Table 1.

Mechanism of action, side effect profile, and risk factors of anti-seizure drugs based on clinical and preclinical studies.

Anti-seizure Drug	Mechanism of Action	Study Subjects	Side Effect Profile	Risk Factors	References
Broad Spectrum ASD
Valproate	▪ Enhance GABA levels ▪ Block sodium (Na+), calcium (Ca2+) and potassium (K+) channels ▪ NMDA receptor antagonist	Women with epilepsy who were pregnant or who were of childbearing age	Teratogenic effects	* Pregnancy * Child bearing age * Pediatric patients * Genetic mutations (POLG)	[23]
		Human placentas	Reduced placental folate concentrations		[24]
		Human placentas	Decreased mRNA expression of genes encoding folate and amino acid and fatty acid transporters		[25]
		Alpers syndrome patients	Increased apoptotic sensitivity		[26]
		Valproate-induced rats	Increased thiobarbituric acid reagent content and NO		[27]
		Epileptic children on a low therapeutic dose of valproate monotherapy	Decreased appetite, abdominal pain, vomiting, diarrhea, enuresis, skin rash and abnormal color vision		[28]
Topiramate	▪ Enhance GABA-chloride influx ▪ Block sodium (Na+) channels ▪ NMDA antagonist ▪ Block carbonic anhydrase	Adults with epilepsy or migraine	Impairment of verbal function, memory, and attention	* High dosage * Infants * Pregnancy * Drug interaction with other ASD	[29]
		1–24 months of age with refractory partial-onset seizure	Hyperammonemia		[30]
		Children with West syndrome	Sleeping state, poor oral intake, and numbness		[31]
		Pregnant women	Increased seizure frequency		[32]
Lamotrigine	▪ Block sodium (Na+) and calcium (Ca2+) channels	Patients with eosinophilia and systemic symptoms (DRESS)	Hypersensitivity	* Chronic usage *Age (older)	[33]
		Patients with SJS or TEN	SCAR		[34]
Levetiracetam	▪ Inhibit sodium (Na+) channels ▪ Increase GABAergic transmission ▪ Bind to SV2A	Patients with epilepsy	Decreased dopaminergic activity and aggression side effects	* High dosage	[35]
Felbamate	▪ NMDA-glutamate receptor antagonist ▪ Blocks sodium and calcium conduction	Children with drug-resistant epilepsy	Aplastic anemia, liver failure, decreased appetite, insomnia, fatigue, irritability, leukopenia, rash, hyperactivity, weakness, vomiting, cognitive deterioration, behavioral change	* Drug interaction with other ASD	[36]
		Children, adolescents, and adults with epilepsy	Nausea, vomiting, and stomach upset		[37]
		Adult rats	Lowest learning tasks		[38]
Zonisamide	▪ Blocks sodium (Na+) and T-type calcium channels	Patients with epilepsy	Major depression	* Drug withdrawal * Gender (males)	[39]
Rufinamide	▪ Inhibits sodium-dependent action potentials	CF1 mice and Sprague–Dawley rats	Decreased motor activity, ataxia, muscle relaxation, and decreased respiration	* Pediatric patients *LGS patients	[40]
		Patients with LGS	Increased in height and weight		[41, 42]
		Patients with LGS	Headache, dizziness, drowsiness, vomiting, nausea, fatigue and diplopia		[43]
Anti-seizure Drug	Mechanism of Action	Study Subjects	Side Effect Profile	Risk Factors	References
Brivaracetam	▪ Binds to SV2A	Children with epilepsy	Systemic side effects	* Pregnancy	[44, 45]
		Patients with intellectual disability and epilepsy	Behavioral disorder side effects		[191]
		Women with epilepsy	Embryo death		[46]
Perampanel	▪ AMPA-glutamate receptor antagonist	WAG/Rij rats	Psychiatric (depressive-like) comorbidity	* High dosage	[47]
		Patients with epilepsy	Increase in depressive symptoms		[48]
		Patients with drug-resistant partial seizures	Dizziness, drowsiness, and headache		[108]
Narrow Spectrum ASD
Phenytoin	▪ Reduce action potential amplitude ▪ Block sodium (Na+) channels	Pediatric patients with convulsive status epilepticus	Hypotension, cardiac arrhythmias and serious extravasation injuries	* Pediatric patients * Drug interaction with other ASD * Status epilepticus patients * Patients with cardiovascular problems * Genetic mutations (HLA-B, CYP2C variant) * Pregnancy * High dosage	[49]
		Phenytoin induced-anticonvulsant hypersensitivity syndrome	Cross-reactivity, fever, liver enzyme elevation, and increased skin problems		[50]
		Patients with drug-induced hypersensitivity syndrome	Severe facial edema, erythema, hyperbilirubinemia, and elevated liver transaminases		[51]
		Animal models treated with 100 mg or 200 mg of phenthionine	Increased ALT levels		[52]
