Pharmacogenomics Practice Questions

Q: What genetic variation in a drug metabolism pathway is known to cause severe toxicity with fluorouracil?

Dihydropyrimidine dehydrogenase. **Explanation:** **Dihydropyrimidine dehydrogenase (DPD)** is the rate-limiting enzyme responsible for the catabolism of over 80% of administered **5-Fluorouracil (5-FU)** and its oral prodrug, Capecitabine. In individuals with **DPD deficiency** (caused by mutations in the *DPYD* gene), the body cannot effectively clear the drug. This leads to an accumulation of active metabolites, resulting in severe, life-threatening toxicities such as profound myelosuppression, intractable diarrhea, neurotoxicity, and hand-foot syndrome. **Analysis of Incorrect Options:** * **CYP2C9:** This enzyme metabolizes drugs like **Warfarin**, Phenytoin, and NSAIDs. Variations lead to an increased risk of bleeding with warfarin. * **Thiopurine-S methyltransferase (TPMT):** This enzyme is responsible for the metabolism of 6-Mercaptopurine and Azathioprine. Deficiency leads to severe bone marrow toxicity when these drugs are used. * **CYP2D6:** This is a highly polymorphic enzyme involved in the metabolism of ~25% of drugs, including **Codeine** (conversion to morphine), Tamoxifen, and many antidepressants/antipsychotics. **High-Yield Clinical Pearls for NEET-PG:** * **DPD Testing:** Pre-therapeutic screening for *DPYD* variants is increasingly recommended to prevent fatal 5-FU toxicity. * **Uridine Triacetate:** This is the specific **antidote** used for 5-FU or Capecitabine overdose or early-onset severe toxicity. * **TPMT vs. DPD:** Do not confuse them; both cause chemo-toxicity, but TPMT is for thiopurines (6-MP) and DPD is for pyrimidines (5-FU).

Q: Which of the following drugs causes hemolytic anemia in individuals with glucose-6-phosphate dehydrogenase deficiency?

Chloramphenicol. **Explanation:** **Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency** is an X-linked recessive disorder where the RBCs are unable to regenerate NADPH, making them vulnerable to oxidative stress. When exposed to certain oxidizing agents, hemoglobin denatures into **Heinz bodies**, leading to hemolysis. **1. Why Chloramphenicol is Correct:** Chloramphenicol is a classic "oxidizing drug." In G6PD-deficient individuals, it induces oxidative stress that the depleted glutathione system cannot neutralize. This leads to the oxidation of sulfhydryl groups in hemoglobin, resulting in acute hemolytic anemia. **2. Why the Other Options are Incorrect:** * **Acetaminophen:** While metabolized by the liver and capable of causing hepatotoxicity via the NAPQI metabolite, it is generally considered safe in therapeutic doses for G6PD-deficient patients. * **Prednisolone:** This is a corticosteroid with anti-inflammatory and immunosuppressive properties; it does not possess oxidizing potential and does not trigger hemolysis. * **Griseofulvin:** An antifungal drug primarily known for causing photosensitivity and inducing cytochrome P450 enzymes. It is also contraindicated in **Porphyria**, but it is not a primary trigger for G6PD-related hemolysis. **High-Yield Clinical Pearls for NEET-PG:** * **Mnemonic for G6PD Triggers:** "**AAA**" – **A**ntimalarials (Primaquine, Chloroquine), **A**ntibiotics (Sulfonamides, Nitrofurantoin, Chloramphenicol), and **A**spirin (high doses). * **Other Triggers:** Fava beans (Favism), Naphthalene balls, and Infections (most common cause). * **Peripheral Smear Findings:** Look for **Heinz bodies** (supravital stain) and **Bite cells** (degluticytes) resulting from splenic macrophage action. * **Note:** Chloramphenicol is also famously associated with **Gray Baby Syndrome** and **Aplastic Anemia**.

