Ethanol & other Alcohols - Pharmacology II

Final Exam

Describe the Absorption of Alcohol

Rapid Absorption (Peaks in about 30 mins in fasted state) from:

• GIT—stomach, small intestine, colon

• Vaporized alcohol can be absorbed through the lungs

Eating food before or during drinking retards absorption in the _________ but not from the ___________.

Stomach; Intestines

Describe gender differences in alcohol absorption

Women achieve higher BAC than men following consumption of same quantity of alcohol because:

• Women have a lower total body water

• Gastric metabolism of alcohol is lower in women than in men

Describe alcohol distribution is normal and pregnant individuals

• Uniformly distributed throughout all tissues into the total body water

• Rapidly crosses the placenta, attaining concentrations in fetus similar to that in maternal blood

What enzyme does the fetus lack that makes alcohol so toxic?

Alcohol Dehydrogenase (ADH)

Describe the 1st step in the Alcohol Metabolism process

ADH converts NAD+ to NADH

• Excessive NADH generated contributes to alcohol toxicity (e.g. fatty liver)

• Gastric ADH levels higher in men, thus females absorb more alcohol than men

Describe some Genetic Variations to ADH

It has several Isoforms—ADH1A, 1B, and 1C that facilitate faster metabolism in some populations

• These isoforms are associated with lower risk for heavy dirinking due to accelerated accumulation of acetaldehyde, leading to release of histamine; PGs etc:

  • Characterized by Flushing, Nausea, Hypotension

When does alcohol metabolism switch from first-order to zero-order kinetics?

≥100mg/dL BAC

• This is due to saturation of the enzyme system at alcohol levels ≥100mg/dL

Describe the role of Microsomal Mixed Function Oxidases (MEOS)

• Located in the liver; minor contribution below 100mg/dL

• Consequences of ↑CYP2E1:

  • Inc clearance of alcohol and other drugs metabolized by CYP2E1

  • ↑NADP⁺ depletes NADPH needed for regeneration of glutathione—hence inc. oxidative stress

Describe the role of Acetaldehyde dehydrogenase

Mitochondrial enzyme that rapidly metabolizes acetaldehyde to acetate

• Mutations in ALDH2 results in non-functions enzyme

• Leads to severe, disulfiram-like reactions in response to alcohol consumption due to accumulation of acetaldehyde

• ALDH2 heterozygous in ~30-40% Asians; flushing flushing & ↑ alcohol sensetitves

What does the Acetate do?

↑ Acetate leads ↑ Acetyl CoA, which together with NADH+cause inc. NADH cause ↑fatty acid synthesis

Between 90-98% of ethanol is oxidized in the ________.

Liver

Typical adult eliminates ______g of alcohol per hour

7-10 (a normal drink is about 8g)

Compare ethanol conc. in urine to blood

130% of blood ethanol conc.

Compare ethanol conc. in expired air to blood

0.05% of blood ethanol conc.

Effect of alcohol on GABAa

Enhancement of GABAa-mediated inhibition similar to actions of benzos

Effect of alcohol on Ca²⁺

Inhibition of Ca²⁺ entry though voltage gated calcium channels

Effect of alcohol on NMDA

Inhibition of NMDA (Excitatory receptors) + kainite subtyles of glutamate receptors

Effect of alcohol on Enzymes

Effects Monoamine Oxidase, Adenylyl Cyclase, acetylcholinesterase, Na/K-ATPase, & Ca²⁺-ATPase

Effect of alcohol on Dopamine Receptors

Increases synaptic dopamine, increases effects on ventral tegmentum/nucleus accumbans reward

Effect of alcohol on Opioid Receptors

Release of β endorphins, activation of µ receptors

Effect of alcohol on 5-HT

Increased 5-HT in synaptic space

Acute Effects of Alcohol on the CNS: Low Concentrations

Apparent stimulation due to depression of inhibitory control mechanisms (46mg/dL)

Acute Effects of Alcohol on the CNS: Moderate Concentrations

Uncontrolled mood swings, slurred speech, impaired motor function

Acute Effects of Alcohol on the CNS: Higher Concentrations

Coma, respiratory depression, death

Acute effects of alcohol: <50mg/dL

Increased sociability; euphoria

Acute effects of alcohol: 50-100mg/dL

Disturbances in gait; lack of concentration; increased reaction time (slow response); sedation

