CNS Pharmacology- IInd MBBS (Alcohols and associated drugs)

1. THE ALCOHOLS
Shivankan Kakkar, MD

2. INTRODUCTION
• Alcohol is widely consumed.
• Like other sedative- hypnotic drugs, alcohol in low to
moderate amounts relieves anxiety and fosters a
feeling of well-being or even euphoria.
• However, alcohol is also the most commonly abused
drug in the world, and the cause of vast medical and
societal costs.
• Ethanol and many other alcohols with potentially toxic
effects are also used as fuels and in industry—some in
enormous quantities. In addition to ethanol, methanol
and ethylene glycol toxicity occurs with sufficient
frequency to warrant discussion.

3. ALCOHOL-USE DISORDERS
• Individuals who use alcohol in dangerous situations (eg,
drinking and driving or combining alcohol with other
medications) or continue to drink alcohol despite adverse
consequences related directly to their alcohol consumption
suffer from alcohol abuse.
• Individuals with alcohol dependence have characteristics of
alcohol abuse and additionally exhibit physical dependence
on alcohol (tolerance to alcohol and signs and symptoms
upon withdrawal). They also demonstrate an inability to
control their drinking and devote much time to getting and
using alcohol, or recovering from its effects.
• The alcohol-use disorders are complex, with genetic as well as
environmental determinants.

4. BASIC PHARMACOLOGY OF ETHANOL
• Pharmacokinetics
• Ethanol is a small water-soluble molecule that is absorbed rapidly from the
gastrointestinal tract. After ingestion of alcohol in the fasting state, peak blood
alcohol concentrations are reached within 30 minutes. The presence of food in
the stomach delays absorption by slowing gastric emptying. Distribution is rapid,
with tissue levels approximating the concentration in blood. The volume of
distribution for ethanol approximates total body water (0.5–0.7 L/kg). In the
central nervous system (CNS), the concentration of ethanol rises quickly, since the
brain receives a large proportion of total blood flow and ethanol readily crosses
biologic membranes.
• Over 90% of alcohol consumed is oxidized in the liver; much of the remainder is
excreted through the lungs and in the urine. The excretion of a small but
consistent proportion of alcohol by the lungs can be quantified with breath alcohol
tests that serve as a basis for a legal definition of “driving under the influence”
(DUI) in many countries.
• The typical adult can metabolize 7–10 g (150–220 mmol) of alcohol per hour.

5. BASIC PHARMACOLOGY OF ETHANOL
• Two major pathways
of alcohol metabolism
to acetaldehyde have
been identified
(Figure–1).
• Acetaldehyde is then
oxidized to acetate by
a third metabolic
process.

6. • Which metabolite of ethanol is
responsible for causing headache,
hypotension, nausea, and vomiting
(“hangover”)?
• Acetaldehyde

7. BASIC PHARMACOLOGY OF ETHANOL
A. Alcohol Dehydrogenase Pathway
The primary pathway for alcohol metabolism involves alcohol
dehydrogenase (ADH), a family of cytosolic enzymes that catalyze the
conversion of alcohol to acetaldehyde.
B. Microsomal Ethanol-Oxidizing System (MEOS)
This enzyme system, also known as the mixed function oxidase system,
uses NADPH as a cofactor in the metabolism of ethanol and consists
primarily of cytochrome P450.
C. Acetaldehyde Metabolism
Much of the acetaldehyde formed from alcohol is oxidized in the liver
in a reaction catalyzed by mitochondrial NAD-dependent aldehyde
dehydrogenase (ALDH). The product of this reaction is acetate, which
can be further metabolized to CO2 and water, or used to form acetyl-
CoA.

8. • What is the first step in ethanol metabolism?
• Alcohol dehydrogenase converts ethanol to
acetaldehyde.
• What is the second step in ethanol
metabolism?
• Acetaldehyde dehydrogenase converts
acetaldehyde to acetate.

