SCRIPT: adverse drug reactions Flashcards
Patient on several drugs develops muscle weakness and dark urine.
a) Possible diagnosis
b) Possible cause - give risk factors for this
c) Management
a) Rhabdomyolysis
b) Statin-related myotoxicity
- Higher dose, increased age, female, renal failure and concurrent treatment with amlodipine/ diltiazem* increase risk
*Max dose of simvastatin is 20 mg if also on diltiazem or amlodipine (usual max dose is 40 mg)
c) - IV access and bloods (raised CK, raised K+, deranged renal function)
- IV fluids
- Cardiac monitoring (?hyperkalaemia)
- Manage renal failure
- Manage hyperkalaemia (insulin + dex / Ca-gluc, etc.) and any other electrolyte abnormality
- Consider sodium bicarbonate to alkilinise the urine and reduce myoglobin precipitaton in the tubules
- Stop / treat any precipitants (eg. statin)
Define.
a) Adverse event
b) Adverse drug reaction (ADR)
a) - Any harmful or unpleasant event that the patient experiences while using a drug,
- … whether or not it is related to the drug
b) - “A harmful or unpleasant reaction,
- … that is SUSPECTED* to be due to a medicinal product,
- … that warrants prevention or specific treatment, or alteration of the dose, or withdrawal of the product”
- Only suspicion of causation is needed, due to either:
- a plausible pharmacological mechanism
- an absence of alternative explanation
- an appropriate temporal relationship
All ADRs are adverse events, but not all adverse events are ADRs
ADR types.
a) Type A (augmented)
b) Type B (bizarre)
c) Type C (chronic)
d) Type D (delayed)
e) Type E (end of treatment)
f) Type F (failure)
a) Type A (augmented) reactions are generally:
- Dose-related
- Common, predictable
- Related to the pharmacology
- Unlikely to be fatal
E.g. digoxin toxicity, constipation with opioids, intracerebral haemorrhage on warfarin
b) Type B (bizarre) reactions are generally:
- Not dose-related (within the therapeutic dose range)
- Uncommon, unpredictable
- Not related to the pharmacology
- Often fatal
- Discovered after licensing
E.g. penicillin hypersensitivity, malignant hyperthermia and hepatitis caused by anaesthetic agents, angio-oedema on ACE inhibitor
c) Type C (chronic)
- Related to Cumulative dose/ Chronic treatment
E.g. Adrenal suppression with long-term corticosteroids
d) Type D (delayed)
- Occurs/presents some time after use of the drug
- Usually dose-related
E.g. Carcinogenesis
e) Type E (end)
- Occurs after withdrawal of treatment
E.g. opiate withdrawal syndrome
f) Type F (failure)
- Often caused by drug interactions
- Common
E.g. Contraceptive failure in presence of enzyme inducer
Dose-dependent classification of ADRs (3)
- Hypersusceptibility reactions — occur at doses much lower than therapeutic
- Collateral effects — occur at therapeutic doses
- Toxic effects — occur at doses higher than those used therapeutically
Time-dependent ADRs.
a) Rapid reactions - eg. in vancomycin given too rapidly
b) Early reactions (abate with tolerance) - examples
c) First dose reactions - main example
d) Intermediate reactions
e) Late reactions
f) Delayed reactions
a) Red man syndrome
b) - Nitrate - headaches
- Metformin - diarrhoea, nausea
c) ACE inhibitors - first dose hypotension (hence need to be started at low-dose and titrated up carefully)
d) Some allergic reactions
e) - Chronic (type C) reactions - eg. adrenal suppression with long-term steroids
- Withdrawal (type E reactions) - eg. opiate withdrawal
f) - Carcinogenesis
Risk factors for adverse drug reactions.
- mnemonic: I GASPED
- Immunological reactions (e.g. allergies)
- Genetics (e.g. G6PD deficiency)
- Age (e.g. the elderly and children)
- Sex - F > M (e.g. drug causes of long QT, perhaps due to longer QT interval in women vs. men)
- Physiology (e.g. pregnancy)
- Exogenous (e.g. other drugs the patient may already be taking, foods, temperature)
- Disease states affecting the patient (e.g. renal dysfunction, liver disease, multiple comorbidities)
HLA-B*1502 allele is associated with SJS/TEN reactions on administration of which drugs?
