Q. What are the possible mechanisms involved in the occurrence of tolerance to chronic alcohol intake?

Tolerance is a complex process involving both changes in the CNS & pharmacokinetic processes. Tolerance may result from ethanol-induced up-regulation of a pathway in response to continuous presence of ethanol. Up-regulation of the NMDA subtype of Glutamate receptors & voltage-sensitive Ca2+ channels (cause of the seizures that accompany alcohol withdrawal symptoms). Like other drugs of abuse, ethanol modulates neural activity in the brains’ mesolimbic dopaminergic pathway (dopamine reward circuit) leading to an increase in DA release in the nucleus accumbens. This produces that feeling of euphoria often associated with alcohol consumption. Chronic alcohol drinkers, when forced to reduce/ stop experience withdrawal symptoms which indicates physical dependence.

Q. What are the toxic effects of chronic alcohol consumption on the liver and hepatic metabolism?

LIVER: Progressive ↓ liver function, hepatitis & cirrhosis. Liver disease is most common medical complication of alcohol abuse. Alcoholic fatty liver progress into alcoholic hepatitis & liver cirrhosis. & liver failure. Chronic alcohol abuse is the leading cause of liver cirrhosis & need for liver transplantation.

Pathogenesis of alcoholic liver disease is multifactorial process involving:

• • Metabolic repercussions of ethanol oxidation in the liver
  • Dysregulation of FA oxidation & synthesis (fat accumulation)
  • Gluconeogenesis ↓, hypoglycemia

Q. What is Wernicke-Korsakoff-syndrome and how is it treated?

Relatively uncommon syndrome characterized by paralysis external eye muscles, ataxia, paralysis of facial muscles, confused state develops to coma/ death. It is associated with chronic alcoholism and thiamine deficiency, therefore receive parenteral thiamine therapy. Ataxia & confusion improve with thiamine administration. Thiamine therapy also prevent permanent brain damage.

Q. Fully explain the foetal alcohol syndrome.

Chronic maternal alcohol abuse during the 1^st trimester of pregnancy is associated with teratogenic effects. Ethanol rapidly crosses the placenta and reaches concentrations in the fetus that are similar to those in maternal blood. The fetal liver has little or no alcohol dehydrogenase activity (foetus is still developing), so the fetus must rely on maternal and placental enzymes for elimination of alcohol. Alcohol is the leading cause of mental retardation & congenital malformation. This is a syndrome of craniofacial dysmorphia, heart defects, and mental retardation caused by teratogenic effects of ethanol or alcohol consumption during pregnancy.

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. 

Q. How do the pharmacokinetic interactions of acute alcohol consumption differ from that of chronic alcohol consumption?

Chronic alcohol usage induce cytochrome P450 enzymes leading to increased ↑ metabolism of other drugs. The most common pharmacokinetic alcohol-drug interactions stem from alcohol-induced increases of drug-metabolizing enzymes. Thus, prolonged intake of alcohol without damage to the liver can ↑ enhance the metabolic biotransformation of other drugs.  

Acute alcohol usage: ↓ metabolism of drugs. Acute alcohol use can inhibit metabolism of other drugs because of decreased enzyme activity or decreased liver blood flow. Phenothiazines, tricyclic antidepressants, and sedative- hypnotic drugs are the most important drugs that interact with alcohol by this pharmacokinetic mechanism. 

Q. Name 4 drug interactions with alcohol where the pharmacological effects of the other drugs are potentiated by alcohol.

CNS depression is potentiated. The additive CNS depression that occurs when alcohol is combined with other CNS depressants, particularly sedative-hypnotics. Alcohol also potentiates the pharmacologic effects of many non-sedative drugs, including vasodilators and oral hypoglycaemic agents. And last but not the least, ↑ anti- platelet aggregation effects of aspirin.