alcohol and the brain prof. hanan hagar dr. ishfaq a. bukhari medical pharmacology unit, ksu 1

Alcohol and the brain

Prof. Hanan Hagar Dr. Ishfaq A. BukhariMedical Pharmacology Unit, KSU

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Ethyl alcohol (ethanol)

Ethyl alcohol (ethanol) is the most commonly abused drug in the world.

Pharmacokinetics is a small lipophilic molecule is water-miscible molecule Readily crosses all biological membranes completely absorbed from GIT volume of distribution = Total Body Water

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Pharmacokinetics of ethanol metabolized in gastric mucosa & liver (90%).

Oxidation of ethanol to acetaldehyde via alcohol dehydrogenase or cyt-p450 (CYP2E1).

Acetaldehyde is converted to acetate via acetaldehyde dehydrogenase which also reduces NAD+ to NADH.

Acetate ultimately is converted to CO2 + water.

Excreted unchanged in urine (2-8%). Excretion unchanged via lung (basis for breath

alcohol test).3

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Alcohol MetabolismCH3CH2OH (Ethanol) NAD+

Alcohol dehydrogenase (ADH)

NADH

CH3CHO (Acetaldehyde) more toxic than alcoholNAD+

Acetaldehyde dehydrogenase (ALDH)

NADH

CH3COOH (Acetic acid)

Mitochondrion

Peroxisome

Hepatic Cellular Processing of alcohol

Ethanol

Acetaldehyde

Acetate

CytosolER

ADHNAD+

NADHCAT

H2O2

H2O

AlDHNAD+

NADH

NADP+

NADPHO2

CYP450

Extra-hepatic tissue

Pharmacokinetics of ethanol Crosses placenta and excreted in milk Rate of elimination is zero-order kinetic (not

concentration-dependent) i.e. rate of elimination is the same at low and high concentration.

Alcohol is enzyme inhibitor (P450 2E1) in acute alcohol consumption and enzyme inducer in chronic alcoholics.

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Acute alcohol consumption inhibits CYP450 2E1 so metabolized drugs as (phenytoin & tolbutamide slowly).

In chronic alcoholics:Alcohol induces CYP450 2E1, which leads to significant increases in ethanol metabolism (Tolerance) & the clearance of other drugs eliminated by the microsomal enzymes.

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Metabolism: Genetic VariationAldehyde Dehydrogenase (ALDH) Asian populations have ALDH genetic deficiency. develop “Acute acetaldehyde toxicity” after alcohol

intake characterized by nausea, vomiting, dizziness, vasodilatation, headache and flushing.

mimicked by disulfiram (used for chronic alcoholics)

Mechanism of action of alcohol is a CNS depressants has no specific receptors affects a large number of membrane proteins that are

involved in signaling pathways as neurotransmitter receptors for amines, amino acids, opioids; Ca2+ ion channels.

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Alcohol effects on central neurotransmittersAcute alcohol causes:

Activation of GABAA receptors in brain leading to CNS depression

Inhibition of glutamate receptors (NMDA) leading to disruption in memory, consciousness, alertness, learning.

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Alcohol effects on central neurotransmittersChronic use of alcohol leads to up-regulation of NMDA receptors & voltage-sensitive Ca Channels (Ca influx to nerve cells) leading to alcohol tolerance & withdrawal symptoms (tremors, exaggerated response & seizures).

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Pharmacological actions of alcohol: In low-moderate amounts (CNS):

relieves anxiety, euphoria (feeling of well-being). Sedation, hypnosis Slurred speech, ataxia (motor incoordination) Impaired judgment Loss of consciousness

CVS Myocardial contractility depression Vasodilatation due to vasomotor center depression & direct

smooth muscle relaxation caused by acetaldehydeAt high blood concentrations it induces coma, respiratory depression, and death

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Acute ethanol intoxication:- CNS depression:

- Sedation, relief anxiety- Slurred speech, ataxia, impaired judgment

- Respiratory depression: leading to respiratory acidosis & coma

- CVS depression - Myocardial contractility depression - Hypotension

- Volume depletion, hypothermia- Death can occur from respiratory depression.

