Pharmacogenomics Practice Questions

Q: Which drugs should be avoided in G6PD deficiency?

Dapsone. **Explanation:** **1. Why Dapsone is the Correct Answer:** Glucose-6-Phosphate Dehydrogenase (G6PD) is a critical enzyme in the pentose phosphate pathway that maintains the pool of **reduced glutathione** in red blood cells (RBCs). Reduced glutathione acts as an antioxidant, neutralizing free radicals and reactive oxygen species (ROS). **Dapsone** is a potent oxidizing agent. In G6PD-deficient individuals, the RBCs cannot regenerate enough reduced glutathione to combat the oxidative stress caused by Dapsone. This leads to the oxidation of hemoglobin into **Heinz bodies**, resulting in membrane damage and **acute hemolytic anemia**. **2. Analysis of Incorrect Options:** * **Metformin (B):** A biguanide used in Type 2 Diabetes. Its primary side effect is lactic acidosis; it does not cause oxidative stress or hemolysis. * **Pregabalin (C):** A gabapentinoid used for neuropathic pain and seizures. It has no known interaction with the G6PD enzyme pathway. * **Rituximab (D):** A monoclonal antibody against CD20. While it can cause infusion reactions or cytopenias, it is not an oxidizing drug and is safe in G6PD deficiency. **3. High-Yield Clinical Pearls for NEET-PG:** * **The "AAA" Rule:** Common triggers for G6PD hemolysis include **A**ntimalarials (Primaquine, Chloroquine), **A**ntibiotics (Sulfonamides, Dapsone, Nitrofurantoin), and **A**ntipyretics (high-dose Aspirin). * **Fava Beans:** Ingestion causes "Favism," a classic trigger for hemolysis in these patients. * **Peripheral Smear Findings:** Look for **Heinz Bodies** (denatured hemoglobin) and **Bite Cells** (degmacytes) formed when splenic macrophages pluck out these bodies. * **Inheritance:** It is an **X-linked recessive** disorder, making it more common in males.

Q: Variation in the sensitivity of response to increasing doses of a drug in different individuals can be obtained from which type of dose-response curve?

Quantal dose-response curve. **Explanation:** The core of this question lies in distinguishing between how an individual responds to a drug versus how a population responds. **1. Why Option B is Correct:** A **Quantal Dose-Response Curve (QDRC)** describes an "all-or-none" response (e.g., sleep/no sleep, death/survival) across a population. It plots the fraction of the population that manifests a specific effect at increasing doses. Because individuals have different genetic makeups and physiological states (**inter-individual variation**), they require different doses to achieve the same effect. The QDRC is the primary tool used to visualize this variation in sensitivity and to determine the **Therapeutic Index (TI)**. **2. Why Other Options are Incorrect:** * **A. Graded Dose-Response Curve:** This measures the intensity of a response in a **single individual** as the dose increases (e.g., the increase in heart rate with increasing doses of Adrenaline). It defines efficacy and potency but does not account for population-wide sensitivity variations. * **C. Potency:** This refers to the amount of drug (dose) required to produce an effect of a given intensity. It is determined by the $EC_{50}$ on a Graded curve. * **D. Efficacy:** This refers to the maximal response ($E_{max}$) a drug can produce, regardless of dose. **NEET-PG High-Yield Pearls:** * **Graded Curve:** Tells us about **Efficacy** (Maximal effect) and **Potency** ($EC_{50}$). * **Quantal Curve:** Tells us about **Selectivity**, **Safety**, and **Variability** ($ED_{50}$, $TD_{50}$, $LD_{50}$). * **Therapeutic Index (TI):** Calculated from the Quantal curve as $TI = LD_{50} / ED_{50}$. A higher TI indicates a safer drug. * **Standard Safety Margin:** Also derived from the Quantal curve: $[(LD_1 - ED_{99}) / ED_{99}] \times 100$.

Q: What is the primary purpose of pharmacovigilance?

To monitor adverse effects of drugs. **Explanation:** Pharmacovigilance (PV) is defined by the WHO as the science and activities relating to the **detection, assessment, understanding, and prevention of adverse effects** or any other drug-related problems. Its primary goal is to ensure patient safety by identifying previously unrecognized adverse drug reactions (ADRs) after a drug has been released into the market (Phase IV clinical trials). **Analysis of Options:** * **Option C (Correct):** The core mandate of pharmacovigilance is the continuous monitoring of the safety profile of drugs. Since clinical trials (Phases I-III) involve limited populations, rare or long-term adverse effects are often only discovered through post-marketing surveillance. * **Option A:** Regulating pharmaceutical companies is the role of national regulatory authorities (like the CDSCO in India or the FDA in the USA), not the specific process of pharmacovigilance. * **Option B:** While efficacy is monitored during clinical trials, pharmacovigilance focuses specifically on *safety* rather than how well the drug works (efficacy) or its chemical strength (potency). * **Option D:** Ethical drug practices are governed by Bioethics committees and Good Clinical Practice (GCP) guidelines. **High-Yield Clinical Pearls for NEET-PG:** * **Phase IV Clinical Trial:** This is synonymous with post-marketing surveillance and is the stage where pharmacovigilance is most active. * **Pharmacovigilance Programme of India (PvPI):** Launched in 2010; the National Coordinating Centre is the Indian Pharmacopoeia Commission (IPC), Ghaziabad. * **Uppsala Monitoring Centre (UMC):** Located in Sweden, it is the WHO collaborating centre for international drug monitoring. * **Spontaneous Reporting:** This is the most common method used in pharmacovigilance to identify new ADRs.

Q: Which of the following drugs is NOT bound to alpha-1-acid glycoprotein?

