Pharmacology of Ethanol Flashcards
Describe the absorption, distribution, and metabolism of ethanol and their relationship to the blood alcohol concentration (BAC).
Ultimate determinants of BAC, absorption occurs throughout the GI tract, extremely rapid in small intestine.
• More rapid ingestions – more rapid the absorption (conc gradient based).
• Food slows absorption by delaying passage to small intestine – heavy meal decreases peak conc by 30%.
Describe the site of action of Antabuse (disulfiram) and the aversive actions of acetaldehyde.
Antabuse: (disulfiram), a drug that blocks conversion of acetaldehyde to acetate by the enzyme aldehyde dehydrogenase.
• Causes an acute sensitivity to alcohol.
• Used for alcoholics – makes them feel the effects of hangover almost immediately (ew).
• Results in 5-10x increase in acetaldehyde levels = Nausea/vomiting, respiratory and cardio collapse, and convulsions, facial flushing.
Describe the role of NADH in alcohol metabolism and the metabolic disruptions associated with alcohol abuse.
NADH is produced both in converting ethanol to acetaldehyde and then to acetate.
• For oxidative reactions to continue, NADH must be oxidized to NAD.
• Mitochondrial oxidation is insufficient to keep up w/ the increased levels of NADH.
↑ levels of NADH»_space; ↓ Krebs activity-gluconeogenesis à hypoglycemia
↑ blood lactate»_space; acidosis, behavioral disturbances
↑ Mg++ excretion»_space; can lead to convulsions
↑ Acetyl CoA»_space; ↑ F.A. synthesis + ↓ fat breakdown»_space; fatty liver
↓ uric acid excretion»_space; may precipitate gout attacks
Explain withdrawal from ethanol
Early: mild agitation, anxiety, restlessness, tremor, anorexia, insomnia
Late/delirium tremens: disorientation, confusion, disordered sensory perception.
- Timing post-alcohol: 0-48 hrs (early), 24-150 hrs (late/major).
- Time of peak symptoms after onset: 24-36 hrs (early), 72 to 96 hrs (late/major).
- Severity: early is mild/severe and late (potentially life-threatening).
- Seizures: 6-48 hrs after onset of AWS for early and none for late.
List the major drug-drug interactions associated with alcohol use.
• Aspirin – alcohol w/ aspirin promotes GI bleeding.
• Altered liver drug metabolism:
Non-alcoholics: any acute alcohols can interfere w/ metabolism.
Alcoholic w/ nm liver function: faster metabolism (CYP2E1 that reduces concomitant drug effects to potentiate acetaminophen toxicity.
Alcoholic w/ mild liver disease: normal metabolism.
Alcoholic w/ severe liver disease: slower metabolism (enzyme loss) w/ increasing effects of concomitantly administered drugs.
• Disulfiram-like symptoms – when take metronidazole or oral hypoglycemics
Describe the management of acute alcohol intoxication and withdrawal
Benzodiazepines (chlordiazopoxide, lorazepam) which act via principle of cross-dependence or alpha2 adrenergic agonists (clonidine) for autonomic hyperactivity signs.
- Benzos: 3 act on GABA receptors to prevent emergence of CNS hyperexcitability that follows alcohol withdrawal. This is due to down-regulation of GABA function and increased glutamate receptor activity.
- Reduction of consumption: disulfiram (antabuse), opioid antagonists (reduce alcohol craving), and NMDA receptor drugs (reduce cravings).
Describe the metabolism of ethanol and their relationship to the blood alcohol concentration (BAC).
Responsible for 90-98% of alcohol disappearance. Liver primary organ of metabolism, but a very small amount is excreted unchanged in expired air.
• Zero order kinetics – 7-10g of alcohol/hour. Maximum rate is 220g/day.
• Biochemical: even at low BAC, biochemical oxidation of alcohol occurs at full capacity.
• 2 enzymes change EtOH to acetaldehyde: alcohol dehyrogenase (liver) and CYP2E1, 10-25% of EtOh at ↑BACs. Acetaldehyde converted to acetate by aldehyde dehydrogenase
Describe the distribution of ethanol and their relationship to the blood alcohol concentration (BAC).
Ultimate determinant of BAC as evently distributed throughout all tissues/fluids of body.
• Distributed in total body water because ethanol is water soluble.
• Placenta permeable to ethanol
• Distribution most rapid in areas of high blood flow (brain, liver, kidney, lung).
Describe the effects of ethanol on: the CNS (esp. the mechanism of acute neuronal actions)
Effects of EtOH toxicity and malnutrition:
- Wernicke’s Disease: EtOH toxicity, malnutrition, confusion, diplopia, nyastagmus, ataxia, and periph neuropathy from thiamine deficiency.
- Korsakoff’s Psychosis: disorientation, amnesia, confabulations (amazing word!). from thiamine deficiency 2ndary to alcohol intake. Not completely reversible.
- Cerebral atrophy: frontal lobe degeneration, personality disintegration, irreversible dementia.
- Cerebellar atrophy: irreversible ataxia.
Describe the effects of ethanol on: the Liver
Causes fatty liver, alcoholic hepatitis, alcoholic cirrhosis due to increased NADH and direct toxicity of EtOH. Clinically will see enlarged liver, jaundice, ascites, vomiting, anorexia, portal HTN and esophageal varices
Describe the effects of ethanol on: the kidney
Diureses due to decreased ADH secretion and incressed fluid intake
Describe the effects of ethanol on: GI tract
Esophagitis, ulcers, gastritis, pancreatitis
GI effets are the result of inflammatory and secretory effects of EtOH
Describe the effects of ethanol on: Fetus (Fetal Alcohol Syndrome).
Prenatal or postnatal growth retardation, altered morphogenesis (esp. facial dysmorphology) and CNS involvement (often mental retardation).
• Facial
• 1st trimester effects: major morphologic abnormality
• 2nd trimester effects: increased risk of spontaneous abortions
• 3rd trimester effects: decreased fetal growth.
FDA recommendations: no safe level is established, risk w/ 6 drinks a day (3 oz). , Peak BAC is critical, pregnancy should be discouraged until consumption is controlled/ceased
Explain tolerance to, dependence on ethanol
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