Phenyltriazine Intestine


Lamotrigine, an AED of the phenyltriazine class, has been found effective against refractory partial seizures. Like phenytoin and CBZ, its main mechanism of action appears to be blockade of sodium channels that is both voltage- and use-dependent. It also inhibits the high-threshold calcium channel, possibly through inhibition of presynaptic N-type calcium channels and also blocks glutamate release.18,19 Lamotrigine is metabolized predominantly by glucuronida-tion. The major inactive urinary metabolites isolated are 2-N-glucuronide (76%) and 5-N-glucuronide (10%) because the aromatic ring is somewhat deactivated by the presence of chlorine atoms toward arene oxide formation.56 Coadministration of lamotrigine with valproate, however, greatly increases the incidence of its idiosyncratic reactions.56 It is conceivable that in the presence of VPA, an inhibitor of UDP-glucuronyl transferase, the concentration of the reactive arene oxide intermediate may be increased because of the reduced capacity of UDP-glucuronyl transferase to metabolize lamotrigine via normal glucuronidation pathways.


TPM is a sulphamate-substituted monosaccharide, a derivative of the naturally occurring sugar D-fructose that exhibits broad and potent AED actions at both glutamate and GABA receptors.19 It has good oral bioavailability of 85% to 95%, most likely resulting from its structural similarity to D-glucose. Thus, it may be actively transported into the brain by the D-glucose transporter. (Recall that D-fructose and D-glucose have identical stereochemistry at many of their chiral centers.) Only about 20% of the drug is eliminated by hepatic metabolism (CYP2C19), the remaining drug is excreted unchanged by the kidneys.57 The sulphamate ester is hydrolyzed by sulfatases to the corresponding primary alcohol, which is further oxidized to the corresponding carboxylic acid. Even though there are no reports of significant interactions between TPM and other AEDs, TPM is said to have a weak carbonic anhydrase inhibitory activity because of the presence of the sulphamate moiety. Thus, concomitant use of TPM with other carbonic anhydrase inhibitors should be avoided.57 The exact mechanism of actions are still unknown, but TPM appears to block glutamate release, antagonize glutamate kainic acid/AMPA receptors, and increase GABAergic transmission by binding to a site distinct from BZDs or barbiturates on the GABAA receptor complex.19


Zonisamide, a sulfonamide-type anticonvulsant was recently approved for adjunctive therapy in the treatment of partial seizures in adults with epilepsy.43 Zonisamide is primarily metabolized by reductive ring cleavage of the 1, 2-benzisoxazole ring to 2-sulfamoyl-acetyl-phenol (Fig. 14.11). This biotransformation is mainly carried out by the intestinal bacteria rather than the mammalian cytosolic aldehyde oxidase suggested earlier.58 Again, because of the presence of a sulfonamide moiety in zonisamide molecule, precaution should be given to patients who have a history of hypersensitivity reactions toward sulfonamide drugs and concomitant use of zonisamide with other carbonic anhydrase inhibitors should also be avoided.59


LEV is an analog of the nootropic agent, piracetam. Only the S-isomer shown in Figure 14.11 has any anticonvulsant activity. Unlike piracetam, LEV does not have any affinity for the AMPA receptor thereby has no nootropic activity for the treatment of Alzheimer disease. LEV also has no affinity for GABA receptors, BZD receptors, the various excitatory amino acid related receptors, or the voltage-gated ion channels.43,60 For this reason, its mechanism of anticonvul-sant action remains unclear, but it appears to exert its antiepileptic action by modulating kainite/AMPA-induced excitatory synaptic currents, thus decreasing membrane conductance.60 Furthermore, the anticonvulsant activity of this drug appears to be mediated by the parent molecule rather than by its inactive metabolite, (S)-a-ethyl-2-oxo-1-pyrrolidineacetic acid (i.e., via the hydrolysis of amide group).61 Like gabapentin, LEV has few drug interactions with other AEDs thereby can be used in combination to treat refractory epilepsy.10,56

Anticonvulsants Acts on a Selective Molecular Target


A glance at tiagabine's structure (Fig. 14.12) suggests an uptake inhibitor. Reportedly, it blocks GABA reuptake as a major mode of its anticonvulsant activity. Its use is against partial seizures. Inhibitors of GABA transporter-1 (GAT-1 inhibitors) increase extracellular GABA concentration in the hippocampus, striatum, and cortex, thereby prolonging the inhibitory action of GABA released synap-tically. Nipecotic acid is a potent inhibitor of GABA reup-take into synaptosomal membranes, neurons, and glial cells. However, nipecotic acid fails to cross the blood-brain barrier following systemic administration because of its high degree of ionization. Tiagabine, marketed as the single R(-)-enantiomer, a potent GAT-1 inhibitor structurally related to nipecotic acid, has an improved ability to cross the blood-brain barrier, and it has recently received Food and Drug Administration (FDA) approval as an AED.43 It is well absorbed and readily metabolized by CYP3A4 to an inactive metabolite, 5-oxo-tiagabine (oxidation of the thiophen ring) or eliminated as glucuronide of the parent molecule.

Over 90% of tiagabine is metabolized by CYP3A4 isozymes.62 The primary site of metabolic attack is the oxidation of the thiophen rings leading to 5-oxo-tiagabine that lacks anticonvulsant activity and the glucuronidation via the carboxylic function. Thus, the plasma concentrations of tiagabine would be greatly effected by any compound that induces or inhibits CYP3A4.


Ethosuximide is considered the prototypical anticonvulsant needed for treating patients with absence seizures.6,19,25 Ethosuximide and the N-dealkylated active metabolite of methsuximide (Fig. 14.12) work by blocking the low-threshold T-type calcium channels, thereby reducing the hyperexcitability of thalamic neurons that is specifically associated with absence seizure.20


Nipecotic acid moiety

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