a primer on pharmacology - universiteit utrechtengel110/faro2017/faro2017 pk.pdf · adme=...

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A primer on pharmacology

Universidade do AlgarveFaro 2017

by Ferdi Engels, Ph.D.

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

Division of Pharmacology

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Bachelor and master education

PhD training

Research expertise

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

of Science

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for today

1. Understand the main concepts of pharmacokinetics

Main concept

2. Be able to apply this new knowledge

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Pharmacologyis about drugs……….

Drugs = chemicals that alter physiological processes in the bodyfor treatment, prevention, or cure of diseases

input output

‐ dose‐ frequency of administration‐ route of administration

‐ no effect‐ beneficial effects‐ adverse / toxic effects

(administration of the drug) (biological response)

7onset, intensity, and duration of therapeutic effects

Pharmacologyis about drugs……….

Drugs = chemicals that alter physiological processes in the bodyfor treatment, prevention, or cure of diseases

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What does the body do to the drug?

What does the drug do to the body?

pharmacokinetics

pharmacodynamics

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9Rosenbaum ‐ Basic pharmacokinetics and pharmacodynamics: an integrated textbook and computer simulations, 1st ed. (2011)

Course Topic 1 Course Topic 2

Thursday, June 15Lecture on topic 1Workshop on topic 1

Friday, June 16Lecture on topic 2Workshop on topic 2


Examples of common daily doses and dosing intervals

input output

‐ dose‐ frequency of administration‐ route of administration

‐ no effect‐ beneficial effects‐ adverse / toxic effects

(administration of the drug) (biological response)

onset, intensity, and duration of therapeutic effects

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Pharmacokinetics

derives from Greek words:pharmackon = drugkinetikos = moving

Study of drug movement into, around, and out of the bodyor

ADME = absorption, distribution, metabolism, and elimination

Time course of drug concentrations in body compartmentsLippincott’s illustrated reviews: Pharmacology 5th ed (2012)


Assumption: plasma concentration reflects drug concentration at site of action

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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

GentamycinantibioticWarfarinanticoagulantLithiumbipolar disorderDigoxinatrial fibrillationTheophyllineCOPD, asthma

Methotrexateoncolytic, DMARDPhenytoinantiseizureInsulinantidiabeticCiclosporinimmunosuppressant

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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

Rosenbaum ‐ Basic pharmacokinetics and pharmacodynamics: an integrated textbook and computer simulations, 1st ed. (2011)

MEC = minimum effective concentrationMTC = maximum tolerated concentration

Therapeutic range – between MEC and MTC

unsafeunsafe

uneffectiveuneffective

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Routes of drug administration

Meyer & Quenzer – Psychopharmacology: Drugs, the Brain and Behavior (2005)

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Oral vs. intravenous administration

absorption phase

elimination phase

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ADME ‐ Drug absorption

Drug absorption requires movement across membranes(except after intravenous application)

Goldberg & Gomez‐Orellana ‐ Nature Reviews Drug Discovery 2, 289‐295 (April 2003)

a = transcellular pathwayb = paracellular pathwayc = transcytosis and receptor‐

mediated endocytosisd = absorption into the

lymphatic circulation viaM‐cells of Peyer's patches

most usual

antigen‐presentingcells

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Rate of transmembrane diffusion determined by:‐ concentration gradient‐ permeability of barrier (membrane)

Lipid diffusion

Lipophilic and uncharged drug molecules are absorbed fastest !!

logP pKa

therefore

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tan[ ]

[ ]oc ol

water

drug

drug

2 1log 2 10

100P P

2 100log 2 10

1P P lipophilic

hydrophilic

Partition coefficient P

Lipophilic drugs are absorbed faster

Log P instead of P (smaller range of values)separatory funnel

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Acid dissociation constant pKa• quantitative measure of the strength of an acid in solution

[ ]log

[ ]

ApH pKa

HA

• at pH = pKa, half of the acid is protonated

[ ] [ ] [ ]aK

HA A H

Henderson‐Hasselbalch equation

Uncharged drugs are absorbed faster

The effect of pH on drug ionisation

Waller et al ‐Medical Pharmacology and Therapeutics (2005)

Drug ionisation is dependenton pH and pKa

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Aspirin (a.k.a. acetylsalicylic acid) – pKa = 3.5

Stomach: pH ≈ 2Intestines: pH ≈ 6‐7

example

example

Q: Where is aspirin absorbed best?

Q: Explain alkaline diuresis used withaspirin poisoning.

by IV sodium bicarbonate

A: Uncharged in stomach, charged in intestines

BUT

What about its dissolution in acid environment?What about surface area for uptake?

