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Advanced Neurology Seizures and CKD

Dialysis‑related dose adjustments US: 50% daily dose needed as post-HD supplementation UK: No additional post-HD dose supplementation needed Dialysis‑related dose adjustments US: Supplemental dose in full daily after HD. 50% supplemental dose may be needed for post-HD seizures UK: No dosing adjustments recommended, but to titrate dose slowly

(mL/min/1.73 m 2 ) reduction needed UK: An initial 50% dose reduction before a gradual titration of dose upwards according to patient response when eGFR < 20

eGFR related dose adjustments US: 50% dose for eGFR < 60 eGFR (mL/min/1.73 m 2 ) related dose adjustments US: No dosing adjustments needed for eGFR ≥ 30. Prescribe with caution advised for eGFR < 30 –evidence remains unclear to recommend dosing adjustments UK: No dosing adjustments needed but to titrate doses slowly

Potential nephrotoxicities Metabolic acidosis (renal tubular acidosis) Nephrolithiasis (due to build-up of calcium phosphate) Potential nephrotoxicities Metabolic acidosis (renal tubular acidosis) Nephrolithiasis (due to build-up of calcium phosphate)

Interactions with other AEDs Reduces valproic acid levels Increases phenytoin levels Interactions with carbamazepine-10,11

% of urinary excretion Between 60% and 70% % of urinary other AEDs Increases Between 30% epoxide levels

Metabolism Depends on any concurrent AEDs prescribed – Hepatic metabolized, the activity of enzymes affecting metabolic homeostasis for this drug is dependent on the interaction with these enzymes by other AEDs. AED: Antiepileptic drug; eGFR: estimated glomerular filtration rate; GABA: Gamma-aminobutyric acid; HD: Hemodialysis; UK: United Kingdom; US: United States Metabolism excretion and 35% metabolism through CYP450

Protein binding Approximately 20% Protein binding Hepatic Between 40% and 60% system

Table 8. Properties and metabolism of topiramate

Primary mechanism of action Multiple major mechanisms of action: inhibition of kainate/ AMPA-type glutamate receptors, inhibition of voltage-gated sodium channels in reducing sustained repetitive firing, enhancement of GABA-mediated chloride flux at GABA-A receptors, limiting high threshold voltage-gated calcium currents Table 9. Properties and metabolism of zonisamide Primary mechanism of action Inhibits the repetit

AED (reference range in mg/L) Topiramate [9,130,135,139,156,157] (5–20) AED (reference range in mg/L) Zonisamide [9,130,131,135,158,159] (10 – 40)

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