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Advanced Neurology Seizures and CKD

Table 3. Properties and metabolism of phenytoin and fosphenytoin
AED Primary Protein Metabolism % of Interactions Potential eGFR Dialysis‑
(reference mechanism binding urinary with other nephrotoxicities (mL/min/ related dose
range in mg/L) of action excretion AEDs 1.73 m )‑ adjustments
2
related dose
adjustments
Phenytoin [131-135] Blockade of Approximately Hepatic <5% Reduces Interstitial nephritis US: Loading US: Loading
(10–20) voltage-gated 90%; binding metabolism carbamazepine, with antiepileptic dose not not needed,
sodium decreases in through the clobazam, hypersensitivity needed, no dosing
channels, uremia CYP450 ethosuximide, syndrome no dosing adjustment
reduction of system lamotrigine, Exacerbate anemia adjustment needed
glutamate, felbamate, and Vitamin D needed UK: Loading
enhancement lacosamide, deficiency for CKD UK: Loading not needed,
of GABA levetiracetam, patients dose not no dosing
release oxcarbazepine, needed, adjustment
primidone, no dosing needed
pregabalin, adjustment
topiramate, needed
valproic acid and
zonisamide levels
Increases
phenobarbital
levels
Fosphenytoin [136] Blockade of Approximately Hepatic <5% Reduces Interstitial nephritis US: Loading US: Loading
(1.5–2.5) voltage-gated 90%; binding metabolism carbamazepine, with antiepileptic dose not not needed,
sodium decreases in through the clobazam, hypersensitivity needed, no dosing
channels, uremia CYP450 ethosuximide, syndrome no dosing adjustment
reduction of system lamotrigine, Exacerbate anemia adjustment needed
glutamate, felbamate, and Vitamin D needed UK: Loading
enhancement lacosamide, deficiency for CKD UK: Loading not needed,
of GABA levetiracetam, patients dose not no dosing
release oxcarbazepine, Smaller risks of needed, adjustment
Water-soluble primidone, phlebitis and no dosing needed
prodrug of pregabalin, cardiotoxicity adjustment
phenytoin topiramate, compared to needed
valproic acid and phenytoin,
zonisamide levels particularly
Increases important for those
phenobarbital with renovascular
levels disease
AED: Antiepileptic drug; CKD: Chronic kidney disease; CYP450: Cytochrome P450; eGFR: estimated glomerular filtration rate;
GABA: Gamma-aminobutyric acid; UK: United Kingdom; US: United States

typically binds to serum albumin and only 10% is free of treatment of status epilepticus [135] . Fosphenytoin is a
and biologically active in normal states [131] . In CKD, the popular alternative to phenytoin in acute settings such
unbound phenytoin fraction may be increased to 30%, as this. It is a water-soluble prodrug of phenytoin, which
but without an absolute increase in free level [131] . As total carries a lower risk of phlebitis and cardiotoxicity [136] .
phenytoin levels are likely to be lower than expected, 4.2. Phenobarbital and primidone
clinicians in the US are advised to use the free level of
phenytoin as a guide for AED dosing in CKD patients [9,131] . Table 4 presents a summary of phenobarbital and
The updated Renal Drug Handbook (RDH), a widely used primidone [9,130,131,135,137-141] . Phenobarbital is another
reference for prescribers when managing patients with AED which, in the past, has been frequently prescribed
kidney impairment in the UK, suggests that phenytoin to treat focal and generalized seizures. Newer AEDs
dosing in patients with eGFR impairment should not differ have gradually replaced phenobarbital, because of its
from dosing in normal kidney function [130] . significant adverse effect profile including sedation and
risk of inducing withdrawal seizures. Phenobarbital acts
Despite its declining use for focal and generalized through positive allosteric regulation of the barbiturate-
seizures, phenytoin-based AEDs remain one of the mainstays binding site in the GABA-A receptor. It is metabolized

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