Idiosyncratic drug reactions

Today we discussed many types of drug reactions. Some important points:

These are immune-mediated, which is distinct from drug toxicity, which everyone will get at high enough level. Idiosyncratic drug reactions (IDRs) are not anaphylactic reactions

IDRs may be single-organ (e.g. hepatitis) or multi-system ("drug hypersensitivity syndrome")

1) Drug hypersensitivity syndrome
Characterized by fever, rash (with or without mucosal involvement), and internal organ involvement (failure). Occurs with incidence of 1 in 1000 to 10000 with these culprit drugs: anticonvulsants (almost all of them), sulfonamides, allopurinol, and dapsone. Timeframe is 2-8 wks after initiation. Sometimes also called "DRESS" or drug reaction with eosinophilia and systemic symptoms)
Most serious:
Stevens-Johnson's, Toxic Epidermal Necrolysis: desquamating skin and mucosal involvement; organ failure. Distinguished by surface area involved. Less than 30% BSA = SJS. More than 50% = TEN; overlap = between. Tx: supportive (inc. burn unit), possible role for steroids, IVIG.

2) Serum sickness-like reaction
Causes fever, arthritis, lymphadenopathy, rash. No internal organ involvement. Timeframe is 7-14d after initiation. Major culprits are cefaclor, minocycline, and bupropion.

3) Drug-induced lupus
Clinically, mainly arthritis, serositis, wt loss. 95% have anti-histone AB, negative anti dsDNA, normal complements.
Major culprits are procainamide, dilantin, INH, hydralazine, methyldopa, quinidine, chlorpromazine, minocycline.
Timeframe may be up to 1-2 years after initiation of therapy

General approach to treatment is to D/C drug, supportive therapy, steroids as dictated by severity.

Some specific drug-rash combinations:
Urticaria: codeine, ASA
Photosensitivity: hydroxychloroquine, chlorpromazine
Psoriasis: lithium, B-blockers
Serum sickness-like reaction: Cefaclor
Fixed drug eruption: Anticonvulsants, sulfonamides

Dilantin kinetics:

Remember that phenytoin exhibits zero-order kinetics after a certain level. This means that only a fixed amount (not proportion) of drug is metabolized after a certain point (which is unknown for a given patient). If this threshold is crossed, a very small increase in dose can cause a big increase in level and toxicity. Increase doses slowly and by small increments (e.g. 25-50mg/d at a time, checking levels).

Links:
Click here for a good overview of idiosyncratic drug reactions
Click here for a NEJM case conference which discusses severe drug reactions
Click here for study of anticonvulsant teratogenicity
Click here for a summary of phenytoin kinetics