1. INTRODUCTION TO PHARMACOKINETICS M. Kršiak Department of Pharmacology, Third Faculty of Medicine, Charles University in Prague, Charles University in Prague, Third Faculty of Medicine Cycle II, Subject: General Pharmacology CVSE3P0012 General Pharmacology ID 15034 http://vyuka.lf3.cuni.cz 2014-2015

2. ABSORPTION depends on - membrane penetration depends on -lipid solubility - ionization (depends on pH) - routes of administration DISTRIBUTION- Volume of distribution ELIMINATION - Clearance ONLY A FREE DRUG ACTS! FIRST-PASS EFFECT, BIOAVAILABILITY depends on - metabolic - excretion FATE OF DRUGS IN THE BODY ADMINISTERED ABSORBED „HIDDEN“ ELIMINATED ACTING WHAT HAPPENS TO DRUGS INSIDE THE BODY PRIMARY PHARMACOKINETIC PARAMETERS: Volume of distribution, Clearance - protein binding (reversible) - membrane penetration

3. FIRST-PASS EFFECT: loss of a drug by a metabolism mostly in the liver that occurs en route from the gut lumen to the systemic circulation e.g. in nitroglycerin, morphine

4. Clinical consequence of the first-pass effect: limited effect after oral administration great interindividual differences in dosage

5. BIOAVAILABILITY: the proportion of drug that reaches the systemic circulation per os: paracetamol 90% > morphine 30% > buprenorphine ≈0%

6. 1.3 ELIMINATION: METABOLIC (biotransformation) mostly in the liver ENZYME INDUCTION/ INHIBITION oxidase enzymes - cytochrom P450 (CYP2D6 etc) GENETIC POLYMORPHISM EXCRETION kidneys metabolites or unchanged (almost completely unchanged e.g. digoxin, gentamycin) GIT... enterohepatic circulation e.g. tetracyclines

7. the half-life is the time taken for the plasma concentration to fall by half [plasmatic half-life]

8. Linear kinetics (First order) [t 1/2 is stable] In most drugs after therapeutic doses: plasma concentration falls exponentially The rate of elimination is proportional to the concentration

9. In most drugs after therapeutic doses: plasma concentration falls exponentially because elimination processes are not saturated [some robustness to dose increase ] Elimination is the bigger the higher is the level C max C min Linear kinetics (First order) The rate of elimination is proportional to the concentration

10. T 1/2 as a guide to asses: 1/ At a single-dose: duration of drug action 2/ During multiple dosing: to asses whether a drug is accumulated in the body (it is - if the drug is given at intervals shorter than 1,4 half-lifes) and when a steady state is attained (in 4-5 half-lifes) 3/ After cessation of treatment: to asses the time taken for drug to be eliminated from the body (in 4-5 half-lifes)

11. [t 1/2 = 1 - 2 h] Ampicillin - single dose

12. T 1/2 as a guide to asses: 1/ At a single-dose: duration of drug action 2/ During multiple dosing: to asses whether a drug is accumulated in the body (it is accumulated if the drug is given at intervals shorter than 1,4 half-lifes) and when a steady state is attained (in 4-5 half- lifes) 3/ After cessation of treatment: to asses the time taken for drug to be eliminated from the body (in 4-5 half-lifes)

13. „PRINCIPLE OF 4-5 HALF-LIFES“: If a drug is administered in intervals shorter than 1.4 half-life, then a steady state is attained after approximately 4-5 half-lifes The time to attain the steady state is independent of dose. Steady state t 1/2 Plasma concentration

14. Attainment of steady state (SS) during multiple dosing of drug at intervals of 1 half-life Why SS is attained after 4-5 half-lifes?

15. T 1/2 as a guide to asses: 1/ At a single-dose: duration of drug action 2/ During multiple dosing: to asses whether a drug is accumulated in the body (it is - if the drug is given at intervals shorter than 1,4 half-lifes) and when a steady state is attained (in 4-5 half-lifes) 3/ After cessation of treatment: to asses the time taken for drug to be eliminated from the body (in 4-5 half-lifes)

16. Elimination of a drug during 5 half-lifes of initial level % of total elimination

17. TIME TO STEADY STATE ( attained after 4-5 half-lifes) independen of dose FLUCTUATIONS proportional to dose intervals blunted by slow absorption STEADY-STATE LEVELS (CONCENTRATIONS) proportional to dose t 1/2 REPEATED ADMINISTRATION OF DRUGS

18. How to reduce fluctuations in drug concentrations? by administering drugs continually, e.g.: infusion, sustained–release (SR) tablets, slow release from depots (e.g. from patches transdermally, depot antipsychotics injected i.m.) by administering a total dose (e.g. a daily dose) in parts at shorter intervals (mostly inconvenient) or

19. Effects of drug correlate with plasma concentrations Therapeutic Drug Monitoring (TDM) (eg. gentamicin, lithium, some antiepileptics) do not correlate with plasma concentrations - „hit and run“ - tolerance or sensitisation - active metabolites