Pharmacology of Alcohols
Dr Javaria Arshad
History and overview
• Arabs developed distillation about 800 C.E
• Word Alcohol derived from Arabic for
‘something subtle’
• Alcohol abuse
• Alcoholic content of beverages ranges
between 4% to 6%
• Wine contain 10% to 15% Alcohol.
• In USA 75% of adult population drink
alcohol regularly
Alcoholism
• People continue to drink alcohol in spite
of
adverse
medical
or
social
consequences
• Complex disorder with genetic as well as
environmental determinants
• Each year tens of thousands of children
are born with morphologic and functional
defects because of maternal alcohol
intake
• Alcohol abuse:
Psychiatric diagnosis describing
the recurring use of alcoholic beverages
despite its negative consequences
Alcohol dependence:
Physical dependence on alcohol
(tolerance and signs and symptoms upon
withdrawal )
structure
• Ethanol, CH3 CH2 OH
• Methanol, Methyl alcohol
• Ethylene glycol
Routes of Administration
• Topical
• Inhalation
• Intravenous injection
• Oral ingestion
Pharmacokinetics
• Ethanol rapidly absorbed from stomach
and intestine
• PPL are reached in 30 mins in empty
stomach.
• Distributed to total body water (0.5-0.7
L/Kg)
• In CNS concentration rises quickly, it can
readily cross biologic membranes.
Metabolism
• Zero order kinetics (independent of time
and concentration of drug)
• Constant amount of drug is eliminated in
unit time
• Two pathways of alcohol metabolism
• 1- Alcohol dehydrogenase pathway
• 2- Microsomal ethanol oxidizing system
(MEOS)
• Gastric metabolism of ethanol is lower in
women than in men
Alcohol dehydrogenase pathway
• Alcohol dehydrogenase enzyme present in
liver, brain and stomach
• Converts alcohol to acetaldehyde and
NAD+ is converted to NADH
• Excess NADH production lead to
metabolic disorders, lactic acidosis and
hypoglycemia
Microsomal ethanol oxidizing system
• Mixed function oxidase system (MFO)
• MEOS work when ethanol concentration
rises above 100 mg/dl.
• During chronic alcohol consumption,
MEOs activity is induced.
• As a result metabolism of other drugs
which are metabolized by cytochrome
P450 increases.
Acetaldehyde metabolism
• Acetaldehyde is oxidized in liver by
mitochondrial NAD dependent aldehyde
dehydrogenase
• Acetate is formed which is further
metabolized to CO2 and water
• Disulfiram inhibit this metabolism.
• Facial flushing, nausea, vomiting,
dizziness and headache
• Metronidazole, cefotetan and trimethoprim
Excretion
• Small but a consistent proportion of
alcohol is excreted through lungs.
• ‘Breath alcohol test’ serve as a basis for a
legal definition of ‘ driving under the
influence’ .
Breath alcohol test
• Ratio of ethanol in end-expiratory alveolar
air and ethanol in the blood is relatively
consistent.
• Blood ethanol levels in humans can be
estimated by measurement of alcohol
levels in expired air
• Legally allowed BELs are set below
80mg%
Pharmacodynamics
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•
•
•
•
GIT
CVS
CNS
Effects on disease processes
Effects on prenatal development
CNS
• Alcohol is a CNS depressant
• Disturbs the fine balance between
excitatory and inhibitory influences in the
brain.
• Sedation, relief of anxiety.
• Slurred speech, ataxia, impaired judgment
and disinhibited behaviour (drunkenness)
• Coma, respiratory depression and death
Molecular mechanism
• Effect membrane proteins that participate
in signaling pathways, neurotransmitter
receptors for amines, amino acids, opioids
and neuropeptides.
• Na+, K+ ATPase
• Adenylyl cyclase
• Phosphoinositide- specific phospholipase
C.
• Enhance the action of GABA at GABAA
receptors
• Ethanol inhibits the ability of glutamate to
open the NMDA subtype of glutamate
receptors. Related to cognitive functions
learning and memory
Heart and other organs`
• Significant depression of myocardial
contractility.
• Vasodilatation
• Relaxation of uterine muscles.
