PHARMACOLOGY 2 Chapter 23: The Alcohols

AY 2022-2023 Dra. Aquitania

2nd Semester MM/DD/YYYY

Alcoholic beverages
- provided calories and some nutrients and served as a main
source of daily liquid intake.

Alcohol (low-moderate amounts)

- relieves anxiety and fosters a feeling of well-being or even
euphoria.

Alcohol
- most commonly abused drug in the world

Alcohol-use disorder
- individuals who use alcohol in dangerous situations (eg, drinking
and driving or combining alcohol with other medications)
- genetic and environmental determinants

Alcohol abuse
- individuals who continue to drink alcohol in spite of adverse
consequences related directly to their alcohol consumption

Alcohol dependence - have characteristics of alcohol abuse and

additionally exhibit physical dependence on alcohol.

I. BASIC PHARMACOLOGY OF ETHANOL

A. Pharmacokinetics
● During conversion of ethanol by ADH to acetaldehyde,
● Absorption hydrogen ion is transferred from ethanol to the cofactor
→ water-soluble molecule that is absorbed rapidly from the nicotinamide adenine dinucleotide (NAD+) to form NADH
gastrointestinal tract ● Excess NADH contributes to metabolic disorders that
→ Peak blood alcohol concentrations are reached within 30 accompany chronic alcoholism and to both the lactic acidosis
minutes and hypoglycemia that frequently accompany acute alcohol
→ Presence of food in the stomach delays absorption by poisoning.
slowing gastric emptying
● Distribution B. Microsomal Ethanol-Oxidizing System
→ rapid (MEOS)
→ Women have higher peak concentration than men
● Also known as the mixed function oxidase system
▪ Women have a lower total body water content due to
● Uses NADPH as a cofactor in the metabolism of ethanol (Figure
difference in first-pass metabolism
23-1, right) and consists primarily of cytochrome P450, 2E1,
→ In CNS, concentration of ethanol rises quickly
1A2, and 3A4
▪ Brain received large portion of total blood flow and ethanol
● During chronic alcohol consumption, MEOS activity is induced
readily crosses biologic membranes
→ increase in clearance of other drugs eliminated by the
● Metabolism
cytochrome P450s that constitute the MEOS system
→ Over 90% of alcohol consumed is oxidized in the liver
→ Remainder is excreted through the lungs and urine
→ Major pathways of alcohol metabolism to acetaldehyde: C. Acetaldehyde Metabolism
● Formed Acetaldehyde is oxidized in the liver in a reaction
catalyzed by mitochondrial NAD-dependent aldehyde
dehydrogenase (ALDH)
● Oxidation of acetaldehyde is inhibited by disulfiram
A. Alcohol Dehydrogenase Pathway → used to deter drinking by patients with alcohol dependence
● When ethanol is consumed in the presence of disulfiram,
● Primary pathway for alcohol metabolism that catalyze the
acetaldehyde accumulates and causes unpleasant reactions:
conversion of alcohol to acetaldehyde
→ facial flushing, nausea, vomiting, dizziness and headache.

