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Advanced Neurology Seizures and CKD

following HD [159] . The RDH maintains no dose adjustments involves inhibition of N-, P-, and Q-type voltage-gated
are indicated while receiving HD [130] . In terms of side effects, calcium channels at the presynaptic membrane [166] .
zonisamide inhibits carbonic anhydrase which may cause Gabapentin is only minimally protein-bound and has a
mild metabolic acidosis [158] . Urinary acidification may low volume of distribution. Gabapentin is almost entirely
contribute toward the development of nephrolithiasis [158] . excreted by the kidney [135] . Gabapentin levels can rapidly
increase in CKD given its exclusive excretion through
4.8. Lacosamide the kidneys, which may lead to adverse effects such as
Table 10 presents a summary of lacosamide [9,130,131,135,160-162] . myoclonus and somnolence, thereby mimicking the classic
Lacosamide is an AED which has grown in popularity over signs of uremic encephalopathy [131,135] . Another common
recent years and is used to treat focal and generalized seizures. side-effect is the risk of peripheral edema, which can be
Its mechanism of action focuses on the inactivation of slow exacerbated in the presence of CKD and heart failure [131,135] .
voltage-gated sodium channels, whilst not interfering Both US and UK guidelines suggest that dosing should be
with fast inactivation (findings from basic science studies titrated and renally adjusted, alongside consideration of
have recently questioned whether its true mechanism supplemental dosing for dialysis patients because clearance
is binding to inactivated states of fast sodium channels, is significant during dialysis [9,131] .
similar to other AEDs, but instead with slower kinetics) Pregabalin is an alternative prescription with similar
[160] . Lacosamide is metabolized by the CYP450 system and pharmacological actions to gabapentin. It also displays very
approximately 95% of the drug is excreted in urine, 40% high levels of renal excretion, has low or negligible protein-
in unchanged form [161] . In the US, it is recommended that binding, and a low volume of distribution [135] . Similar to
the upper limit of dosing is set at 300 mg/day for patients gabapentin, dose adjustment for pregabalin is indicated
with eGFR <30 mL/min/1.73 m 2[9,161] . The RDH advises the in kidney disease. The RDH advises for eGFR between
upper limit of dosing to be 250 mg/day for patients with 15 and 30 mL/min/1.73 m , initial dosing should be between
2
eGFR <30 mL/min/1.73 m 2[130] . For patients receiving HD, 25 and 50 mg daily and titrated up according to tolerability
US-based practice guideline recommends a 50% dosing and response [130] . For eGFR <15 mL/min/1.73 m , initial
2
supplementation because an HD session typically reduces dosing should be 25 mg daily, again titrated according
the serum concentration by 50% [9,131,135,162] . Similar dosing to tolerability and response [130] . US-based practice
supplementation post-HD is advised in the RDH [130] . recommendations note that supplementary dosing is also
likely needed post-HD [9,131,135] .
4.9. Lamotrigine
Table 11 presents a summary of lamotrigine [9,130,131,135,139,163-165] . 4.11. Benzodiazepines (clonazepam, diazepam,
Lamotrigine is an AED prescribed for focal and generalized lorazepam, and midazolam)
seizures and bipolar disorders. The primary mechanism of Table 13 presents a summary of the benzodiazepine-
action of lamotrigine is similar to that of phenytoin and class medications [9,130,131,167] . Benzodiazepine-class
carbamazepine. Lamotrigine also inhibits high-voltage- medications such as clonazepam, diazepam, lorazepam,
gated calcium currents through inhibition of presynaptic and midazolam are administered for a wide variety
N-, P-, and Q-type calcium channels; such activity is of purposes, including for sedation and pain-control.
dose-dependent [131,163] . Lamotrigine is metabolized in They are approved for the treatment of various seizure
the liver to an inactive metabolite; approximately 55% is syndromes as well but are primarily used in management
protein-bound, and around 10% is excreted in urine in of status epilepticus. These effects are achieved through
unchanged form [131] . The previous reports suggest that binding to the benzodiazepine site of the GABA-A
17–20% of lamotrigine is removed through HD [131,135] . receptor and increasing its opening frequency, therefore
There is no clear consensus in the literature regarding a increasing GABA currents and promoting neuron
recommended strategy for renal-adjusted or post-HD inhibition [131,167] . Benzodiazepines are mostly metabolized
supplemental dosing [9,130,131,135,139,164] . Therefore, therapeutic by the liver (majority through the CYP450-3A4 system)
drug monitoring is recommended [9,165] . Greater caution is and are highly protein-bound [131] . The metabolites are
advised when prescribing lamotrigine concurrently with excreted through the kidneys and only a small percentage
other AEDs which are metabolized in the liver [131] . of the administered dose is excreted in the unchanged
form [131] . Patients with CKD do not require a dosing
4.10. Gabapentin and pregabalin
adjustment [9,130] . The RDH recommends benzodiazepines
Table 12 presents a summary of gabapentin and should be commenced in small doses and titrated, as
pregabalin [9,130,131,135,166] . Gabapentin is prescribed to treat dictated by seizure control or side effects, in individuals
focal and generalized seizures. The mechanism of action with renal impairment [130] .

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