Pharmacogenomics Practice Questions

Q: Which HLA gene is associated with abacavir hypersensitivity?

B57. **Explanation:** **Correct Option: D (HLA-B*57:01)** Abacavir is a Nucleoside Reverse Transcriptase Inhibitor (NRTI) used in HIV treatment. Approximately 5–8% of patients develop a potentially fatal **Abacavir Hypersensitivity Syndrome (AHS)**, characterized by fever, rash, and gastrointestinal symptoms. This reaction is strongly associated with the **HLA-B*57:01** allele. The drug binds to the antigen-binding cleft of this specific HLA molecule, altering the repertoire of self-peptides presented to T-cells, which triggers an autoimmune-like systemic inflammatory response. Screening for this allele is mandatory before initiating abacavir to prevent AHS. **Incorrect Options:** * **A (B5):** This is a broad serotype that includes B51 and B52 but is not specifically linked to abacavir. * **B (B51):** This allele is the classic genetic marker associated with **Behçet’s Disease** (characterized by oral/genital ulcers and uveitis). * **C (DQ2):** This is an HLA Class II allele strongly associated with **Celiac Disease** (along with HLA-DQ8). **High-Yield Clinical Pearls for NEET-PG:** 1. **Mandatory Screening:** If a patient tests positive for HLA-B*57:01, Abacavir is strictly **contraindicated** and should be listed as an allergy in their records. 2. **Re-challenge Warning:** Never re-challenge a patient with abacavir if AHS is suspected; it can lead to rapid, fatal hypotension and multi-organ failure. 3. **Other HLA-Drug Associations:** * **HLA-B*15:02:** Carbamazepine-induced Stevens-Johnson Syndrome (SJS) (especially in Asians). * **HLA-B*58:01:** Allopurinol-induced severe cutaneous adverse reactions (SCAR).

Q: Which of the following does not cause hemolysis in G6PD deficiency?

Estrogen. ### Explanation **Concept Overview:** Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency is an X-linked recessive disorder where RBCs lack the enzyme necessary to maintain levels of reduced glutathione. Reduced glutathione is essential for neutralizing reactive oxygen species (ROS). When patients are exposed to oxidative stress (drugs, infections, or fava beans), hemoglobin denatures into **Heinz bodies**, leading to hemolysis. **Why Estrogen is the Correct Answer:** * **Estrogen (Option A):** Estrogen and other hormonal preparations (like oral contraceptives) do not possess oxidative properties and do not interfere with the pentose phosphate pathway. Therefore, they do not trigger hemolytic episodes in G6PD-deficient individuals. **Why the Other Options are Incorrect:** * **Primaquine (Option C):** This is the classic "prototype" drug that causes hemolysis. It is an antimalarial that generates significant oxidative stress. Testing for G6PD deficiency is mandatory before prescribing Primaquine. * **Nitrofurantoin (Option D):** A common urinary antiseptic that undergoes redox cycling, producing superoxide radicals that overwhelm the limited antioxidant capacity of G6PD-deficient cells. * **Salicylates (Option B):** High doses of aspirin or salicylates can induce oxidative damage to RBC membranes, though they are considered "low-risk" compared to Primaquine, they are still documented triggers. **NEET-PG High-Yield Pearls:** * **Mnemonic for G6PD Triggers:** "**S**ell **P**ie **N**ow" (**S**ulfonamides/Salicylates, **P**rimaquine, **N**itrofurantoin). * **Peripheral Smear Findings:** Look for **Heinz Bodies** (denatured Hb) and **Bite Cells** (deformed RBCs after splenic macrophages remove Heinz bodies). * **Other Triggers:** Dapsone, Chloroquine, Rasburicase, and Fava beans (Favism). * **Inheritance:** X-linked recessive; more common in males of Mediterranean or African descent.

Q: All of the following drugs cause hemolysis in G-6PD deficiency except?

