Antiepileptic drugs in critically ill patients

Table 5 Interaction of selected antiepileptic drugs with commonly used medications in the intensive care unit [113, 115, 117–124]

Antiepileptic drug	Therapeutic group	Selected examples
Phenytoin, phenobarbital, carbamazepine	Psychotropic agents	↓ Amitriptyline, nortriptyline, imipramine, bupropion, paroxetine, citalopram, Haloperidol, chlorpromazine, olanzapine, risperidone, quetiapine, ziprasidone
Valproic acid		↑ Amitriptyline, nortriptyline, paroxetine
Topiramate		↑ Haloperidol
Phenytoin, phenobarbital, carbamazepine	Antimicrobials	↓ Doxycycline, metronidazole, itraconazole, retrovirals
Valproic acid	Antimicrobials	↑ Zidovudine
Phenytoin	Cardiovascular agents	↓ Amiodarone, nimodipine, diltiazem, verapamil, ticagrelor, atorvastatin, dabigatran, apixaban, rivaroxaban (↑ warfarin effects with phenytoin load, ↓ warfarin effects with maintenance dose of phenytoin)^a
Lacosamide		Diltiazem, verapamil (risk of atrioventricular block/bradycardia), ↓ warfarin
Carbamazepine		↓ Nimodipine, diltiazem, verapamil, ticagrelor, atorvastatin, warfarin, dabigatran, apixaban and rivaroxaban
Phenobarbital		↓ Nimodipine, atorvastatin
Valproic acid		↑ Nimodipine, warfarin
Phenytoin, phenobarbital, carbamazepine	Analgesics	↓ Fentanyl, methadone
Phenytoin, phenobarbital, carbamazepine	Immunosuppressant	↓ Cyclosporine, sirolimus, tacrolimus, corticosteroids

↑ and ↓ indicate increased and decreased levels and/or effects, respectively
^aThe interaction between phenytoin and warfarin is complicated and unpredictable. Close monitoring of the international normalized ratio (INR) as well as serum phenytoin levels are critical if this combination is clinically necessary. Upon initiation of phenytoin, there may be transient increases in the INR as a result of protein binding displacement of warfarin by phenytoin, and enhanced anticoagulant effect. This may be followed by a reduction in anticoagulant activity as result of phenytoin’s induction of warfarin metabolism [125, 126]

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