Pharmacovigilance + Pharmacogenetics Flashcards
Define pharmacovigilance
Indentification, assessment and prevention of adverse drug reactions while optimising benefits
What is the most common clinical adverse event?
Drug reaction
How many cases of adverse drug reactions would be enough to stop use of drug today?
10 cases internationally would be enough
Adequate testing, government regulation, reporting systems, most medications cross the placenta (avoiding use in pregnancy)
What is thalidomide used for currently?
- Leukaemia
- Elder patients
Balance between risks + harm
Give some examples of adverse drug reactions that are considered serious
- Fatal, life threatening
- Prolonged hospitalisation
- Long term disability
- Congenital abnormalities
Define ‘adverse drug reactions’ and give the 2 main types
- ADR’s = response attributable to therapeutic when given within normal therapeutic range (happens when drug given within therapeutic range)
Unintended
Noxious (causing harm)
Distinguish between Type A (augmented) and Type B (bizarre) adverse drug reactions
Type A (augmented):
- Dose related
- Predictable
- Common
- Reversible (on stopping/reducing dose)
- Dose adjustment
Type B (bizarre):
- Not dose related
- Unpredictable
- Uncommon
- Serious/irreversible
- Need to stop treatment
Give some examples of Type A and Type B adverse drug reactions
Type A:
- Bleeding; warfarin
- Hypoglycaemia; diabetes medication
Type B:
- Anaphylaxis; penicillin
- Agranulocytosis; clozapine (schizophrenia)
What is agranulocytosis?
Acute condition involving a severe and dangerous leukopenia (lowered white blood cell count), most commonly of neutrophils, and thus causing a neutropenia in the circulating blood.
What is a risk of the COCP?
Which generation of oral contraceptives are used currently?
VTE
2nd generation oral contraceptives (safer than 3rd generation)
Define pharmacogenetics
How individual gene may affect response to drug or drug response on body
How phenotypic differences affect therapeutics
Population vs individual
Consideration of pharmacogenetics with pharmacovigilance to reduce preventable adverse drug reactions
Person to person variability explained; eg drug reactions, response to therapeutics
Give some examples of drugs that are affected by pharmacogenetics
- Statins
- B-blockers
Give 2 examples where knowledge of pharmacogenetics has improved patient care
- Abacavir + hypersensitivity; in some patients treated for HIV
- Split antigen reaction
- Screening for split antigen resulted in reduction in reactivity
- Cutaneous reaction; Stevens-Johnson syndrome/severe toxic epidermal necrolysis); in patients taking carbamazepine (anti-epileptic)
- Reaction to another split antigen; predominantly in asian populations
- Screening, identification + avoidance in certain patient groups
Explain the involvement of pharmacogenetics in primary step 1 antihypertensive treatment
Response to medications dictated by RAAS activity
Renin lower in African/Carribean populations so ACEi/ARB not primary choice for reducing BP (use CCB’s instead 1st line)
Lower response to ACEi/ARB compared to white cuacasians
CCB’s work in both populations
Is angioedema more prevalent in African Carribean or young white caucasian populations?
African/Carribean
GIve some exmaples of how genetic polymorphisms can affect PK and PD
- Chnages in PK
- Receptor structure
- Enzyme activity
- Immune response
How can a point mutation of ALDH2 coding for aldehyde dehydrogenase in East Asian and Northern European populations affect their alcohol handling?
Aldehyde dehydrogenase deficiency
Single amino acid change
Accumulation of acetaldehyde; red flushing
Reduced acetate production
Give 2 other examples where genetic polymorphisms influence prescribing
- Metabolic CYP 450 enzymes
- Warfarin + INR: metabolised by different CYP’s thus no standard dose warfarin (variability of handling between individuals)
The CYP 2D6 isoform is responsible for metabolising what kinds of drugs?
- 25% of drugs metabolised by CYP 2D6
- Antidepressants
- Antipsychotics
- B-blockers
- Opioid analgesics
Great variability in rate of drug metabolism by CYP 2D6
6% of the Caucasian population carry 2 null alleles at the CYP 2D6 gene. How can this affect drug metabolism?
- No ability to metabolise drugs usually metabolised by CYP 2D6 isoform
- Decreased first pass metabolism; B-blockers (metoprolol) + bradycardia due to reduced metabolism thus accumulation of metoprolol
How can PG be applied to therapeutics?
- Personalised drug therapy
- Screening for gene variants/polymorphism
- Genetic sequences of target receptors/enzymes
- To predict ADR’s: statins and muscle damage/rhabdomyolysis, myalgia - monitoring outcomes + adherence
- Vaccines for allergies; prophylactic vaccine failure + ADRS, following genetic polymorphisms and their effect on innate + adaptive immune response
Explain the effects of CYP 2D6 mutations on codeine metabolism
Codeine is a pro-drug, which is metabolised into its active form morphine, by CYP 2D6