Chronic Alcohol Consumption
• Tissue damage result from direct effect of
ethanol and the effect of metabolite.
• Liver:
Alcoholic fatty liver
Alcoholic hepatitis
Cirrhosis
Liver failure
• Increased oxidative stress coupled with
depletion of glutathione, damage to
mitochondria and potentiation of cytokine
induced injury
• Chronic pancreatitis
• Gastritis leading to blood and plasma
protein loss
CNS
• Tolerance and dependence:
Alcohol withdrawal leads to
hyperexcitability, seizures, toxic psychosis
and delirium tremens (hallucinations,
delirium , fever and tachycardia)
Psychological dependence.
Neurotoxicity:
Neurologic deficits.
Generalized symmetric peripheral nerve
injury.
Wernicke-Korsakoff syndrome
• Paralysis of external eye muscles, ataxia
and a confused state that can progress to
coma and death
• Thiamine deficiency + alcoholism
• korsakoff’s psychosis
• Impair visual acuity
CVS
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•
•
•
•
Dilated cardiomyopathy
Ventricular hypertrophy and fibrosis.
Atrial and ventricular arrhythmias
Hypertension
Coronary heart disease (moderate alcohol
consumption prevent heart disease)
• Increased risk of hemorrhagic and
ischemic stroke
Blood
• Inhibit the proliferation of cellular
elements in bone marrow.
Endocrine system and electrolyte balance
Gynecomastia, testicular atrophy.
Ascites, edema and effusions.
Chronic alcohol use lead to increase risk of
cancer of mouth, pharynx, larynx,
esophagus and liver
Clinical uses of alcohol
• Dehydrated alcohol may be injected in
close proximity to nerves and sympathetic
ganglia to relieve long standing pain.
• Systemically ---- poisoning by methyl
alcohol and ethylene glycol
Fetal Alcohol Syndrome
• Chronic maternal alcohol abuse
• Fetal liver has no alcohol dehydrogenase
activity
• Intrauterine growth retardation.
• Microcephaly
• Poor coordination
• Underdevelopment of midfacial region
• Minor joint anomalies
Alcohol-Drug interactions
• Induction of cytochrome P450 enzyme
• Liver toxicity enhanced with parracetamol
• Phenothiazines, tricyclic antidepressants
and sedative hypnotics.
• Additive CNS depression with sedativehypnotics.
Acute alcohol intoxication
• Gidddiness , muscle relaxation, impaired
judgement ------ nystagmus, failing vital
signs, coma and death.
Management of acute alcohol
intoxication
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Prevent respiratory depression.
Prevent aspiration of vomitus.
Glucose
Thiamine (Wernicke-Korsakoff syndrome)
Electrolyte solutions
Management of alcohol withdrawal
syndrome
• Substituting a long-acting sedative
hypnotic drug for alcohol and then
gradually reducing the dose of drug.
• Benzodiazepines are preferred.
Treatment of alcoholism
• Naltrexone
• Acamprosate
• Disulfiram
Cause discomfort in alcoholics
Flushing, throbbing headache,
nausea, vomiting, sweating, hypotension
and confusion.
Inhibit aldehyde dehydrogenase
Acetaldehyde accumulates
Naltrexone
• Related to naloxone Opioid-receptor
antagonist naloxone
• It is given after detoxification and for
several months
Acamprosate
• An analogue of GABA
• Decreases Alcohol intake
Methanol
• Used in industrial production of synthetic
organic compounds and as a constituent
of many commercial solvents
• Accidental ingestion occur when it is
misguidedly ingested as ethanol
substitute
• Absorbed through skin, respiratory and
gastrointestinal tract and well distributed
• Oxidized to formaldehyde, formic acid and
CO2
• Visual disturbances (like being in a snow
storm) lead to blindness
• Bradycardia, prolonged coma, seizures
and acidosis
Treatment
Fomepizole (alcohol dehydrogenase
inhibitor)
Bicarbonate for metabolic acidosis
Ethylene glycol
• Used as heat exchangers in antifreeze
formulations
• Transient excitation followed by CNS
depression , metabolic acidosis and renal
insufficency
• Fomepizole I/V administration
•Thank you