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Advanced Neurology Seizures and CKD

attributed to its efficacy and tolerability. Levetiracetam’s enhancement of GABA-mediated chloride flux at GABA-A
primary mechanism of action is its binding to synaptic receptors, and limiting high threshold voltage-gated
vesicle glycoprotein 2A, which is involved in controlling calcium currents [156] . Topiramate may also inhibit carbonic
exocytosis from the neurotransmitter-containing secretory anhydrase isoenzyme II and IV (enzymes which modulate
vesicle membrane [147,148] . Levetiracetam renders its primed pH-dependent activation of voltage and receptor-gated
synaptic vesicles fully calcium-responsive [149] . This AED ion channels) although this mechanism is weaker [156] .
also regulates cellular calcium homeostasis by blocking Topiramate is metabolized by the liver and its levels may
ryanodine and inositol trisphosphate receptor-dependent be affected by concurrent medications which interact
calcium release from the endoplasmic reticulum, and with hepatic enzymes [135,139] . Around 20% of topiramate is
inhibiting calcium entry by blocking long-lasting and protein-bound [135,139] . Depending on whether topiramate
non-long lasting-type voltage-gated calcium channels [150] . is prescribed as monotherapy, or together with other liver
The modulation of α-amino-3-hydroxy-5-methyl-4- enzyme-inducing AEDs, the extent to which topiramate is
isoxazolepropionic (AMPA) receptors by levetiracetam excreted through the urine unchanged can range from 40%
generates an antiepileptic effect [151] . As opposed to the to 80% [135,139] . US-based practice recommendations, based
AEDs discussed so far in this section, levetiracetam is on the expectation that HD will reduce the topiramate
generally not metabolized by the liver, is not dependent concentration by 50%, suggest supplemental dosing of 50%
on the CYP450 system, and has minimal levels of protein of the daily topiramate dose [9,135,139] . The RDH recommends
binding [131] . Approximately 67% of levetiracetam is excreted an initial 50% dose reduction before a gradual titration of
unchanged in urine. Dose adjustment is important for dose upward according to patient response when eGFR
patients with advanced CKD (eGFR <15 mL/min/1.73 m ) <20 mL/min/1.73 m with no supplemental dosing required
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because its half-life markedly increases from 7 to 25 h [131] . following HD [130] . A delayed time to reach steady state is to
In the US, a supplemental post-HD dose is advised for be expected in CKD patients (approximately 10 – 15 days
patients receiving HD, since around 50% of levetiracetam as opposed to 4 – 8 days in non-CKD patients) [130] . Further
is removed during HD [9,131] . On the other hand, the RDH work is required to reach a greater consensus on topiramate
recommends an initial 750 mg loading dose for HD dosing strategy. Potential side effects of topiramate include
patients, then 500–1000 mg once daily thereafter [130] . nephrolithiasis (likely due to urinary acidification and
Brivaracetam, an analog of levetiracetam, is also hypocitrauria leading to kidney stone formation) and
used in the treatment of focal and generalized seizures. mild metabolic acidosis (because of carbonic anhydrase
Its mechanism of action is almost identical to that of inhibition) [157] .
levetiracetam, but with up to a 30-fold higher affinity 4.7. Zonisamide
for the SV2A protein [152] . Basic science studies involving
audiogenic susceptible mice found brivaracetam displaying Table 9 presents a summary of zonisamide [9,130,131,135,158,159] .
greater speed of entering the brain compared with Zonisamide is prescribed for both focal and generalized
levetiracetam, correlating with its quicker ability to respond seizures. A sulfonamide derivative and zonisamide
against seizures in these in vivo studies [153,154] . In contrast inhibits the repetitive firing of voltage-gated sodium
to levetiracetam, brivaracetam has low protein binding channels, resulting in a reduction of T-type calcium
of approximately 18% and is metabolized by the liver to channel currents [158] . Zonisamide is also considered to be
inactive metabolites, which are in turn excreted through the a neuroprotective AED. The CYP450 system metabolizes
kidneys [155] . The previous reports note that approximately it to form an inactive metabolite [158] . An advantage of
5 – 8% of brivaracetam is excreted in unchanged form. Both zonisamide is its lack of interaction with concurrently
US-based practice recommendations and the RDH suggest administered AEDs [131] . Typically, 40–60% of zonisamide
renal-specific dosing. Supplemental dosing following HD is protein-bound. There is a greater affinity towards
is unlikely to be required, due to the very weak CYP3A4 erythrocytes compared with other AEDs [131] . Few studies
metabolism of brivaracetam [9,129,130,155] . have evaluated zonisamide clearance and around 30%
of zonisamide appears unchanged on excretion in
4.6. Topiramate urine [135,158] . Current US-based practice recommendations

Table 8 presents a summary of topiramate [9,130,135,139,156,157] . advise no dose adjustments among patients living with
Topiramate is an AED that can be prescribed for focal mild and moderate CKD, similar to RDH guideline, which
and generalized seizures. It has multiple mechanisms also advises that dosing should be titrated slowly [9,130,135,158] .
of action, including the inhibition of kainate/AMPA- However, US-based practice guideline recommends
type GluRs, and the inhibition of voltage-gated sodium dosing supplementation of zonisamide following HD,
channels, thus reducing sustained repetitive firing and given reports of a 50% reduction in serum concentration

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