[ ] [ ] [ ]aK

HA A H Le Chatelier’s principleWhen a change is imposed on a systemat equilibrium, the equilibrium will shiftto counteract the change.

buzzing moment

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kabs = Absorption rate constant

http://www.boomer.org/c/p4/c03/c0318.html

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http://tmedweb.tulane.edu/pharmwiki/doku.php/bioavailability_the_first_pass_effect

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

First‐pass effect:1 g vs. 2 g dose

Barr – Drug Inform. Bull. 3: 27‐45 (1969)

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F = BioavailabilityExtent to which a drug reachesthe systemic circulation

Example: Diclofenac Fiv = ?100% Ftabl = 50%

( )*100tablet

iv

AUCF AUC

http://tmedweb.tulane.edu/pharmwiki/doku.php/bioavailability_the_first_pass_effect

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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

Serum• plasma without fibrinogen and other clotting factors

albumin

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Drugs may bind to plasma proteins

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[ ] [ ] [ ]k

kD P DP

free drug bound drug+ = plasma concentration Cp

clinically important easy (and cheap) to measure


according to the law of mass action:

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Raffa et al – Netter’s illustrated pharmacology (2005)

Central compartment Peripheral compartment

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70 kg maleplasma 3.5 Lextracellular fluid 14 Lbody water 42 L

https://www.easycalculation.com/medical/plasma‐volume‐calculator.php

500 mg paracetamol143 mg/L36 mg/L12 mg/L

Plasma concentration after:

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Vd = Volume of distributionDistribution of drug between plasmaand tissues

0

( )

( / )d

total amount of thedrug inthebody mg DV

drug blood plasma concentration mg L C

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from: Brown & Tomlin, Pharmacokinetic principles. In: Tomlin, Pharmacology & Pharmacokinetics (2010)

Extracellular fluid volume0.2 L/kg

Total body water0.6 L/kg

Plasma volume0.05 L/kg

logP = 4.63

42,658 fold preferencefor octanol

www.drugbank.ca

115 L/kg =8000 L for a 70 kg male

Apparent volumeof distribution

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31https://youtu.be/0IWMlf7b1M4

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ADME ‐ Drug metabolism

Brown & Tomlin, Pharmacokinetic principles. In: Tomlin, Pharmacology & Pharmacokinetics (2010)

• Mainly in the liver• To make drugs morehydrophilic (for betterelimination by kidney)

• To inactivate drugs

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Brown & Tomlin, Pharmacokinetic principles. In: Tomlin, Pharmacology & Pharmacokinetics (2010)

“DNA passport for everyone”

“Asians, start low doseEast Africans, increase dose quickly”

fast vs. poormetabolizers


http://genomemag.com/whats‐your‐metabolizer‐rate

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ADME ‐ Drug elimination

Drug excretion can occur through:• exhalation• bile ‐‐> faeces• sweat, saliva• kidney

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http://tmedweb.tulane.edu/pharmwiki/doku.php/pharmacokinetics

Cl = Clearance

Volume of plasma completelycleared of drug in a unit of time

ADME ‐ Drug elimination

kel = Elimination rate constant

Fraction of drug eliminated per unit time (hour‐1)

el dCl k V

Looking at it from 2 angles….

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ADME – The whole stuff

Q: how to calculate plasma drug concentrationat any given time?

0elk t

tC C e 0ln lnt elC C k t

i.e. first order elimination kinetics& 1‐compartment model

intravenousadministration

distribution is fast cf. with absorption and elimination

y = b + ax

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Drug rapidly equilibrateswith tissue compartment

Drug equilibrates with tissuecompartment much slower

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t½ = Elimination half‐lifeTime taken for a drug concentrationto be reduced by a half

0elk t

tC C e

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0 00.5elk t

C C e

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0.693el

t k

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oraladministration

intravenousadministration

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ADME – Multiple dose drug administration

Adams et al – Pharmacology for nurses. A pathophysiological approach, 2nd ed (2008)

Loading dose

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Summary – 5 pharmacokinetic parameters

Distribution Metabolism

Elimination

Absorption

kabs F Vd Cl t½

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• Adams, Holland, Bostwick – Pharmacology for nurses.A pathophysiological approach, 3rd ed (2010)

Further reading

• Goodman And Gilman‘s The pharmacological basisof therapeutics, 12th ed (2010)

• Hitner, Nagel – Pharmacology. An introduction.6th ed (2011)

(there are so many good pharmacology books……)

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Further reading

• Rang and Dale’s Pharmacology. 7th ed (2011)

• www.rxkinetics.com/pktutorial/1_1.html

• http://pharmacologycorner.com/

• http://handwrittentutorials.com/

• Pea – Pharmacokinetics in everyday clinicalpractice. 1st ed (2012)

• Lecture handouts: www.staff.science.uu.nl/~engel110/Faro2017

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