Antiepileptics: carbamazepine, phenytoin, lamotrigine
- consider screening for allele in South East Asian patients before prescribing
G6PD deficiency - example common drug triggers
- Anti-malarials (e.g. primaquine and chloroquine)
- Nitrofurantoin
- Quinolone antimicrobials (e.g. ciprofloxacin)
- Rasburicase
- Sulphonamides (e.g. co-trimoxazole)
Porphyrias
a) Incidence
b) Triggers
c) Presentation
a) 1 in 75,000
- disorder of haem synthesis (usually inherited)
b) Several drugs
c) - acute abdomen
- neuropsychiatric
Explain.
a) Drug de-challenge
b) Drug re-challenge
- The symptoms improve after reducing or stopping treatment (de-challenge)
- The symptoms return on reintroducing treatment (re-challenge)
Yellowcard reporting scheme.
a) What adverse events should be reported? (established drugs vs. new/black triangle drugs)
b) How are ADRs distinguished from adverse events unrelated to the drug?
c) Who can report to the Yellowcard scheme?
d) Which medicines can be reported?
e) What 4 pieces of information are required to report?
f) Should poor practice by a colleague be reported?
a) - For established drugs - any serious reaction*, even if well-known (eg. angio-oedema on ACE inhibitors)
- If drug has an inverted black triangle, ANY suspected ADRs should be reported, no matter how mild (eg. cough in a NEWLY-licensed antihypertensive)
*Only need a suspicion, not confirmation, of ADR
A serious reaction is one that results in:
- Death (or may be life-threatening)
- Disability
- Hospitalisation
- Congenital defect
(Note: mild reactions like cough with ACE inhibitors or mild rash with penicillin do NOT need reporting as they are not serious ADRs)
b) Proportional reporting ratios:
- Comparing incidence of a particular adverse event in people on one drug compared to all other drugs in the database
- eg. Proportional reporting of ‘cough’ was far higher for patients on ACE inhibitors than all other drugs - this made it likely cough was an ADR related to ACE inhibitors
c) - All healthcare professionals
- Patients and carers
d) - Both licensed and unlicensed
- Prescribed, OTC, herbal, vaccines, devices, counterfeit drugs, e-cigarettes, etc. (basically anything)
e) - An identified patient (e.g. hospital number)*
- A suspected reaction
- A suspected drug
- A reporter identifier
(additional info such as concomitant drugs or relevant PMHx may also be provided)
*Do not need patient’s consent as it is anonymous
f) No, as it should be a system of openness and learning, rather than apportioning blame
- This gives confidence in reporters that their reports will not be used against them in the future
Common and rare ADRs.
a) Why are rare ADRs often not picked up in Phase III trials?
b) What is the ‘rule of 3’ ?
c) What is the natural frequency for:
- ‘very common’
- ‘common’
- ‘uncommon’
- ‘rare’
- ‘very rare’
a) - When a drug is initially licensed after phase III trials, it has probably been taken by around 3000 patients.
- This means that when a medicine is licensed after 3000 patients have taken it, we may have observed only adverse drug reactions with a frequency of 1 in 1000 or less
b) A statistical rule known as the “rule of 3” says that if we see no events in N patients*, the actual risk of an event happening is probably somewhere between 0 (it never happens) and 3/N.
* where multiple studies have been done, sum the total number of patients to get N
c) - Very common: > 1 in 10 (> 10%)
- Common: from 1 in 100 to 1 in 10 (1 - 10%)
- Uncommon: from 1 in 1000 to 1 in 100 (0.1 - 1%)
- Rare: from 1 in 10 000 to 1 in 1000 (0.01 - 0.1%)
- Very rare: < 1 in 10 000 (< 0.01%)
Interactive Drug Analysis Profile (iDAP)
a) what is it?
b) caveats
a) Summarise the reports received via the Yellow Card scheme. They list all reported reactions
b) - They only contain reported reactions (95% of ADRs are not reported)
- There is no data on the number of prescriptions issued (so incidence cannot be calculated)
- They are ‘suspected reactions’, so no causality can be implied
- Comparison of different drugs is not possible, due to biases in reporting rates
ADR sources
- BNF - listed by frequency
- MHRA - publish a ‘Drug Safety Update’
- Electronic medicines compendium
