Voltage gated ion channels
What are the classical sodium channel blocking ASMs
Phenytoin, (ox)carbamazepine, and lamotrigine
Lacosamide does as well though enhances the slow inactivation (unlike most Na channel blockers, which enhance fast sodium channel inactivation)
2 benzos used for chronic epilepsy management
Clonazepam and Clobazam
MoA: act on the GABA A receptor, increasing the frequency of GABA-mediated chloride channel openings
Indicated for use in generalized seizure types, and typically used as adjunctive therapy
Tolerance may develop to the therapeutic effect of benzos, but is less likely with clobazam
binding to the synaptic vesicle protein SV2A → nonspecific decrease in neurotransmitter release in a state of neuronal hyperactivation
Levetiracetam
Effective for focal, GTCs, and generalized myoclonic seizures. (Only ASM with Class 1 evidence for efficacy against myoclonic seizures).
Can be loaded, 60mg/kg
Brivaracetam: MoA is similar to Keppra but with 20 fold higher affinity. It also has higher brain permeability. Behavioral s/e from levetiracetam can improve after switching to brivaracetam.
Patient on this long-standing ASM who presents for Parkinsonism
Valproic acid: Chronic use in seniors → reversible parkinsonism, gait disorder, dementia, brain atrophy
MoA: GABA potentiation, blocking T-type calcium channels, and blocking Na channels. Those related to GABA mechanisms are among the most likely to be relevant to valproate's antiseizure activity. Despite efficacy in absence epilepsy, there is little support for effects on T-type calcium channels.
Broad spectrum of efficacy for all focal and generalized seizures, including absence and myoclonic; can be loaded (40 mg/kg)
Adverse effects: GI, drowsiness, tremor, weight gain, hair loss, peripheral edema, confusion, dose-related thrombocytopenia
Endocrine effects most common in women → PCOS, hyperandrogenism, hyperinsulinemia, and insulin resistance
Encephalopathy and hyperammonemia may occur in polytherapy
Hepatotoxicity and pancreatitis can be life-threatening but are rare
Teratogenic: NTDs, renal/urogenital malformations (higher than any other ASM), in-utero exposure is associated with dose-dependent reduced IQ and autism
The enzyme inducing antiseizure medications are
phenobarbital, phenytoin, (ox)carbamazepine, primidone, and topiramate (mildly)
This ASM plays a role in the intrinsic thalamocortical oscillations
Ethosuximide (in part Zonisamide)
T-type calcium channels in the thalamus and cortex contribute to the abnormal behavior of the circuit --> generate low-threshold spikes, leading to burst firing and oscillatory behavior
Methsuximide is similar to ethosuximide though better tolerated in adults for treatment of absence seizures
Phenobarbital - used 1st line for neonatal seizures, and in developed countries d/t its low cost
MoA: binding of GABA A receptor and prolonging the opening of the associated chloride channel
Effective for focal and GTC seizures, not absence seizures
Can be used for status epilepticus
Long-term use is associated with decreased bone density, dupuyten contractures, plantar fibromatosis, and frozen shoulder.
Teratogenic: increased risk of cardiac malformations and decreased cognitive abilities in males
Act by binding to the α2δ-1 protein, which is an accessory subunit of voltage-gated calcium channels
Gabapentin and pregabalin
The precise way in which binding of gabapentin and pregabalin to the α2δ-1 protein confers seizure protection is not well understood à they do seem to block the release of various neurotransmitters (glutamate) and this may account for the antiseizure activity
NMDA receptor antagonist, GABA enhancement, and sodium channel blocker
Felbamate
Effective for focal and generalized seizures in the setting of Lennox-Gastaut syndrome
Most concerning toxicity is aplastic anemia (can be fatal) and hepatic failure, both are unlikely after 1 year of treatment (these 2 adverse effects have resulted in a boxed warning such that felbamate should be used only for severe epilepsy where treatment benefits outweigh risks)
Due to its potential toxicity, it is not indicated as a 1st line treatment and is therefore used as adjunctive therapy when safer options have failed
Significant increases in GFR can occur in the first ?? weeks of pregnancy, resolving between 1–8 weeks post-partum
20 weeks
Thus, ASMs cleared mainly through the renal route may have reduced serum concentrations early in pregnancy
You increased the dose of a patient's ASM and 1 week later they developed ataxia, dysarthria, and nystagmus, and they started having increased frequency of their seizures.
Phenytoin - its metabolism is saturable, resulting in nonlinear kinetics. As the serum concentration increases, it reaches a point within the recommended therapeutic range after which the half-life starts increasing. Beyond that point, the phenytoin plasma level increases disproportionately with an increase in the dose
Can be loaded (20mg/kg)
Paradoxical increase in seizures with doses exceeding 30 ug/mL
Adverse effects with long-term use: gingival hyperplasia, acne, hirsutism, cerebellar atrophy, osteoporosis, anemia, and peripheral neuropathy
GAT-1 GABA transporter
Tiagabine is a highly selective inhibitor of GAT-1 in neurons and glia --> suppresses the translocation of extracellular GABA into the intracellular compartment, thus raising extracellular GABA levels (inhibits GABA reuptake at the synapse)
GAT-1 is the predominant form in the forebrain (including the neocortex and hippocampus), is localized to GABA-ergic terminals as well as to glial processes near GABA synapses.