Erythromycin. ### Explanation **Concept Overview:** Glucose-6-Phosphate Dehydrogenase (G6PD) is a critical enzyme in the pentose phosphate pathway that maintains the supply of **reduced glutathione**. This molecule protects red blood cells (RBCs) from oxidative stress. In G6PD deficiency, exposure to oxidizing agents leads to the denaturation of hemoglobin (forming **Heinz bodies**) and subsequent hemolysis. **Why Erythromycin is the Correct Answer:** **Erythromycin** is a macrolide antibiotic that does not possess significant oxidizing properties. It is considered safe to use in patients with G6PD deficiency. It does not interfere with the redox state of the erythrocyte or trigger the destruction of RBCs. **Analysis of Incorrect Options:** * **Primaquine:** This is the classic "textbook" trigger. It is an antimalarial that generates reactive oxygen species (ROS), causing severe hemolysis in G6PD-deficient individuals. * **Nitrofurantoin:** A urinary antiseptic known to cause oxidative stress. It is strictly contraindicated in G6PD-deficient patients due to the high risk of hemolytic anemia. * **Sulfonamides (e.g., Sulfamethoxazole):** These drugs act as oxidizing agents. They are well-documented triggers for hemolytic crises in affected patients. **High-Yield Clinical Pearls for NEET-PG:** * **Inheritance:** G6PD deficiency is an **X-linked recessive** disorder (more common in males). * **Peripheral Smear Findings:** Look for **Heinz bodies** (denatured hemoglobin) and **Bite cells** (degmacytes) formed by splenic macrophages removing these bodies. * **Other Common Triggers:** Dapsone, Rasburicase, Methylene blue, and **Fava beans** (Favism). * **Safe Alternatives:** Penicillins, Cephalosporins, and Macrolides (like Erythromycin) are generally safe. * **Key Contraindication:** Never give **Primaquine** without first screening the patient for G6PD levels.

Q: Therapeutic drug monitoring is used in which of the following medications?

Digoxin. **Explanation:** **Therapeutic Drug Monitoring (TDM)** is the clinical practice of measuring drug concentrations in the blood to maintain a constant concentration within a specific **therapeutic window**. It is primarily indicated for drugs with a **narrow therapeutic index**, where the difference between the effective dose and the toxic dose is minimal. **Why Digoxin is the Correct Answer:** Digoxin has a very narrow therapeutic index (typically **0.5–2.0 ng/mL**). Small fluctuations in serum levels can lead to life-threatening toxicity (arrhythmias, xanthopsia, or gastrointestinal distress). Factors like renal impairment, hypokalemia, and drug interactions (e.g., with Amiodarone or Verapamil) significantly alter its pharmacokinetics, making TDM essential for safety and efficacy. **Why Other Options are Incorrect:** * **A. Diuretics:** Their effect is easily monitored clinically by measuring urine output, body weight, blood pressure, and serum electrolytes. * **B. Metformin:** Its efficacy is monitored by measuring clinical markers like blood glucose levels and HbA1c, rather than plasma drug concentrations. * **C. Levodopa:** The clinical response (improvement in Parkinsonian symptoms) and the appearance of side effects (dyskinesia) are used to titrate the dose. **High-Yield Clinical Pearls for NEET-PG:** * **Indications for TDM:** Remember the mnemonic **"THEAL"** – **T**ricyclic antidepressants, **H**eart meds (Digoxin, Quinidine), **E**pilepsy meds (Phenytoin, Carbamazepine), **A**minoglycosides (Gentamicin), and **L**ithium. * **Sampling Time:** For Digoxin, TDM should be performed at least **6–8 hours after the last dose** (post-distribution phase) to ensure accurate results. * **Exceptions:** TDM is **not** useful for drugs with "hit and run" pharmacokinetics (e.g., Omeprazole) or those with easily measurable physiological endpoints (e.g., Warfarin via PT/INR).

Q: Which of the following drugs is hydrolyzed by a plasma esterase that has abnormally low activity in about 1 in every 2500 humans?

Succinylcholine. **Explanation:** **1. Correct Option: Succinylcholine** Succinylcholine is a depolarizing neuromuscular blocker used for rapid sequence induction. Its action is normally terminated within 5–10 minutes because it is rapidly hydrolyzed by **Butyrylcholinesterase (BChE)**, also known as **Pseudocholinesterase** or **Plasma Cholinesterase**. About 1 in 2500 individuals (of European descent) carries an autosomal recessive trait for **atypical pseudocholinesterase**. In these patients, the enzyme has a low affinity for the drug, leading to a failure to hydrolyze succinylcholine. This results in prolonged neuromuscular blockade and life-threatening respiratory paralysis, a clinical condition known as **Succinylcholine Apnea**. **2. Incorrect Options:** * **Ethanol:** Primarily metabolized in the liver by Alcohol Dehydrogenase (ADH) and Aldehyde Dehydrogenase (ALDH). While ALDH deficiency is common in Asian populations (causing "flushing"), it is not a plasma esterase. * **Rifampicin:** A potent inducer of Cytochrome P450 enzymes. It is metabolized via hepatic deacetylation, not plasma esterases. * **Cimetidine:** An H2 blocker and a well-known enzyme inhibitor. It is eliminated via a combination of hepatic metabolism and renal excretion. **3. High-Yield Clinical Pearls for NEET-PG:** * **Dibucaine Number:** This is the diagnostic test for atypical pseudocholinesterase. Dibucaine inhibits normal enzyme by 80%, but atypical enzyme by only 20%. A **low Dibucaine number** indicates a high risk for apnea. * **Management:** If apnea occurs, the patient must be maintained on **mechanical ventilation** until the drug wears off naturally. * **Mivacurium:** Another neuromuscular blocker also metabolized by pseudocholinesterase that can cause prolonged paralysis in these patients.