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Elevated acetaldehyde during ethanol intoxicationcauses:- Euphoric effects that may reinforce alcohol

consumption.- Nausea & headache - Vasodilatation & facial flushing- Increase skin temperature (hyperthermia) - Lower BP- Sensation of dry mouth & throat- Bronchial constriction- Increase incidence of GI & upper airway cancers- Liver cirrhosis.

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Alcohol abuse & alcoholism: Chronic alcohol consumption results into(alcoholism) and may cause severe detrimental healtheffects such as alcoholic liver and heart disease,increased risk for stroke, alcohol dementia.

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Medical complications of chronic alcoholism

Liver: The most common medical complication accumulated acetaldehyde hepatotoxicity. Fatty liver/ alcoholic steatosis due to acetyl CoAaccumulation & increased FA synthesis & direct oxidation of ethanol for energy instead of using body fat stores. Hyperlipidemia & fat deposition arecommon in chronic alcohol use Alcoholic hepatitis Hepatic cirrhosis: jaundice, ascites, bleeding,

encephalopathy. Irreversible liver failure. 16

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Healthy Liver Liver in chronic alcoholics

Healthy Liver vs Fatty Liver

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Normal liver Fatty liver

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Alcoholic Liver Disease

Steatosis

SteatohepatitisCirrhosis

Normal

Hepatic Ethanol Metabolism

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ADHADH

Acetaldehyde

AcetateAcetyl CoA

Citric Acid Cycle

Fatty Acid synthesis

Energy

AlcoholAlcohol

NAD+ NADH

AlDHAlDHNAD+

NADH

RATE-LIMITING STEPRATE-LIMITING STEP

Chronic intake→ induction of CYP2E1

Fatty liver

Cardiovascular System:Chronic alcohol abuse can lead to Cardiomyopathy- Degeneration of myocardium (due to direct toxic

effects of alcohol on cardiac muscles)- Cardiac Hypertrophy- Congestive heart failure.- Arrhythmia (due to electrolyte imbalance and conduction

delays induced by alcohol & its metabolites).- Hypertension: due to Ca & sympathetic activity.

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Hematological complication: Iron deficiency anemia (due to inadequate dietary

intake & GI blood loss). Megaloblastic anemia: (due to folate deficiency,

malnutrition, impaired folate absorption). Hemolytic anemia. Thrombocytopenia (suppressing platelet

formation, prolong bleeding times). Decreased Vitamin-K dependent clotting

factors production (due to hepatotoxic action).

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Fetal Alcohol Syndrome: Irreversible• Ethanol rapidly crosses placenta• Pre-natal exposure to alcohol causes: - Intrauterine growth retardation (due to hypoxia)- Congenital malformation (teratogenicity):

- Microcephaly- Impaired facial development- Congenital heart defects- Physical and mental retardation.

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Fetal Alcohol Syndrome ( FAS )

G.I.Tract• Diarrhea, weight loss, and Malnutrition Gastritis, hemorrhagic esopahgitis, ulcer diseases,

pancreatitis (due to direct toxic action on epithelium) Gastroesophageal reflux disease, esophageal

bleeding (reversible). Mal-absorption of water-soluble vitamins In heavy drinkers : increased risk of oral and

esophageal cancer.

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Endocrine system: (Hypogonadism)In women: ovarian dysfunction, amenorrhea, anovulation, hyperprolactinemia &, infertility.

In men: (hypogonadism), loss of facial hair, gynecomastia, muscle & bone mass, testicular atrophy & sexual impotence.

due to inhibition of luteinizing hormone (LH) , decrease in testosterone, estradiol, progesterone.

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Endocrine system:Hypoglycemia due to impaired hepatic gluconeogenesis.

