PHARMACOLOGY: ALCOHOLS

Reference: Basic and Clinical Pharmacology Katzung et al (2012) 12th Edi

Transcriber: docdemetillo@icloud.com
To toil and not to seek for rest...

ALCOHOLS
Pp: 389 400
TOPIC OUTLINE
I.
II.

Introduction
Basic Pharmacology of Ethanol
a.
Pharmacokinetics
i. Introduction
ii. Alcohol Dehydrogenase Pathway
iii. Microsomal Ethanol Oxidizing System
iv. Acetaldehyde Metabolism
b.
Pharmacodynamics of Acute Ethanol Consumption
i. Central Nervous System
ii. Heart
iii. Smooth Muscle
c.
Consequence of Chronic Alcohol Consumption
i. Introduction
ii. Liver and Gastrointestinal Tract
iii. Nervous System
1.
Intolerance and Dependence
2.
Neurotoxicity
iv. Cardiovascular System
1.
Cardiomyopathy and Heart Failure
2.
Arrhythmias
3.
Hypertension
4.
Coronary Heart Disease
5.
Blood
6.
Endocrine System and Electrolyte Imbalance
7.
Fetal Alcohol Syndrome
8.
Immune System
9.
Increased Risk of Cancer
d.
Alcohol Drug Interactions
III. Clinical Pharmacology of Ethanol
a.
Introduction
b.
Management of Acute Alcohol Intoxication
c.
Management of Alcohol Withdrawal Syndrome
d.
Treatment of Alcoholism
i. Introduction
ii. Naltrexone
iii. Acamprosate
iv. Disulfiram
v. Other Drugs
IV. Pharmacology of Other Alcohols
a.
Methanol
b.
Ethylene Glycol

BASIC PHARMACOLOGY OF ETHANOL

II.
a.

Basic Pharmacology of Ethanol

Pharmacokinetics
Introduction
o Ethanol
o Small water soluble molecule
o Rapidly absorbed in the GIT.
o If ingested in fasting state peak level achieved in 30 minutes.
o Presence of food in the stomach delays absorption by slowing gastric
emptying.
o Distribution is rapid, with tissue levels approximating concentration in the
blood
o Volume of distribution approximates total body water (0.5 0.7L/Kg)
o Women have higher peak concentration than men because women
have lower total body content and differences in first pass effect
o Rapid high concentration in the CNS d/t:
Ethanol can readily crosses biologic membranes
Brain receives large portion of total blood flow
o 90% of OH is oxidized in the liver, rest is excreted in lungs and urine
o Excretion of a small but consistent proportion of OH by the lungs can be
quantified legal basis for driving under the influence
o At levels of ethanol usually achieved in the blood, rate of oxidation follows
zero order kinetics
Independent of time and concentration of the drug
o Typical adult can metabolize 7 10 gram (150 220 mmol) per hour,
equivalent in:
10 oz or 300 mL beer; 3.5 oz or 105 mL of wine; 1 0z or 30 mL distilled
80 proof spirits
o Pathways of OH metabolisms is shown below:

INTRODUCTION
I.

Introduction
In low to moderate amounts, relieves anxiety and fosters a feeling of well being
or even euphoria.
If abused, individual could developed alcohol use disorder.
If individual have alcohol dependence, they have the characteristic of alcohol
abuse with physical dependence on alcohol.
People with chronic alcoholism generally have poorer outcomes when they are
in the hospital.
Prenatal exposure to ethanol are born with morphologic or functional defects.
Alcoholism still a common chronic disease that is difficult to treat
Toxicity occurs in ethanol, methanol, and ethylene glycol with sufficient
frequency.

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Alcohol Dehydrogenase Pathway

The primary pathway
Involves alcohol dehydrogenase [ADH] convert OH to Acetaldehyde
Located mainly in the liver, small amounts in brain and stomach
ADH Enzyme Genetic variation
o Affects ethanols rate of metabolism and appears to alter vulnerability to
OH abuse d/o.

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PHARMACOLOGY: ALCOHOLS
Reference: Basic and Clinical Pharmacology Katzung et al (2012) 12th Edi

Transcriber: docdemetillo@icloud.com
To toil and not to seek for rest...

