A Primer on Pharmacology

A primer on pharmacology

Universidade do Algarve Faro 2017

by Ferdi Engels, Ph.D. 1

1 3

Utrecht university campus ‘de Uithof’ Dept. of Pharmaceutical Sciences Division of Pharmacology

2 Bachelor and master education

Ferdi Engels, PhD ‐ Associate professor of pharmacology ‐ Director of Undergraduate School of Science

PhD training

Research expertise

for today

1. Understand the main concepts of pharmacokinetics Main concept

2. Be able to apply this new knowledge

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

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

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

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

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  102  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

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

ADME ‐ Drug distribution

Drugs may bind to plasma proteins according to the law of mass action:

k1 [][]DP  [ DP ] k1

free drug+= bound drug plasma concentration Cp

clinically important easy (and cheap) to measure

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

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

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

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

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

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

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)