Q: All drugs are metabolized by acetylation EXCEPT:

Phenytoin. ### Explanation The correct answer is **Phenytoin**. **1. Underlying Medical Concept: Acetylation** Acetylation is a **Phase II metabolic reaction** catalyzed by the enzyme **N-acetyltransferase (NAT)**. This pathway is genetically determined, leading to the classification of individuals as "fast acetylators" or "slow acetylators." **Phenytoin** is primarily metabolized by **Phase I oxidation** (hydroxylation) via the cytochrome P450 system, specifically **CYP2C9** and **CYP2C19**. It does not undergo acetylation. Phenytoin also follows zero-order kinetics at high therapeutic concentrations, making its metabolism easily saturable. **2. Analysis of Incorrect Options** The other three drugs are classic examples of drugs metabolized by acetylation. A helpful mnemonic to remember these is **SHIP**: * **S**ulfonamides * **H**ydralazine (Option D) * **I**soniazid (Option B) * **P**rocainamide (Option C) **3. Clinical Pearls for NEET-PG** * **Drug-Induced Lupus Erythematosus (DILE):** Slow acetylators are at a significantly higher risk of developing DILE when taking Hydralazine, Procainamide, or Isoniazid because the drugs persist longer in the body. * **Isoniazid Toxicity:** Slow acetylators are more prone to peripheral neuropathy (due to Vitamin B6 deficiency), while fast acetylators may be more prone to isoniazid-induced hepatotoxicity (due to rapid conversion to acetyl-hydrazine). * **Genetic Polymorphism:** The NAT2 gene is the most clinically relevant polymorphic gene governing acetylation rates in humans. * **Phenytoin Side Effects:** Remember the mnemonic **HOT MALAI** (Hirsutism, Osteomalacia, Teratogenicity, Megaloblastic anemia, Ataxia, Lymphadenopathy, Arrhythmias, Insulin inhibition).

Q: Which of the following drugs can cause drug-induced lupus erythematosus, particularly in individuals with slow N-acetyltransferase activity?

Hydralazine. **Explanation:** The correct answer is **Hydralazine**. This question tests the concept of **Pharmacogenomics**, specifically the role of the **N-acetyltransferase (NAT2)** enzyme in drug metabolism. **1. Why Hydralazine is correct:** Hydralazine is metabolized in the liver via **Phase II Acetylation**. The population is genetically divided into "Fast Acetylators" and "Slow Acetylators." In **Slow Acetylators**, the drug remains in the systemic circulation for a longer duration at higher concentrations. This prolonged exposure promotes the formation of antinuclear antibodies (ANA), leading to **Drug-Induced Lupus Erythematosus (DILE)**. **2. Why other options are incorrect:** * **Propranolol:** A beta-blocker primarily metabolized by CYP2D6 and CYP1A2. It is not associated with DILE or NAT2 activity. * **Digoxin:** A cardiac glycoside primarily excreted unchanged by the kidneys (P-glycoprotein substrate). It does not undergo acetylation. * **Captopril:** An ACE inhibitor that contains a sulfhydryl group. While it can rarely cause skin rashes or neutropenia, it is not metabolized by NAT2 and is not a classic cause of DILE. **3. NEET-PG High-Yield Pearls:** * **Mnemonic for DILE drugs (SHIP):** **S**ulfonamides, **H**ydralazine, **I**soniazid, **P**rocainamide. * **Procainamide** carries the highest risk of inducing DILE, but **Hydralazine** is the most frequently cited in the context of slow acetylation. * **Clinical Distinction:** Unlike systemic lupus (SLE), DILE usually spares the kidneys and CNS, and symptoms typically resolve upon drug discontinuation. * **Serological Marker:** **Anti-histone antibodies** are present in >95% of DILE cases (Highly specific). Anti-dsDNA is usually negative.

Q: HLA-B* 1502 is a genetic marker for which of the following conditions?