E.g.:
ADH allele ADH1B*2 allele associated with rapid conversion of
ethanol to acetaldehyde protective against OH dependence
Some metabolism occurs in the stomach, smaller amounts in women, they
have lower levels of gastric enzyme sex related difference in blood OH
concentrations.
NADH excess in the liver.
o d/t OH oxidation, this reducing equivalent is generated
o occurs when Hydrogen ion is transferred to the NAD+
o excessive NADH metabolic d/o; lactic acidosis; & hypoglycemia
Microsomal Ethanol Oxidizing System [MEOS]
AKA mixed function oxidase system.
Uses NADPH as cofactor
Consists of cytochrome P450 2E1, 1A2, 3A4
Chronic alcohol consumption MEOS is activated increase ethanol
metabolism and other drugs eliminated by P450s that constitute MEOS
system
Acetaldehyde Metabolism
Aldehyde is oxidized in the liver by mitochondrial NAD dependent
aldehyde dehydrogenase [ALDH]
Product is acetate metabolized further to CO2 and H2O or used to form
acetyl CoA
Oxidation of acetaldehyde is inhibited by Disulfiram used deter drinking
by alcohol dependent individuals

If ethanol is consumed with Disulfiram acetaldehyde accumulates

unpleasant reaction of facial flushing, nausea, vomiting, dizziness and
headache.

Other drugs with Disulfiram like reaction:

Metronidazole, cofetan, trimethoprim

many of the acute effects of Alcohol and GABAA antagonists to attenuate

some of the actions of ethanol
o
Ethanol and Glutamate
The former inhibits the ability of the latter to open the cation channel
associated with NMDA subtype of glutamate receptors
NMDA receptors are associated with cognitive function, learning and
memory.
Blackouts period of memory loss that occurs with high levels of
alcohol may result from inhibition of NMDA receptors activation.

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b.

Pharmacodynamics of Acute Ethanol Consumption

Central Nervous System
o
See table below

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CNS is markedly affected by acute OH consumption

Causes sedation, relief of anxiety, and at higher concentration slurred
speech, ataxia, impaired judgment, and disinhibited behavior (intoxication
or drunkenness)
Marked as the blood level is rising acute tolerance to the effects of OH
occurs after a few hours of drinking
Chronic drinkers needed higher concentrations to elicit these CNS effects
Chronic drinker is still sober at 300 400 mg/dl, but in nontolerant
individual this can cause coma or marked intoxication already
OH is an alcohol depressant like sedative hypnotics, thus can cause
coma, respiratory depression, and death.
Ethanol affects the following:
NT receptors for amines, amino acids, opioids, and neuropeptides;
Enzymes like Na+/K+ - ATPase, adenylyl cyclase, phosphoinositide
specific phospholipase C;
Nucleoside transporter; and
Ion channels.
Ethanol and GABA
Acute exposure to ethanol enhances the action of GABA at GABAA
receptors consistent with the ability of GABA mimetics to intensify

Heart
Blood level of 100 mg/dL significant depression of myocardial
contractility

Smooth Muscle
o
Ethanol is a vasodilator d/t depression of vasomotor center and direct
smooth muscle relaxation by acetaldehyde
o
Vasodilation hypothermia is marked in cold environments
o
Relaxes the uterus
c.

Consequence of Chronic Alcohol Consumption

Introduction
o
Profoundly affects the function of liver, nervous system, gastrointestinal,
cardiovascular, and immune system
o
Ethanol has low potency and it requires thousand so times higher to
produce its intoxicating effects
o
Damaging effects is due to combination of ethanol and acetaldehyde and
the metabolic consequences of processing heavy load of a metabolically
active substance

Oxidative stress with depletion of glutathione

Damage to mitochondria

Growth factor dysregulation

Potentiation of cytokine induced injury

o
Chronic consumption of OH is associated with an increased risk of death
d/t liver disease, cancer, accidents, and suicide
o
Common cause of pancreatitis
Liver and Gastrointestinal Tract
o
Liver diseases

Most common medical complication

Chronic drinker developed severe liver disease

Alcohol Fatty Liver

Reversible may progress to alcoholic hepatitis cirrhosis liver
failure

Women is more susceptible to hepatotoxicity

Concurrent infection with hepatitis B or C virus increases risk of severe

liver disease

Pathogenesis is multifactorial:
Ethanol oxidation in the liver
Dysregulation of fatty acid oxidation and synthesis
Activation of the innate immune system tumor necrosis factor -

Alcoholics are prone to gastritis and have increased susceptibility to

blood and plasma protein loss during drinking anemia and protein
malnutrition

OH damages small intestine diarrhea, weight loss, and multiple

vitamin deficiencies

Malabsorption of water soluble vitamins is severe

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Nervous System
Tolerance and Dependence

There is limit to tolerance relative small increase in the lethal dose

occurs with increasing alcohol use

Withdrawal symptoms consist of hyperexcitability, seizures, toxic

psychosis, and delirium tremens

Dose rate and duration of alcohol consumption determine the intensity

of the withdrawal syndrome

Psychological dependence:
Compulsive desire for alcohols rewarding effect

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PHARMACOLOGY: ALCOHOLS
Reference: Basic and Clinical Pharmacology Katzung et al (2012) 12th Edi

Transcriber: docdemetillo@icloud.com
To toil and not to seek for rest...

