Medical Consequences of Interactions between Alcohol and Drugs
Jörn Schneede, M.D.
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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
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Peth/FAEE – non-oxidative metabolism
28 days!
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2 Pharmacology
Pharmacodynamics
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Alcohol – mechanisms of action a lot of putative mechanisms!
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3 Alcohol – mechanisms of action a lot of putative mechanisms! #2
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Alcohol – mechanisms of action a lot of putative mechanisms! #3
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4 Pharmacology
Pharmacokinetics
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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
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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
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6 Interactions
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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
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7 Search in Janusmed
• Seven D-interactions • Eight C-interactions
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8 Disulfiram-like reactions
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Disulfiram-like reactions
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9 Other D-interactions miscellaneous/CNS-depression
But, what about warfarin?
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C-interactions Risk of hypotension
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10 C-interactions Risk of dermatologic adverse effects / flush
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Other C-interactions miscellaneous - paracetamol
But, what about warfarin?
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11 Other C-interactions miscellaneous #2
But, what about warfarin?
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Warfarin och alcohol
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12 Warfarin and alcohol
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Warfarin and alcohol
Moderate/severe alcohol misuse 26 26
13 Summary
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Alcohol Res Health. 1999;23(1):40-54. 28 28
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