Stevens-Johnson syndrome. **Explanation:** **HLA-B*1502** is a strong genetic predictor for the development of **Stevens-Johnson Syndrome (SJS)** and **Toxic Epidermal Necrolysis (TEN)**, specifically when triggered by the anticonvulsant drug **Carbamazepine**. This association is most prevalent in populations of Han Chinese, Southeast Asian, and Indian descent. The presence of this allele leads to an altered immune response where cytotoxic T-cells are inappropriately activated against keratinocytes, causing widespread epidermal detachment. **Analysis of Options:** * **Option C (Correct):** HLA-B*1502 is the specific marker for Carbamazepine-induced SJS/TEN. Screening for this allele is now mandatory in high-risk populations before initiating therapy. * **Option A (Incorrect):** Systemic Lupus Erythematosus (SLE) is more commonly associated with **HLA-DR2** and **HLA-DR3**. Drug-induced lupus (e.g., by Hydralazine or Procainamide) is linked to the **Slow Acetylator** phenotype (NAT2 deficiency). * **Option B (Incorrect):** Polyarteritis Nodosa (PAN) is a systemic necrotizing vasculitis strongly associated with **Hepatitis B virus (HBV)** infection rather than a specific HLA-B marker. * **Option D (Incorrect):** Seronegative spondyloarthritis (including Ankylosing Spondylitis) is classically associated with **HLA-B27**. **High-Yield Clinical Pearls for NEET-PG:** * **HLA-B*5701:** Associated with hypersensitivity to **Abacavir** (Antiretroviral). * **HLA-B*5801:** Associated with SJS/TEN induced by **Allopurinol**. * **HLA-A*3101:** Another marker for Carbamazepine hypersensitivity, more common in Europeans. * **Drug of Choice for SJS/TEN:** Supportive care and IV Immunoglobulins (IVIG). Cyclosporine is also used.

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

Succinylcholine. **Explanation** The correct answer is **Succinylcholine**. This drug is a depolarizing neuromuscular blocker used for rapid sequence induction. **1. Why Succinylcholine is Correct:** Succinylcholine is rapidly metabolized by **Pseudocholinesterase** (also known as Butyrylcholinesterase or Plasma Cholinesterase). In approximately 1 in 2500 individuals, there is a genetic polymorphism resulting in **Atypical Pseudocholinesterase**. These patients cannot hydrolyze the drug efficiently, leading to a prolonged neuromuscular block and life-threatening respiratory paralysis, a condition known as **Succinylcholine Apnea**. **2. Why the Other Options are Incorrect:** * **Ethanol:** Primarily metabolized in the liver by Alcohol Dehydrogenase (ADH) and Aldehyde Dehydrogenase (ALDH). While genetic variations exist (e.g., ALDH2 deficiency in Asians), it is not an esterase-mediated process. * **Rifampicin:** A potent inducer of Cytochrome P450 enzymes. It is metabolized via hepatic deacetylation, not plasma esterases. * **Cimetidine:** A known enzyme inhibitor (CYP450) that is excreted largely unchanged in the urine; it is not subject to plasma esterase deficiency issues. **3. Clinical Pearls for NEET-PG:** * **Diagnosis:** The presence of atypical pseudocholinesterase is confirmed by the **Dibucaine Number**. Dibucaine inhibits normal enzyme activity by 80%, but atypical enzyme by only 20%. A low Dibucaine number indicates a high risk for apnea. * **Management:** If a patient develops Succinylcholine Apnea, the immediate treatment is **mechanical ventilation** until the drug wears off. Fresh frozen plasma (FFP) can theoretically provide the enzyme but is rarely used in practice. * **Other drugs** metabolized by pseudocholinesterase include Mivacurium, Cocaine, and Procaine.

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

Atropine. Glucose-6-Phosphate Dehydrogenase (G-6-PD) deficiency is an X-linked recessive disorder [1] where erythrocytes lack the ability to regenerate reduced **glutathione**. This makes them highly susceptible to oxidative stress, leading to hemoglobin denaturation (Heinz bodies) and hemolysis when exposed to certain oxidizing agents. **Why Atropine is the correct answer:** **Atropine** is a muscarinic antagonist (anticholinergic). It does not possess oxidizing properties and does not interfere with the redox machinery of the red blood cell. Therefore, it is safe to use in G-6-PD deficient patients. **Analysis of incorrect options:** * **Primaquine:** This is the classic "high-risk" drug for G-6-PD deficiency. It is an 8-aminoquinoline that generates reactive oxygen species (ROS), causing severe oxidative hemolysis [1]. * **Chloroquine & Quinine:** Both are antimalarials that can induce hemolysis in G-6-PD deficient individuals, though the risk is significantly lower compared to Primaquine. They are generally considered "intermediate risk" but are contraindicated or require close monitoring in severe deficiency. **High-Yield Clinical Pearls for NEET-PG:** * **Common Triggers:** Mnemonic **"AAA"** – **A**ntimalarials (Primaquine), **A**ntibiotics (Sulfonamides, Nitrofurantoin, Dapsone), and **A**spirin (in high doses). Fava beans (Favism) are a classic dietary trigger. * **Diagnosis:** Peripheral smear shows **Heinz bodies** (denatured hemoglobin) and **Bite cells** (result of splenic macrophages removing Heinz bodies). * **Key Contraindication:** Never give Primaquine without screening for G-6-PD levels, as it can precipitate a life-threatening hemolytic crisis.