PHARMACODYNAMICS OF ACUTE ETHANOL

CONSUMPTION

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 A. CENTRAL NERVOUS SYSTEM → Liver disease: the most common medical complication of
alcohol abuse.
→ The CNS is affected by acute alcohol consumption. → Alcohol fatty liver: may progress to alcohol hepatitis,
→ Alcohol causes: cirrhosis, and liver failure.
▪ Sedation → Chronic alcohol abuse is the cause of liver cirrhosis
▪ Relief of anxiety which needs liver transplantation.
▪ At higher concentrations: slurred speech, ataxia, impaired → Average amount of daily consumption and duration of
judgment, and disinhibited behavior, a condition usually alcohol abuse leads to risk of developing liver disease.
called intoxication or drunkenness. → Women appear to be more susceptible to alcohol
→ CNS effects are most marked as the blood level is rising, hepatotoxicity than men.
because effects of acute tolerance to alcohol occur after a → Pathogenesis of alcohol liver disease: a multifactorial
few hours of drinking. process involving metabolic repercussions of ethanol
→ For chronic drinkers who are tolerant to the effects of oxidation in the:
alcohol, higher concentrations are needed to remove these ▪ Liver
CNS effects. ▪ Dysregulation of fatty acid oxidation and synthesis
→ Alcohol is a CNS depressant. ▪ Activation of the innate immune system by a combination
▪ At high blood concentrations, it induces coma, respiratory of direct effects of ethanol.
depression, and death. → Tumor necrosis factor-α: a proinflammatory cytokine,
→ Ethanol affects a large number of membrane proteins that which appears to play a pivotal role in the progression of
participate in signaling pathways, including: alcoholic liver disease.
▪ Neurotransmitter receptors for amines, amino acids, → Chronic alcohol ingestion: most common cause of chronic
opioids, and neuropeptides. pancreatitis in the Western world.
→ Ethanol inhibits the ability of glutamate to open the cation ▪ Alcohol alters pancreatic epithelial permeability
channel associated with NMDA. ▪ Alcohol promotes the formation of protein plugs and
→ Acute ethanol exposure enhances the action of GABA at calcium carbonate-containing stones
GABAA receptors, which is consistent with the ability of → Individuals with chronic alcoholism are prone to gastritis
GABA-mimetics to intensify acute effects of alcohol. and have increased susceptibility to blood and plasma loss
→ “Blackouts”: periods of memory loss that occur with high during drinking.
levels of alcohol. → Malnutrition from dietary deficiency and vitamin deficiencies
▪ Blackouts may result from inhibition of NMDA receptor due to malabsorption are common in alcoholism.
activation. ▪ Malabsorption of water-soluble vitamins are severe.

B. HEART B. NERVOUS SYSTEM

● Depression of Myocardial Contractility 1. Tolerance and Dependence: due to consumption of alcohol in

→ has been observed in individuals who acutely consume high doses over a long period.
moderate amounts of alcohol. → As with other sedative-hypnotic drugs, only a small increase
▪ Ex. at a blood concentration above 100 mg/dL in the lethal dose occurs with increasing alcohol use.
→ Chronic alcohol drinks, when forced to reduce or
C. SMOOTH MUSCLE discontinue alcohol, experience withdrawal syndrome,
indicating dependence of alcohol.
→ Ethanol is a vasodilator, as a result of both CNS effects and → Alcohol withdrawal symptoms consist of:
direct smooth muscle relaxation caused by acetaldehyde. ▪ Hyperexcitability in mild cases
▪ It relaxes the uterus and was used intravenously for the ▪ Seizures
suppression of premature labor. ▪ Toxic psychosis
→ In cases of severe overdose: ▪ Delirium tremens in severe ones
▪ Hypothermia may be marked in cold environments. → Dose, rate, and duration of alcohol consumption:
▪ Determine the intensity of the withdrawal syndrome.
CONSEQUENCES OF CHRONIC ALCOHOL → Psychological dependence on alcohol: characterized by a
compulsive desire to experience the effects of alcohol.
CONSUMPTION
→ Tolerance may result from ethanol-induced up-regulation of
a pathway in response to the continuous presence of
→ Chronic alcohol consumption affects the function of vital
ethanol.
organs (liver) and the nervous, gastrointestinal,
→ Dependence may result from overactivity of that same
cardiovascular, and immune systems.
pathway after the ethanol effect dissipates and before the
→ Ethanol has low potency which requires concentrations
system has time to return to a normal ethanol-free state.
thousands of times higher than other misused drugs to
→ Alcohol affects local concentrations of serotonin,
produce its intoxicating effects.
opioids, and dopamine and has complex effects on the
→ The tissue damage caused by chronic alcohol ingestion
expression of receptors and signaling pathways.
results from a combination of the direct effects of alcohol and
→ Naltrexone: helps patients who are recovering from
acetaldehyde.
alcoholism.
→ Large amounts of alcohol consumption leads to risk of death.
→ CB1 receptor: the molecular target of active ingredients in
→ Death caused by:
marijuana.
▪ Liver disease
→ Two important neuroendocrine systems
▪ Cancer
▪ Appetite-regulating system: uses peptides such as
▪ Accidents
leptin, ghrelin, and neuropeptide Y.
▪ Suicide
▪ Stress response system: controlled by corticotropin-
releasing factor.
A. LIVER AND GASTROINTESTINAL TRACT 2. Neurotoxicity
→ Neurologic deficits: due to consumption of large amounts
of alcohol over extended periods.

