Pharmacogenomics Practice Questions

Q: Testing of HLA-B' 5701 is recommended prior to initiation of which antiretroviral agent?

Abacavir. The correct answer is **Abacavir (Option D)**. **1. Why Abacavir is Correct:** Abacavir is a Nucleoside Reverse Transcriptase Inhibitor (NRTI) associated with a severe, potentially life-threatening **Hypersensitivity Reaction (HSR)** [1]. This reaction is strongly linked to the presence of the **HLA-B*57:01** allele. In individuals carrying this allele, abacavir binds to the HLA-B*57:01 protein, altering the shape of the antigen-binding cleft [1]. This causes the immune system to recognize self-peptides as foreign, triggering a massive T-cell response. Screening for this allele is now a standard of care; if a patient tests positive, abacavir is strictly contraindicated [1]. **2. Why Other Options are Incorrect:** * **Atazanavir (A):** A Protease Inhibitor (PI) known for causing unconjugated hyperbilirubinemia (jaundice) by inhibiting the UGT1A1 enzyme, but it is not linked to HLA-B*57:01 [1]. * **Nelfinavir (B):** An older PI primarily associated with gastrointestinal side effects (diarrhea). No specific HLA screening is required. * **Raltegravir (C):** An Integrase Strand Transfer Inhibitor (INSTI). While it can rarely cause Stevens-Johnson Syndrome (SJS), there is no routine pharmacogenetic screening recommended prior to its use. **3. High-Yield Clinical Pearls for NEET-PG:** * **Abacavir HSR Symptoms:** Fever, rash, GI distress, and respiratory symptoms. **Re-challenge** after a suspected reaction is **fatal**. * **Other High-Yield HLA Associations:** * **HLA-B*15:02:** Carbamazepine-induced SJS/TEN (specifically in Asian populations). * **HLA-B*58:01:** Allopurinol-induced severe cutaneous adverse reactions (SCAR). * **Mnemonic:** "A-B-C" — **A**bacavir **B**inds **C**left of HLA-B*57:01.

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: 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 is an ionotropic receptor?

Nicotinic cholinergic receptor. **Explanation:** Receptors are classified into four major types based on their structure and signaling mechanism. **Ionotropic receptors** (Ligand-gated ion channels) are transmembrane proteins that open or close in response to the binding of a chemical messenger, allowing the rapid flow of ions across the cell membrane. **Why Option B is Correct:** The **Nicotinic Cholinergic Receptor (nAChR)** is a classic example of an ionotropic receptor. It is a pentameric structure that, upon binding with Acetylcholine, undergoes a conformational change to open a central pore. This allows the influx of **Sodium (Na+)** and efflux of **Potassium (K+)**, leading to rapid depolarization. These are found at the neuromuscular junction (NMJ) and autonomic ganglia. **Why Other Options are Incorrect:** * **A. Muscarinic Cholinergic Receptor:** These are **G-Protein Coupled Receptors (GPCRs)** or metabotropic receptors. They act via second messengers (like IP3/DAG or cAMP) and are slower than ionotropic receptors. * **C. Glucocorticoid Receptor:** These are **Intracellular/Nuclear receptors**. They act as ligand-activated transcription factors that regulate gene expression in the nucleus. * **D. Insulin Receptor:** This is an **Enzyme-linked receptor** (specifically, a Receptor Tyrosine Kinase). Binding of insulin leads to autophosphorylation of tyrosine residues. **High-Yield Clinical Pearls for NEET-PG:** * **Fastest Receptors:** Ionotropic receptors (milliseconds) > GPCRs (seconds) > Enzyme-linked (minutes/hours) > Nuclear receptors (hours/days). * **Other Ionotropic Examples:** GABA-A (Chloride channel), Glycine, 5-HT3 (the only ionotropic Serotonin receptor), and NMDA/AMPA receptors. * **Pharmacogenomics Link:** Mutations in the subunits of the nicotinic receptor can lead to conditions like Congenital Myasthenic Syndromes.

Q: HLA* 1502 is a genetic marker associated with which of the following conditions?

Stevens-Johnson Syndrome. ### Explanation **Correct Answer: C. Stevens-Johnson Syndrome** The **HLA-B*1502** allele is a critical pharmacogenetic marker strongly associated with an increased risk of **Stevens-Johnson Syndrome (SJS)** and **Toxic Epidermal Necrolysis (TEN)** in patients treated with **Carbamazepine**. This association is particularly prevalent in populations of **East Asian and Southeast Asian** descent (e.g., Han Chinese, Thai, Indians). The mechanism involves a T-cell mediated hypersensitivity reaction where the drug (Carbamazepine) binds to the HLA-B*1502 molecule, triggering an immune response against keratinocytes. Due to this high correlation, the FDA recommends screening for this allele in high-risk populations before initiating Carbamazepine therapy. **Analysis of Incorrect Options:** * **A. Systemic Lupus Erythematosus (SLE):** Associated primarily with **HLA-DR2** and **HLA-DR3**. Drug-induced SLE is linked to "slow acetylators" (NAT2 deficiency) taking drugs like Procainamide or Hydralazine. * **B. Polyarteritis Nodosa:** Strongly associated with **Hepatitis B surface antigen (HBsAg)** positivity, not a specific HLA-B allele. * **D. Seronegative Spondyloarthritis:** This group of disorders (including Ankylosing Spondylitis) is classically associated with **HLA-B27**. **High-Yield Clinical Pearls for NEET-PG:** * **HLA-B*5701:** Associated with hypersensitivity to **Abacavir** (NRTI). * **HLA-B*5801:** Associated with SJS/TEN induced by **Allopurinol** (especially in Han Chinese). * **HLA-A*3101:** Another marker for Carbamazepine-induced skin reactions, more common in Europeans and Japanese. * **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 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.

Question 1

Testing of HLA-B' 5701 is recommended prior to initiation of which antiretroviral agent?

Accepted Answer

Abacavir

Answer

Atazanavir

Answer

Nelfinavir

Answer

Raltegravir

Question 2

Which HLA gene is associated with abacavir hypersensitivity?

Accepted Answer

B57

Answer

B5

Answer

B51

Answer

DQ2

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 is an ionotropic receptor?

Accepted Answer

Nicotinic cholinergic receptor

Answer

Muscarinic cholinergic receptor

Answer

Glucocorticoid receptor

Answer

Insulin receptor

Question 6

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

Accepted Answer

Thyroxine

Answer

Corticosteroids

Answer

Vitamin D

Answer

Aldosterone

Question 7

What is true about tachyphylaxis?

Accepted Answer

Indirect sympathomimetics involved

Answer

Direct sympathomimetic involved

Answer

Mechanism clearly understood

Answer

Ephedrine tachyphylaxis reversed with noradrenaline

Question 8

HLA* 1502 is a genetic marker associated with which of the following conditions?

Accepted Answer

Stevens-Johnson Syndrome

Answer

Systemic Lupus Erythematosus (SLE)

Answer

Polyarteritis Nodosa

Answer

Seronegative Spondyloarthritis Syndrome

Question 9

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 10

Which statement related to the expiry date of a drug is true?

Accepted Answer

It is the date up to which the drug is likely to be fully potent and safe to take based on scientifically-sound product testing, if stored properly.

Answer

The maximum period of expiry is 3 years from the date of manufacture.

Answer

After the expiry period, there is a fall in the efficacy of the drug.

Answer

After the expiry period, the drug changes to more toxic compounds.

Pharmacogenomics — MCQs

Pharmacogenomics — MCQs

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