Q: Which antitubercular drug metabolism is under genetic control?

Isoniazid. **Explanation:** The correct answer is **Isoniazid (INH)**. Its metabolism is a classic example of pharmacogenetics, specifically involving the **N-acetyltransferase 2 (NAT2)** enzyme in the liver. **1. Why Isoniazid is Correct:** Isoniazid is metabolized via **acetylation**. Due to genetic polymorphism in the *NAT2* gene, individuals are categorized into two phenotypes: * **Fast Acetylators:** They metabolize the drug quickly, leading to lower plasma levels and a higher risk of **treatment failure** or sub-therapeutic responses. * **Slow Acetylators:** They metabolize the drug slowly, leading to higher plasma levels and an increased risk of **peripheral neuropathy** (due to Vitamin B6 deficiency) and drug-induced lupus. **2. Why other options are incorrect:** * **Rifampicin:** It is primarily metabolized by deacetylation and is a potent inducer of CYP450 enzymes, but its metabolism is not significantly dictated by a specific genetic polymorphism like INH. * **Cyclosporine:** This is an immunosuppressant (not an antitubercular drug) metabolized by CYP3A4. While CYP3A4 has variations, it is not the classic example of genetic control in the context of TB therapy. * **Pyrazinamide:** It is converted to pyrazinoic acid by the enzyme pyrazinamidase. While resistance can occur due to bacterial gene mutations (*pncA*), its human metabolism is not a major focus of clinical pharmacogenetics. **High-Yield Clinical Pearls for NEET-PG:** * **Acetylation** also affects the metabolism of **Hydralazine, Procainamide, and Sulfonamides** (Mnemonic: **SHIP** - Sulfonamides, Hydralazine, Isoniazid, Procainamide). * **Slow acetylators** are more prone to **Drug-Induced Lupus Erythematosus (DILE)**. * To prevent peripheral neuropathy in slow acetylators taking INH, always co-administer **Pyridoxine (Vitamin B6)** at 10–50 mg/day.

Q: Which drug may lead to hemolysis in a child with G6PD deficiency?

Primaquine. **Explanation:** **1. Why Primaquine is Correct:** Glucose-6-Phosphate Dehydrogenase (G6PD) is a critical enzyme in the pentose phosphate pathway that maintains the levels of **reduced glutathione** in red blood cells. Reduced glutathione acts as an antioxidant, protecting RBCs from oxidative stress. **Primaquine**, an antimalarial used for the radical cure of *P. vivax* and *P. ovale*, is a potent oxidizing agent. In G6PD-deficient individuals, the inability to regenerate glutathione leads to the oxidation of hemoglobin, forming **Heinz bodies**, which results in acute hemolysis and hemoglobinuria. **2. Why Other Options are Incorrect:** * **Penicillin & Ceftriaxone (Beta-lactams):** These drugs are generally safe in G6PD deficiency. While they can occasionally cause immune-mediated hemolytic anemia (Type II hypersensitivity), they do not cause oxidative hemolysis. * **Erythromycin (Macrolide):** This antibiotic is not associated with oxidative stress or hemolysis in G6PD-deficient patients. **3. High-Yield Clinical Pearls for NEET-PG:** * **Other common triggers:** Sulfonamides (Dapsone, Cotrimoxazole), Nitrofurantoin, Nalidixic acid, and Fava beans (Favism). * **Diagnosis:** Peripheral smear shows **"Bite cells"** (degmacytes) and **Heinz bodies** (denatured hemoglobin visible with supravital stains like Crystal Violet). * **Inheritance:** G6PD deficiency is an **X-linked recessive** disorder, making it more common in males. * **Screening:** Always screen for G6PD deficiency before initiating Primaquine or Dapsone therapy.

