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Advanced Neurology Seizures and CKD

inhibitors in serum, and alteration of the albumin 4.1. Phenytoin and fosphenytoin
molecule may also be relevant [131] . The free serum levels of Table 3 presents a summary of phenytoin and
these highly protein-bound AEDs should also be closely fosphenytoin [131-136] . Phenytoin has historically been the
monitored; although their total serum concentration most frequently prescribed AED for focal and generalized
may be low, the concentration of the unbound fraction seizures, over the last century. The subsequent development
could be unchanged [131] . Uremic toxins downregulating
the cytochrome P450 (CYP450) system may affect AED of newer AEDs has diminished its popularity, mainly
metabolism although clinical effects are unlikely to be because of long-term adverse effects such as osteoporosis
[132,133]
significant, given the large hepatic reserve capacity [129] . and a detrimental lipid profile . Its primary mechanism
Drug interactions are probably more important, between of action is the blockade of voltage-gated sodium channels
AEDs, or AED with other medications (i.e., post-transplant leading to stabilization of the channels’ inactivated state,
immunosuppression and others) [129-131] . Clinicians should and consequent reduction of glutamate and enhancement
be vigilant in monitoring these potential interactions, of GABA release [134] . Phenytoin is metabolized by the
particularly in patients with polypharmacy. CYP450 system. It is also an enzyme-inducing AED that
decreases the levels of other drugs metabolized in the liver.
In this paper, we describe the properties of many AEDs 5-(p-hydroxyphenyl)-5-phenylhydantoin glucuronide, a
currently available for CKD patients presenting with major metabolite of phenytoin, accumulates with kidney
seizure(s), and the management of AEDs in CKD. Figure 2 failure [134] . This is unlikely to be clinically relevant because
summarizes the available AEDs in clinical practice and it is an inactive metabolite. Phenytoin has rarely been
highlights the key differences between each, and with associated with interstitial nephritis [135] .
non-AED treatments [9,16,130-179] . Tables 3-15 describe the
properties and metabolism for each of the AEDs discussed A non-linear elimination mechanism exists and this
in this section in greater detail, as well as recommendations can cause significant increase in serum phenytoin levels,
for their use in CKD [9,16,130-179] . There are country-specific if doses are increased too rapidly [135] . Less than 5% of
differences in AED prescription for patients with kidney phenytoin is excreted in the urine and dose adjustments
impairment. We outline US and United Kingdom are not required in CKD patients [135] . However, phenytoin
(UK)-based practice recommendations and highlight may require dose supplementation in patients suffering
differing approaches in our review. from post-HD seizures [131,135] . Up to 90% of phenytoin

Figure 2. Summary of non-AED and AED options in clinical practice.
AED: Antiepileptic drug; CKD: Chronic kidney disease; GABA: Gamma-aminobutyric acid; NMDA: N-methyl-D-aspartate; AMPA: Alpha-amino-3-
hydroxy-5-methyl-4-isoxazolepropionic acid.

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