Pharmacogenetics and Personalized Medicine — MCQs

10 questions

HLA-B*5701 is an allele associated with hypersensitivity to abacavir. Which of the following is the parent allele of HLA-B*5701?

Mutation in GLUT-2 causes which syndrome?

Variation in sensitivity of response to different doses of a drug in different individuals is obtained from?

Mutations are due to changes in:

What is the primary purpose of xenobiotic metabolism?

Which of the following statements about phase IV clinical trials is correct?

Which of the following cytochromes is involved in monooxygenase mediated detoxification of drugs?

A patient is on warfarin therapy. All of the following drugs increase the risk of bleeding with warfarin except?

Q10

Morphine should not be used in the treatment of:

Pharmacogenetics and Personalized Medicine Indian Medical PG Practice Questions and MCQs

Question 1: HLA-B5701 is an allele associated with hypersensitivity to abacavir. Which of the following is the parent allele of HLA-B5701?

A. HLA-B*5
B. HLA-B*51
C. HLA-DQ2
D. HLA-B*57 (Correct Answer)

Explanation: ***HLA-B\*57*** - **HLA-B*57** is the parent allele for **HLA-B*5701**, indicating it is the broader serotype under which specific alleles like *5701 are classified [1]. - The notation **HLA-B\*57** signifies a specific **HLA class I** allele group [1]. *HLA-B\*5* - This option is **incomplete** as an HLA allele notation; it lacks the specific group designation often indicated by two or three digits following the asterisk. - While "B5" exists as a serotype, **"HLA-B*5"** itself is not a standard, complete allele designation reflecting a specific gene variant. *HLA-B\*51* - **HLA-B\*51** is a specific **HLA class I** allele, but it is not directly related to or the parent group of **HLA-B\*5701**. - It is known to be associated with Behcet's disease, a different clinical condition not related to abacavir hypersensitivity. *HLA-DQ2* - **HLA-DQ2** is an allele of **HLA class II**, while **HLA-B\*5701** is an **HLA class I** allele. - Though both are HLA alleles, they belong to different classes and are associated with different disease contexts, with **HLA-DQ2 typically linked to celiac disease**.

Question 2: Mutation in GLUT-2 causes which syndrome?

A. Dandy walker syndrome
B. Beckwith-Wiedemann syndrome
C. Menke's disease
D. Fanconi-Bickel syndrome (Correct Answer)

Explanation: ***Fanconi-Bickel syndrome*** - This syndrome is caused by a **mutation in the GLUT-2 gene**, leading to dysfunctional glucose transport in the liver, kidneys, and intestines. - Key features include **hepatorenal glycogen accumulation**, **renal tubulopathy** (Fanconi syndrome), and **impaired glucose and galactose utilization**. *Dandy-Walker syndrome* - This is a **congenital brain malformation** involving the cerebellum and fourth ventricle. - It is often associated with hydrocephalus, but not directly linked to glucose transporter defects. *Beckwith-Wiedemann syndrome* - This is an **overgrowth disorder** characterized by a high risk of childhood cancer and congenital anomalies. - It is primarily caused by genetic abnormalities on **chromosome 11p15.5** and is unrelated to GLUT-2 mutations. *Menke's disease* - This is a rare X-linked recessive disorder of **copper metabolism**, leading to severe neurological degeneration. - It results from mutations in the **ATP7A gene**, which encodes a copper-transporting ATPase.

Question 3: Variation in sensitivity of response to different doses of a drug in different individuals is obtained from?

A. Dose-response relationship (Correct Answer)
B. Therapeutic index
C. Bioavailability
D. Phase 1 clinical trials

Explanation: ***Dose-response relationship*** - The **dose-response relationship** (particularly the **graded dose-response curve**) describes how the magnitude of a drug's effect changes with different doses. - When plotted for different individuals or populations, these curves reveal **variation in sensitivity** through differences in potency (horizontal shift) and efficacy (maximum response). - This relationship helps characterize inter-individual variability in drug response and is the fundamental concept for understanding differential sensitivity. *Therapeutic index* - The **therapeutic index** is a measure of drug safety, representing the ratio between the toxic dose and the effective dose (TD50/ED50 or LD50/ED50). - It does not directly explain the variation in sensitivity to different doses among individuals, but rather provides information about the drug's overall safety margin. *Bioavailability* - **Bioavailability** refers to the fraction of an administered drug that reaches the systemic circulation unchanged. - While it influences the drug concentration at the site of action, it doesn't directly measure the variability in physiological response to that concentration among individuals. *Phase 1 clinical trials* - **Phase 1 clinical trials** are the first stage of testing a new drug in humans, primarily focusing on safety, dosage range, and pharmacokinetics in a small group of healthy volunteers. - While variability in response may be observed during these trials, they are not the *pharmacological concept* that describes this variation; rather, dose-response relationships are used to interpret findings from these trials.

