Lecture 20/21

Question 1

What is the current method for drug therapy ?

Answer 1

Drugs are developed and prescribed for an average person with a one dose fits all mentality and a trial and error approach used to determine which drug and what dose to use

Question 2

How can pharmacogenetics change the current method of drug therapy?

Answer 2

Pharmacogenetics is the study of unusual drug responses which have a genetic basis in the hope to determine what causes the variability in response so that better predictions can be made about what drugs and doses will be effective

Question 3

What are the different frequency distributions for drug response, and what does this tell us about the underlying genetic factors of variability?

Answer 3

Unimodal distribution with only one peak showing that there is only one gene responsible for the variation
Bimodal variation with two distinct populations showing that more than gene is causing the difference in response

Question 4

What is the classical example of drug polymorphic drug metabolism?

Answer 4

suxamethonim is used as a short term anaesthetic in surgery is normally cleared through hydrolysis by cholinesterase in just a few minutes while in a1/2500 of the population there is a choline esterase with low affinity for this drug causing the effects to last for up to 3 hours, these individuals require 1/60 the normal dose or fatal inhibition of the respiratory system may occur

Question 5

How is acetylation affected by pharmacogenetics?

Answer 5

Acetylation via N-acetyl-transferase enzyme is a major metabolic pathway of a number of drugs such as some of the sulphonamides and isoniazid
Acetylation rate shows a distinctive bimodal distribution in the population with the proportion of fast and slow metabolizers varying between ethnic groups

Question 6

What is the clinical relevance of slow acetylation?

Answer 6

There will be an enhanced response to treatment including a greater incidence of adverse side effects (such as increased functional disturbances in the peripheral nervous system with isoniazid)
As well as increased susceptibility to certain drug interactions such as phenytoin toxicity with concurrent isoniazid and increased risk of liver toxicity with antituberculosis regimens containing rifampicin

Question 7

What is the impact of pharmacogenetics on CYP2D6 oxidation status?

Answer 7

Two distinct averages in the populations ability to oxidise a number of drugs such as codeine and debrisoquine with this isozyme with poor metabolizers having 20 fold reduction in the ability to hydroxylate debrisoquine compared to extensive metabolizers

Question 8

What are the clinical implications of CYP2D6 genetic polymorphism?

Answer 8

There is an increased response to treatment in a small proportion of the population who may require a dose reduction as the poor metabolizers are more prone to adverse effects
There is an increase in bioavailability in poor metabolizers particularly if the drug experiences first pass metabolism
There is little or no response to codeine

Question 9

What is the impact of pharmacogenetics on CYP2C19?

Answer 9

There is a difference in the oxidation of mephenytoin and various proton pump inhibitors such as omeprazole

Question 10

What is the effect of pharmacogenetics on thiopurine methyltransferase?

Answer 10

This enzyme catalyzes the S-methyltransferase (inactivation) of thiopurine drugs such as mercaptopurine which is used as an immunosuppressant
Deficiency in this enzyme can result in fatal bone marrow suppression from high concentrations of this drug therefore deficient patients require 5-10% of the conventional dose

Question 11

What is the impact of pharmacogenetics on aldehyde dehydrogenase?

Answer 11

This enzyme is involved in the metabolism of alcohol as ethanol is first broken down into aldehydes which are broken down by ALDH2
Deficiency in this enzyme results in facial flushing, nausea, headaches, palpitations and tachycardia

Question 12

What is an example of pharmacogenetics effecting a pharmacodynamic reaction?

Answer 12

Glucose-6-dehydrogenase deficiency where there is hemolysis of red blood cells on exposure to oxidising drugs such as antibacterials, antimalarials and sulphones
This condition has a high prevalence in areas around the Mediterranean as it confers malarial protection

Question 13

How is malignant hyperthermia an example of pharmacogenetics?

Answer 13

This is the most common cause of death from anaesthetics in fit patients and is due to defect in the Ca myoplasm influx mechanism
This causes uncontrolled increase in cytoplasmic Ca, muscle rigidity resulting in a rise in temperature, cerebral edema, coma and death

Question 14

How can porphyria be impacted by pharmacogenetics?

Answer 14

Group of genetically distinct disorders involving porphyrin and haem biosynthesis
A common feature is an increase in activity of aminolaevulinic acid synthetase which is the rate limiting enzyme in haem synthesis
This results in overproduction of ALA causing neurological symptoms such as neurosis and psychosis
Drugs such as barbiturates, ethanol can induce porphyria attacks

Question 15

What is pharmacogenomics?

Answer 15

Genome wide approach to identifying the network of genes that govern an individuals response to drug therapy
Allowing the safety and efficacy of drug therapy through use of genetically guided, individualized treatments

Question 16

What are the potential opportunities from pharmacogenomics?

Answer 16

Development of personalized drugs and dosing regimens
Imporved diagnosis and earlier detection and monitoring of some diseases
Identification of new molecular targets for drug development
More efficient development and approval of new drugs

Question 17

What types of genotype testing is already present for use in drug therapy?

Answer 17

There is an FDA approved device (CYPChip)
Which identifies poor metabolizers for CYP2D6 and 2C19
There is also identification of appropriate patient populations such as HER2 positive patients for Herceptin treatment allowing more economical spending