Pharm of Ethanol Flashcards
Antabuse
f
role of NADH in alcohol metabolism
f
most commonly abused and misused drug in US
ethanol
most deaths due to single substance
potency of ethanol
low potency, need large amounts to exert effects (grams)
Absorption of ethanol
- rapid throughout GI tract esp in small intestine
- more rapid ingestion,more rapid absorption (depends on conc gradient)
- presence of food slows absorption via delaying passage to small intestine (heavy meal can decrease peak concentration by 30%)
distribution of ethanol
- water soluble and distributed in total body water
- crosses placenta
- distrib/equilib is most RAPID in areas of high blood flow (brain, liver, kidney, lung)
- CNS effects in 5 mins, peaks within 15-60 mins
- Fat contains less water and thus less alcohol. Women have more adipose and less water per kg of total body weigh. Women given same dose of ethanol as man will have higher blood alcohol conc.
- r: factor that corrects for the volume of distribution of alcohol (0.68 men, 0.55 for women)
Metabolism of ethanol
- metabolism is responsible for 90-98% of disappearance of alcohol from body
- Liver mostly, some thru expired air and urine
- first pass in gastric mucosa may be important in sex differences in BAC (female gastric metab less than male)
completely metabolized–>7calories/gram
kinetics
ethanol: zero order kinetics
-metabolism occurs at constant rate (zero order)
7-10g/hr
MAX rate: 220 g/day (can increase by 50-60% in chronic alcoholics)
two enzymes that can convert ethanol to acetaldehyde
- alcohol dehydrogenase (ADH): present in liver cytosol (90% of Asian pop have ADH with increased activity)
- CYP2E1: 10-25% of ethanol metab at HIGHER BACs
aldehyde dehydrogenase (AlDH)
CH3-COOH+NADCH2-COH +NADH
converts acetaldehyde to acetate
-in liver cytosol, mitochondria
- high affinity (low Km) and low affinity forms
- high affinity missing in many Asians allowing acetaldehyde levels to build up—>flushing rxn and protection of alcoholism
-AlDH is inhibited by disulfiram (Antabuse)–>increased acetaldehyde lvls–>n/v, resp and cv collapse, convulsions
CH3-COOH + CoA+ATP–>acetyl CoA+AMP +PP
acetyl coa then metabolized into FA and chol, CO2, H2O, Energy.
Hepatic metabolism disruption via elevated NADH
the NADH that is formed must be oxidized to NAD. Mitochondrial oxidation of NADH to NAD is insufficient with the increased levels of NADH leading to disruptions in hepatic metabolic pathways:
- increased levels of NADH–>decreased Krebs activity–gluconeogenesis–>hypoglycemia
- increased blood lactate–>acidosis, behavioral disturbances
- increased Mg2+ excretion–>can lead to convulsions
- increased Acetyl CoA–>increased FA synthesis, decreased fat breakdown–>fatty liver
- decreased uric acid excretion: may precipitate gout attacks.
ethanol at GABAergic synapses
potentiation
ethanol at glutamatergic synapses
inhibition
Acute CNS effects of ethanol
- effects proportional to BAC
- dose dependent CNS depressant effect similar to BARBs.
- NOT a stimulant at any dose
Anticonvulsive effects
good anticonvulsant initially, but hyperexcitability upon withdrawal
-may precipitate convulsions (contraindicated in epilepsy)
Analgesic effects
concurrent w/ analgesia is obliteration of other senses
-similar to morphine analgesia (perceives pain, but pt doesn’t care)
sleep effects
-similar to BARBs–suppression of stage IV REM–>rebound upon withdrawal
emetic effect
stimulation of CTZ plus gastric irritation induces vomiting
hangover
via alcohol or acetaldehyde or contamination product–>probably represents mild withdrawal
tolerance
- tolerance can develop (limited compared to opioids) as can physical dependence
- cross tolerance with other CNS depressants like anesthetics and BDZs
Alcohol withdrawal syndrome
early: mild agitation, anx, restless, tremor, anorexia, insomnia
later or major withdrawal or delirium tremens: extreme overactivity (speech, psychomotor, autonomic) disorientation* confusion* disordered sensory perception* -can be lifethreatening
Seizures:
early: yes 6-8 hrs after onset of AWS
later: no
Drug interactions
- additive effects with all CNS depressants (acute)
- cross tolerance to sedative-hypnotic drugs and GAs (chronic use)
- can promote GI bleeding if taken with aspirin
- increase risk of hepatotox w/ acetaminophen
Altered disposition of durgs metabolized by liver
if non-alcoholic: acute alcohol can interfere with metab.
if alcoholic with normal liver func: faster metab (enz induction, CYP2E1), may reduce concomitant drug effect and can potentiate acetaminophen toxicity
if alcohol w/ mild liver disease: normal metab
if alcoholic w/ severe liver disease: slower metab (enzyme loss) increasing effects of concomitantly administered drugs
When can disulfiram-like sx occur (DDI)?
take w/ metronidazole or oral hypoglycemics
treatment of acute alcohol intoxication
Support of respiration, administration of IV fluids; glucose, thiamine, and electrolytes (K+ and Mg++).
No specific antidote available
AWS Tx
BDZs (chlordiazepoxide, lorazepam)
action @ GABA receptors prevents emergence of CNS hyperexcitability (which is due to down reg of GABA func and increased glut receptor activity)
-act via principle of cross dependence
alpha2 adrenergic agonists (clonidine): effective for signs of autonomic hyperactivity
alcohol sensitizing drugs
Disulfiram (antabuse)
-little evidence of clinical efficacy
block aldehyde dehydrogenase
-vasodilation, HA, n/v, resp difficulties, chest pains, orthostatic htn
opioid antagonists
Naltrexone
shown to reduce alcohol craving, consumption, and relapse rates when used in combo with psychotherapy
NMDA receptor drugs
Acamprosate
- some reduction in alcohol craving and relapse rates in combination with psychotherapy
- wear block of NMDA receptor function
- may mitigate glutamate hyperexcitability during withdrawal