Acute effects of alcohol: 100-200mg/dL

Ataxia; impaired mental and motor skills; impaired short-term memory (alcoholic blackouts); slurred speech

Acute effects of alcohol: 200-300mg/dL

No response to sensory stimuli; emesis; stupor

Acute effects of alcohol: 300-400mg/dL

Coma

Acute effects of alcohol: >400mg/dL

Respiratory depression; death

Describe the Chronic Neurological Effect of Alcohol use: Brain Skrinkage

This is due to loss of both Gray & White matter

Describe the Chronic Neurological Effect of Alcohol use: Wernicke’s Encephalopathy

Mental confusion, ataxia, abnormal ocular mobility (Nystagmus) & polyneuropathy due to deficiency of thiamin (Vit B₁)

Reversible with treatment!

Describe the Chronic Neurological Effect of Alcohol use: Korsakoff’s Psychosis

Learning and short-term memory impairment due to thiamin (Vit B₁) deficiency

Responds slowly to treatment; not completely reversible!

Describe the Chronic Neurological Effect of Alcohol use: brain metabolism

Reduction in brain metabolism (reverses with alcohol detoxification)

Describe the Chronic Neurological Effect of Alcohol use: Seizures

Increase in risk of unprovoked seizures

Describe the Chronic Neurological Effect of Alcohol use: Sleep

Marked fragmentation of sleep

Describe the Chronic Neurological Effect of Alcohol use: Psychiatric Syndromes

Temporary suicide ideation, anxiety, panic attacks

Describe the Chronic Neurological Effect of Alcohol use: Peripheral Nerves

Peripheral nerve injury beginning with peripheral paresthesias of hands and feet

Describe the acute effects of Alcohol on the Cardiovascular System

• Direct effect vasodilator effect on blood vessels; account for hypothermia in severe intoxication

• Depression of myocardial contractility (at blood concentration [BAC] above 100mg/dL)

Describe the chronic effects of Alcohol on the Cardiovascular System — SMALL AMOUNTS

• Reduces risk of Coronary heart disease

• Increases HDL

• Decrease MI

• Red wine is particularly protective

• Beneficial effect of alcohol can be attributed to the protein “reveratrol” found on skin of red grapes

• Not yet confirmed

Describe the chronic effects of Alcohol on the Cardiovascular System — EXCESSIVE AMOUNTS

• Irreversible cardiomyopathy

• Non-specific EEG abnormalities

• Hypertension

• Enlarged heart (ventricular hypertrophy)

• Biventricular heart failure

• Atrial arrhythmias

• Increase incidence of hemorrhagic & ischemic stoke

Acute effects of alcohol on liver function

No lasting changes on hepatic system

Chronic effects of alcohol intoxication on liver function

• Accounts for about 50% of liver disease in US; about 15-30% of chronic alcohol drinkers get severe liver disease

• Triggers a sequence of events, ranging from increased fat accumulation, progresses to hepatitis, irreversible hepatic necrosis, hepatic fibrosis, ultimately causing liver cirrhosis

Accumulation of what two chemicals leads to Fatty liver (Stenosis)

↑ADH and Acetate lead to ↑NADH and AcetylCoA respectfully, which lead to fatty liver

Deposition of _________ facilitates fibrosis in the liver

Collagen

At what point does liver damage become irreversible?

After Hepatitis (“Hepatitis Necrosis”)

Effects of Acute Intoxication on the endocrine system

• Marked diuresis via inhibition of antidiuretic hormone secretion

• Catecholamine release from the adrenal medulla

• Depression of sexual responsiveness in humans

Effects of Chronic Intoxication on the endocrine system

• Alteration of the regulation of endocrine systems

• Lead to endocrine-related complications (hypothyroidism, growth retardation, compromised bone health)

• Decreased sexual function in both males and females

• Disorders of fluid electrolyte balance, including ascites, edema, and effusion may occur

Symptoms of Fetal Alcohol Syndrome are more severe if abuse occurs in which trimester?