Tolbutamide. ### Explanation The binding of drugs to plasma proteins is a crucial pharmacokinetic concept. In the blood, drugs primarily bind to two types of proteins: **Albumin** and **Alpha-1-acid glycoprotein (AAG)**. **1. Why Tolbutamide is the Correct Answer:** Tolbutamide is an acidic drug (Sulfonylurea). As a general rule, **acidic drugs bind primarily to Plasma Albumin**, while **basic drugs bind to Alpha-1-acid glycoprotein (AAG)**. Since Tolbutamide is acidic, it does not bind to AAG, making it the correct choice. **2. Analysis of Incorrect Options:** * **Lignocaine (Option A):** This is a basic drug (local anesthetic) and is a classic example of a drug that binds extensively to AAG. * **Quinidine (Option B):** An alkaloid and a basic drug used as an antiarrhythmic; it binds significantly to AAG. * **Propranolol (Option D):** A basic beta-blocker that shows high affinity for AAG. **3. Clinical Pearls & High-Yield Facts for NEET-PG:** * **The "Acid-to-Acid" Rule:** Remember **A**cidic drugs bind to **A**lbumin (e.g., NSAIDs, Warfarin, Phenytoin, Penicillins, and Sulfonylureas like Tolbutamide). * **The "Basic-to-Glycoprotein" Rule:** **B**asic drugs bind to **A**AG (e.g., Lidocaine, Propranolol, Quinidine, Tricyclic Antidepressants, and Bupivacaine). * **Clinical Significance of AAG:** AAG is an "acute-phase reactant." Its levels increase during inflammation, infection, or malignancy. This can lead to decreased free (active) fractions of basic drugs like Lignocaine, potentially requiring dosage adjustments in such patients. * **Albumin Levels:** Conversely, albumin levels often decrease in chronic liver disease or nephrotic syndrome, leading to increased toxicity of acidic drugs like Warfarin.

Q: Which drug has a wide therapeutic index?

Penicillin. ### Explanation **Therapeutic Index (TI)** is a quantitative measurement of a drug's safety. It is defined as the ratio of the dose that produces toxicity to the dose that produces a clinically desired effect ($TI = TD_{50} / ED_{50}$). **1. Why Penicillin is Correct:** Penicillin has a **wide therapeutic index**, meaning there is a large margin between the effective dose and the toxic dose. This is primarily because penicillin targets the bacterial cell wall (peptidoglycan synthesis), a structure that does not exist in human cells. Consequently, even very high doses are generally well-tolerated by the human body, unless the patient has a specific hypersensitivity/allergy. **2. Why the Other Options are Incorrect:** * **Digoxin (A):** A classic example of a **narrow therapeutic index** drug. It requires therapeutic drug monitoring (TDM) because the dose required to treat heart failure/arrhythmias is very close to the dose that causes life-threatening digitalis toxicity. * **Lithium (B):** Used in bipolar disorder, lithium has an extremely narrow window (therapeutic range: 0.6–1.2 mEq/L). Levels above 1.5 mEq/L can lead to severe neurotoxicity and renal impairment. * **Phenytoin (C):** This antiepileptic follows **zero-order kinetics** (saturation kinetics) at higher therapeutic concentrations. Small dose increases can lead to disproportionately large increases in plasma levels, causing toxicity (ataxia, nystagmus). **3. NEET-PG High-Yield Pearls:** * **Mnemonic for Narrow Therapeutic Index drugs:** "**W**arning, **T**hese **L**ethal **D**rugs **P**revent **C**uring" (**W**arfarin, **T**heophylline, **L**ithium, **D**igoxin, **P**henytoin/Phenobarbitone, **C**arbamazepine). * Drugs with a wide TI (e.g., Penicillin, Paracetamol, Benzodiazepines) are generally safer and do not require routine TDM. * **Low TI** = High risk of toxicity; **High TI** = Safer profile.

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).

Question 1

A drug that binds to a receptor at a site distinct from the active site and alters the affinity of the receptor for the endogenous ligand is a:

Accepted Answer

Allosteric modulator

Answer

Competitive antagonist

Answer

Inverse agonist

Answer

Partial agonist

Question 2

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 3

Which drugs should be avoided in G6PD deficiency?

Accepted Answer

Dapsone

Answer

Metformin

Answer

Pregabalin

Answer

Rituximab

Question 4

Loading dose depends on the following factors except:

Accepted Answer

Clearance of the drug

Answer

Drug concentration to be achieved

Answer

Volume of distribution

Answer

Bioavailability of drug

Question 5

Variation in the sensitivity of response to increasing doses of a drug in different individuals can be obtained from which type of dose-response curve?

Accepted Answer

Quantal dose-response curve

Answer

Graded dose-response curve

Answer

Potency

Answer

Efficacy

Question 6

What is the primary purpose of pharmacovigilance?

Accepted Answer

To monitor adverse effects of drugs

Answer

To regulate pharmacy companies

Answer

To monitor drug potency and efficacy

Answer

To ensure ethical drug practices

Question 7

Which of the following drugs is NOT bound to alpha-1-acid glycoprotein?

Accepted Answer

Tolbutamide

Answer

Lignocaine

Answer

Quinidine

Answer

Propranolol

Question 8

Which drug has a wide therapeutic index?

Accepted Answer

Penicillin

Answer

Digoxin

Answer

Lithium

Answer

Phenytoin

Question 9

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 10

Which is the most appropriate definition of spare receptors?

Accepted Answer

Receptors that remain unoccupied even after a drug produces its maximal response.

Answer

Receptors involved in the binding of inverse agonists.

Answer

Receptors that are responsible for producing adverse drug effects.

Answer

Receptors that are unable to produce a maximum response.

Pharmacogenomics — MCQs

Pharmacogenomics — MCQs

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