Pharmacology of Alcohol Flashcards
What is the yearly prevalence of any alcohol disorder in the U.S.?
8.5%
What is the yearly percentage of alcohol abuse in the U.S.?
4.7%
What is the yearly percentage of alcohol dependence in the U.S.?
3.8%
What is the gender prevalence of alcohol disorder?
men>>female *especially under 30 for both sexes
What are alcohol’s effects on GABA?
Alcohol increases GABA: -Binds to GABA-A receptor, increasing GABA effect -Major action: inhibitory -Effects: relaxation, loss of coordination, motor slowing, sedation/CNS depressant, slurred speech
What are alcohol’s effects on NMDA/glutamate?
Alcohol decreases NMDA/glutamate: - NMDA antagonist: inhibits release of glutamate, the excitatory neurotransmitter - Presynaptic actions on metabotropic glutamate receptors (mGluR) and presynaptic voltage-sensitive calcium channels - Inhibits post-synaptic ionotropic glutamate receptors (iGluR) eg NMDA: - Reduction of actions of glutamate at postsynaptic NMDA, AMPA receptors - Net effects: Sedation; impaired memory, cognition
What are alcohol’s effects on opioid receptors?
-Indirect stimulation of beta endorphins -Pleasurable, euphoric effects via m receptors: reinforcenent
What are alcohol’s effects on dopamine?
-Indirect stimulation of dopamine neurons in the VTA -Dopamine release: pleasure/reward, motivation and goal pursuit
What delays the absorption of alcohol?
Food delays absorption by slowing gastric emptying.
Describe the gender differences in alcohol absorption.
Women have a smaller amount of body water and lower activity of the alcohol metabolizing enzyme ADH in the stomach (first-pass metabolism) - Safe drinking recommendations about 50% compared to men
Which membranes does alcohol diffuse through?
Alcohol diffuses across all body membranes (inc. breast milk and placenta) except skin and bladder
How does alcohol distribute after it has been absorbed?
After absorption it distributes in total body water
Describe the rate of alcohol concentration increase in the CNS.
Concentration of ethanol in CNS rises quickly
How is alcohol excreted?
Sweat Urine Breath (breath alcohol test → DUI test)
How is alcohol metabolized?
-90 % ethanol removed by oxidation. - Most of this ethanol oxidation occurs in the liver via degradative enzymes
What does an increase in NADH/NAD+ lead to?
- Increased production of lactic acid from pyruvate and may result in hyperuricemia and gout. - Increased production of ketone bodies to produce ketosis. - Increased triglyceride synthesis results in a fatty liver. - Decreased gluconeogenesis and liver glycogen cause hypoglycemia.
Where is Alcohol Dehydrogenase found?
Alcohol dehydrogenase is a cytosolic liver enzyme
What is the consequence of the microsomal ethanol oxidizing system?
NADPH (cytochrome P450) –> Acetaldehyde
Describe acetaldehyde metabolism.
- Metabolism occurs in the liver - 2nd liver enzyme-Aldehyde Dehydrogenase—-> Acetate - Acetate oxidized by body organs —-> CO2 + H2O —-> Acetyl-CoA
What is an inhibitor of acetaldehyde dehydrogenase?
Disulfiram (Antabuse) inhibits acetaldehyde dehydrogenase and causes acetaldehyde to accumulate - Causes extreme discomfort in patients who drink alcoholic beverages - The effect may last 30 min in mild cases or several hours in severe ones
Describe alcohol metabolism in the GI tract.
- ADH in the Stomach and small intestine - Gender Differences Exist: - Men have increased levels of GI ADH compared to women - Early metabolism translates to lower BAC levels
Describe alcohol metabolism in the liver.
-Plasma disappearance curve follows zero order kinetics once enzymes are saturated: - Constant amount of ethanol is eliminated during each unit of time. It is caused by the saturation (or overload) of ADH - The only known procedure for hastening rate of elimination is hemodialysis
Describe the pharmacokinetics of alcohol.
- Disappearance rates of 15mg% per hour (.015) are probably average for moderate drinkers - The rate of metabolism of alcohol increases with dependence—some alcoholics can metabolize 20–25mg/dL/hr
Describe the symptoms of alcohol intoxication.
What are the adverse nervous system effects of alcohol?
