Alcohol and the brain

§ Addi-onal  Notes  
§ Important  
§ Explana-on  –Extra-­‐  

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 Alcohol and Brain
Ethyl alcohol (ethanol): is the most commonly abused drug in the world.
- We don’t use alcohol as drugs, we’ll just discuss pharmacological and toxic effects.

1-Pharmacokinetics.
• Small lipophilic molecule.
• Small molecular weight + Lipophilic molecules = lipid soluble = can cross any cell membrane à cross BBB.
• Crosses all biological membranes.
• Rapidly and completely absorbed from GIT. It has complete absorption if it takes orally.
• Large Vd (distributed in all body tissues); Volume distribution = Total body water.
• Recall: VD is mathematical factor to measure distribution of drug through body fluid “mainly total body water’ so because here we have small molecule
+ lipophilic that is why it’s = TBW.
• Crosses placenta excreted in milk. it will harm the fetus in pregnant and breast feeding
• Acute alcohol consumption: inhibits CYP450 2E1 so decrease metabolism of other drugs taken concurrently as (warfarin, phenytoin:
anticonvulsant in the treatment of epilepsy).
• Chronic alcohol consumption: induces liver microsomal enzyme CYP450 2E1, which leads to significant increases in ethanol metabolism
(Tolerance) & metabolism of other drugs as warfarin (increase  risk  of  clot) = (Drug interactions).

2-Alcohol Metabolism. Metabolism in gastric mucosa & liver (mainly).

• Oxidation of ethanol to acetaldehyde (more toxic than alcohol) via alcohol dehydrogenase (ADH) or
cyt-p450 (CYP2E1) à Acetaldehyde is converted to acetate via aldehyde dehydrogenase (ALDH)
which also reduces NAD+ to NADH à Acetate ultimately is converted to CO2 + water.
• At low ethanol conc.,. minor metabolism by MEOS (microsomal ethanol-oxidizing system) mainly cyt-
p450 (CYP2E1). Upon continuous alcohol use, this enzyme is stimulated and contribute significantly
to alcohol metabolism & tolerance.

Genetic variation of alcohol metabolism. (Aldehyde Dehydrogenase polymorphism)

