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

The consumption of high doses of alcohol over long periods result in tolerance and in physical and psychological dependence. Via poorly understood changes in the nervous system and pharmacokinetic changes such as: up regulation of Microsomal ethanol oxidising system, responsible for metabolising higher concentrations of blood alcohol levels is induced with chronic alcohol consumption leading to an increased amount of ethanol metabolism and also the clearance of other drugs eliminated by cytochrome P450s. Down regulation of GABA_A responses with chronic alcohol exposure indicates subsensitivity after continues exposure. 

Low tolerance to alcohol can be explained via ADH1B*2 allele in some populations which are protective against alcohol dependence because of rapid conversion of ethanol to acetaldehyde and thus individuals will feel the effects of alcohol at lower blood concentration levels and can help decrease the urge to drink more.

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

Tissue damage caused by chronic alcohol consumption results from the combination of direct effects of ethanol and acetaldehyde and the metabolic consequences of processing a heavy load of active metabolites. Increased oxidative stress coupled with depletion of glutathione, damage to mitochondria, growth factor dysregulation and potentiation of cytokine induced injury all contribute to liver disease. Alcoholic hepatitis, cirrhosis and liver failure means a vital organ is compromised and n need for a liver transplant since the removal of toxic products in the body is compromised. Cirrhosis contributes to elevated portal blood pressure and esophageal and gastric venous varices

• What is Wernicke-Korsakoff-syndrome and how is it treated?

This syndrome is characterized by paralysis of external eye muscles, ataxia and a confused state that can progress to coma and death. It is associated with thiamine deficiency and therefore treatment includes administration of parenteral thiamine. Tis syndrome is very rarely seen in the absence of alcoholism nut is characterized by generalized symmetric peripheral nerve injury.

• Fully explain the foetal alcohol syndrome.

Chronic alcoholic abuse during pregnancy is associated with these teratogenic affects where alcohol is the leading cause of mental retardation and congenital malformation of foetuses. This syndrome is characterized by intrauterine growth retardation, microcephaly, poor coordination, underdevelopment of midfacial region and minor joint anomalies. In severe cases congenital heart defects and mental retardation. The mechanisms underlying ethanol’s teratogenic effects are unknown. Since ethanol is very water soluble and rapidly dissolves it crosses the placenta and reaches concentrations in the fetus similar to that of the mother’s blood. A foetal liver however has little to no alcohol dehydrogenase and thus the effects are extremely damaging and harmful and the fetus must rely on maternal and placental enzymes for elimination of alcohol. Alcohol syndrome indicates that ethanol triggers apoptotic neurodegeneration and aberrant neuronal and glial migration in a developing nervous system.

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

Acute alcohol use can inhibit/ decrease metabolism because of decreased enzyme activity or decreased liver blood flow. Rate and extent of absorption with more limited effects on clearance of drugs such as phenothiazine’s, tricyclic antidepressants and sedative hypnotic drugs.  Chronic alcohol consumption without damage to the liver can enhance the metabolic transformation of drugs especially those eliminated by cytochrome P450 like acetaminophen since increased metabolism of acetaminophen to reactive hepatotoxic metabolites  (NAPQI) that increases the risk of hepatotoxicity and should be avoided in alcoholics

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

Phenothiazines, tricyclic antidepressant and sedative hypnotics like diazepam, oxazepam and midazolam are all potentiated by alcohol consumption since they all cause CNS depression in an additive manner and is thus very dangerous to combine with the use of alcohol. It can lead to respiratory and cardiac depression working on GABA_A potentiation. Vasodilatos combined with alcohol can cause extreme vasodilation and a drop in blood pressure this can cause heart rate to increase and respiratory rate as well to maintain sufficient blood flow rates to vital organs, ethanol potentiates the anti-platelet effects of aspirin by decreasing the number of platelets via suppression bone marrow production as well as causing the platelets to be less sticky and hypoglycemic/diabetic medications are potentiated by alcohol causing the pancreas to not be able to release glucose into the blood but he excess sugar in alcoholic drinks causes an increased release of insulin and thus in combination with hypoglycemic drugs this can lead to insulin shock and very low blood glucose levels.

 

 

Katzung, B.G., 2018. Basic & Clinical Pharmacology. 14th ed. United States of America: McGraw-Hill Education.

Brand, L. 2021. Sedative Hypnotic drugs. Study Unit 3 [PowerPoint Presentation]. Unpublished lecture notes on eFundi, FKLG 312. Potchefstroom, NWU.

Renaud, S. C., & Ruf, J. C. (1996). Effects of alcohol on platelet functions. Clinica chimica acta; international journal of clinical chemistry, 246(1-2), 77–89. https://doi.org/10.1016/0009-8981(96)06228-6