Anticonvulsants : Introduction, Classification, general mechanism of action and pharmacology.

An over all glance on the pharmacology of anticonvulsant drugs.
It provides a quick review for the students.

1. ANTICONVULSANTS By N.Usha Latha (II/VI Pharm.D) S.Chamanthi (II/VI Pharm.D) N.Vennala (II/VI Pharm.D)

2. Introduction Anticonvulsants, also known as antiepileptic drugs, are a varied group of medications used to treat epileptic seizures.They suppress the excessive rapid firing of neurons during seizures and also prevent the spread of the seizure within the brain.

3. Classification 1. Barbiturate - Phenobarbitone 2.Aliphatic carboxylic acid – Valproate,Divalproex 3.Deoxybarbiturate – Primidone 4.Benzodiazepines –Clonazepam,Diazepam,Lorazepam 5.Hydantoin - Phenytoin,Fosphenytoin 6.Phenyltriazine – Lamotrigine 7.Iminostilbene – Oxcarbazepine,Carbamazepine 8.Cyclic GABA analogues – Pregabalin,Gabapentin 9.Succinimide – Ethosuximide 10.Newer drugs-Vigabatrin,Levetiracetam,Topiramate, Felbamate, rufinamide and few other newer antiseizure drugs have been introduced in some countries as second line/add-on drugs for refractory partial seizures .

4. General mechanism of action Anticonvulsant drugs in clinical use can be categorized based on their mechanism of action into three main groups: 1. Drugs that facilitate gamma- aminobutyric acid (GABA) ergic neurotransmission: - Modulate transmission through chloride channels (e.g., barbiturates, benzodiazepines).
- Reduce GABA degradation by blocking GABA transaminase (e.g., vigabatrin ).
- Inhibit GABA reuptake into the presynaptic terminal.

5. 2. Drugs that block neuronal ion channels: - Block voltage-operated sodium channels, leading to decreased electrical activity and possibly reduced glutamate release (e.g., lamotrigine, phenytoin, carbamazepine). Fig:2.1 - Block voltage-operated calcium channels, especially those mediating calcium currents in thalamic neurons (e.g., ethosuximide ). Fig:2.2 3. Drugs with unresolved mechanisms of action: - Sodium valproate is a prime example, with its mechanism not fully understood. - Some newer compounds under evaluation may exert their effects through antagonistic action at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. Fig:2.2 Fig:2.1

6. HYDANTOINS Phenytoin , a type of hydantoin , has pharmacological effects in the central nervous system, effectively controlling focal and tonic- clonic seizures without causing general CNS depression. Its mechanism of action involves slowing the rate of recovery of Na+ channels from inactivation. However, at higher concentrations, it can lead to unwanted toxicity. Phenytoin’s pharmacokinetics are complex, influenced by various factors. Drug interactions are common due to competition for protein-binding sites and enzyme induction. Adverse effects range from CNS effects to hematological reactions and teratogenicity. Monitoring plasma concentrations is important for its efficacy and safety. Phenytoin is mainly used for epilepsy and occasionally for trigeminal neuralgia, requiring careful consideration of formulations and potential drug interactions in clinical practice.

7. Benzodiazepines are mainly utilized as sedative-antianxiety medications but also possess broad antiseizure property. ADME - Orally absorbed well, with peak plasma levels reached within 1-4 hours.
- Diazepam exhibits high lipid solubility, fast redistribution, and a redistribution half-life of about 1 hour.
- Metabolism varies between different benzodiazepines, with unique pathways and half-lives for drugs like clonazepam, lorazepam, and clobazam .
- Most benzodiazepines are metabolized by cytochrome P450 enzymes (phase I), combined with glucuronide (phase II), and primarily excreted through urine. Adverse effects: - Common side effects include drowsiness, lethargy, and a decrease in anticonvulsant activity in around 30% of patients over time.
- Muscle incoordination, ataxia, aggression, hyperactivity, irritability, and difficulty concentrating are other potential adverse reactions.
- Abrupt cessation may trigger seizures or status epilepticus.
- Cardiovascular and respiratory depression may occur, especially through intravenous administration.

