Alcohol Flashcards
Describe the potency of alcohol
Alcohol is not a potent drug
50-100mg/dL or 11-22 mM alcohol
sedation, subjective “high”, slower reaction times
100-200mg/dL 22-44 mM alcohol
impaired motor function, slurred speech, ataxia
200-300 mg/dL 44-66 mM alcohol
emesis, stupor unwanted falling asleep
300-400 66-88 mM alcohol
coma
over 400 mg/dL or over 88mM alcohol
respiratory depression, death
what is the primary route of administration for alochol
oral
describe the absorption
- rapid
- primarily from the proximal small intestine, but can be absorbed throughout the GI tract
- increased by gastric emptying
- enhanced by carbonated beverages
- decreased by the presence of food
- rate of absorption is influence by:
- ethanol concentration
- rate of ethanol consumption
what is alcohol metabolized to
90-98% of ethanol is metabolized to acetaldehyde
- 2 major enzymatic routes
- remainder is eliminated unchanged in the breath, sweat and saliva
Describe the metabolism of ethanol
- major first pass effect by both gastric and liver alcohol dehydrogenase
1. Alcohol dehydrogenase-lower stomach ADH in women
- Microsomal Ethanol-Oxidizing Systems (MEOS)
* primarily cytochrome P450 2E1, 1A2, and 3A4
* induction by chronic alcohol intake, increases clearance of other drugs
**catalase also is a minor metabolic pathway of alcohol that also yields acetaldehyde
What cofactor is used a . lot to metabolize alchol
NAD
it is used when ethanol is converted to acetaldehyde and when acetaldehyde is converted acetate by aldehyde dehydrogenase
Describe something that can influence aldehyde dehydrogenase
-mitochondrial genetic polymorphism affect activity
Compare alcohol metabolism to methanol metabolism
Alcohol: Ethanol **ADH or MEOS** Acetaldehyde **Aldehyde Dehydrogenase** Acetate
Methanol: Methanol **Alcohol dehydrogenase (ADH)** Formaldehyde **aldehyde dehydrogenase** Formate **Folate dependent pathway
So both alcohol metabolism and methanol metabolism use alcohol dehydrogenase
Ethylene glycol metabolism
ethylene glycol **alcohol dehydrogenase** glycoaldehyde **aldehyde dehydrogenase** glycolate
So what are the enzymes that are as the first step for ethanol methanol and ethylene glycol metabolism. and what enzyme is used as the second step in metabolism for all of them
- alcohol dehydrogenase
2. aldehyde dehydrogenase
What limits alcohol metabolism
NAD availability limits ethanol metabolism
**saturation results in zero order kinetics
Major metabolic consequences of alcohol metabolism
- increase NADH/NAD ratio inhibits TCA cycle
- accumulation of Acetyl CoA
- promotion of lactic acidosis
- accumulation of ketones, can exacerbate lactic acidosis
- increased NADP/NADPH ratio
- limited regeneration of GSH (which is important antioxidant)
- Increase acetaldehyde
- generates adducts
- inhibits microtubules
Metabolic changes from alcohol result in
- fatty liver
- hepatic inflammation
- induction of CYP2E1
- metabolism of xenobiotics to carcinogenic agents
***bad news for the liver
Excretion of ethanol
90-98% of ethanol that is ingested is metabolized via enzymatic routes
*remainder is eliminated unchanged in the breath, sweat and saliva
Mellanby effect
- actue functional tolerance
* symptoms associated with dose during ascending limb of curve are greater than descending limb
CNS effects of ethanol
- potentiates GABA-A receptor ligand gated chloride channel
- normally suppresses neuronal transmission
- helps maintain resting membrane potential in some neurons
- NMDA receptor antagonist
- cognitive function, learning and memory
- alcohol disturbs the balance between excitatory and inhibitory neurotransmission in the brain
- promotes inhibition
-several ion channels are sensitive to the presence of ethanol
describe alcohol relationship with the GABA A receptor
- alcohol is a positive allosteric (competitive) modulator of the GABA A receptor
- alcohol potentiates GABA and sedative hypnotics
- chronic alcohol use results in cross tolerance to sedative hypnotics
