L8: Pharmacogenetics

Question 1

What is Pharmacogenetics?

Answer 1

It is the study of variation in response to a single drug due to genetic variation of SINGLE for a few gene(s).

Question 2

What is pharmacogenomics?

Answer 2

It is a broader term, which studies how ALL of the genes (the genome) can influence the responses to drugs

Currently, variations in around 20 genes provide useful predictions of reactions to 80 - 100 drugs

Question 3

What are succinylcholine and mivacurium? And what are they used for?

Answer 3

They are neuromuscular blockers, often used during general anesthesia to relax skeletal muscles.

Question 4

What are succinylcholine and mivacurium metabolized by?

Answer 4

These drugs are metabolized by the pseudocholinesterase (PChE) enzyme in plasma.

Question 5

What is the rate of occurrence of PCHE deficiency?

Answer 5

1:3000

Question 6

What are the adverse effects of PCHE Deficiency?

Answer 6

when they receive these drugs during general anesthesia, they develop prolonged paralysis of respiratory muscles (succinylcholine apnea)

Question 7

How are the side effects of PCHE Deficiency managed?

Answer 7

include fresh plasma transfusion and mechanical ventilation until the drugs are cleaned from the body.

Question 8

What is the most common human enzyme defect?

Answer 8

G6PD deficiency is the most common human enzyme defect (X-linked recessive most often affects males).

Question 9

What is the function of G6DP?

Answer 9

• G6PD enzyme catalyzes the reduction of NADP+ into NADPH which maintains glutathione in the RBCs in its reduced form.
• Reduced glutathione keeps hemoglobin in the reduced (ferrous) form and prevents its oxidation into methemoglobin (by oxidizing drugs) which leads to cell membrane injury and hemolysis (ideosacritic reaction)
• Individuals with a deficiency of G6PD may suffer acute hemolysis with jaundice if they are exposed to many oxidizing drugs (e.g. nitrates and antimalarial drugs), and fava beans.

Question 10

What are the oxidizing Agents that affect RBCs?

Answer 10

aspirin, nitrates, antimalarial drugs, sulfonamides, and fava beans

Question 11

What is the function of Thiopurine methyltransferase (TPMT)?

Answer 11

It is an enzyme that methylates thiopurine anticancer drugs (e.g. 6-mercaptopurine and 6-thioguanine) into less toxic compounds.

Question 12

What are the adverse effects that happen due to Thiopurine methyltransferase (TPMT) Deficiency? And how to avoid it?

Answer 12

• Some people (1:300) have a genetic deficiency in WWI when they take thiopurine drugs for cancer treatment, they develop severe myelotoxicity and bone marrow suppression due to the conversion of these drugs into more toxic compounds
• Screening for TPMT deficiency is necessary for patients planning to be treated with thiopurine anticancer drugs.

Question 13

What are examples of drugs that are metabolized by acetylation and where?

Answer 13

Many drugs are metabolized in the liver by acetylation (e.g. isoniazid)

Question 14

What is acetylation controlled by?

Answer 14

genetic control and people can be classified according to their rate of acetylation into rapid and slow acetylators

Question 15

What are the adverse effects that happen in rapid acetylators?

Answer 15

excess toxic metabolites of isoniazid accumulate in the liver causing hepatotoxicity

Question 16

What are the adverse effects that happen in slow acetaylators?

Answer 16

Accumulation of Isoniazid
↓
Inhibition of pyridoxine "vit B6"
↓
Inhibition of synthesis of the myelin sheath
↓ 
Neurotoxicity.

Accumulation of hydralazine
↓
SLE like syndrome

Question 17

What is warfarin and what is its function?

Answer 17

Warfarin is an anticoagulant drug used to prevent thrombosis in high-Risk patients

Question 18

What is the mechanism of action of warfarin?

Answer 18

• Inhibition of VKOR enzyme by warfarin leads to inhibition of vitamin K-dependent clotting factors (II, IIV, IX, X).
• Some people (rare) have a genetic abnormality of VKOR enzyme that makes it less able to bind to warfarin, thus less able to inhibit.
• People carrying the mutant enzyme either need high doses of warfarin to get the usual anticoagulant effect or do not respond to the drug at all.

Question 19

What is clopidogrel and what is its function?

Answer 19

Clopidogrel is an antiplatelet drug used to prevent thrombosis in high-risk patients.

Question 20

What are the side effects of resistance to clopidogrel?

Answer 20

 The drug itself is inactive and must be catalyzed by the hepatic enzyme CYP2C19 to exert its antiplatelet effect.

 Some people (14%) have a genetic deficiency of this enzyme (called CYP2C19 poor metabolizers),

 thus their livers can not activate clopidogrel and so they are at risk of therapeutic failure.

Question 21

What is the metabolizer of clopidogrel?

Answer 21

hepatic enzyme CYP2C19