• Asian populations (including Chinese, Japanese, Taiwanese, Korean) have genetic variation in aldehyde dehydrogenase resulting in a
variant allele ALDH2*2 Asian populations don’t have risk or reduced risk of addiction because they don’t have the step” metabolism of Acetaldehyde “
because the efficient of Aldehyde Dehydrogenase less than other people ”not work properly’ à accumulation of Acetaldehyde “ will not transform to acetate“
§ They metabolized alcohol at slower rate than other populations.
§ Can develop “Acute acetaldehyde toxicity” after alcohol intake characterized by nausea, vomiting, dizziness, headache,
vasodilatation, and facial flushing and prevent them from becoming alcoholic.
3-Alcohol Excretion. Acute Action of Alcohol Chronic Actions of Alcohol
• Excreted unchanged in urine (2-8%).
v In mild-moderate amounts: v Chronic ethanol abuse (alcoholism) is associated with many
• Excretion unchanged via lung (basis CNS depression. Degree of
for breath alcohol test). complications:
depression depend on the dose • Tolerance, dependence (physical & psychological), addiction,
• Rate of elimination is zero-order taken
kinetic (not concentration-dependent) behavioral changes
• relieves anxiety, euphoria
i.e. rate of elimination is the same at (feeling of well-being). • Liver: hepatic cirrhosis & liver failure.
• Nystagmus, slurred speech, Acetate  converted  to  other  product  Acetyl  co  A  “other  than  CO2+  H2O”.  In  over  
low and high concentration.
impaired judgment, ataxia drinking  à  consump-on  of  NAD  à  will  be  in  reduced  form    >  all  enzymes  depend  on  
• Sedation, hypnosis, loss of NAD  will  not  work  à  That  lead  to  accumula-on  of  Acetyl  co  A  à  converted  into  faSy  
4-Mechanism of Action. consciousness acid  à  deposi-on  in  liver  à  first  step  injury  happen  in  liver  on  drinking  alcohol.
is a CNS depressants
CVS depression. v Most common medical complication occurs with liver.
• Myocardial contractility Fatty liver > inflammation > hepatitis > fibrosis “liver not functioning” > cirrhosis
Acute alcohol causes: • Reduction of gluconeogenesis Reduc-on  of  gluconeogenesis  >  
depression
1. Enhance the effect of GABA • Vasodilatation due to accumula-on  of  Acetyl  co  A  >  energy  produc-on  from  alcohol  rather  than  
(inhibitory neurotransmitter) on its vasomotor center from  fat  >  accumula-on  of  fat  
GABA receptors in brain à CNS depression & direct smooth • Fatty liver/alcoholic steatosis Hepatitis
depression. muscle relaxation caused • Hepatic cirrhosis: jaundice, ascites, bleeding, encephalopathy
2. Inhibition of glutamate action by acetaldehyde. (liver metabolism not going properly>accumulation ammonia > enter brain >
(excitatory neurotransmitter) on NMDA Vasodilation à flush sensation encephalopathy)
(N-methyl-D-aspartate receptor) • Irreversible liver failure.
v In severe amounts:
receptors leading to disruption in
memory, consciousness, alertness. • Severe CNS depression • CVS: hypertension (CVS damage of endothelium + NO “nitric
• Respiratory depression. oxide” inhibited >hypertension), myocardial infarction
Chronic alcohol leads to • Respiratory acidosis • CNS: cerebral atrophy, cerebellar degeneration, and
Up-regulation of NMDA receptors & • Nausea, vomiting, peripheral neuropathy. Wernicke encephalopathy or Korsakoff
aspiration of vomitus. psychosis may occur. Vitamins deficiency> A,D,B”B1”> Wernicke
voltage sensitive Ca channels (Ca influx
• CVS depression encephalopathy or Korsakoff psychosis may occur.
to nerve cells) leading to alcohol • Volume depletion • GIT system: irritation, inflammation, bleeding, nutritional
tolerance & withdrawal symptoms • Hypotension deficiencies worsen the ulcer
(tremors, exaggerated response & • Hypothermia • Endocrine system: gynecomastia & testicular atrophy
seizures). • Coma, death. • Hematological disorders (all anemia types), neoplasia.
 Alcoholism Complications
1. Gastritis, hemorrhagic esopahgitis, ulcer diseases, pancreatitis (due to direct toxic action on epithelium), Diarrhea.
2. Deficiency of vitamins. (Vit  A  deficiency>  alcohol  dehydrogenase  metabolize  “re-nol  form”  +  Vit  D  deficiency>need  to  be  in  ac-ve  form  
and  this  need  a  healthy  liver  +  Vit  B  deficiency>  cause  CNS  ac-on)
GIT System
3. Exacerbates nutritional deficiencies
4. weight loss, and malnutrition (weight loss > because there is no absorption).
5. In heavy drinkers : increased risk of oral and esophageal cancer.
Chronic alcohol abuse can lead to cardiomyopathy
§ Cardiac hypertrophy
CSV § Congestive heart failure.
§ Arrhythmia (due to potassium and magnesium depletion)
§ Hypertension: due to increased calcium & sympathetic activity.
• Iron deficiency anemia (due to inadequate dietary intake & GIT blood loss).
• Megaloblastic anemia: (due to folate deficiency, malnutrition, impaired folate absorption).
Hematological • Hemolytic anemia.
Complications • Bone marrow suppression
• Thrombocytopenia (suppressing platelet formation, prolong bleeding times).
• Impaired production of vitamin-K dependent clotting factors leading to prolonged prothrombin time.
v Hypogonadism:
• In women: ovarian dysfunction, amenorrhea, anovulation, hyperprolactinemia, infertility.
• In men: gynecomastia, decreased muscle & bone mass, testicular atrophy, sexual impotence due to inhibition of
Endocrine
luteinizing hormone (LH) , decrease in testosterone, estradiol, progesterone.
§ Hypoglycemia & ketoacidosis due to impaired hepatic gluconeogenesis & excessive lipolytic factors, especially
increased cortisol and growth hormone.
• Tolerance
• Physiological and psychological dependence
CNS • Addiction: dopamine, serotonin and opioids are involved.
• Neurologic disturbances
• Wernicke-Korsakoff syndrome
 Alcoholism Associated Syndromes
Fetal Alcohol Syndrome (FAS): Irreversible Wernicke-Korsakoff Syndrome
v Ethanol rapidly crosses placenta. It is a combined manifestation of 2 disorders:
Pre-natal exposure to alcohol causes:
• Intrauterine growth retardation (due to hypoxia). Wernicke's encephalopathy:
• Congenital malformation (teratogenesis): • ocular disturbances - unsteady gait
• Microcephaly. • changes in mental state as confusion,
• Impaired facial development. delirium, ataxia
• Congenital heart defects.
• Physical and mental retardation. Korsakoff's psychosis:
• impaired memory & cognitive and
behavioral dysfunction.
• Cause: thiamine (vitamin B1) deficiency
• Treated by: thiamine + dextrose-
containing IV fluids
 Alcoholism Alcoholism Withdrawal Management of Alcoholism
Tolerance Symptoms Withdrawal

