Variation In Response To Drugs

19.2.07

What is pharmacogenetics?

We all vary in response to…
• Environmental chemicals.
• Nutrients.
• Drugs…

• ~15% smokers develop lung cancer.
• 20% of alcoholics will develop liver cirrhosis.
• With medicines:
-Patients may respond well.
-Patients may not respond at all.
-Patients may respond adversely.

Variability is an issue for:
1. Drug efficacy.
2. Drug safety.

"One dose fits all" - variable efficacy
• 6.5% (n=1225) admissions due to adverse drug reactions.
• Seven 800-bed hospitals occupied by adverse drug reaction patients.
• Cost £446m per annum.
• Death in 0.15% - equivalent to 5700 deaths per year.

Definitions
• Pharmacogenetics = Study of genetic basis for difference between individuals in response to drugs.
• Pharmacogenomics = Used in wider sense.

"The right medicine for the right patient"
• Rapid sequencing for specific gene polymorphisms.
• Knowledge of genetic sequences of target genes coding for enzymes, ion channels etc.

• 3 billion base pairs contain all information necessary to make a human being.
• Similarities and differences: 99.9% same, 0.1% different.

Potential benefits
1. Drug efficacy.
2. Drug safety.
3. Pharmacoeconomics.
4. Drug development.

Continuous variability
• Some patients: usual response.
• Some patients: less-than-usual response.
• Some patients: more-than-normal response.
• Continuous distribution.

Factors
• Genetic and environmental.
• Multiple genes.
• Race.
• Sex.
• Diet.
• Weight.
• Etc…

Discontinuous variability
• Discrete proportion (large/small).
• Respond differently from rest.
• Most often single gene.
• Genetic polymorphism.
• Mutation >1% of population.
• Simple inheritance.
• Two or more discontinuous forms.

Some examples
• Cytochrome p450 oxidation.
• Acetylation.
• Porphyrias.
• Abacavir hypersensitivity.

CYP 2DG
• Defective oxidation.
• First identified in debrisoquine.
• Extensive metabolisers (most).
• Poor metabolisers.
• Intermediate metabolisers.
• Ultra-rapid metaboliser.
• Variability in drug concentrations.
• Ethnic variability (6% in white populations).
• Metoprolol.
• Codeine.
• Haloperidol.
• Flecainide.
• Nortriptyline.
• CYP 2C9.
• Warfarin.
• Most sulphonylureas.

Acetylator status
• Important route of metabolism.
• Rapid/slow acetylators.
• Ethnic variability again:
-90% Japanese rapid acetylators.
-50% Western rapid acetylators.

Porphyrias
• Congenital/acquired disturbances in haem biosynthesis.
• Concomitant environmental/genetic factors.
• Acute = Neurovisceral presentation.
• Cutaneous = Photosensitive skin lesions.

Acute intermittent porphyria
• Autosomal dominant.
• Variable penetrance.
• PBG deaminase = Deficient enzyme.
• Enormous number of mutations found to be associated with acute intermittent porphyria - family specific.
• No accurate calculation of frequency.
• Acute intermittent porphyria most common acute porphyria.


Provocative factors
• Alcohol.
• Many drugs.
• Barbiturates.
• Anticonvulsants.
• Oestrogens (including OCP).
• Infection/surgery.
• Low-carbohydrate diets/fasting.

Abacavir hypersensitivity
• Nucleoside reverse transcriptase inhibitor used in HIV disease.
• 5% patients develop hypersensitivity reaction within 6 weeks.
• Rechallenge results in more serious reaction.
• HLA-B*5701 = Genetic predisposing factor (odds ratio of 29).

Thioprine methyl transferase (TPMT)
• Metabolises azathioprine and 6-mercaptopurine.
• Critical pathway in haemopoietic tissue.
• Associated with severe haemopoietic toxicity.