Question 4: Mutations are due to changes in:

A. DNA nucleotide sequence (Correct Answer)
B. RNA nucleotide sequence
C. Amino acid sequence of ribonuclease
D. Cell membrane

Explanation: ***DNA nucleotide sequence*** - **Mutations** are defined as changes in the **genetic material**, which is primarily composed of **DNA**. - These changes in the **nucleotide sequence** of DNA can alter the genetic code, leading to changes in **protein structure and function**. *RNA nucleotide sequence* - While RNA can have its nucleotide sequence altered, these changes are generally not considered true **mutations** in the heritable sense for most organisms. - RNA is typically a temporary molecule, and changes to its sequence are usually not passed down to subsequent generations. *Amino acid sequence of ribonuclease* - An altered **amino acid sequence** in a protein like ribonuclease is a consequence of a **mutation in the DNA**, not the mutation itself. - **Ribonucleases** are enzymes that catalyze the degradation of RNA, and their structure is determined by the **DNA sequence**. *Cell membrane* - The cell membrane is a **lipid bilayer** with embedded proteins that regulates cellular transport and communication. - While its components can be affected by genetic mutations, alterations in the cell membrane itself do not constitute the primary definition of a **mutation**.

Question 5: What is the primary purpose of xenobiotic metabolism?

A. Increase water solubility (Correct Answer)
B. Increase lipid solubility
C. Make them nonpolar
D. None of the above

Explanation: ***Increase water solubility*** - The primary goal of xenobiotic metabolism is to make these foreign compounds more **hydrophilic** (water-soluble). - This increased water solubility facilitates their **excretion** from the body via urine or bile. *Increase lipid solubility* - Increasing **lipid solubility** would make xenobiotics more likely to accumulate in **adipose tissue** and pass through cell membranes, hindering their excretion. - This is the opposite of the desired outcome for xenobiotic elimination. *Make them nonpolar* - Making xenobiotics **nonpolar** would be equivalent to increasing their lipid solubility, as nonpolar molecules tend to be lipid-soluble. - This would impede excretion and potentially lead to **bioaccumulation**, which is harmful. *None of the options* - This option is incorrect because xenobiotic metabolism specifically aims to increase **water solubility** for elimination.

Question 6: Which of the following statements about phase IV clinical trials is correct?

A. It is primarily focused on the efficacy of the drug.
B. It involves monitoring the long-term effects and safety of drugs. (Correct Answer)
C. It is conducted before a drug is submitted for approval.
D. It focuses primarily on determining the optimal dosage for patients.

Explanation: ***It involves monitoring the long-term effects and safety of drugs.*** - **Phase IV clinical trials** are conducted **after a drug has been approved and marketed** to monitor its performance in the general population. - The primary goals include assessing the **long-term safety profile**, identifying rare adverse effects, and evaluating effectiveness under real-world conditions. *It is primarily focused on the efficacy of the drug.* - The primary focus on **drug efficacy** is typically addressed in **Phase II and Phase III clinical trials**, where controlled studies evaluate if the drug works as intended. - While efficacy is re-evaluated in real-world settings during Phase IV, it's not the primary or exclusive focus, which broadens to safety and comparative effectiveness. *It is conducted before a drug is submitted for approval.* - Trials conducted **before drug submission for approval** are typically **Phase I, Phase II, and Phase III clinical trials**, which are designed to establish safety, dosage, and initial efficacy. - **Phase IV trials** specifically begin **after a drug has received regulatory approval** and is available to the public. *It focuses primarily on determining the optimal dosage for patients.* - **Optimal dosage determination** is largely the domain of **Phase I and Phase II clinical trials**, where escalating doses are tested in small groups to identify a safe and effective range. - Phase IV studies might explore different dosing regimens in specific patient populations, but they do not primarily determine initial optimal dosing.

Question 7: Match the following drugs in Column A with their contraindications in Column B. | Column A | Column B | | :-- | :-- | | 1. Morphine | 1. QT prolongation | | 2. Amiodarone | 2. Thromboembolism | | 3. Vigabatrin | 3. Pregnancy | | 4. Estrogen preparations | 4. Head injury |

A. A-1, B-3, C-2, D-4
B. A-4, B-1, C-3, D-2 (Correct Answer)
C. A-3, B-2, C-4, D-1
D. A-2, B-4, C-1, D-3

Explanation: ***A-4, B-1, C-3, D-2*** - **Morphine** is contraindicated in **head injury** as it can increase intracranial pressure and mask neurological symptoms. - **Amiodarone** is contraindicated in patients with **QT prolongation** due to its risk of inducing more severe arrhythmias like Torsades de Pointes. - **Vigabatrin** is contraindicated during **pregnancy** due to its potential for teratogenicity and adverse effects on fetal development. - **Estrogen preparations** are contraindicated in patients with a history of **thromboembolism** due to their increased risk of blood clot formation. *A-1, B-3, C-2, D-4* - This option incorrectly matches **Morphine** with QT prolongation and **Estrogen preparations** with head injury, which are not their primary contraindications. - It also incorrectly links **Vigabatrin** with thromboembolism and **Amiodarone** with pregnancy. *A-3, B-2, C-4, D-1* - This choice incorrectly associates **Morphine** with pregnancy and **Vigabatrin** with head injury, which are not the most critical or direct contraindications. - It also misaligns **Amiodarone** with thromboembolism and **Estrogen preparations** with QT prolongation. *A-2, B-4, C-1, D-3* - This option incorrectly matches **Morphine** with thromboembolism and **Amiodarone** with head injury, which are not their most significant contraindications. - It also incorrectly links **Vigabatrin** with QT prolongation and **Estrogen preparations** with pregnancy.

