Lecture 11

Question 1

Pharmacogenetics

Answer 1

the study of variation in drug responses by focusing on the variations in a targeted gene
or a group of functionally related genes.

Question 2

Balanced polymorphisms

Answer 2

→ a substantial fraction of a population differs from the remainder in such a way over many generations

→ individuals carrying both versions (heterozygotes) of a gene can survive better (selective advantage)
than those with two copies (alleles) of either version alone

Question 3

Defining an individual’s DNA sequence

Answer 3

→ select a drug that will be effective without
adverse effects

→ E.g., genotyping thiopurine methyl-transferase
that inactivates 6-mercaptopurine (6-MP)
→ guide dosing of 6-MP in children with acute
lymphocytic leukaemia (ALL)

Question 4

Genetic Influences on Drug Metabolism

Answer 4

a. Abnormal Sensitivity to drugs
b. Inheritance
c. Dominant Inheritance
d. Balanced polymorphisms
e. Different Ethnic Populations

Question 5

Phase 1 Drug Metabolism:
CYP2D6

Answer 5

It is located on chromosome 22 that encodes cytochrome P450 family 2 subfamily D member 6 (CYP2D6), with >50 polymorphic
variants

Question 6

Four phenotypes of genetic variants of CYP2D6:

Answer 6

a. Poor metabolisers (PM) → 7-10% Caucasians
b. Intermediate metabolisers (IM)
c. Extensive metabolisers (EM)
d. Ultra-rapid metabolisers (UM) → 1-2% Caucasians; 30% Egyptians

IM and EM are 85 -90% Caucasians

Question 7

Drugs that are metabolised by CYP2D6:

Answer 7

a. Opioids (e.g., pethidine, morphine and dextromethorphan)

b. β-blockers (e.g., metoprolol and propranolol)

c. Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine)

d. Antipsychotics (e.g., haloperidol)

Question 8

Hydroxylation polymorphisms in CYP2D6:

Answer 8

• leads to increased susceptibility to several ADRs.

a. Nortriptyline
b. Codeine
c. Phenformin

Question 9

Phase 1 Drug Metabolism: CYP2C9 Polymorphism (Tolbutamide Polymorphism)

Answer 9

• It is located on chromosome 10 that encodes Cytochrome P450 family 2 subfamily C member 9 (CYP2C9).
• An enzyme that is found in the cell structure called endoplasmic
  reticulum.

Question 10

Drugs that are metabolised by CYP2C9:

Answer 10

a. S-warfarin
b. losartan
c. celecoxib
d. sulphonylureas

Question 11

Phase 1 Drug Metabolism: CYP2C19 Polymorphism

Answer 11

• It is located on chromosome 10 that encodes Cytochrome P450
  family 2 subfamily C member 19 (CYP2C19).
• An enzyme that is found in the cell structure called endoplasmic
  reticulum.

Question 12

lower doses of drugs metabolised by the
CYP2C19 enzyme:

Answer 12

a. Pump inhibitors (e.g., omeprazole, lansoprazole & pantoprazole

b. Anticonvulsants (e.g., phenytoin and phenobarbitone)

Question 13

Phase 1 Drug Metabolism: Suxamethonium Sensitivity

Answer 13

The usual response of a single intravenous dose of suxamethonium is
muscular paralysis for 2-6 min → rapid hydrolysed by plasma
pseudocholinesterase

Question 14

Phase 2 Drug Metabolism: Acetylator Status (N-Acetyltransferase-2)

Answer 14

• Isoniazid (INH) is metabolised in the liver by acetylation.

slide 14

Question 15

Phase 2 Drug Metabolism: Acetylator Status (N-Acetyltransferase-2)

Answer 15

INH toxicity:
a. Poor acetylators
b. Rapid acetylators

Slide15

Question 16

Phase 2 Drug Metabolism: Sulphation

Answer 16

Sulphation by sulfotransferase (SULT) enzymes shows polymorphic variations.

slide 16 -17

Question 17

Phase 2 Drug Metabolism: Receptor/Drug Targets Polymorphisms

Answer 17

Many polymorphic variants in receptors:
a. oestrogen receptors
b. β-adrenoceptors
c. dopamine D2
receptors
d. opioid µ receptors

slide 18

Question 18

Phase 2 Drug Metabolism: Warfarin Susceptibility

Answer 18

It inhibits the vitamin K epoxide reductase complex subunit 1 (VKORC1).

slide 19

Question 19

Phase 2 Drug Metabolism: Familial Hypercholesterolemia (FH)

Answer 19

Statin (β-hydroxy-β-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor) is an important drug class for lowering
circulating cholesterol levels.

slide 20

Question 20

Phase 2 Drug Metabolism: Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

Answer 20

• G6PD catalyses the formation of NADPH → maintaining
  glutathione in its reduced form.
• The gene for G6PD is located on the X-chromosome → sex-linked
  inheritance

slide 21, 22

Question 21

Inherited Diseases Predisposing to Drug Toxicity: Methaemoglobinaemia

Answer 21

Several xenobiotics oxidise haemoglobin to methaemoglobin, including
a. Nitrates
b. Nitrites
c. Chlorates
d. Sulphonamides
e. Sulphones
f. Nitrobenzenes
g. Nitrotoluenes
h. Anilines
i. Topical local anaesthetics

slide 23

Question 22

Inherited Diseases Predisposing to Drug Toxicity: Gilbert’s Disease

Answer 22

It is a benign chronic form of primarily unconjugated
hyperbilirubinaemia → inherited reduced
activity/lack of hepatic conjugating enzyme uridine
phosphoglucuronyl transferase (UGT1A1)

slide 24

Question 23

Amphichip – CYP450 Testing (clinical test)

Answer 23

Purpose:
→ finding specific gene types or patterns of a patient in
drug metabolism
→ guiding the physicians to prescribe medicine for best
effectiveness and avoid adverse side effects

Question 24

Pharmacogenomics

Answer 24

It is a study of how genes affect a person’s response to drugs. This relatively new field combines pharmacology (the science of drugs) and genomics (the study of genes and their functions) to
develop effective, safe medications and doses that will be tailored to a person’s genetic makeup.

slide 26

Question 25

Principles of Pharmacogenomics

Answer 25

slide 27, 28, 29

Question 26

Advantages of Pharmacogenomics

Answer 26

1. To predict a patient’s response to drugs by examining the genetic makeup 2. To develop “customised” or personalised prescriptions 3. To minimise or eliminate adverse events 4. To improve efficacy and patient compliance 5. To improve the accuracy of determining appropriate dosages of drugs 6. To advance screen and monitor certain diseases 7. To develop more powerful and safer vaccines 8. To allow improvements in drug search and development and the approval of new drugs

Question 27

Single Gene Versus Multiple Genes

Answer 27

slide 31

Question 28

Combinatorial Pharmacogenomics: Warfarin Resistance

Answer 28

* VKORC1 encodes the component of vitamin K receptor complex → warfarin target slide 32

Question 29

Combinatorial Pharmacogenomics: Clopidogrel

Answer 29

The reduction-of-function variants in CYP2C19 increased the risk of cardiovascular events after stent replacement.

Question 30

Pharmacogenomics Testing

Answer 30

1. Microarrays 2. Sequencing 3. Genome-wide association study (GWAS) slide 34 - 37

Question 31

Barriers of Pharmacogenomics

Answer 31

1. Complexity of finding gene variations that affect drug response 2. Educating healthcare providers and patients 3. Disincentives for drug companies to make multiple pharmacogenomic products