Describe alcohols interaction with other CNS depressants, drug metabolism, and acetaminophen
- CNS depressant are additive
- barbituates, benzodiazipines, opioids and neuroleptics
- interactions with drug metabolism
- acute high doses can inhibit CYP mediated metabolism
- chronic ethanol induces CYP2E1, therefore accelerates metabolism of some drugs
- Acetaminophen toxicity
- is worse in alcoholics or when intoxicated because glutathione is depleted
Ethanol as food
- there are about 7.1 calories/gram of alcohol so one drink is 100 calories
- heavy ethanol load produces transient hypoglycemia (due to insulin secretion)
- alcohol induced ketoacidosis
- increase in serum ketones
Chronic ethanol liver and GI effects
- steatosis: fatty liver
- hepatitis C: often a comorbid disease
- cirrhosis: due to liver necrosis and chronic inflammation
- gastritis, pancreatitis, malabsorption of vitamins
- chronic diarrhea
- cancers, including esophageal, liver and bladder
Alcohol tolerance occurs and is a combination of
- adaptive neuronal changes
- chronic ethanol leads to CNS depression leads to upregulation of excitatory transmission to compensate
- metabolic tolerance
- up-regulation of CYP2E1
psychological (craving) and physical dependence of alcohol
- both psychological and physical dependence can occur
- withdrawal can be dangerous, can get seizures but usually only if metabolic imbalance occurs as well
- alcohol addiction occurs in 5-10% of men and 3-5% of women
Neurotoxicity in alcoholism
- neuralgias and peripheral nerve injury
- memory impairment; blackouts
- cerebral/cerebellar atrophy
- thought to arise form direct neurotoxicity
- thiamine deficiency associated with chronic alcohol use can produce “dry” beriberi
- peripheral neuropathy
- wernickes encephalopathy
- Korsakoff psychosis
-thiamine deficiency also associated with wet beriberi cardiovascular
teratogenic Effects
- associated with chronic maternal alcohol abuse
- triad of symptoms
- pre or post natal growth deficiencies
- facial abnormalities
- CNS dysfunction (structural functional)
- ethanol and/or acetaldehyde affect embryonic cell proliferation
- dose dependent, but minimum dose is not known
- American academy of pediatrics recommends no alcohol
How do you diagnose acute alcohol intoxication
- measure blood ethanol concentration for proper diagnosis
- similar presentations can be a result of:
- diabetic coma: acidosis can produce a similar smell on the breath
- drug intoxication
- CV accidents
- brain injury
Treatment for acute alcohol intoxication
- treatment based on severity of respiratory and CNS depression
- common treatment=observation for 4-6 hours while ethanol is metabolized
- support respiration and prevent aspiration of vomit if necessary
- correct any metabolic problems such as:
- dehydration
- hypoglycemia
- ketosis
- electrolyte imbalance
Treatment: Acute alcohol withdrawal
- signs
- goal
- therapy
- signs: alcohol craving, agitation, anxiety, insomnia, seizures, mood swings, sweating, tachycardia
- goal: prevent seizures, delirium, arrhythmias
- therapy: benzodiazepines: diazepam and chlordiazepoxide
- substitute for alcohol and then hey can taper off gradually
- remember that the brain has increased excitatory transmission in response to chronic alcohol
- atenolol i used to prevent cardiac arrhythmias
Drugs for alcloholism
- naltrexone
- acamprosate
- Disulfiram
naltrexone
- mu opioid receptor agonist
- can reduce craving, increase self-control
- best when used in combination with psychosocial therapy
Acamprosate
-GABAA agonist
decreases drinking frequency and relapse in abstinent individuals, ma not be as effective in those still drinking
-thought to normalize dysregulated neurotransmission
*remove ethanol, left with unopposed increase in excitation
-can cause diarrhea
Disulfiram
- inhibits aldehyde dehydrogenase
- results in the accumulation of acetaldehyde, which is very uncomfortable
- aversion therapy
- not very effective, requires considerable will-power to conform