–Cognitive: repeated detox assoc with impaired executive function and social abilities
•Increased risk of relapse and social isolation
–Generalized symmetric peripheral nerve injury (most common neurologic abnormality)
What is Wernicke-Korsakoff syndrome?
Wernicke-Korsakoff syndrome is a thiamine deficiency:
- Wernicke’s encephalopathy:
- Ophthalmoplegia (paralysis of the EOM), nystagmus, Ataxia, confusion
-Korsakoff’s psychosis:
–Anterograde and retrograde amnesia
–Confabulation
–Lack of Insight
–Apathy
What is the treatment for Wernicke-Korsakoff syndrome?
•Tx: Thiamine 200mg-500mg IV TID initially, followed by PO
What is the effect of chronic alcohol consumption on the liver?
–Liver disease is the most common medical complication: 15-30% of heavy drinkers
•Alcoholic fatty liver (reversible condition) à
•Alcoholic hepatitis à
•Cirrhosis (accelerated with hep C) à
•Liver failure (Tx à liver transplantation)
–Women seem more susceptible than men
What GI symptoms are associated with chronic alcohol consumption?
- Increased susceptibility to gastritis
- Pancreatitis (most common cause in Western world)
- Anemia and protein malnutrition (blood and plasma loss during drinking).
- Malabsorption of water-soluble vitamins.
What cardiac symptoms are associated with chronic alcohol consumption?
- Cardiomyopathy and heart failure
- Arrhythmias
- Hypertension (more than 3 drinks per day)
- Coronary heart disease (one drink per day helps to prevent CHD)
- Anemia: macrocytic (folic acid deficiency)
What cancers are chronic alcohol consumers at increased risk for?
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Increased risk of cancer
- Mouth, pharynx, larynx, esophagus and liver
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Describe alcohol tolerance biochemically(ie effect on neurotransmitters).
–Induction of hepatic enzymes with increased metabolism
–Neuroadaption by GABA, Glutamate, and Dopamine pathways mentioned above
•Compensatory decreased GABA, **increased **glutamate, **decreased **dopamine
•Receptor density: **decreased **GABA-A, **increased **NMDA, **decreased **dopamine
Describe what happen with acute cessation of alcohol (in terms of effects on NT).
Increased glutaminergic activity: “glutamate storm”: neuroexcitation including seizures, delirium
–Locus Ceruleus: chronic ETOH: increase DA → ** increase **NE→ increase BP, P
• **Decreased intrinsic GABA activity: neuromuscular excitation: tremor, seizures
•Decreased **dopamine activity: anhedonia, lack of motivation, dysphoria
What are the primary treatment goals in alcohol withdrawal syndrome?
•Prevent seizures, delirium, Wernicke-Korsakoff syndrome
How is alcohol withdrawal treated?
–Glucose (dextrose, 25–50 g IV)
–Thiamine (100 mg IV)
–Multivitamins (1 ampule; gives yellow color)
–Folate 1mg (if not in multivitamin amp)
–Potassium 40 meq/L if needed
–Correct other electrolyte/metabolic abnormalities
What benzodiazepines are given in alcohol withdrawal syndrome?
- Lorazepam or oxazepam (shorter duration of action)
- Chlordiazepoxide or diazepam (longer duration of action)
What is thiamine used for?
Thiamine is a vitamin used by the body to break down sugars in the diet.
- It helps correct nerve problems due to the lack of thiamine in Wernicke-Korsakoff syndrome
Describe the kinetics of thiamine.
Absorbed from the GI tract.
Metabolized by the liver.
Elimination is renal, the majority being metabolites.
Describe the adverse drug reactions to thiamine.
Hypersensitivity reactions after injection may accour.
Some tenderness or muscle soreness may result after IM injection
What reactions should be considered with patients on thiamine?
Thiamine may enhance the activity of neuromuscular blocking agents; clinical significance is unknown.
What class of drug is Lorazepam/Ativan?
Benzodiazepine (BZD), GABA modulator, anti-anxiety agent.
How does lorazepam act?
Binds to central benzodiazepine receptors which interact allosterically with GABA receptors.
- This potentiates the effects of the inhibitory neurotransmitter GABA.
- Used to treat withdrawal syndrome.
Describe the kinetics of lorazepam.
Absorbed rapidly (90%) and metabolized by the liver. Excreted in urine.
Peak onset 1-2 hrs; half-life 10-20 hrs
What are the advantages of lorazepam?