Ketosis, caused by excessive lipolytic factors, especially increased cortisol and growth hormone

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Nervous System Physiological and psychological tolerance Dependence Addiction Neurologic disturbances

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Wernicke-Korsakoff syndromeIt is a combined manifestation of 2 disorders:Wernicke's encephalopathy: acute neurologicdisorder characterized by confusion, coma,polyneuropathy, ataxia (motor incoordination),ocular disorder (impairment of visual acuity)Korsakoff's psychosis: amnesia & cognitive andbehavioral dysfunction.Cause: thiamine deficiency due to:

inadequate nutritional intake decreased uptake of thiamine from GIT decreased liver thiamine stores

Treated: thiamine + dextrose-containing IV fluids.29

Alcoholism Tolerance

Tolerance can develops due to:Metabolic tolerance: due to induction of livermicrosomal enzymes.

Functional tolerance (Pharmacodynamic ): due to change in CNS sensitivity (Neuro-adaptation ).

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Alcoholism withdrawal symptoms depend upon severity, duration of preceding drinkingperiod. Autonomic hyperactivity & craving for alcohol Vomiting & thirst Tremors, anxiety, agitation, insomnia transient visual/ auditory illusions Grand mal seizures (after 7-48 hr alcohol cessation) delirium tremens”delirium tremens” profuse sweating, delirium,

intense vasodilatation, severe tachycardia, fever, violent behavior, hallucinations.

Super-sensitivity of glutamate Rs & hypo-activityof GABAergic Rs are possibly involved.

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Management of alcoholism withdrawal - Substituting alcohol with a long-acting sedative

hypnotic drug then tapering the dose. - Benzodiazepines as (chlordiazepoxide, diazepam)

or lorazepam that is preferable (shorter duration of action).

- Efficacy: IV/ po- Manage withdrawal symptoms & prevent

irritability, insomnia, agitation & seizures.- Dose of BDZs should be carefully adjusted to

provide efficacy & avoid excessive dose that causes respiratory depression & hypotension.

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- Clonidine & Propranolol: inhibits the action of exaggerated sympathetic activity

- Naltrexone: (an opioid antagonist with weak partial agonist activity), reduces psychic craving for alcohol.

- Acamprosate: a weak NMDA-R antagonist & GABA activator, reduce psychic craving.

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• For adjunctive treatment of alcohol dependence: Disulfiram therapy: 250 mg daily• blocks hepatic AlDH, this will increase blood level

of acetaldehyde. • Acetaldehyde produces extreme discomfort,

vomiting, diarrhea, flushing, hotness, cyanosis, tachycardia, dyspnea, palpitations & headache.

• Disulfiram-induced symptoms render alcoholics afraid from drinking alc.

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Mitochondrion

Peroxisome

Disulfiram action

Ethanol

Acetaldehyde

Acetate

CytosolER

ADHNAD+

NADHCAT

H2O2

H2O

AlDHNAD+

NADH

MEOSNADP+

NADPHO2

P450

Extra-hepatic tissue

Pyrazole

Disulfiram(antabuse)

Chlorpropamide(diabetes)

Aminotriazole

Alcohol and drug interactions • Acute alcohol use causes inhibition of liver

enzyme and increases toxicity of some drugs such as bleeding with warfarin

• Chronic uses of alcohol induces liver enzymes and increase metabolism of drugs such as propranolol and warfarin etc

• Alcohol suppresses gluconeogenesis, which may increase risk for hypoglycemia in diabetic patients

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Drugs (metronidazole, tolbutamide, cephalosporins) can inhibit ALDH enzyme “potential drug interactions with alcohol”.

• NSAIDs + alcohol: Increase in the risk of developing a major GI bleed or an ulcer.

• Acetaminophen + alcohol (chronic use): risk of hepatotoxicity.

• Narcotic drugs (codeine and methahdone) + alcohol: risk of respiratory and CNS depression.

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