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 ▪ Generalized symmetric peripheral nerve injury: most ▪ Indirectly affects hematopoiesis through metabolic and
common neurologic abnormality and it begins with distal nutritional effect
paresthesias of the hands and feet. ▪ Directly inhibit the proliferation of all cellular elements in
▪ Degenerative changes: result in gait disturbances and bone marrow.
ataxia. → Mild anemia: most common hematologic disorder seen in
▪ Other neurologic disturbances: dementia, and chronic drinkers which result from alcohol-related folic
demyelinating disease. deficiency.
→ Wernicke-Korsakoff syndrome: uncommon but important → Iron deficiency anemia: may result from gastrointestinal
entity characterized by paralysis of the external eye bleeding.
muscles, ataxia, and a confused state that can progress to
coma and death. E. ENDOCRINE SYSTEM AND
▪ Thiamine therapy: patients with Wernicke-Korsakoff ELECTROLYTE BALANCE
syndrome receive this kind of treatment because it has the
absence of toxicity associated with thiamine → Chronic alcohol: has important effects on the endocrine
administration. system, fluid, and electrolyte balance.
▪ Ocular signs, ataxia, and confusion improve after → Individuals with chronic liver disease may have disorders of
administration of thiamine. fluid and electrolyte balance including:
→ Alcohol: may impair visual activity, with painless blurring that ▪ Ascites
occurs over several weeks of heavy alcohol consumption. ▪ Edema
▪ Ingestion of methanol: causes severe visual ▪ Effusions
disturbances. → Alterations of whole body potassium induced by vomiting
and diarrhea, and severe secondary aldosteronism, may
C. CARDIOVASCULAR SYSTEM contribute to muscle weakness and can be worsened by
diuretic therapy.
1. Cardiomyopathy and Heart Failure
→ Heavy alcohol consumption of long duration: associated F. FETAL ALCOHOL SYNDROME
with a dilated cardiomyopathy with ventricular hypertrophy
and fibrosis. → Chronic maternal alcohol abuse during pregnancy is
→ In animals and humans: alcohol induces a number of associated with teratogenic effects.
changes in heart cells that may contribute to → Alcohol is a leading cause of mental retardation and
cardiomyopathy. congenital malformation.
→ Include: → The abnormalities as fetal alcohol syndrome:
▪ Membrane disruption 1. Intrauterine growth retardation
▪ Depressed function of mitochondria and sarcoplasmic 2. Microcephaly
reticulum 3. Poor coordination
▪ Intracellular accumulation of phospholipids and fatty acids 4. Underdevelopment of midfacial region
▪ Up-regulation of voltage-gated calcium channels 5. Minor joint anomalies
→ Poorer prognosis: due to interference by ethanol with the → The fetal has little or no alcohol dehydrogenase activity.
beneficial effects of β blockers and ACE inhibitors.
2. Arrhythmias G. IMMUNE SYSTEM
→ Heavy drinking and binge drinking: associated with both
atrial and ventricular arrhythmias. → Immune function in some tissues is inhibited, whereas
→ Alcohol withdrawal due to arrhythmias: pathologic, hyperactive immune function in other tissues
▪ Seizures is triggered.
▪ Syncope → Types of immunologic changes for lungs:
▪ Sudden death ▪ Suppression of the function of alveolar macrophages
3. Hypertension ▪ Inhibition of chemotaxis of granulocytes
→ Alcohol: responsible for 5% of cases of hypertension, ▪ Reduced number and function of T cells
making it one of the most causes of reversible hypertension. → Types of immunologic changes for liver:
→ Associated with independent of: ▪ Enhanced function of key cells of the innate immune
▪ Obesity system
▪ Salt intake ▪ Increased cytokine production
▪ Coffee drinking
▪ Cigarette smoking
H. INCREASED RISK OF CANCER
→ Reduction of alcohol intake: effective in lowering blood
pressure in hypertensive individuals who are heavy drinkers.
→ Chronic alcohol use increases the risk for cancer of:
4. Coronary Heart Disease
▪ Mouth
→ Moderate alcohol consumption prevents:
▪ Pharynx
▪ Coronary heart disease
▪ Larynx
▪ Ischemic stroke
▪ Esophagus
▪ Peripheral arterial disease
▪ Liver
→ J-shaped: a type of relationship between mortality and the
→ Alcohol: doesn’t appear to be a carcinogen in most test
dose of a drug.
systems.
→ HDL cholesterol: inhibits some of the inflammatory
→ Acetaldehyde: can damage DNA, as can the reactive
processes that underlie atherosclerosis, and with alcoholic
oxygen species produced by increased CYP450 activity.
beverages of antioxidants may protect against
atherosclerosis.
D. BLOOD
→ Alcohol:
ALCOHOL-DRUG INTERACTION

