Medical Consequences of Interactions between and Drugs

Jörn Schneede, M.D.

1 1

Effects of in general • Direct physico-chemical interactions with cell membranes – Direct cell injury • Dehydration • Precipitation of cytoplasm • Neurolysis (trigeminal neuralgia) – Integration in cell membranes: • PEth formation / fatty acid ethyl esters (FAEE) • Bacteriocidal / antifungal (dehydration, precipitation of proteins)

• Interaction with a large number of receptors (GABA A, glycin, glutamate/NMDA, serotonin, acetylcholine, ion channels) • Enzyme induction (CYP 2E1, CYP1A2, CYP3A4, ALAT/ASAT, GGT) • Metabolic effects (formation of NADH during ADH-reaction; inhibition of gluconeogenesis and stimulation of liponeogenesis: AFLD) 2 2

1 Biological Markers in Clinical Diagnosis of Alcoholism • Ethyl glucuronide • • Fatty acid ethyl esters (FAEE) • 5-hydroxy- • CDT • PEth • GGT • MCV (>90) • AST/ALT

3 3

Peth/FAEE – non-oxidative metabolism

28 days!

4 4

2 Pharmacology

Pharmacodynamics

5 5

Alcohol – mechanisms of action a lot of putative mechanisms!

6 6

3 Alcohol – mechanisms of action a lot of putative mechanisms! #2

7 7

Alcohol – mechanisms of action a lot of putative mechanisms! #3

8 8

4 Pharmacology

Pharmacokinetics

9 9

Ethanol – key pharmacokinetic data • Vd: 37 l/70kg • First pass metabolism in liver – Extraction ratio 0.2

• Km at blood concentrations of 80 mg/L or 0.075‰ (rattfyllerigränsen går vid 0,2 ‰) • Zero order kinetics – no half life • Vmax elimination: 0.1 g/kg/h • Renal clearance 1 ml/min

10 10

5 ADH/ALDH/CYP-enzymes indirect effects on metabolism

Antidiabetics

Inducible (upp to 10 x)

CYP2E1 CYP1A2/CYP3A4 MEOS: Microsomal ethanol- oxidizing system 11

Alcohol and CYP-enzymes: Induction and occupation

Occupation

Induction

Occupation >> induction

12 12

6 Interactions

13 13

Alcohol and drugs: complex interrelationship • Pharmacodynamic – Complex interactions with many receptors – Increased CNS-depression • Pharmacokinetic – Complex • Induction / occupation / combinations (CYP2E1, CYP1A2, CYP3A4) • Acute effects / chronic effects • Sober / intoxicated • Indirect – Effects on metabolism in general (NADH/NAD) – Effects on cell-membranes (PEth, FAEE) – Inhibition of ALDH (disulfiram-like effects) – Glutathione depletion: increased toxicity of drugs

14 14

7 Search in Janusmed

• Seven D-interactions • Eight C-interactions

15 15

16 16

8 Disulfiram-like reactions

17 17

Disulfiram-like reactions

18 18

9 Other D-interactions miscellaneous/CNS-depression

But, what about warfarin?

19 19

C-interactions Risk of hypotension

20 20

10 C-interactions Risk of dermatologic adverse effects / flush

21 21

Other C-interactions miscellaneous - paracetamol

But, what about warfarin?

22 22

11 Other C-interactions miscellaneous #2

But, what about warfarin?

23 23

Warfarin och alcohol

24 24

12 Warfarin and alcohol

25 25

Warfarin and alcohol

Moderate/severe alcohol misuse 26 26

13 Summary

27 27

Alcohol Res Health. 1999;23(1):40-54. 28 28

14