• Substituting alcohol with a long-acting

• Autonomic hyperactivity & sedative hypnotic drug then tapering the
craving for alcohol dose.
v Chronic consumption
• Vomiting, thirst • Benzodiazepines as (chlordiazepoxide,
of alcohol leads to
• Profuse sweating, severe diazepam) or lorazepam that is preferable
tolerance that
tachycardia (shorter duration of action).
develops due to:
• Vasodilatation, fever • Efficacy: IV/ po
• Delirium, tremors, anxiety, • Manage withdrawal symptoms & prevent
• Metabolic tolerance irritability, insomnia, agitation & seizures.
agitation, insomnia
(pharmacokinetic): • Dose of BDZs should be carefully adjusted
• transient visual/ auditory
due to induction of to provide efficacy & avoid excessive dose
illusions, violent
liver microsomal that causes respiratory depression &
• behavior, hallucinations.
enzymes. hypotension.
• Grand mal seizures (after 7-48
hr alcohol cessation) • Fluoxetine
• Functional tolerance • Clonidine & Propranolol: (Beta blockers)
• Due to super-sensitivity of
(Pharmacodynamics): inhibits the action of exaggerated
glutamate receptors &
due to changes in sympathetic activity
hypoactivity of GABA receptors
CNS sensitivity • Acamprosate: a weak NMDA receptor
are possibly involved.
antagonist & GABA activator, reduce
psychic craving.
To prevent alcohol relapse:
Disulfiram therapy: 250 mg daily
• Inhibits hepatic aldehyde dehydrogenase, this
will increase blood level of acetaldehyde.
• Disulfiram-induced symptoms render alcoholics
afraid from drinking alcohol.
• Acetaldehyde produces extreme discomfort,
vomiting, diarrhea, flushing, hotness, cyanosis,
tachycardia, dyspnea, palpitations &
headache.

Alcohol and Drug Interactions

Acute Alcohol Use Chronic Alcohol Use Others
• causes inhibition of
• Alcohol suppresses gluconeogenesis, which may
liver enzyme,
• induces liver microsomal increase risk for hypoglycemia in diabetic patients.
decreases
enzymes and increases • Acetaminophen + alcohol (chronic use): risk of
metabolism of some
metabolism of drugs hepatotoxicity. (release free radicals)
drugs and increases
such as warfarin, • NSAIDs + alcohol: Increase in the risk of developing
their toxicities e.g.
propranolol and etc. a major GI bleed or an ulcer.
bleeding with
• Narcotic drugs (codeine and methahdone) +
warfarin.
alcohol: risk of respiratory and CNS depression.
 Pharmacokinetics Alcohol Metabolism Alcohol Excretion Mechanism of Action
• Small lipophilic molecule. Metabolism in gastric mucosa & liver. • Excreted unchanged • is a CNS depressants
• Crosses all biological in urine (2-8%).
membranes. • Oxidation of ethanol to acetaldehyde (more toxic • Acute alcohol causes:
than alcohol) via alcohol dehydrogenase or cyt-p450