Desire to avoid the negative consequences of withdrawal

People who have recovered from alcoholism and become abstinent
still experience period of intense craving especially with cues
Tolerance may result from ethanol induced up regulation of a
pathway in response to the continuous presence of ethanol
Dependence d/t over activity of that same pathway after the ethanol
effect dissipates and before the system has time to return to a normal
ethanol free state.
Seizure in alcohol withdrawal:
Due to up regulation of the NMDA subtype of glutamate receptors
and voltage sensitive Ca++ channels
Changes in GABA transmission play a role in tolerance and
withdrawal. This is based on:
The effect of sedative hypnotics to enhance GABAergic
neurotransmission to substitute for alcohol during withdrawal
Down regulation of GABAA mediated responses with chronic alcohol
exposure
Ethanol:
Modulates neural activity in mesolimbic dopamine reward circuit
Alcohol affects the NTs involved in brain reward system like
serotonin, opioids, and dopamine by complex effects on the
concentration of receptors for these NT and their signaling pathway.
Naltrexone nonselective opioid receptor antagonists helps
patient to recover from alcoholism abstain from drinking
supports the idea that a common neurochemical reward system is
shared by very different drugs associated with physical and
psychological dependence.
Increases dopamine release in the nucleus accumbens
Ethanol intake cannabinoid CB 1 receptor
Seeking behavior is reduced by antagonizing the CB 1 receptor.
CB 1 is the molecular target of marijuana
Two neuroendocrine System and the Ethanol seeking behavior:
Appetite regulating system leptin, ghrelin, and neuropeptide Y
Stress response system corticotropin releasing factor

Neurotoxicity
d/t large consumption of OH
common neurologic deficits:
Generalized symmetric peripheral nerve injury distal paresthesia of
hands and feet
Degenerative changes gait disturbance and ataxia
Dementia
Demyelinating disease
Wernicke Korsakoff Syndrome
Characterized by:
Paralysis of the external eye muscles
Ataxia
Confused state coma death
Associated with THIAMINE deficiency patient suspected to have
this condition is subjected to thiamine therapy
Upon administration ocular signs, ataxia and confusion abates
Most patients are left with Korsakoff psychosis A chronic disabling
memory disorder
Visual acuity and alcoholism
Visual acuity is impaired
Painless blurring occurs over several weeks of heavy alcohol
consumption
Changes are bilateral and symmetric followed by optic nerve
degeneration
If methanol is ingested severe visual disturbances

Cardiovascular System
Cardiomyopathy and Heart Failure
Heavy alcohol consumption dilated cardiomyopathy with ventricular
hypertrophy and fibrosis
Alcohol and myocytes disturbances:

Membrane disruption

Depressed function of mitochondria and endoplasmic reticulum

Intracellular accumulation of phospholipids and fatty acids

Up regulation of voltage gated Ca++ channels

Alcohol induced cardiomyopathy is worse than idiopathic dilated

cardiomyopathy even though cessation of drinking improves function,
and cardiac size
Poorer prognosis is due to interference of ethanol to beneficial effects
of beta blockers and ACE inhibitors

Arrhythmias
Binge drinking associated with atrial and ventricular arrhythmia
Patient undergoing withdrawal syndrome develop severe arrhythmias
reflects abnormalities of Mg++ and K+ metabolism and enhanced
release of catecholamines
Arrhythmias seizures, syncope and sudden death

Hypertension
3 OH drinks per day hypertension (5%)
Independent of obesity, salt intake, coffee drinking, and cigarette smoking
Decrease intake decreases BP in hypertensive
Responsive in anti HTN drugs

Coronary Heart Disease (CHD)

Moderate OH intake prevents CHD, ischemic stroke, and peripheral
arterial disease
Ethanol Benefits:
Raises level of HDL cholesterol
Inhibit some of the inflammatory process underlying atherosclerosis
Increases production of endogenous anticoagulant t-PA
Presence of anti oxidants protects us from atherosclerosis
Blood
Affects hematopoiesis
Directly inhibit proliferation of all cellular elements in the bone marrow
Mild Anemia d/t OH related folic acid deficiency
GI bleeding iron deficiency anemia
Hyperlipidemia and severe liver disease several hemolytic syndromes