9. BASIC PHARMACOLOGY OF ETHANOL
• Pharmacodynamics of Acute Ethanol Consumption
A. Central Nervous System
The CNS is markedly affected by acute alcohol consumption. Alcohol
causes sedation, relief of anxiety and, at higher concentrations,
slurred speech, ataxia, impaired judgment, and disinhibited behavior,
a condition usually called intoxication or drunkenness.
B. Heart
Significant depression of myocardial contractility has been observed
in individuals who acutely consume moderate amounts of alcohol.
C. Smooth Muscle
Ethanol is a vasodilator, probably as a result of both CNS effects
(depression of the vasomotor center) and direct smooth muscle
relaxation caused by its metabolite, acetaldehyde. In cases of severe
overdose, hypothermia—caused by vasodilation—may be marked in
cold environments.

10. BASIC PHARMACOLOGY OF ETHANOL
• Consequences of Chronic Alcohol Consumption
A. Liver and Gastrointestinal Tract
Liver disease is the most common medical complication of alcohol abuse; an
estimated 15–30% of chronic heavy drinkers eventually develop severe liver disease.
B. Nervous System
1. Tolerance and dependence—The consumption of alcohol in high doses over a long
period results in tolerance and in physical and psychological dependence.
2. Neurotoxicity—Consumption of large amounts of alcohol over extended periods
(usually years) often leads to neurologic deficits. The most common neurologic
abnormality in chronic alcoholism is generalized symmetric peripheral nerve injury,
which begins with distal paresthesias of the hands and feet. Degenerative changes
can also result in gait disturbances and ataxia. Other neu-rologic disturbances
associated with alcoholism include dementia and, rarely, demyelinating disease.
Wernicke-Korsakoff syndrome is a relatively uncommon but important entity
characterized by paralysis of the external eye muscles, ataxia, and a confused state
that can progress to coma and death.

11. • A 40-year-old man with a 20-year history of alcohol abuse is
brought to the hospital by his friends because he was difficult to
rouse. He ate a large meal several hours ago. He is emaciated and
lethargic. Examination shows severely restricted horizontal eye
movements and ataxia of both upper extremities. The most likely
cause of these findings is a deficiency of which of the following
nutrients?
A. Folic acid
B. Vitamin A
C. Vitamin B1 (thiamine)
D. Vitamin B6 (pyridoxine)
E. Vitamin B12 (cobalamin)
• Correct answer : C. Vitamin B1 (thiamine)
• The clinical features are characteristic of Wernicke
encephalopathy seen in chronic alcoholics due to thiamine
deficiency.

12. BASIC PHARMACOLOGY OF ETHANOL
C. Cardiovascular System
1. Cardiomyopathy and heart failure—Alcohol has complex effects on the
cardiovascular system. Heavy alcohol consumption of long duration is associated with
a dilated cardiomyopathy with ventricular hypertrophy and fibrosis.
2. Arrhythmias—Heavy drinking—and especially “binge” drinking—are associated
with both atrial and ventricular arrhythmias.
3. Hypertension—A link between heavier alcohol consumption (more than three
drinks per day) and hypertension has been firmly established in epidemiologic studies.
4. Coronary heart disease—Although the deleterious effects of excessive alcohol use
on the cardiovascular system are well established, there is strong epidemiologic
evidence that moderate alcohol consumption actually prevents coronary heart
disease (CHD), ischemic stroke, and peripheral arterial disease.
D. Blood
Alcohol indirectly affects hematopoiesis through metabolic and nutritional effects
and may also directly inhibit the proliferation of all cellular elements in bone marrow.
The most common hematologic disorder seen in chronic drinkers is mild anemia
resulting from alcohol-related folic acid deficiency. Iron deficiency anemia may result
from gastrointestinal bleeding.

13. BASIC PHARMACOLOGY OF ETHANOL
E. Endocrine System and Electrolyte Balance
Chronic alcohol use has important effects on the endocrine system and on fluid and electrolyte
balance. Clinical reports of gynecomastia and testicular atrophy in alcoholics with or without
cirrhosis suggest a derangement in steroid hormone balance.
F. Fetal Alcohol Syndrome
Chronic maternal alcohol abuse during pregnancy is associated with teratogenic effects, and
alcohol is a leading cause of mental retardation and congenital malformation. The abnormalities
that have been characterized as fetal alcohol syndrome include (1) intrauterine growth
retardation, (2) microcephaly, (3) poor coordination, (4) underdevelopment of midfacial region
(appearing as a flattened face), and (5) minor joint anomalies. More severe cases may include
congenital heart defects and mental retardation.
G. Immune System
The effects of alcohol on the immune system are complex; immune function in some tissues is
inhibited (eg, the lung), whereas pathologic, hyperactive immune function in other tissues is
triggered (eg, liver, pancreas).
H. Increased Risk of Cancer
Chronic alcohol use increases the risk for cancer of the mouth, pharynx, larynx, esophagus, and
liver.

