Medical Consequences of Interactions between Alcohol and Drugs Jörn Schneede, M.D. 1 1 Effects of ethanol 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 • Ethyl sulfate • Fatty acid ethyl esters (FAEE) • 5-hydroxy-tryptophol • 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.