Endocrine System and Electrolyte Imbalance

Deranges steroid hormone balance gynecomastia and testicular
atrophy
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Chronic liver disease
Ascites, edema, effusions.
Vomiting and diarrhea, Secondary aldosteronism, diuretic therapy
altered K+
Large amount of ethanol metabolized impairs hepatic gluconeogenesis
hypoglycemia
Increased cortisol and growth hormone excessive lipolytic factors
ketosis
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Fetal Alcohol Syndrome (FAS)

Chronic maternal OH consumption teratogenic mental retardation
and congenital malformations
FAS Characteristics:
IUGR
Microcephaly
Poor coordination
Underdeveloped midfacial region flattened face
Minor joint abnormalities
Congenital heart defects
Mental retardation
Ethanol rapidly crosses the placenta reaches OH concentration same
as mums fetal liver has little alcohol dehydrogenase activity fetus
rely on maternal and placental enzymes for OH elimination
Ethanol triggers apoptotic neurodegeneration and aberrant neuronal and
glial migration in developing nervous system
Ethanol causes striking reduction in neurite growth

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PHARMACOLOGY: ALCOHOLS
Reference: Basic and Clinical Pharmacology Katzung et al (2012) 12th Edi

Transcriber: docdemetillo@icloud.com
To toil and not to seek for rest...

Immune System
OH and immune function

Decreased in lungs
Suppressed function of alveolar macrophages
Inhibition of granulocytes chemotaxis
Reduced number and function of T cells
Lungs is predisposed to infections
Increases morbidity a and mortality risk for patients with pneumonia

Hyperactive in liver and pancreas

Liver
Enhanced function of Kupffer cells and hepatic stellate cells
Increased cytokine production

Increased Risk of Cancer

Increased risk for cancer of the mouth, pharynx, larynx, esophagus, and
liver
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Small increase in the risk of breast cancer in women
o
Acetaldehyde and ROS by increased activity of cytochrome P450
damages DNA
o
Implicated links b/w Oh and cancer includes changes in folate metabolism
and growth promoting effects of chronic inflammation
o

d.

Alcohol Drug Interactions

Increased activity of drug metabolizing enzymes
Prolonged intake of OH without damage to the liver enhance metabolic
biotransformation of drugs
Hepatic cytochrome P450 3 or more drinks per day increased enzyme
activity increased conversion of acetaminophen to reactive hepatotoxic
metabolites increased risk for hepatotoxicity
Acute OH abuse inhibit metabolism of phenothiazines, tricyclic
antidepressants, and sedative hypnotics
CNS depressants (sedative hypnotics) plus OH increase CNS
depression
OH potentiates effects of vasodilators and hypoglycemic agents

CLINICAL PHARMACOLOGY OF ETHANOL

III.
a.

Clinical Pharmacology of Ethanol

Introduction
There is a large genetic contribution to the development of alcoholism
Polymorphism in alcohol DHN protect us against alcoholism
Polymorphism associated with relative insensitivity to alcohol and presumably
thereby a greater risk of alcohol abuse. Genes identified:
o
Alpha subunit of GABAA receptor
o
M2 muscarinic receptor
o
Serotonin transporter
o
Adenylyl cyclase
o
Potassium channel

b.

Management of Acute Alcohol Intoxication

Prevent respiratory depression and aspiration of vomitus
>400mg/dL fatal
Give glucose to treat hypoglycemia and ketoacidosis
Thiamine is given to prevent Wernicke Korsakoff syndrome
Give potassium if vomiting is severe

c.

Management of Alcohol Withdrawal Syndrome

Withdrawal syndrome:
Motor agitation
Anxiety
Insomnia
Reduction in seizure threshold
Degree of withdrawal symptom is proportional to degree and duration of alcohol
abuse
See figure in the next column.

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Mild:
Increased pulse and BP
Tremor
Anxiety
Insomnia occurs 6 8 hours after Oh consumption stopped
Lessen after 1-2 days
Anxiety and sleep disturbances is decreasing for several months
Delirium tremens::
o Delirium
o Agitation
o Autonomic NS instability
o Low grade fever
o Diaphoresis
Drug treatment for detoxification
o Benzodiazepine
Long acting chlordiazepoxide and diazepam
If with liver disease lorazepam and oxazepam

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d.

