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Advanced Neurology Seizures and CKD

4.12. Clobazam commonly used in clinical practice. Tiagabine acts by inhibiting

Table 14 presents a summary of clobazam [9,129,130,168] . the GABA uptake mechanism [175] . This AED is extensively
Clobazam is an AED which treats a wide variety of seizures metabolized by the CYP450 system and is highly protein-
[175]
[129]
and has been approved for the treatment of rarer seizure- bound . Only around 1% of tiagabine is renally excreted .
[9,130]
associated conditions such as Lennox-Gastaut syndrome . Dosing adjustments are therefore not indicated .
[9]
In contrast to the AEDs discussed in the previous Vigabatrin has been prescribed for the treatment of
paragraph, which are all 1,4-benzodiazepines, clobazam refractory focal seizures and infantile spasms or West
is a long-acting 1,5-benzodiazepine which renders it less syndrome. It acts through the irreversible inhibition of
sedating [168] . Clobazam is metabolized by the CYP450 GABA transaminase [176] . This AED is not significantly
pathway and is approximately 90% protein-bound. Its metabolized in the system nor is it protein-bound [129] .
main metabolite is N-desmethylclobazam, which is active Between 70% and 80% of vigabatrin is excreted through the
and also metabolized by the liver [129] . The previous studies kidneys in unchanged form [129] . Therefore, dosing should be
have shown that there is accumulation of clobazam in adjusted to an individual’s creatinine clearance, according
CKD and no supplemental dosing is required [9,129,130] . to both US-based and RDH practice recommendations [9,130] .
For patients receiving HD, US-based practice guidelines
4.13. Other anti-epileptic drug options recommend a post-HD supplemental dosing of 50%
There are several more rarely used AEDs documented because HD removes up to 60% of this AED [9,129] . The RDH
in the literature, for use in patients with CKD. These advises giving 25% of the patient normal dose for patients
AEDs (felbamate, ethosuximide, tiagabine, vigabatrin, receiving HD and titration according to response [130] .
rufinamide, and perampanel) are summarized in Rufinamide is prescribed for the treatment of focal
Table 15 [9,129-131,138,169-179] .
seizures and drop attacks of Lennox-Gastaut syndrome.
Felbamate is rarely used, and almost only prescribed Its primary mechanism of action is the inhibition
for severe refractory epilepsy, because of its adverse of voltage-gated sodium channels by stabilizing the
effects, especially aplastic anemia and acute liver failure . inactive state [177] . The previous studies report that
[9]
Felbamate acts by open-channel blockade of the NMDA approximately 34% of rufinamide is protein-bound [129] .
receptors and associated strychnine-insensitive glycine It is extensively metabolized, through hydrolysis, to a
receptor, resulting in inhibition of sodium and calcium renal-excreted inactive metabolite [129] . US-based practice
excitatory currents [169,170] . Felbamate is metabolized by the recommendations suggest that between 20% and 30%
CYP450 system to weakly active and inactive metabolites. post-HD supplemental dosing should be administered
About 20% of felbamate is protein-bound and 50% is for patients receiving HD, given that approximately 30%
excreted unchanged in urine [129] . Felbamate clearance is of rufinamide is removed from each HD session [129] . The
decreased in CKD and therefore, initial and maintenance RDH advises that no dose adjustment is needed in patients
dosing should be reduced by approximately 50% when with kidney impairment or receiving dialysis [130] .
this AED is prescribed for CKD patients [9,129] . New-onset Perampanel is an AED used for the treatment of focal
urolithiasis has been reported with felbamate use [171] .
and generalized seizures. This AED is a highly selective
Ethosuximide is a narrow-spectrum AED, which and non-competitive AMPA-type GluR antagonist [178,179] .
is primarily effective for the management of absence The mechanism of action of perampanel allows it to
seizures. Its mechanism of action involves the reduction limit excitatory drive in neurons, which makes it unique
of low-threshold T-type calcium current in thalamic compared to other AEDs [178] . The majority of this drug is
neurons [172] . Ethosuximide is metabolized by the liver to metabolized by the CYP3A4 system and approximately
an inactive metabolite. [131] It is not protein-bound and only 95% is protein-bound [138] . Only around 2% of perampanel
about 20% is excreted unchanged in urine. Ethosuximide is excreted in urine unchanged, and post-HD supplemental
can be removed by both HD and peritoneal dialysis dosing is not indicated for those receiving HD [9,130,138] . The
(PD) [173,174] . The RDH recommends no dosing changes RDH recommends starting with a low dose and titrating
in kidney impairment or dialysis [130] . On the other hand, slowly for those with kidney impairment, including those
US-based practice guideline advises regular serum level receiving dialysis [130] .
monitoring and dosage adjustments for patients with
eGFR <30 mL/min/1.73 m . A 50% dose supplementation 5. Summary and future directions
2
is recommended following dialysis [131] . Over recent years, the issue of seizures in CKD patients
Tiagabine is another narrow-spectrum AED used is attracting greater attention, discussion and research.
as adjunctive therapy in focal seizures, although it is not Our review summarizes the known pathophysiological

https://doi.org/10.36922/an.314
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Volume 2 Issue 2 (2023) olume 2 Issue 2 (2023)
V 25 https://doi.org/10.36922/an.314