4 - Pharmacovigilence and Pharmacogenetics Flashcards
What is pharmacovigilance?
- Pharmacovigilance is the process of identifying and then responding to safety issues about marketed drugs
- It involves surveying the safety of drugs and developing strategies to minimise the risk and optimise benefits
- Most common clinical adverse event is a drug reaction
What are the aims of pharmacovigilance?
- Identify previously unrecognised drug safety hazards
- Elucidate factors predisposing to toxicity
- Obtain evidence of safety so that a new drug’s uses may be widened
- ‘False positive’ adverse drug reaction
What is an adverse drug reaction and what are some serious ADR’s?
A response that occurs in a patient to a drug, even though it has been given in the therapeutic range. Can have type A and B
What are type A and type B ADRs?
Type A: usually a consequence of the drug’s primary pharmacological effect (e.g. bleeding when using the anticoagulant warfarin) or a low therapeutic index of the drug
- Exaggerated pharmacological respons, predictable, dose dependent, common, high morbidity, low mortality
Type B: bizarre or novel responses that cannot be predicted from the known pharmacology of a drug
- Not expected from known pharmacology, unpredictable, independent of dose, rare, high mortality
What are some examples of type A and type B ADRs?
Type A:
- Bleeding with warfarin
- Hypoglycaemia with metformin
Type B:
- Anaphylaxis with penicillin
- Agranulocytosis with clozapine
What are the limitations of pre-marketing clinical studies in identifying drug safety issues?
- Small number of patients treated
- Frequent exclusion of patients who might be at greater risk of ADRs
- Selected following precise diagnoses
- Limited duration of treatment
- Restricted doses
STUDY POPULATION NOT REPRESENTATIVE OF WHOLE
How can we identify ADRs?
- Spontaneous reporting
- Cohort studies
- Case control studies
Describe the three steps involved in the spontaneous reporting of ADRs
⇒ Recognition of a possible ADR
⇒ Establishing possible causal relationship
⇒ Reporting observations
What are the advantages of spontaneous reporting?
- Operates as soon as drug is marketed
- Involves all doctors worldwide
- Overlooks all drugs so simple
- Inexpensive
- Continues indefinitely
- Accessible by all health care professionals and patients and carers
What are the limitations of spontaneous reporting?
- Delays in reporting
- Poor quality data
- Misleading reports
- No control group
- Gross under-reporting of possible ADRs
- Effect of publicity
- Duplication
What are the four mechanisms of action for an ADR?
What is the process in the UK of spontaneous reporting of ADRs?
Yellow Card Scheme
Report all suspected ADRs even minor ones
What are the factors affecting the under-reporting of ADRs?
What is pharmacogenetics?
- Pharmacogenetics is the science of understanding how different individual genotypes relate to different drugs
- It enables physicians to know which drugs will therefore be safe and effective for an individual patient
What is pharmacogenomics?
Pharmacogenomics is pharmacogenetics applied to an entire genome
What are the potential risk factors for drug inefficacy or toxicity?
- Drug-drug interactions
- Age
- Renal and liver function
- Concurrent illness
- Genetic variation have different ADRs and efficacy e.g statins and beta blockers
- Lifestyle variables e.g. smoking and alcohol consumption
What are some examples of split antigen hypersensitivity reactions to drugs that show genetic variation?
- Abacavir for HIV treatment caused hypersensitivity in 8% of patients treated. Now screen for split antigen first
- Carbamazepine in Asian patients was causing TEN and Stevens-Johnson syndrome
What is the variation in genetics and the Renin-Angiotensin System?
An individual’s response to ACEi / ARB is dependent on their own RAS activity:
- Young Caucasians have higher RAS activity – ACEi / ARB treatment will lower BP more effectively
- Older and Afro-caribbean patients have lower RASS activity (renin) and angiooedema with ACEi– first line therapy is thiazide diuretics and CCBS
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Compare and contrast Type A and B adverse drug reactions based on the following characteristics:
- Dose dependency
- Predictable
- Frequency
- Severity
- Host factors
- Clinical burden
- %ADRs
Where might genetic polymorphisms affect the pharmacodynamics of a drug ?
- Receptors
- Ion channels
- Enzymes (e.g aldehyde dehydrogenase mutated in east asian and northern european and CYPs)
- Immune systems
What is CYP2D6 responsible for and why is it a common CYP involved in pharmacogenetics?
- Metabolises 25% of drugs including antidepressants, antipsychotics, Beta blockers, opioid analgesics
- High genetic variability
- 6% of Caucasians carry two null alleles for this so can’t metabolise drugs, e.g metoprolol and therefore increased amount in blood so bradycardia. Can also cause rerouting of metabolism e.g paracetamol
Absent/reduced CYP 2D6 activity can lead to ADRs by three mechanisms. What are these mechanisms?
- Decreased first pass metabolism and drug elimination e.g. metoprolol and bradycardia
- Accumulation of drug as a result of reduced metabolism e.g. perhexilene and hepatotoxicity
- Re-routing of metabolism e.g. paracetamol and methaemoglobinaemia
How can we use our knowledge about a patients pharmacogenetics?
- Personalise drug therapy by rapid screening of gene variants
- Can target somatic changes in cancer
- Can predicts ADRs, e.g statins and rhabdomyolysis
