Phenytoin (Dilantin) toxicity

Yesterday we discussed dilantin toxicity. Dilantin is an anticonvulsant that can cause a number of drug reactions of different types:

Pharmacology:
Phenytoin binds to and inhibits sodium channels in neurons and in cardiac tissue

It is cleared by the liver via the CYP450 system.

An important clinical point about phenytoin pharmacokinetics is that it exhibits "zero-order" kinetics. 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).

There are many drugs that can increase and decrease phenytoin levels via CYP450 interections. Click here for a complete list.

Phenytoin toxicity ("poisoning")
The earliest sign is nystagmus (usually horizontal) and unsteady gait. More severe toxicity causes slurred speech, lethargy, confusion, and eventually coma.
It can rarely cause cardiac arrhythmias (mainly bradycardia, AV blocks, sinus arrest)
There is no specific antidote for phenytoin; treatment is supportive.

Chronic effects/toxicity
Neurological involvement as above, gingival hyperplasia

Idiosyncratic reactions
These are non-dose related effects.

Drug hypersenitivity syndrome
Characterized by fever, rash (with or without mucosal involvement), and internal organ involvement. Sometimes also called "DRESS" or "drug reaction with eosinophilia and systemic symptoms". Dilantin is a rare, but very well described culprit, along with sulfonamides, allopurinol, dapsone, and many others. Timeframe is 2-8 wks after initiation.

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. Dilantin is a well described culprit. Tx: supportive (inc. burn unit), possible role for steroids, IVIG.

Drug-induced lupus
Clinically, mainly arthritis, serositis, wt loss. 95% have anti-histone AB, negative anti dsDNA, normal complements.

Others
Isolated hepatitis
Leukopenia, thromboctyopenia, agranulocytosis

Lymphadenopathy
IV preparation can cause hypotension during infusion (treatment is fluid)

Links
Click here for a good overview of idiosyncratic drug reactions

Click here for a summary of phenytoin kinetics

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