adverse drug reactions

Question 1

define adverse drug reaction

Answer 1

Any response to a drug which is noxious, unintended and occurs at doses used in man for prophylaxis, diagnosis or treatment
An appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product

Question 2

frequency of ADRs

Answer 2

• 6.5% of all hospital admissions occur as a result of an ADR, 10-20% of inpatients suffer ADR, 0.25-3% of all hospital deaths (5000-12000 a year), 2-30% of outpatients treated in GP suffer from an ADR at any time
  Cost of £1.25bln/annum
• Non-steroidal anti-inflammatory drugs, anticoagulants and antiplatelets cause over 1/3 of admissions due to avoidable ADRs
  Errors were more likely in older people, or in the presence of co-morbidity and polypharmacy

Question 3

classification of onset

Answer 3

acute - within 1hr (bronchoconstriction)
sub-acute - 1-24hrs (rash, serum sickness)
latent - >2days (eczematour eruptions)

Question 4

classification of severity

Answer 4

mild - bothersome but requires no change in therapy e.g. metallic taste with metrondiazole
moderate - requires change in therapy, additional treatment, hospitalisation e.g. amphotericin induced hypokalaemia
severe - disabling or life threatening or death e.g. kidney failure –> dialysis

Question 5

classification of ADRs

Answer 5

Type A - augmented
Type B - bizarre
Type C - chronic 
Type D - delayed
Type E - end of treatment 
type F - failure of treatment

Question 6

type A

Answer 6

normal but augmented response to the pharmacological action of a drug
dose related and predictable
easily reversible on reducing the dose or stopping the drug
most common and not usually life threatening
two types: augmentation of the 1y effect, 2y pharmacology of the drug unrelated to the therapeutic effect

e.g. dry mouth with tricyclic antidepressants

Question 7

reasons for type a ADR

Answer 7

too high a dose
pharmaceutical variation
pharmacokinetic variation (ADME) - pharmacogenetics (10% of pop are slow metabolisers)
liver disease
renal disease, reduced GFR
pharmacodynamic variation - natural variability in pharmacodynamic response

Question 8

type B

Answer 8

bizarre effects, idiosyncratic and unpredictable
rare, cause serious illness/death
unrelated to the dose, no readily reversed
generally immune modulated reaction and more common with macromolecules
presence of particular HLA increases risk of type B reaction

Question 9

mechanisms of type b

Answer 9

idiosyncratic: inherit abnormal response, genetic abnormality
drug allergy/hypersensitivity: immunological, no relation to pharmacological action of the drug, delay between exposure and ADR (due to antigen-antibody interaction)
pharmacogenetic - differences in response to drugs may be considered as genetic or immunological (enzyme and receptor abnormality)

Question 10

type C

Answer 10

• related to the duration of the treatment and dose (doesnt occur with single dose)
  semi-predictable - but cant predict in who it will occur
  can occur years after taking the drug
  e.g. latrogenic cushing’s disease

Question 11

type D

Answer 11

occur a long time after treatment
teratogenesis (abnormal congenital malformation in the foetus following in-utero exposure during 1st trimester)
foetogenesis - toxicity towards the foetus when taken during 3rd trimester
carcinogenesis - children of treated patients (teratogenesis, carcinogens in patients years after treatment has stopped)
2nd cancers in those treated with alkylating agents or immunosuppressive agents
cranio-facial malformations in children whose mothers were treated with isotretinoin

Question 12

type E

Answer 12

adverse effects occur when a drug treatment is stopped especially suddenly following long term use
rebound phenomena: occur when a drug is suddenly withdrawn
advice is to slowly reduce the dose over a period of wks/mths to prevent ADRs
e.g. alcohol withdrawal, addisonian crisis when long term steroids are suddenly stopped

Question 13

type F

Answer 13

failure of therapy 
common 
dose related - usually too small a dose
effect on patient depends on severity of the disease
frequently cause by drug interactions

Question 14

predisposing factors

Answer 14

multiple drug therapy - incidence of ADRs increases with number of medicaments
inter-current disease - renal and hepatic impairment, drug levels in the blood increase
race and genetic polymorphisms
age
sex - more common in women

Question 15

diagnosis

Answer 15

1. differential diagnosis
2. medication history
3. assess time of onset and dose relationship
4. lab investigations(plasma concs, allergy tests)

Question 16

who is most at risk

Answer 16

extremes of age 
multiple medications and co-morbid conditions
inappropriate medication prescribing 
end-organ dysfunction
altered physiology 
prior history of ADRs
extent and duration of exposure
genetic predisposition

Question 17

drugs commonly involved

Answer 17

antineoplastic
cardiovascular drugs
CNS drugs

also: antibiotics, anticoagulants, hypoglycaemics, antihypertensives, NSAID, diagnostic agents, opiates

Question 18

body systems commonly involved

Answer 18

haematologic 
CNS
dermatologic 
metabolic
cardiovascular
GI
renal/genitourinary 
respiratory 
sensory

Question 19

reporting ADRs

Answer 19

• Yellow cards
• On line reports for all medicines including vaccines, blood factors and immunoglobulins, herbal medicines and homeopathic remedies and all medical devices
• Report all significant or unusual adverse drug reactions as well as unanticipated or novel events that are suspected to be drug related
  All ADRs affecting black triangle drugs/products