kg Extracellular fluid volume 0.2 L/kg Total body water 0.6 L/kg 30 15
16 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
17 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 your metabolizer rate 17
18 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 k el = Elimination rate constant Fraction of drug eliminated per unit time (hour 1 ) Cl k V el d 36 18
19 ADME The whole stuff Q: how to calculate plasma drug concentration at any given time? C C e k el t t 0 ln t ln 0 el y = b + ax C C k t 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
20 ADME The whole stuff t ½ = Elimination half life Time taken for a drug concentration to be reduced by a half k el C C e t 0 kel 0.5C C e 0 0 t t 1 2 t k el 39 ADME The whole stuff intravenous administration oral administration 40 20
21 ADME Multiple dose drug administration Loading dose Adams et al Pharmacology for nurses. A pathophysiological approach, 2 nd ed (2008) 41 Summary 5 pharmacokinetic parameters k abs F V d Cl t ½ Absorption Distribution Metabolism Elimination 42 21
22 Further reading (there are so many good pharmacology books ) Hitner, Nagel Pharmacology. An introduction. 6 th ed (2011) Adams, Holland, Bostwick Pharmacology for nurses. A pathophysiological approach, 3 rd ed (2010) Goodman And Gilman s The pharmacological basis of therapeutics, 12 th ed (2010) 43 Further reading Rang and Dale s Pharmacology. 7 th ed (2011) Pea Pharmacokinetics in everyday clinical practice. 1 st ed (2012) Lecture handouts:
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