Question 8: Which of the following cytochromes is involved in monooxygenase mediated detoxification of drugs?

A. Cytochrome b5
B. Cytochrome P450 (Correct Answer)
C. Cytochrome c
D. NADPH-cytochrome P450 reductase

Explanation: ***Cyt P 450*** - **Cytochrome P450** enzymes are a superfamily of **monooxygenases** that play a critical role in the metabolism and detoxification of a wide variety of endogenous and exogenous substances, including drugs. - They facilitate phase I reactions (e.g., **oxidation**, reduction, hydrolysis), which typically introduce or expose functional groups to make compounds more polar and easier to excrete. *Cytochrome b5* - **Cytochrome b5** is involved in various metabolic reactions, including **fatty acid desaturation** and cholesterol biosynthesis, and can sometimes interact with P450 systems but is not the primary monooxygenase for drug detoxification. - It also participates in the reduction of methemoglobin and can act as an electron donor, but its role in drug detoxification is secondary and accessory to P450. *Cytochrome c* - **Cytochrome c** is a key component of the **electron transport chain** in mitochondria, primarily involved in cellular respiration and ATP production. - It has a crucial role in **apoptosis** when released into the cytosol, but it is not directly involved in drug monooxygenase detoxification. *NADPH-cytochrome P450 reductase* - **NADPH-cytochrome P450 reductase** is an enzyme that transfers electrons from NADPH to **cytochrome P450 enzymes**, enabling their monooxygenase activity. - While essential for P450 function, it is the **reductase** (electron donor) and not the monooxygenase enzyme itself, which is Cytochrome P450.

Question 9: A patient is on warfarin therapy. All of the following drugs increase the risk of bleeding with warfarin except?

A. Isoniazid
B. Amiodarone
C. Carbamazepine (Correct Answer)
D. Cimetidine

Explanation: ***Carbamazepine*** - Carbamazepine **induces cytochrome P450 enzymes**, specifically **CYP3A4** and **CYP2C9**, which are responsible for warfarin metabolism. - This induction leads to a **faster metabolism of warfarin**, thus **decreasing its anticoagulant effect** and thereby reducing the risk of bleeding. *Isoniazid* - Isoniazid is an **inhibitor of cytochrome P450 enzymes**, primarily **CYP2C9**, which metabolizes the more potent S-warfarin isomer. - This inhibition **decreases warfarin metabolism**, leading to **increased anticoagulant effect** and higher risk of bleeding. *Amiodarone* - Amiodarone is a potent **inhibitor of cytochrome P450 enzymes**, significantly **CYP2C9** and **CYP3A4**. - It leads to a **reduced metabolism of warfarin**, causing **elevated INR** and an increased risk of bleeding. *Cimetidine* - Cimetidine is a known **inhibitor of various cytochrome P450 enzymes**, particularly **CYP1A2**, **CYP2C9**, and **CYP3A4**. - Its inhibitory action on warfarin metabolism results in **higher warfarin levels** and an **increased risk of bleeding**.

Question 10: Morphine should not be used in the treatment of:

A. Cancer pain
B. Ischemic pain
C. Biliary colic (Correct Answer)
D. Postoperative pain

Explanation: ***Biliary colic*** - Morphine can cause **spasms of the sphincter of Oddi**, leading to an increase in biliary pressure and potentially exacerbating the pain of biliary colic. - This adverse effect can worsen the patient's condition rather than alleviate it, making alternative analgesics like **pethidine (meperidine)** or **NSAIDs** more appropriate for biliary pain. *Cancer pain* - Morphine is a **first-line opioid** for managing moderate to severe cancer pain, providing effective analgesia as part of a comprehensive pain management strategy. - Its efficacy in cancer pain is well-established, and doses can be titrated to achieve optimal pain control without significant risk of addiction in this context. *Postoperative pain* - Morphine is widely used for **postoperative pain management** due to its potent analgesic effects and predictable pharmacokinetics. - It is effective in reducing acute surgical pain and can be administered via various routes, including intravenous and epidural, to suit patient needs. *Ischemic pain* - Morphine is effective in treating ischemic pain, particularly in conditions like **myocardial infarction**, where it helps to reduce pain, anxiety, and **myocardial oxygen demand**. - While it was favored historically because of its action as a **venodilator** and **anxiolytic**, it is now used with caution in acute coronary syndromes, specifically because it can delay the absorption of oral antiplatelet drugs.

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