Pharmacogenetics Flashcards
What is the definition of Pharmacogenetics?
- Refers to the study of inherited differences in drug metabolism and response
- Single gene/phenotype
What does Pharmacogenetics aim to do?
Links differences in gene structure (polymorphisms) to drug metabolism and response. Genetic Variation (genotype) has interaction with drug metabolism and response (phenotype)
What are pharmacogenetic consequences on pharmacokinetics?
Decreased first-pass effect
- Greater bioavailability
- Higher peak concentration
Reduced parent drug elimination
- Longer half-life
- More/fewer active metabolites
Altered concentration-effect relationship between poor and good metabolisers
How can Pharmacogenetics be applied?
- Drug development: More targeted, more powerful drugs
- Individualisation of therapy: The right drug and the right dose for every patient
- Predicting ADRs (& reducing mortality)
- Defining susceptibility
- Identifying potential addiction
- Reducing cost of health care
- Don’t treat non-responders (stratification)
- Don’t treat those most susceptible to toxicity (stratification)
- Adjust dose to maximise efficacy while avoiding toxicity
What are clinical applications of Pharmacogenetics?
- Anti-coagulation: Warfarin
- Psychiatry: Tricyclic anti-depressants, Atomoxetine
- Oncology: Thiopurines (TPMT), 5-fluorouracil, Herceptin (Her-2/neu), Tamoxifen (CYP2D6/ABCC2), Cetuximab (KRAS)
- Cardiovascular: Statins, Clopidogrel
- Pain control: Codeine, methadone
- Epilepsy: Phenytoin, Carbamazepine
- Infection: Abacavir
What s the effect of Pharmacognetics on Cholinesterase?
Enzyme required to breakdown short acting muscle relaxant suxamethonium or mivacurium
Genetic variants result in prolonged paralysis requiring ventilation support
Determine patient’s phenotype, Family studies
- UU phenotype is usual/normal activity
- UA and UF may have increased risk
- FF, FS and AF intermediate sensitivity
What are feature of Thiopurine Drugs?
- Used in the routine treatment of inflammatory and autoimmune diseases
- Highly efficacious but ADRs are common
- TPMT testing used routinely to tailor individual drug dose
- Steroid sparing reagent
What are the TPMT genetics?
- TPMT coded by 27 kb gene, 10 exons, located on 6p22.3
- Wild-type is TPMT*1
- Very low activity associated with ~41 variants, most common = TPMT*3 (80-90%)
How is TPMT tested?
Phenotype testing is first-line test
Genotype testing appropriate in some patient groups
- Children with acute lymphocytic leukaemia
Recommended in NICE guidelines for Crohn’s disease, Recommended in BNF
TPMT phenotype/genotype can prospectively identify
- Deficient patients at risk of life-threatening toxicity
- Heterozygotes who will respond well to low-dose aza therapy
- Patients with high TPMT activity who will need high doses from the start
What is the epidemiolgy of Thiopurine drugs?
In caucasians:
- 1 in 300 - Very low TPMT activity
- 6 – 11% - Intermediate TPMT activity
- 2% - Ultra high TPMT activity
Very low TPMT activity can lead to potentially fatal myelosuppression when treated with standard drug doses
Describe how dosing of Azathioprine and 6-MP is affected by Pharmacognenetics?
Phenotype
AZA Dosing
6-MP Dosing
Normal/High Activity
Start with normal starting dose (2-3 mg/kg/d) then disease specific guidelines
Start with normal starting dose (1.5 mg/kg/d)
Intermediate Activity
Start at 30-80% of target dose (e.g. 1-1.5 mg/kg/d) and titrate to tolerance
Start at 30 – 80% of target dose (e.g. 0.75 mg/kg/d)
Deficient Activity
Consider Alternative agents. If using AZA drastically reduce dose to 10% of target and only give thrice weekly
For non-malignant conditions consider alternative non-thiopurine immunosuppressant therapy
What are enzymes of Drug metabolism?
Phase 1 (oxidative) – SER
- CYP 1A2, CYP2B, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4,NADPH-quinone oxidoreductase
Phase 2 (conjugative) - cytosol
- Glutathione S-transferase, N-acetyltransferase, UDP-glucuronosyltransferase, Sulphotransferases
What are cytochrome P450 enzymes?
- Superfamily of enzymes that catalyze the metabolism of drugs and other substances
- Endogenous substrates of CYPs include eicosanoids, estradiol, arachidonic acids, cholesterol, vitamin D and neurotransmitters
- Genetic polymorphisms of CYPs may affect the enzyme catalytic activity
- Association with both disease states and ADRs
- 57 CYP genes and 58 pseudogenes arranged into 18 families and 43 subfamilies in man
What are types of Cytochrome P450 enzymes?
CYP2D6
- Debrisoquine, Tricyclics, Antipsychotics, SSRI’s, Anti-arrhythmics, Anti-hypertensives, Morphine derivs
CYP2C19
- Sedatives, Barbiturates, Tricyclics
CYP3A4
- Tricyclics, Antipsychotics, SSRI’s, Sedatives
CYP1A2
- Tricyclics, Antipsychotics, SSRI’s, Sedatives
CYP2C9
- Antiepileptics, Anticoagulants
What are features ofWarfarin?
- Narrow therapeutic window requires careful monitoring and strict compliance
- Multiple clinically important drug interactions and erratic safety profile
- 10-fold variability around dose, target INR and side-effects
- Polymorphisms account for 30-50% of the variability in dosing
- Very commonly prescribed for prophylaxis and treatment of thromboembolic disorders, atrial fibrillation and systemic embolism after MI