Summary
• Rapidly and completely • Excretion unchanged
absorbed from GIT. (CYP2E1). 1. Enhancement the
via lung (basis for
• Large Vd (distributed in all effect of GABA
breath alcohol test).
body tissues). • Acetaldehyde is converted to acetate via aldehyde (inhibitory
• Volume distribution= Total dehydrogenase which also reduces NAD+ to NADH. neurotransmitter) on its
• Rate of elimination is GABA receptors in
body water.
• Acetate ultimately is converted to CO2 + water. zero-order kinetic (not brain leading to CNS
• Crosses placenta excreted
concentration- depression
in milk. • At low ethanol conc., minor metabolism by MEOS dependent)
(microsomal ethanol-oxidizing system) mainly cyt- 2. Inhibition of glutamate
• Acute alcohol
p450 (CYP2E1). Upon continuous alcohol use, this action (excitatory
consumption inhibits i.e. rate of elimination is
enzyme is stimulated and contribute significantly to neurotransmitter) on
CYP450 2E1 so decrease the same at low and high
alcohol metabolism & tolerance. NMDA receptors
metabolism of other drugs concentration.
taken concurrently as leading to disruption in
Genetic variation of alcohol metabolism: memory,
(warfarin, phenytoin).
consciousness,
Aldehyde Dehydrogenase polymorphism alertness.
• Chronic alcohol
consumption induces liver § Asian populations (including Chinese, Japanese,
microsomal enzyme Taiwanese, Korean) have genetic variation in
CYP450 2E1, which leads to • Chronic alcohol leads to
aldehyde dehydrogenase resulting in a variant
significant increases in allele ALDH2*2 1. up-regulation of NMDA
ethanol metabolism receptors & voltage
(Tolerance) & metabolism § They metabolized alcohol at slower rate than sensitive Ca channels (Ca
of other drugs as warfarin other populations.
(Drug interactions). influx to nerve cells)
§ Can develop “Acute acetaldehyde toxicity” after leading to alcohol
alcohol intake characterized by nausea, vomiting, tolerance & withdrawal
dizziness, headache, vasodilatation, and facial symptoms (tremors,
flushing and prevent them from becoming
exaggerated response &
alcoholic.
seizures).
 one of complication of Alcoholism is Tolerance which of
Minor metabolism of ethanol is done by MEOS " microsomal following is metabolic cause to develop tolerance :
ethanol- oxidizing system " mainly is : a) Induction of liver microsomal enzymes
A) Cytochrome p450 b) Increase of CNS sensitivity
B) Cytochorme p45 c) Decrease of CNS sensitivity
C) Cytochorme C20 d) Inhibition of liver microsomal enzymes
D) Cytochorme a200 one of these drug is used to manage alcoholism withdrawal
One of these drung has Zero-Order kinetic : is :
a) Wafferin a) Lorazepam
b) Pronolol b) Codeine
c) Ethnanol c) Acetaminophen
d) Acamprosate d) Methahdone
Acute using alcohol can lead to disruption in memory due to : Alcoholism having diabetic maltase which one the
a) Increase effect of GABA complication is increase to develop in his condition :
b) Decrease effect of GABA a) Hypogonadism
c) Increase effect of glutamate b) Liver fatty
d) Decrease effect of gluatamate c) Iron dificy anemia
Cause of hypertension in alcoholism is due to : d) Hypoglycemia
A) Decrease of Calcium Disulfiram is used to pervert alcohol relapse which of these is
B) Increase parasympatic MOA of this drug :
C) Increase sympathic activity a) Inhabit Alchoal dehydrogenase
D) Decrease sympathic activity b) Incresae Alchoal dehydrogenase
Alcoholism patient was suffering from sever foliate deficiency c) Inhabit aldehyde dehydrogenase
which type of anemia he will develop : d) Increase aldehyde dehyroganase
a) Megablastic anemia Alcoholic person whose using warfarin which of these drug –
b) Iron deficiency anemia drug interaction will occur :
c) Hemolytic anemia a) Bleeding
d) Aplastic anemia b) CNS depression
c) Hepatotoxicity
d) Hypoglycemia
Ans  :    A-­‐  C  –  D  –C  –  A  –A  –  A  –  D  –  C  –  A    
  
Good luck!
Done by Pharmacology team 434
• Haneen Alkhanbashi
• Maha Alrabiah
• Nouf Alharbi
• Shaikha Aldosari
• Moneera Aldraihem

For  any  correc-on,  sugges-on  or  any  useful  informa-on  do  not  
hesitate  to  contact  us:  Pharmacology434@gmail.com