Page 47 - AN-2-2

Advanced Neurology mainly in the liver by the CYP450 system to inactive
Seizures and CKD

with kidney impairment receiving phenobarbital, the
Dialysis‑related dose adjustments US: 30% supplemental dosing needed post-HD UK: No dose adjustments needed US: Evidence not well-established. No dosing supplementation post-HD likely needed UK: No dosing supplementation post-HD likely needed. To titrate regular dose slowly from a low dose metabolites [137] . It is a CYP450 system inducer. For patients
RDH recommends a 25–50% dose reduction
. US-based
[130]
practice recommendations also suggest dose reductions
for patients with kidney impairment, given approximately
55% of the phenobarbital dose is protein-bound and 25%
of the dose is excreted in urine
. US-based studies
[135,138]
(mL/min/1.73 m 2 ) adjustments needed adjustments needed US: Evidence not well-established. No dosing adjustment adjustment needed, but to start with a low dose and titrate slowly indicate that supplemental dosing may be required for
those receiving HD or PD. Unfortunately, formulae for
supplemental dosing are not currently available, because
of the considerable variability in the level of renal
eGFR related dose adjustments US: No dose UK: No dose likely needed UK: No dose excretion (between 20% and 50%) [9,138,139] . The RDH notes
that phenobarbital is contraindicated in severe renal
impairment [130] . Further studies are needed to reach a more
unified consensus regarding phenobarbital prescription in

Potential nephrotoxicities Not reported Not reported the dialysis population.
Primidone, an AED which displays a similar efficacy
to phenobarbital, has been prescribed for focal and
generalized seizures. As with phenobarbital, its use in
Interactions with other AEDs Reduces carbamazepine and lamotrigine levels Increases phenobarbital and phenytoin levels Reduces carbamazepine, clobazam, midazolam, lamotrigine and valproic acid levels Could either reduce or increase oxcarbazepine clinical practice for seizure treatment has significantly
decreased over the years with the development of newer
AEDs. Primidone is partially protein bound (between
10% and 30%)
. It is metabolized by the liver to
[131]
phenobarbital and phenylethylmalonamide, a less active
% of urinary excretion Approximately 4% Approximately 2% AED: Antiepileptic drug; CYP450: Cytochrome P450; eGFR: estimated glomerular filtration rate; GABA: Gamma-aminobutyric acid; HD: Hemodialysis; RDH: Renal Drug Handbook; metabolite. [131] Significant accumulation of primidone
is observed in CKD. Up to 40% of primidone is excreted
unchanged by the kidney. HD removes between 20%
. In the US, administering a 30%
and 50% of the drug
[131]
supplemental dose before HD sessions, or a full dose
Metabolism Hydrolysis Hepatic metabolism through the CYP450-3A4 system post-HD, has been recommended [9,140,141] . In contrast, the
RDH currently recommends dose reduction by 25–50%
initially, and avoidance of large single doses
. Clearly,
[130]
further work is required to achieve a greater consensus on
the dose adjustments of primidone in this context.
Protein binding Approximately 34% Approximately 95% 4.3. Carbamazepine, oxcarbazepine, and
eslicarbazepine

Table 5 presents a summary of carbamazepine,
Primary mechanism of action Inhibition of voltage-gated sodium channels by stabilizing the inactive state It is a highly selective, noncompetitive AMPA-type glutamate receptor antagonist SLE: Systemic lupus erythematous; UK: United Kingdom; US: United States. oxcarbazepine, and eslicarbazepine . One
[9,130-133,135,139,142-145]
of the first new AEDs to be developed, carbamazepine is
used to treat focal and secondary generalized seizures,
other neurological conditions including trigeminal
neuralgia, neuropathic pain, and psychiatric conditions
such as bipolar disorder . Carbamazepine has a similar
[9]
Table 15. (Continued) AED (reference range in mg/L) Rufinamide [129,130,177] (10 – 40) Perampanel [9,130,138,178,179] (0.05 – 0.4) pharmacodynamic mechanism of action to phenytoin:
blockade of voltage-gated sodium channels, reduction
of glutamate and enhancement of GABA release
. It is
[135]
70%–80% protein bound and is metabolized in the liver by
CYP450-3A4 (CYP3A4) to an active epoxide metabolite,
then further metabolized to inactive metabolites before

V 21 being excreted into urine [135] . Only around 1% of
https://doi.org/10.36922/an.314
21
Volume 2 Issue 2 (2023) olume 2 Issue 2 (2023)
https://doi.org/10.36922/an.314