Q: Which of the following phase II drug metabolism reactions is associated with a genetic polymorphism?

Acetylation. **Explanation:** **Acetylation** is a major Phase II conjugation reaction catalyzed by the enzyme **N-acetyltransferase (NAT2)**. This enzyme exhibits a well-known **genetic polymorphism**, categorizing individuals into two distinct phenotypes: 1. **Fast Acetylators:** Metabolize drugs rapidly, potentially leading to sub-therapeutic levels. 2. **Slow Acetylators:** Metabolize drugs slowly, leading to higher plasma concentrations and an increased risk of toxicity. **Analysis of Options:** * **Acetylation (Correct):** It is the classic example of Phase II polymorphism. Drugs like **Isoniazid (INH), Hydralazine, Procainamide, and Dapsone** (remembered by the mnemonic **SHIP**) are metabolized this way. * **Glucuronidation (Incorrect):** While some polymorphisms exist (e.g., UGT1A1 in Gilbert’s syndrome), Acetylation is the primary high-yield answer for genetic polymorphism in Phase II reactions in the context of standard pharmacology exams. * **Oxidation and Reduction (Incorrect):** These are **Phase I reactions** (Functionalization), not Phase II (Conjugation). While Oxidation (via Cytochrome P450) shows significant polymorphism (e.g., CYP2D6), the question specifically asks for a Phase II reaction. **High-Yield Clinical Pearls for NEET-PG:** * **Drug-Induced Lupus Erythematosus (DILE):** Slow acetylators are at a significantly higher risk of developing DILE when taking Hydralazine or Procainamide. * **Peripheral Neuropathy:** Slow acetylators taking Isoniazid (INH) are more prone to Vitamin B6 deficiency and subsequent neuropathy. * **Bladder Cancer:** Slow acetylators have a higher risk of bladder cancer when exposed to environmental arylamines (e.g., cigarette smoke, industrial dyes).

Q: Which drug can be given in G-6-P-D deficiency?

Probenecid. **Explanation:** Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency is an X-linked recessive disorder where RBCs are unable to regenerate NADPH, making them vulnerable to oxidative stress. When exposed to certain drugs, hemoglobin denatures into **Heinz bodies**, leading to acute hemolysis. **Why Probenecid is the correct answer:** While older literature occasionally listed Probenecid as a potential trigger, modern evidence-based classifications (such as those by the G6PD Deficiency Association) categorize **Probenecid as safe** to use at therapeutic doses. It does not possess significant oxidative potential compared to the other drugs listed. **Analysis of Incorrect Options:** * **Primaquine (Option D):** This is the classic "high-risk" drug. It is a potent oxidant and is **absolutely contraindicated** in G6PD deficiency as it causes severe hemolysis. Patients must be screened for G6PD levels before starting radical cure for *P. vivax*. * **Amidopyrine (Option C):** This is an older NSAID/analgesic known to be a definite trigger for hemolytic crises in G6PD-deficient individuals. * **Chloroquine (Option A):** While generally considered safer than Primaquine, Chloroquine is still classified as a drug that can induce hemolysis in certain variants of G6PD deficiency (especially the Mediterranean type) and is typically avoided if safer alternatives exist. **NEET-PG High-Yield Pearls:** * **Mnemonic for G6PD Triggers:** "**S**ell **P**a**N**IC **D**rugs" (**S**ulfonamides, **P**rimaquine, **N**itrofurantoin, **I**soniazid, **C**hloramphenicol, **D**apsone). * **Fava beans** (Favism) are a classic non-drug trigger. * **Diagnosis:** Peripheral smear shows **Heinz bodies** and **Bite cells** (degluticytes). * **Key Concept:** In G6PD deficiency, the most common cause of hemolysis is actually **infection**, not just drugs.

