Antiepileptic Drugs in Critically Ill Patients

Salia Farrokh; Pouya Tahsili-Fahadan; Eva K. Ritzl; John J. Lewin III; Marek A. Mirski

Disclosures

Crit Care. 2018;22(153) 

In This Article

Pharmacodynamics and Pharmacokinetics of AEDs

Pharmacodynamics

AEDs depress abnormal neuronal firing by various mechanisms of action including altering ion channel activity, enhancing gamma-aminobutyric acid (GABA)-mediated inhibition, or reducing glutamate-mediated excitation. While some AEDs have a single mechanism of action, others have multiple mechanisms of action and, in some, the exact mechanism of action is not yet known (Table 1).

When using multiple AEDs, it is reasonable to select medications with different mechanisms of action.

Pharmacokinetics (absorption, distribution, metabolism, excretion). Alterations in normal physiology and the physical properties of medications can affect the rate and extent of enteral absorption of medications in the ICU, leading to a need for parenteral administration. Deranged gastrointestinal absorption may be expected in circumstances of decreased blood flow, intestinal atrophy, dysmotility, and interactions with enteral nutrition. Pharmacokinetic parameters of selected AEDs, including their oral bioavailability, are summarized in Table 2.

Changes in serum pH as well as both respiratory and renal failure affect the ionized state of many drugs, affecting their penetration across lipophilic-based membranes such as the blood-brain barrier. Bioavailability of active drugs is also affected by alterations in volume of distribution for hydrophilic medications, while hypoalbuminemia increases the unbound (free) fraction of highly albumin-bound medications.

Although drugs are commonly metabolized to less active compounds, prodrugs such as oxcarbazepine and fosphenytoin must be metabolized into their active forms carbamazepine and phenytoin, respectively. Drug metabolism generally occurs in two phases. Phase I involves nonsynthetic reactions to form a modified group. A cytochrome P450 (CYP450) enzyme is frequently involved in such oxidative reactions. Phase II involves synthetic reactions to conjugate the metabolite with an endogenous substance. Metabolism for most anticonvulsants occurs primarily in the liver and is dependent on hepatic blood flow, enzyme activity, and protein binding. Although critical illness often inhibits the CYP450 isoenzymes, drug metabolism may be enhanced over several days as in the cases of pentobarbital and phenytoin, resulting in potential subtherapeutic concentrations.[4–6] Induced hypothermia will also reduce the systemic clearance of many medications mediated by CYP450 (such as phenytoin or propofol), between 7 and 22% for every degree of Celsius below 37.[7]

Regardless of the route of administration, renal elimination of parent drugs or metabolites is the primary excretory pathway for most drugs. For patients on renal replacement therapy (RRT), the type of dialysis that is performed and the frequency/duration should also be considered (see section 8, special therapeutic considerations).

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