In conclusion, although benzodiazepines are mainly used for sedative and anti-anxiety purposes, they also have a significant role in epilepsy treatment, particularly in managing certain seizure types and conditions like status epilepticus. Careful dosing, monitoring, and consideration of potential side effects are crucial in their clinical application.

8. Benzodiazepine FDA Approval Dose Special Notes Clonazepam Lennox-Gastaut syndrome, akinetic, and myoclonic seizures Initial: ≤1.5 mg/day Tolerance may develop after 1–6 months. Intranasal spray is an orphan drug for recurrent acute repetitive seizures. Clorazepate Adjunct therapy for focal seizures Maximal initial: 22.5 mg/day Not recommended for children under 9 years. Midazolam Orphan drug for status epilepticus, nerve agent-induced seizures, acute repetitive seizure clusters - - Diazepam Management of status epilepticus - Not useful orally for seizure disorders. Lorazepam Management of status epilepticus - - Clobazam Lennox-Gastaut syndrome (≥2 years old) Initial: 5 mg every 12 h, Max: 40 mg/day -

9. Barbiturates Medication Mechanism of Action ADME Therapeutic Uses Adverse Effects Phenobarbital Potentiates synaptic inhibition via GABAA receptor; increases duration of GABAA receptor-mediated currents. Oral absorption is slow; metabolized by hepatic enzymes (UGT, CYP2C, CYP3A); therapeutic plasma concentrations: 10-35 μg/mL. Effective for generalized tonic- clonic , focal-to-bilateral tonic- clonic , and focal seizures; not effective for absence seizures. Sedation, nystagmus, ataxia, irritability, hyperactivity. Primidone Metabolized to active metabolites: phenobarbital and PEMA; antiseizure effects of metabolites. Rapid oral absorption; peak plasma concentration in ~3 hours; metabolized to phenobarbital and PEMA; therapeutic plasma concentrations: 8-12 μg/mL. Historically used for focal-onset or generalized epilepsy; first-line therapy for essential tremor (with propranolol). Pronounced drowsiness, ataxia, vertigo.

10. Conclusion : Phenobarbital and primidone , while effective in epilepsy therapy, have significant sedative effects and potential adverse effects. Careful monitoring of plasma concentrations and adverse effects is essential for optimizing therapeutic efficacy while minimizing side effects.  These medications continue to play important roles in epilepsy treatment, particularly for generalized tonic- clonic and focal seizures, but their use requires consideration of individual patient factors and close monitoring.

11. IMINOSTILBENES Carbamazepine Aspect Details Mechanism of Action Derived from iminostilbene, related to tricyclic antidepressants. Acts by slowing Na+ channel recovery from inactivation, limiting action potential firing. ADME Erratically absorbed, peak plasma levels in 4–8 hours. Metabolized primarily by CYP3A4, forming active metabolite 10,11-epoxide. Therapeutic Uses Effective for generalized tonic-clonic, focal aware, and impaired awareness seizures. Used in neuropathic pain like trigeminal neuralgia and bipolar disorder. Adverse Effects Can cause drowsiness, vertigo, ataxia, hematological toxicity, and hypersensitivity reactions. Serious effects include respiratory depression, water retention, and hepatic abnormalities. Interactions Induces metabolism of drugs like valproate, phenytoin, and phenobarbital. May lower concentrations of co-administered drugs like lamotrigine and topiramate .