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 → Pharmacokinetic interaction: prolonged intake of alcohol MANAGEMENT OF ALCOHOL WITHDRAWAL
without damage to the liver can enhance the metabolic
biotransformation of other drugs. ● Abrupt alcohol discontinuation
→ Chronic consumption of three or more drinks per day → leads to a characteristic syndrome of motor agitation,
increases the risk of hepatotoxicity due to toxic or even anxiety, insomnia, and reduction of seizure threshold
high therapeutic levels of acetaminophen.
→ Acute alcohol: can inhibit metabolism of other drugs ● In its mildest form, the alcohol withdrawal syndrome of
because of decreased enzyme activity or decreased liver increased pulse and blood pressure, tremor, anxiety, and
blood flow. insomnia occurs 6-8 hours after alcohol consumption is
→ Drugs that interact with alcohol by pharmacokinetic stopped.
mechanism:
▪ Phenothiazines ● Alcohol withdrawal
▪ Tricyclic antidepressants → one of the most common causes of seizures in adults
▪ Sedative-hypnotic drugs
→ Pharmacodynamic interaction: when alcohol is combined ● Syndrome of Delirium Tremens
with other CNS depressants (sedative-hypnotics), the → characterized by delirium, agitation, autonomic nervous
additive CNS depression occurs. system instability, low-grade fever, and diaphoresis

● The major objective of drug therapy in the alcohol withdrawal

CLINICAL PHARMACOLOGY OF ETHANOL period is prevention of seizures, delirium, and arrhythmias.
● Personality type, severe life stresses, psychiatric disorders, and
parenteral role models are not reliable predictors of alcohol ● Two basic principles for detoxification:
abuse → 1) substituting a long-acting sedative-hypnotic drug for
alcohol
● Although environmental factors clearly play a role, there is a → 2) gradually reducinng (tapering) the dose of the long-acting
large contribution of genetics to the development of alcoholism drug

● Polymorphism in alcohol dehydrogenase and aldehyde ● Chlordiazepoxide & Diazepam (Benzodiazepines)

dehydrogenase protect against alcoholism → long-acting
→ advantage of requiring less frequent dosing
● Polymorphism associated with a relative insensitivity to alcohol → provide a built-in tapering effect
abuse have been identified in genes encoding in: → Disadvantage (long-acting): they and their active metabolites
may accumulate
▪ α subunit of the GABA-A receptor
▪ M2 muscarinic receptor ● Lorazepam & Oxazepam (Benzodiazepines)
▪ Serotonin transporter → short-acting
▪ Adenylyl cyclase → useful in alcoholic patients with liver disease
▪ Potassium Channel
TREATMENT OF ALCOHOLISM
MANAGEMENT OF ACUTE ALCOHOL INTOXICATION
● Psychosocial therapy
→ serves as the primary treatment for alcohol dependence
● There is a typical effects of acute sedative hypnotic drug
overdose along with cardiovascular effects (vasodilation & ● Disulfiram, Naltrexone & Acamprosate
tachychardia) and gastrointestinal irritation for nontolerant → adjunctive treatment of alcohol dependence
individuals who consume alcohol in large quantities.
NALTREXONE
● Individuals with chronic alcohol dependence may become
severely intoxicated if sufficient alcohol is consumed. ● relatively long-acting opioid antagonist
● approved by the FDA for treatment of alcohol dependence
● Most important goals in the treatment of Acute Alcohol ● generally taken once ad ay in an oral dose of 50 mg for the
Intoxication treatment of alcoholism
▪ o Prevent Severe Respiratory Depression ● Naltrexone + Disulfiram should be avoided since both are
▪ o Aspiration of Vomitus potential hepatotoxins
● blocks the therapeutic analgesic effects of usual doses of
● The average blood alcohol concentration in fatal cases is opioids
above 400 mg/dl
ACAMPROSATE
● MANAGEMENT
→ Electrolyte imbalances often need to be corrected ● used in Europe to treat alcohol dependence and is approved for
→ Metabolic alterations may require treatment of hypoglycemia this use by the FDA
and ketoacidosis by administration of glucose ● Molecular effects: actions on GABA; glutamate; serotonergic;
→ Thiamine (given to protect against Wernicke-korsakoff noradrenergic; and dopaminergic receptors
syndrome) ● administered as one or two enteric-coated 333-mg tablets three
→ Patients who are dehydrated and vomiting should receive times daily
electrolyte solutions ● Common adverse effects: GI (nausea, vomiting, diarrhea) &
rash
● should not be used in patients with severe renal impairment
→ If vomiting is severe: large amounts of potassium may be
required
DISULFIRAM