Reserved for use as adjunctive therapy: Effective for focal seizures and may exacerbate absence and myoclonic seizures
Used off-label for spasticity in MS, addiction, and to increase deep sleep promotion
May be associated with dose-related episodes of NCSE or encephalopathy, which can occur in the absence of epilepsy
Noncompetitive antagonist of AMPA receptors
Perampanel is a potent noncompetitive antagonist of AMPA receptors that does not affect NMDA receptor responses and has no known affects on other ion channels or molecular targets at therapeutically relevant concentrations.
Half life of 105 hours
Effective for focal seizures (adjunctive and monotherapy) and GTC (adjunctive)
Low therapeutic window, adverse CNS side effects are common
Associated with increased birth defects, particularly oral clefts
Topiramate
MoA: AMPA antagonist, augmentation of GABA activity, blocking of voltage-gated sodium channels. Action of topiramate on carbonic anhydrase has been assumed not to contribute to its clinical efficacy
Effective for focal and GTC seizures, titrated gradually to avoid cognitive adverse effects
Used for treatment of infantile spasms
Adreocorticotropin (ACTH)- mechanism not understood.
ACTH stimulates glucocorticoid (cortisol) synthesis and release from the zona fasciculata of the adrenal cortex. Cortisol could produce an anti-inflammatory action or have some other action in the brain to influence infantile spasms.
ACTH also stimulates neurosteroid synthesis. ACTH stimulates deoxycorticosterone (DOC) release from the zona glomerulosa of the adrenal cortex. DOC is, in part, converted to the anticonvulsant neurosteroid tetrahydro-DOC, which is a positive allosteric modulator of GABAA receptors
Side effect more likely in those with HLA-B1502
Carbamazepine. HLA-B1502 more common in those of Asian decent
Elevated levels of Carbamazepine can also cause diplopia, nystagmus, incoordination, and tremor
Uncommon side effects: lupus-like reaction, hepatotoxicity
Periodic visual assessment recommended every 3 months
Vigabatrin: Most concerning side effect is a progressive and permanent bilateral concentric visual field constriction (increased risk with higher dose/longer duration of therapy). Periodic visual assessment is recommended at baseline and every 3 months
MoA: irreversible inhibitor of GABA transaminase, resulting in accumulation of GABA (causes an increase in non-synaptic tonic GABAA receptor current)
First line with for patients with tuberous sclerosis who have infantile spasms
Can be used for absence epilepsy (not ethosuximide)
Zonisamide
Similarities between topiramate and zonisamide as they both contain a sulfur atom and both inhibit carbonic anhydrase
MoA: blocks T-type calcium channels (predictive of efficacy against absence seizures) and Na channels
Half-life: 60 hours
A patient with an JME was started on treatment but their seizures worsened.
Sodium channel blocking anti-seizure medications such as carbamazepine, oxcarbazepine, and phenytoin can cause seizure exacerbation in some patients with idiopathic generalized epilepsies, especially those with absence or myoclonic seizures
Its half life is twice as long when used with valproate and half as long when used with an enzyme inducer
Lamotrigine: blocks Na channels but is believed to have unrecognized actions to explain its efficacy against absence seizures
Estrogen and pregnancy increase lamotrigine clearance
It’s a broad spectrum anti-seizure medication, effective for focal/GTC seizures, and LGS
Several trials have favored lamotrigine over other ASMs for focal seizures with regards to tolerability and efficacy. However, it was inferior to VPA for idiopathic generalized epilepsy and inferior to ethosuximide for absence seizures
Approved for cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder in those age > 2
Ganaxalone
Synthetic neurosteroid that is a positive allosteric modulator of GABAA receptor, causes inhibition at both synaptic (phasic) and extrasynaptic (tonic) receptor sites
Research is ongoing for other seizure conditions like tuberous sclerosis and SE
Used as adjunctive treatment for seizures associated with Lennox-Gastaut syndrome
Rufinamide
MoA: Na channel blocker, although additional mechanisms are likely. Rufinamide has only been shown to interact with voltage-gated sodium channels, and the effects are subtle. Relevant concentrations of the drug may cause a depolarization in the activation voltage and slowing of recovery from inactivation, which would be expected to reduce neuronal excitability
When taken with VPA, rufinamide clearance decrease and levels increase by 70
Can case a shortening of the QT interval
FDA indicated for the treatment of seizures associated with LGS, Dravet syndrome, or tuberous sclerosis complex in patients > 1 yo
Cannabidiol
Its MoA is not fully known but it is thought to enhance GABA activity through allosteric modulation of the GABA A receptor and enhance currents elicited by low GABA concentrations. It may also play a role in modulation of intracellular calcium
Its bioavailability is increased by taking with a high fat meal
Interacts with several ASMs, most notably with clobazam
Can increase LFTs, particularly when used with VPA