Treatment of Alcoholism
Introduction
o Treatment of associated d/o and counseling therapy help decrease rate of
relapse.
Naltrexone
o Long acting opioid antagonist
o Taken once a day, 50 mg for alcoholism
o Extended release IM injection once every four weeks
o Causes dose dependent hepatotoxicity
o Combination with Disulfiram is contraindicated
o If given to patient who are physically dependent on opioids precipitate s acute
withdrawal syndrome
o Blocks therapeutic effects of usual doses of opioids
Acamprosate
o Acts on GAAB, glutamate, serotonergic, noradrenergic, and dopaminergic
receptors
o Weak NMDA receptor antagonists and a GABAA receptor activator
o Do not show significant effect if in combination with naltrexone
o Given 1 2 enteric coated 333 mg capsule TID
o Poorly absorbed, food reduces its absorption further
o Distributed widely and eliminated renally, so not used with patient with renal
impairment.
o Causes, vomiting, nausea and diarrhea
Disulfiram
o If taken with alcohol, it causes flushing, throbbing headache, nausea,
vomiting, sweating, hypotension, and confusion that lasts for 30 minutes or
several hours
o Inhibits aldehyde dehydrogenase accumulates acetaldehyde
o 12 hours is required for its action
o Elimination rate is low, thus action persist for several days after the last one
o Inhibit metabolism of phenytoin, oral anticoagulants, and isoniazid
o Not to be administered to medications with alcohol.

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PHARMACOLOGY: ALCOHOLS
Reference: Basic and Clinical Pharmacology Katzung et al (2012) 12th Edi

Transcriber: docdemetillo@icloud.com
To toil and not to seek for rest...

Other Drugs
o Ondansetron 5 HT3 receptor antagonist
o Topiramate drug used in partial and generalized tonic clonic seizure
o Baclofen GABAB receptor antagonists used as spasmolytic
o Rimonabant CB1 receptor antagonist suppress OH related behavior

PHARMACOLOGY OF OTHER ALCOHOLS

IV.
a.

Pharmacology of Other Alcohols

Methanol (Methyl, wood OH)
Constituent of many commercial solvents
Found at home in the form of canned heat or in windshield washing products
Poison if ingested
Absorbed through the skin, respiratory, GIT, and distributed in body water
Mechanism of elimination is by oxidation formaldehyde, formic acid, CO2
Formate and formaldehyde is toxic to humans conversion is slow thus it takes
6 30 hours before severe toxicity occurs
Nonspecific findings include inebriation and gastritis, elevated osmolar gap
Odor of formaldehyde is present urine and breath
Most characteristic symptom:
o Visual disturbances

Describe as being in a snowstorm progresses to blindness

Changes in retina occurs late

o Anion gap metabolic acidosis
Poor prognosis if the ff occurs:
o Bradycardia
o Prolonged coma
o Seizures
o Resistant acidosis
Cause of death is cessation of respiration
Serum level >20mg/dL needs treatment
Serum level >50mg/dL hemodialysis
Serum formate level is a better indication of clinical pathology
Support of respiration is the first treatment
Modalities of treatment:
o Suppression of metabolism by alcohol DH

Fomepizole OH D
H inhibitor

See figure below

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b.

IV, loading dose of 15mg/kg, then 10mg/kg every 12 hours for 48 hours
and then 15 mg/kg every 12 hours thereafter until methanol serum level
is below 20 30 mg/dL
If patient is in hemodialysis, drug is given 6 hours after loading dose and
every 4 hours thereafter
AE: burning at the infusion site, headache, nausea, and dizziness
IV ethanol is alternative to Fomepizole
Has high affinity to OH DH than methanol.
Used for methanol and ethylene glycol poisoning treatment
Dose dependent metabolism and variability of ethanol metabolism
require frequent monitoring of blood levels to ensure appropriate OH
concentration
Hemodialysis enhance removal of methanol and its toxic products
Used for severe poisoning to eliminate both ethanol and formate
Alkalinization to counteract metabolic acidosis
Bicarbonate is given
Folinic acid and folic acid is given to patient with methanol poisoning

Ethylene Glycol
Polyhydric alcohol
Used as heat exchangers, in antifreeze formulations, and industrial solvents
Metabolized to toxic aldehydes and oxalate
Three stages of ethylene glycol overdose:
o First few hours transient excitation followed by CNS depression
o Delay of 4 to 12 hours severe metabolic acidosis develops from
accumulation of acid metabolites and lactate
o >12 hours delayed renal insufficiency follows deposition of oxalate in renal
tubules
o Diagnosis: recognition of anion gap acidosis, osmolar gap, and oxalate
crystals in urine in a patient without visual disturbances
Fomepizole is the standard txt
IV stat and as describe in methanol poisoning till serum is below 20 30 mg/dL
IV ethanol is an alternative
Hemodialysis for patients with serum >50mg/dL, significant metabolic acidosis,
significant renal impairment
Fomepizole reduced the need for hemodialysis esp. in patients with less severe
acidosis and intact renal function.

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