Adverse Drug Reactions & Pharmacogenetics

Question 1

Define the term “ Adverse Drug Reaction”.

Answer 1

• An adverse drug reaction (ADR) is a harmful ( noxious / toxic) , unintended result caused by taking medication.
• May occur at normal doses , may be due to overdose ot even due to drug interactions.

Question 2

Give a brief classification of Adverse Drug Reactions .

Answer 2

• Type A - Augmented
• Type B - bizarre/ idiosyncratic
• Type C - chronic/ continuous
• Type D - delayed type
• Type E - end of treatment effects

Question 3

List 2 examples of Type D Adverse Drug Reactions.

Answer 3

Refers to the delayed type reactions e.g
* Occurrence of secondary cancers years after using alkylating agents to treat the primary cancer.
* Occurrence of clear cell carcinoma ( vaginal cancer ) in girls whose mothers took diethylstilbestrol during pregnancy .

Question 4

Give 3 examples of Type E Adverse Drug Reactions that occur when treatment is stopped suddenly.

Answer 4

• Severe hypertension may occur when Clonidine is stopped suddenly.
• Withdrawal seizures may be seen if phenytoin is stopped.
• Adrenal insufficiency - Prednisone stoppage.
• Give a tapering dose instead of stopping the medication abruptly to avoid Type E ADRs.

Question 5

What are the major risk factors that predispose individuals to Adverse Drug Reactions?

Answer 5

• Extremes of age e.g the very young and the very old have reduced renal and liver activity.
• Sex - females are more likely to experience ADRs due to pharmacokinetic changes in puberty and pregnancy.
• Past history of ADRs .
• History of allergic diseases.
• Genetic factors that may result in some enzyme deficiencies .

Question 6

Give a brief overview of the different mechanisms underlying the major hypersensitivity reactions.

Answer 6

• Type I reactions - IgE mediated, or anaphylactic reactions due to release of histamine, leukotrienes & prostaglandins from basophils & mast cells.
• Type II reactions - antibodies attacking the drug which is covalently bound to the cell , thereby destroying the cell .
• Type III reactions - serum sickness, due to deposition of immune complexes on endothelial surfaces , which interact with Complement causing inflammatory responses.
• Type IV reactions - mediated by sensitized T- cells e.g topically administered drugs can interact with sulfhydryl or amino groups on the skin. These react with sensitized T-lymphocytes resulting in contact dermatitis.

Question 7

Describe the mechanism by which acetaminophen overdose may result in liver hepatotoxicity.

Answer 7

• Acetaminophen is usually converted to NAPQI by Cytochrome P450 enzyme systems.
• NAPQI is a toxic substance and is usually conjugated with glutathione to form less toxic metabolites such as Cyteine and mercapturic acid conjugates which are excreted in urine.
• In acetaminophen overdose, Glutathione is exhausted hence NAPQI cannot be broken down. It accumulates and binds to hepatic proteins leading to liver damage.

Question 8

List down the main remedies used to manage liver toxicity caused by acetaminophen.

Answer 8

• Administration of N- acetyl cysteine - increases availability of GSH.
• Methionine administration

Question 9

Distinction between Pharmacogenetics and Pharmacogenomics.

Answer 9

Pharmacogenetics focuses on how a single genetic variation may affect the metabolism, efficacy and toxicity of a drug while Pharmacogenomics considers all of a person’s genes and goes they may influence their response to drugs.

Question 10

What is the clinical relevance of Plasma Cholinesterase deficiency on Suxamethonium use?

Answer 10

• Suxamethonium is a neuromuscular blocking agent used to administer anaesthesia. It is usually broken down by plasma Cholinesterase enzyme.
• If used in individuals with plasma Cholinesterase deficiency, their bodies fail to inactivate Suxamethonium, and this may lead to prolonged paralysis.