1st trimester

Describe the triad of abnormalities

1. Cluster of craniofacial abnormalities

2. Rand of CNS Dysfunctions

3. Stunt of growth

Describe the 2 proposed mechanisms of Teratogenicity of Alcohol

• Selective fetal malnutrition through injury to the placenta

• Direct action of ethanol (or acetylaldehyde) to inhibit embryonic cellular proliferation early in gestation

  • Fetus LACKS ADH & cannot metabolize ethanol

Describe how ethanol is procarcinogenic

Increased risk for several cancers:

• Oral cavity, pharynx, and larynx

• Colorectal cancer

• Breast cancer

Describe ethanol’s Hematological effects

Increased risk of anemias

• Thrombocytopenia

• Leukopenia

• Increased susceptibility to infection

Describe Withdrawal symptoms of Alcohol

• Vary; most symptoms subside in 2-3 days

• Anxiety, insomnia, tremors, dilated pupils, palpitations, nausea, hallucinations, seizures

• Delirium tremens (DTs) in 48-72 hours; potentially fatal and may last 2-3 weeks or longer

  • CNS: Fever, agitations, confusion

  • CVS Disturbances: Inc BP, palpitations, sweating

  • GIT: cramps, vomiting, loss of appetite

Drugs to help in the Management of Symptoms of Withdrawal

Benzodiazepines

• Diazepam, Lorazepam, and oxazepam are used to manage symptoms

Describe AUD (Alcohol Use Disorder)

A chronic relapsing brain disease characterized by compulsive alcohol use, loss of control over alcohol intake, and a negative emotional state when not using

Describe the MOA of AUD

Not well understood but involves many neurotransmitters

• Dopamine: compulsive behavior

• Glutamate: memory and consolidation

• Opioid Peptides: cravings

• Endocannabinoid system

How is ethanol effected by CNS depressants

Ethanol is enhanced by CNS depressants such as sedatives/hypnotics (date rape drugs)

• Synergistic effect: 1+1=10 → total memory loss is likely

How is ethanol effected by other drugs metabolized by MEOS

Produces a dual effect on these other drugs (steroids, phenobarbital, warfarin)

How is ethanol effected by Vasodilators & Oral Hypoglycemic agents?

Ethanol can potentiate the pharmacologic effects of some non-sedative drugs

How is ethanol effected by Acetaminophen?

Ethanol can enhance acetaminophen toxicity due to the induction of MEOS and depletion of glutathione

What four conditions are Alcohol Contraindicated in?

• Liver disease

• GIT ulcer

• Skeletal or Cardiac Myopathy

• Pregnancy

Therapeutic uses of Ethanol Externally

• Vehicle for medicines

• Ethanol sponges to lower body temp in fever

• Skin disinfectant

Therapeutic uses of Ethanol Systemically

• Treatment of poisoning by methanol

• Injection of relief of pain

  • Due to trigeminal neuralgia and inoperable carcinoma

  • Injected in close proximity of nerves or sympathetic ganglia

Treatment choice for Acute Ethanol Intoxication is based upon severity of ________ & __________

Respiratory & CNS Depression

List treatment Strategy Options for Acute Ethanol Intoxication

• Respiratory Support

• Stomach lavage if GIT absorption is incomplete

• Hemodialysis to reduce systemic alcohol

• Restore electrolyte balance

List the 3 FDA Approved Drugs to Reduce Alcohol Intake

• Disulfiram

• Naltrexone

• Acamprosate

What is the MOA of Disulfiram?

• Inhibits ALDH enzyme, thereby leading to the accumulation of acetylaldehyde

• Acetylaldehyde accumulation causes unpleasant SEs within a few minutes after ingestion of ethanol

Describe the unpleasant effects caused by Disulfiram when mixed with alcohol

Stimulates extreme Hangover

• Pulsating HAs, severe thirst, chest pains, syncope, N/V, blurred vision, orthostatic hypotension, CVS complications, respiratory depression, convulsions and death may occur in severe cases

Describe the use Disulfiram

• Used to manage chronic alcoholism

• It is not a cure for alcoholism; it enforces sobriety

What other drugs with disulfiram-like effect?

• Metronidazole

• Some cephalosporins

• Sulfonyl urea hypoglycemic drugs

How does Naltrexone Work?

• It’s a µ-opioid receptor antagonist that reduces cravings for alcohol & relapses to heavy intake of alcohol

• Blocks opioid recepotrs associated with reward and positive reinforcement that comes from alcohol use, thereby mitigating alcohol cravings

How does Acamprosate work?

Reduces Cravings

• Exact mech unknown, but thought to inhibit the hyper-glutamatergic activity in the alcoholic brain

Which drugs are first line and which are second?

First Line: Naltrexone and Acamprosate

Second Line: Disulfiram

What is the main SE of Methanol Poisoning?

Retinal toxicity, leading to blindness; death may also occur

What is the Treatment for Methanol Toxicity?

Fomepizole