		Patients with localization-related epilepsy	Impairment of cognitive functions, such as attention, memory, and problem solving		[53]
		Embryonic rats	Decreased body weight, cleft lip and/or palate, hydrocephalus, hydronephrosis, long bones growth retardation and ectrodactyly		[54]
		Women exposed to antiepileptic drug monotherapy during pregnancy	Increased risk of major congenital malformations		[55]
Oxcarbazepine	▪ Block sodium (Na+), calcium (Ca2+) and potassium (K+) channels	Patients with idiopathic trigeminal neuralgia	Tiredness, sleepiness, memory problems, disturbed sleep, difficulty concentrating and unsteadiness	* Monotherapy *Pediatric patients *Pregnancy	[56]
		Children with epilepsy	Nausea, vomiting, skin rash, and hyponatremia		[57]
		A 23-year-old pregnant woman with a history of CPS and mild depression	Dizziness and attacks		[58]
Lacosamide	▪ Increase the slow inactivation of sodium (Na+) channels ▪ CRMP2	Children with epilepsy	Cardiopulmonary events	* Patients with liver problems * Monotherapy * Adjunctant therapy	[59]
		Patients with epilepsy	Increased ALT levels		[60]
Gabapentin	▪ Bind to alpha-2-delta subunit of calcium (Ca2+) channels	Patients with partial-onset seizures	Anxiety, agitation, and depression	* Monotherapy * Pregnancy * High dosage * Patients with chronic renal failure * Age (older)	[61]
		Candidates for elective lower limb orthopedic surgery	Chill, headache, nausea, vomiting, dizziness, and fever		[62]
		Older adults given high doses of gabapentin	Increased risk of being hospitalized with a mental state		[63]
		Patients with chronic kidney disease	Toxicity		[64]
Anti-seizure Drug	Mechanism of Action	Study Subjects	Side Effect Profile	Risk Factors	References
1.	2.	24-week-old male albino Wistar rats	Decreased locomotor activity and increased defecation	-	[65]
		Pregnant women (including patients with epilepsy)	Less or similar rates of maternal complications, low birth weight, cesarean section, abortion and malformation		[66]
Vigabatrin	▪ Inhibits GABA transaminase	Infants with new-onset and previously treated infantile spasm	Getting fat, edema, extreme irritability, high blood pressure, heart failure, blood sugar control irregularities, increased risk of infection and kidney calcification	* Patients on hormone/steroids treatment * Infants * Chronic usage * High dosage	[67]
		Patients with epilepsy	Visual field defect		[68]
Carbamazepine	▪ Blocks sodium (Na+) channels	Older adults	Hyponatremia	* High dosage * Age (older and children)	[69]
Tiagabine	▪ Blocks GABA re-uptake	Adult outpatients with epilepsy	Cognitive side effect intolerance	* High dosage * Patients with comorbidities * Drug interaction with comorbid drugs	[70]
Stiripentol	▪ Increase GABAA receptor transmission ▪ Increase inhibitory post-synaptic currents ▪ Prolong decay time constant	Adults with DS	Anorexia, weight loss, imbalance, and fatigue	* Intolerance	[71]
		Patients with a confirmed clinical and genetic diagnosis of DS	Hyperammonemia encephalopathy		[72]
Eslicarbazepine acetate	▪ Enhance slow inactivation of sodium (Na+) channels ▪ Blocks T-type calcium channels	Children with refractory focal-onset seizures	Headache, nasopharyngitis, and drowsiness	* Age (older) * Patients with comorbidities * Drug interaction with other ASD	[73]
		Adults with partial-onset or focal seizures	Dizziness, drowsiness, hyponatremia, headache and ataxia		[74]
Cenobamate	▪ Blocks INaP action ▪ Positive allosteric modulation of GABAA receptors	Adults with uncontrollable focal epilepsy	Dizziness, headache, somnolence, diplopia, fatigue, nystagmus and DRESS	* Pregnancy *Drug interaction with other ASD and/or contraceptives *High dosage *Patients with cardiac comorbidity	[75-78]

Abbreviations: ASD: anti-seizure drug, ALT: alanine transaminase, POLG: DNA-polymerase gamma, CPS: complex partial seizures, DS: Dravet Syndrome, DRESS: drug eruption with eosinophilia and systemic symptoms, INaP: persistent sodium current, LGS: Lennox-Gastaut syndrome, NO: nitric oxide, SCAR: severe cutaneous adverse reactions, SJS: Stevens–Johnson syndrome, TEN: toxic epidermal necrolysis, SV2A: synaptic vesicle protein 2A, AMPA: amino-3-hydroxy 5-methyl-4-isoxazolepropionic acid, NMDA: N-methyl-D-aspartate, CRMP2: collapsin response mediator protein 2, GABA: gamma-amino-butryic-acid.