Q: Which of the following conditions is most likely due to a pharmacogenetic cause?

Primaquine-induced hemolytic anemia. **Explanation:** **1. Why Option D is Correct:** Primaquine-induced hemolytic anemia is a classic example of a **pharmacogenetic disorder** caused by **Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency**. G6PD is an enzyme essential for maintaining the levels of reduced glutathione in red blood cells (RBCs), which protects them from oxidative stress. Primaquine is an oxidizing drug; in G6PD-deficient individuals, the RBCs cannot neutralize the oxidative stress, leading to hemoglobin denaturation (Heinz bodies) and subsequent hemolysis. This is an X-linked recessive trait, making it a genetically determined abnormal response to a drug. **2. Why Other Options are Incorrect:** * **Option A & B:** Hypoglycemia from insulin and tachycardia from albuterol are **Type A (Augmented)** adverse drug reactions. These are predictable, dose-dependent extensions of the drug’s primary pharmacological action and occur in most individuals if the dose is high enough. * **Option C:** Metoclopramide-induced muscle dystonia is an **Extrapyramidal Side Effect (EPS)** due to central dopamine (D2) receptor blockade. While some individuals are more sensitive, it is generally considered a predictable side effect of the drug's mechanism rather than a specific genetic polymorphism. **3. Clinical Pearls for NEET-PG:** * **Other drugs causing hemolysis in G6PD deficiency:** Sulfonamides, Dapsone, Nitrofurantoin, and Chloroquine. * **Succinylcholine Apnea:** Caused by a genetic deficiency of **Pseudocholinesterase** (Butyrylcholinesterase). * **Slow Acetylators (NAT2 polymorphism):** Increased risk of peripheral neuropathy with **Isoniazid** and SLE-like syndrome with **Hydralazine/Procainamide**. * **Malignant Hyperthermia:** Genetic mutation in **Ryanodine receptors (RyR1)** triggered by Halothane or Succinylcholine.

Question 1

What genetic variation in a drug metabolism pathway is known to cause severe toxicity with fluorouracil?

Accepted Answer

Dihydropyrimidine dehydrogenase

Answer

CYP2C9

Answer

Thiopurine-S methyltransferase

Answer

CYP2D6

Question 2

Which of the following drugs causes hemolytic anemia in individuals with glucose-6-phosphate dehydrogenase deficiency?

Accepted Answer

Chloramphenicol

Answer

Acetaminophen

Answer

Prednisolone

Answer

Griseofulvin

Question 3

All drugs are metabolized by acetylation EXCEPT:

Accepted Answer

Phenytoin

Answer

Isoniazid

Answer

Procainamide

Answer

Hydralazine

Question 4

Which of the following drugs can cause drug-induced lupus erythematosus, particularly in individuals with slow N-acetyltransferase activity?

Accepted Answer

Hydralazine

Answer

Propranolol

Answer

Digoxin

Answer

Captopril

Question 5

HLA-B* 1502 is a genetic marker for which of the following conditions?

Accepted Answer

Stevens-Johnson syndrome

Answer

Systemic lupus erythematosus

Answer

Polyarteritis nodosa

Answer

Seronegative spondyloarthritis syndrome

Question 6

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

Accepted Answer

Succinylcholine

Answer

Ethanol

Answer

Rifampicin

Answer

Cimetidine

Question 7

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

Accepted Answer

Atropine

Answer

Primaquine

Answer

Chloroquine

Answer

Quinine

Question 8

Which antitubercular drug metabolism is under genetic control?

Accepted Answer

Isoniazid

Answer

Rifampicin

Answer

Cyclosporine

Answer

Pyrazinamide

Question 9

Which drug may lead to hemolysis in a child with G6PD deficiency?

Accepted Answer

Primaquine

Answer

Penicillin

Answer

Ceftriaxone

Answer

Erythromycin

Question 10

Which of the following conditions is most likely due to a pharmacogenetic cause?

Accepted Answer

Primaquine-induced hemolytic anemia

Answer

Hypoglycemia caused by insulin

Answer

Tachycardia caused by albuterol

Answer

Metoclopramide-induced muscle dystonia

Pharmacogenomics — MCQs

Pharmacogenomics — MCQs

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