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 ● Intravenous ethanol
● inhibits ldehyde dehydrogenase → alternative to fomepizole
● flushing, throbbing headache, nausea, vomiting, sweating, → has a higher affinity than methanol for alcohol
hypotension, and confusion occur w/in few minutes after an dehydrogenase
individual taking disulfiram drinks alcohol → used intravenously as treatment for methanol and ethylene
● rapidly and completelly absorbed from the GI tract glycol poisoning
● inhibits the metabolism of many other therapeutic agents
● no longer commonly used ● Hemodialysis
→ be used to eliminate both methanol and formate from the
OTHER DRUGS blood (cases of severe poisoning)

● Varenicline ETHYLENE GLYCOL

→ this nicotinic agonist drug can reduce binge drinking in mice
(studies) ● used as heat exchangers, in antifreeze formulations, and as
industrial solvents
● Rimonabant ● young children and animals are sometimes attracted by the
→ CB1 receptor antagonist sweet tase
→ shown to suppress alcohol-related behaviors in animal ● sometimes ingested intentionally as an ethanol substitute or in
models and is being tested in clinical trials of alcoholism attempted suicide

PHARMACOLOGY OF OTHER ALCOHOLS ● Three stages of ethylene glycol overdose:

→ 1) transient excitation followed by CNS depression
● Methanol & Ethylene Glycol → 2) severe metabolic acidosis develops
→ two of the most common causes of intoxication → 3) deposition of exalate crystals in renal tubules occurs

● Isopropyl alcohol ● Key to the diagnosis of ethylene glycol poisoning:

→ sometimes ingested when ethanol is not available → a) recognition of anion gap acidosis
→ produces coma, GI irritation, nausea, and vomiting → b) osmolar gap
→ c) oxalate crustals in the urine
METHANOL
● Fomepizole
● aka Methyl alcohol; wood alcohol → standard treatment for ethylene glycol poisoning
● widely used int he industrial production of synthetic organic
compounds
● in the home, it is most frequently found in the form of “caanned
heat” or in windshield-washing products
● can be absorbed through skin or from the respiratory or GI tract
● Primary MOE: by oxidation to formaldehyde, formic acid, and
carbon dioxide

● Visual disturbance
→ most characteristic symptom in methanol poisoning
→ described as “like being in a snowstorm”

● Poor prognosis
→ development of bradycardia, prolonged coma, seizures, and
resistant acidosis

● Support of Respiration
→ first treatment for methanol poisoning

● Three specific modalities for the treatment of methanol

poisoning
→ 1) suppression of metabolism by alcohol dehydrogenase to
toxic products
→ 2) hemodialysis to enhance removal of methanol and its toxic
products
→ 3) alkalinization to counteract metabolic acidosis

● Alcohol dehydrogenase
→ enzyme chiefly responsible for methanol oxidation in the liver

● Fomepizole
→ alcohol dehydrogenase inhibitor
→ treatment of methanol and ethylene glycol poisoning
→ administered intravenously
→ safe during the short time it is administered
→ adverse effects: burning at the infusion site, headache,
nausea, and dizziness

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