14. • Acute alcohol intoxication does what to
warfarin metabolism?
• Inhibits warfarin metabolism, thereby
increasing warfarin blood levels
• Chronic alcohol use does what to warfarin
metabolism?
• Induces warfarin metabolism, thereby
decreasing warfarin blood

15. PHARMACOLOGY OF OTHER
ALCOHOLS
• Methanol (methyl alcohol, wood
alcohol) is widely used in the
industrial production of synthetic
organic compounds and as a
constituent of many commercial
solvents.
• The special susceptibility of humans
to methanol toxicity is due to
metabolism to formate and
formaldehyde, not due to methanol
itself.
• Toxic levels of formate, causes
characteristic visual disturbance plus
coma, seizures, acidosis, and death
due to respiratory failure.
• Fomepizole, an alcohol
dehydrogenase inhibitor, is approved
for the treatment of methanol
poisoning.

16. • A 21-year-old man is brought to the emergency department by friends because of blurred vision,
headache, abdominal pain, nausea, and vomiting for 30 minutes. His friends say that he drank 60
mL of wood alcohol 1 hour ago after a bet at a fraternity house party. His pulse is 58/min and
regular, respirations are 28/min and shallow, and blood pressure is 130/72 mm Hg. Physical
examination shows no other abnormalities. Laboratory studies show:
• Serum
Na+ – 139 mEq/L
Cl− – 85 mEq/L
K+ – 4.5 mEq/L
HCO3− – 13 mEq/L
• Urine
pH – 5
Crystals – none
• Arterial blood gas analysis on room air:
pH – 7.28
PO2 – 108 mm Hg
PCO2 – 22 mm Hg
• Which of the following is the most appropriate initial treatment for this patient?
(A) Intravenous ethanol therapy
(B) Intravenous sodium bicarbonate therapy
(C) Oral acetylcysteine therapy
(D) Oral activated charcoal therapy
(E) Hemodialysis
• Correct answer : (A) Intravenous ethanol therapy
• Explanation: This is a case of methyl alcohol poisoning. Intravenous ethanol is administered to
prevent toxicity and complications like blindness.

17. • In methyl alcohol poisoning there is CNS
depression, cardiac depression and optic nerve
atrophy. These effects are produced due to:
A. Formaldehyde and formate
B. Acetaldehyde
C. Pyridine
D. Acetic acid
• Correct answer : A. Formaldehyde and formate
acid
• Methyl alcohol is converted
into formaldehyde by alcohol dehydrogenase. It
is in turn converted to formic acid by aldehyde
dehydrogenase.

18. PHARMACOLOGY OF OTHER
ALCOHOLS
• Polyhydric alcohols such as ethylene glycol are used as
heat exchangers, in antifreeze formulations, and as
industrial solvents. Young children and animals are
sometimes attracted by the sweet taste of ethylene glycol
and, rarely, it is ingested intentionally as an ethanol
substitute or in attempted suicide. Although ethylene glycol
itself is relatively harmless and eliminated by the kidney, it
is metabolized to toxic aldehydes and oxalate.
• Toxic aldehydes and oxalate, causes kidney damage and
severe acidosis.
• As with methanol poisoning, early fomepizole is the
standard treatment for ethylene glycol poisoning.