- Short duration of action, lack of active metabolites make it attractive for elderly and those with liver disease
- Available PO, IM, IV with similar dosing
What are the disadvantages of lorazepam?
Short-acting means more frequent doses:
- Every hour initially; possibility of BZD-withdrawal seizure
To what class of drug does chlordiazepoxide/librium belong?
Benzodiazepine, GABA modulator, anti-anxiety agent
How does chlordiazepoxide act?
Binds to central benzodiazepine receptors which interact allosterically with GABA receptors.
- Potentiates the effects of the inhibitory neurotransmitter GABA.
- Used to treat withdrawal syndrome.
Describe the kinetics of chlordiazepoxide.
High bioavailability (>90%)
Extensive hepatic metabolism to desmethyldiazepam (active).
Peak onset 1.5-4 hrs
Half-life 5-30 hrs but active metabolites 36-200 hrs
What are the advantages of chlordiazepoxide?
Original BZD: side effects and interactions well-known after decades of use. “Auto-taper”.
Most physicians familiar with drug.
What are the disadvantages of chordiazepoxide?
Build-up of active metabolites make it less appropriate for the elderly:
- Cognitively and neuromuscularly impairing.
Extensive hepatic metabolism make it less suitable for patients with liver disease. C
ognitive effects can persist for days, even weeks. Numerous drug interactions.
What adrugs are used to treat aclohol dependence?
- Naltrexone (p.o.-ReVia; I.M.- Vivitrol)
- Acamprosate (Campral®)
- Disulfiram (Antabuse®)
What are the major effects of “anti-craving” drugs?
•Relapse prevention
–Increases time to first drink
–Increases time to heavy drinking
–Decreases # drinks on drinking days
To what drug class does naltrexone belong?
Opiod antagonist.
How does naltrexone act?
Potent and long-lasting opioid antagonist with highest affinity for the µ-opioid receptor.
Describe the kinetics of naltrexone.
Metabolized by the liver. Renal excretion.
Describe the adverse drug reactions of naltrexone.
- Nausea is the most common side effect.
- Other less common side effects include headache, constipation, dizziness, nervousness, insomnia, drowsiness and anxiety.
- Should be used in hepatic disease with caution since it may produce hepatotoxicity.
What are the major interactions of naltrexone?
Inhibits effects of opiates.
What are the advantages of naltrexone?
Dosing simplicity; FDA-approved; monthly injection improves compliance.
What are the disadvantages of naltrexone?
- Can’t use with patients on opiates
- Non-compliance
- Possible interference with endogenous opioid system?
To what drug class does acamprosate belong?
Analogue of GABA
How does acamprosate act?
- NMDA antagonist + GABAA R activator.
- It acts on serotonergic, noradrenergic and dopaminergic receptors.
- May restore neuronal excitation and inhibition balance
* brain thinks it already has GABA so less inclined to drink
Describe the kinetics of acamprosate.
It is not metabolized.
Renal excretion
Describe the adverse drug effects of acamprosate.
Caution in depressed patients
Should not be used in patients with renal impairment
What are the advantages of acamprosate?
- Well-tolerated with few ADR
- No significant drug interactions
- May be shown to be effective in combination with Naltrexone or Disulfiram
What are the disadvantages of acamprosate?
Studies in US have not consistently shown positive effect
To what drug class does Disulfiram belong?
Alcohol Dependence: deterrent.
What is the action of disulfiram?
Inhibits the metabolism of alcohol by irreversibly binding to Aldehyde Dehydrogenase
=>buildup of Acetaldehyde, with development of “instant hangover”: facial flushing, headache, dizziness, nausea, vomiting, rapid heart rate, hypotension, and mental confusion
Describe the kinetics of disulfiram.
High oral bioavailability
Onset: disulfiram-alcohol reaction 5-30 minutes
Half-life: 7 hrs
Duration of effect: up to two weeks: time to resynthesize ALDH
What are the adverse drug reactions of disulfiram?
Rare fulminant hepatitis: use with caution in liver disease.
Peripheral neuropathy including optic
Neuropsychiatric changes; caution >60
Known or suspected Coronary Artery Disease or Cerebrovascular Disease
What are the advantages of disulfiram?
Helpful in Couples Behavioral Counseling for Alcohol Dependence
Abstinence rates of 50% or more in controlled setting/observed administration
What are the disadvantages of disulfiram?
At one year, no more effective than placebo as sole treatment, self-administered