Q: Which of the following drugs does NOT carry a definitive risk of causing clinical hemolysis in patients with G6PD deficiency?

Chloroquine. **Explanation** Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency is an X-linked recessive disorder where RBCs lack the ability to regenerate reduced glutathione, making them highly susceptible to oxidative stress. When exposed to certain oxidizing drugs, hemoglobin precipitates into **Heinz bodies**, leading to hemolysis. **Why Chloroquine is the Correct Answer:** While Chloroquine is an antimalarial, it is considered **safe** or carries a negligible risk of hemolysis in most individuals with G6PD deficiency at standard therapeutic doses. Unlike its counterparts, it does not exert significant oxidative stress on the erythrocyte membrane. In clinical practice, it is generally administered without prior G6PD screening, unlike Primaquine. **Analysis of Incorrect Options:** * **Primaquine (Option A):** This is the classic "high-yield" trigger. It is a potent oxidizing agent that causes severe acute hemolytic anemia in G6PD-deficient patients. Screening is mandatory before starting radical cure for *P. vivax*. * **Dapsone (Option B):** A sulfone used in leprosy and PCP prophylaxis; it is a well-known inducer of oxidative hemolysis and methemoglobinemia. * **Nalidixic Acid (Option D):** An older quinolone antibiotic that is a documented trigger for hemolytic crises in deficient patients. **NEET-PG High-Yield Pearls:** * **Mnemonic for G6PD Triggers:** "**S**andwich **P**atty **I**s **N**ot **D**elicious" (**S**ulfonamides/Sulfones, **P**rimaquine/Pyridium, **I**soniazid, **N**itrofurantoin, **D**apsone). * **Other Triggers:** Fava beans (Favism), Rasburicase (absolute contraindication), and infections (most common cause). * **Diagnosis:** Peripheral smear shows **Bite cells** (degmacytes) and **Heinz bodies** (supravital staining). * **Timing:** Avoid testing G6PD levels during an acute hemolytic episode, as young reticulocytes have normal enzyme levels, leading to a false-negative result.

Question 1

Which HLA gene is associated with abacavir hypersensitivity?

Accepted Answer

B57

Answer

B5

Answer

B51

Answer

DQ2

Question 2

Which of the following does not cause hemolysis in G6PD deficiency?

Accepted Answer

Estrogen

Answer

Salicylates

Answer

Primaquine

Answer

Nitrofurantoin

Question 3

All of the following drugs cause hemolysis in G-6PD deficiency except?

Accepted Answer

Erythromycin

Answer

Primaquine

Answer

Nitrofurantoin

Answer

Sulfonamides

Question 4

Therapeutic drug monitoring is used in which of the following medications?

Accepted Answer

Digoxin

Answer

Diuretic

Answer

Metformin

Answer

Levodopa

Question 5

Which of the following drugs does not act on cytoplasmic receptors?

Accepted Answer

Thyroxine

Answer

Corticosteroids

Answer

Vitamin D

Answer

Aldosterone

Question 6

Which of the following drugs is hydrolyzed by a plasma esterase that has abnormally low activity in about 1 in every 2500 humans?

Accepted Answer

Succinylcholine

Answer

Ethanol

Answer

Rifampicin

Answer

Cimetidine

Question 7

Which of the following phase II drug metabolism reactions is associated with a genetic polymorphism?

Accepted Answer

Acetylation

Answer

Glucuronidation

Answer

Reduction

Answer

Oxidation

Question 8

Which drug can be given in G-6-P-D deficiency?

Accepted Answer

Probenecid

Answer

Chloroquine

Answer

Amidopyrine

Answer

Primaquine

Question 9

What is true about pKa?

Accepted Answer

The pH at which the ionized fraction of a drug equals its unionized fraction.

Answer

The pH at which the ionized fraction of a drug is greater than its unionized fraction.

Answer

The pH at which the ionized fraction of a drug is less than its unionized fraction.

Answer

The pH at which the ionized fraction of a drug is twice its unionized fraction.

Question 10

Which of the following drugs does NOT carry a definitive risk of causing clinical hemolysis in patients with G6PD deficiency?

Accepted Answer

Chloroquine

Answer

Primaquine

Answer

Dapsone

Answer

Nalidixic acid

Pharmacogenomics — MCQs

Pharmacogenomics — MCQs

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