19. ALCOHOLS- SUMMARY
DRUGS MECHANISM OF
ACTION, EFFECTS
CLINICAL
APPLICATIONS
PHARMACOKINETICS, TOXICITY AND
INTERACTIONS
ETHANOL Multiple effects
of
neurotransmitter
receptors, ion
channels, and
signaling
pathways
Antidote in
methanol
and
ethylene
poisoning;
topical
antiseptic
• Zero-order metabolism: duration
depends on dose
• Toxicity: Acutely, central nervous
system depression and respiratory
failure. Chronically, damage to
many systems, including liver,
pancreas, gastrointestinal tract,
and central and peripheral nervous
systems
• Interactions: Induces CYP2E1,
increased conversion of
acetaminophen to toxic metabolite
• Methanol: Poisonings result in toxic levels of formate, which causes characteristic visual disturbance plus
coma, seizures, acidosis, and death due to respiratory failure
• Ethylene glycol: Poisoning creates toxic aldehydes and oxalate, which causes kidney damage and severe
acidosis

20. DRUGS USED IN ACUTE ETHANOL
WITHDRAWL
DRUGS MECHANISM OF
ACTION, EFFECTS
CLINICAL APPLICATIONS PHARMACOKINETICS,
TOXICITY AND
INTERACTIONS
Benzodiazepines
(Oxazepam;
lorazepam;
diazepam;
chlordiazepoxide)
BDZ receptor
agonists
that facilitate
GABA-
mediated
activation of
GABAA receptors
Prevention and
treatment of acute
ethanol withdrawal
syndrome
See Sedative
hypnotics
Thiamine
(vitamin B1)
Essential vitamin
required for
synthesis of the
coenzyme
thiamine
pyrophosphate
Administered to patients
suspected of having
alcoholism (those
exhibiting acute alcohol
intoxication or alcohol
withdrawal syndrome)
to prevent Wernicke-
Korsakoff syndrome
Administered
parenterally
• Toxicity: None
• Interactions:
None

21. • Which benzodiazepines are commonly used
to treat alcohol withdrawal?
• Oxazepam; lorazepam; diazepam;
chlordiazepoxide

22. DRUGS USED IN CHRONIC
ALCOHOLISM
DRUGS MECHANISM OF
ACTION, EFFECTS
CLINICAL
APPLICATIONS
PHARMACOKINETICS, TOXICITY AND
INTERACTIONS
Naltrexone Nonselective
competitive
antagonist of
opioid
receptors
Reduced risk of
relapse in individuals
with alcoholism
Available as an oral or long-acting parenteral
formulation
• Toxicity: GI effects and liver toxicity; will
precipitate a withdrawal reaction in
individuals physically dependent on opioids
and will prevent the analgesic effect of
opioids
Acamprosate Poorly understood
NMDA receptor
antagonist and
GABAA agonist
effects
Reduced risk of
relapse in individuals
with alcoholism
Toxicity: GI effects and rash
Disulfiram Inhibits aldehyde
dehydrogenase,
resulting in
aldehyde
accumulation
during ethanol
ingestion
Deterrent to drinking
in individuals with
alcohol dependence;
rarely used
Toxicity: Little effect alone but severe and
potentially dangerous flushing, headache,
nausea, vomiting, and hypotension when
combined with ethanol
Topiramate or gabapentin: for patients who do not tolerate or respond to other medications

23. • Which opioid antagonist is given orally to
decrease cravings in alcoholism?
• Naltrexone
• What enzyme does disulfiram inhibit?
• Acetaldehyde dehydrogenase, leading to a
build up of acetaldehyde

24. DRUGS USED IN ACUTE METHANOL
OR ETHYLENE GLYCOL TOXICITY
DRUGS MECHANISM OF ACTION,
EFFECTS
CLINICAL APPLICATIONS PHARMACOKINETICS,
TOXICITY AND
INTERACTIONS
Fomepizole Inhibits alcohol
dehydrogenase,
prevents conversion
of methanol and
ethylene glycol to
toxic metabolites
Methanol and
ethylene glycol
poisoning
Orphan drug
• Toxicity:
Headache, nausea,
dizziness, rare
allergic reactions
• Ethanol: Higher affinity than methanol or ethylene glycol for alcohol
dehydrogenase; used to reduce metabolism of methanol and ethylene glycol to
toxic products

25. • Treatment of alcohol dependence is by all
except?
A. Disulfiram
B. Naltrexone
C. Flumazenil
D. Acamprosate
• Correct answer : C. Flumazenil
• Flumazenil is a benzodiazepine antagonist. It is
not used for the treatment of alcohol
dependence.