12. Aspect Details Mechanism of Action Prodrug converted to eslicarbazepine, the active metabolite. Similar mechanism to carbamazepine, inhibiting fast voltage-gated sodium channels. ADME Rapidly metabolized to eslicarbazepine , with a short half-life of 1–2 hours. Inactivated by glucuronide conjugation and eliminated renally . Therapeutic Uses FDA-approved for focal seizures in adults and children as monotherapy or adjunctive therapy. Associated with fewer hypersensitivity reactions compared to carbamazepine. Adverse Effects Similar adverse effects to carbamazepine, but hyponatremia may occur more commonly. Fewer hypersensitivity reactions, with reduced cross-reactivity with carbamazepine. Oxcarbazepine Eslicarbazepine acetate Prodrug approved for monotherapy and adjunctive treatment of focal-onset seizures. Faster conversion to S- licarbazepine , similar mechanism of action to oxcarbazepine .

13. Ethosuximide SUCCINIMIDES Mechanism of action: Decreases small T-type calcium currents in thalamic neurons. Inhibition of T-type currents likely inhibits absence seizures by modulating thalamic oscillatory activity. ADME: Complete absorption after oral administration, peak concentration within 3 hours. Not significantly bound to plasma proteins, concentration in CSF similar to plasma. Metabolized by hepatic microsomal enzymes, with a plasma half-life of 40-50 hours in adults. Therapeutic uses: Effective against absence seizures but not tonic- clonic seizures. Initial dose varies with age, increased gradually until seizures are controlled or toxicity occurs. Maintenance dose typically 20 mg/kg/day. Adverse effects: Common dose-related side effects include GI complaints and CNS effects. Tolerance may develop to side effects. Serious adverse effects include skin reactions, hematological toxicity, and bone marrow depression.

14. Acetazolamide Limited efficacy against absence seizures due to rapid development of tolerance. Minimal adverse effects with moderate dosage for limited periods. Ezogabine ( retigabine ) First-in-class K+ channel opener. Enhances transmembrane K+ currents mediated by KCNQ family of ion channels. Rapidly absorbed after oral administration, requires thrice daily dosing. Associated with serious adverse effects, including blue discoloration, retinal abnormalities, and neuropsychiatric symptoms . Felbamate Not first-line therapy due to serious adverse effects. Inhibits NMDA-evoked responses and potentiates GABA-evoked responses. Used in patients with refractory focal and secondarily generalized seizures or Lennox- Gastaut syndrome. Gabapentin and Pregabalin Bind to α2δ-1 subunit of Ca2+ channels. Effective for focal onset seizures, with or without progression to bilateral tonic- clonic seizures. Gabapentin also indicated for neuropathic pain associated with postherpetic neuralgia. No known interactions with other antiseizure drugs. OTHER ANTISEIZURE DRUGS

15. Lacosamide Enhances slow inactivation of voltage-gated Na+ channels. Approved for monotherapy and add-on therapy for focal-onset seizures. Generally well tolerated, with minor adverse effects like headache and dizziness. Lamotrigine Blocks sustained repetitive firing of neurons and delays recovery from inactivation of Na+ channels. Useful for monotherapy and add-on therapy of focal and secondarily generalized tonic- clonic seizures. Superior to placebo in children with newly diagnosed absence epilepsy. These drugs offer a spectrum of mechanisms and therapeutic options for managing various types of seizures, with considerations for efficacy and adverse effect profiles. The most common adverse effects of lamotrigine include dizziness, ataxia, blurred or double vision, nausea, vomiting, and rash when added to another antiseizure drug. Rare but serious adverse effects such as Stevens-Johnson syndrome and disseminated intravascular coagulation have been reported. Notably, the incidence of serious rash in pediatric patients is higher (~0.8%) compared to adults (0.3%).

16. Drug Indication Mechanism of Action Levetiracetam Adjunctive therapy for various types of seizures, including partial-onset seizures and generalized tonic-clonic seizures in adults and children over four years old. Binds to synaptic vesicle protein 2A (SV2A), modulating neurotransmission. The exact mechanism is not fully understood. Brivaracetam Adjunctive therapy for partial-onset seizures in patients aged 16 years and older. Binds to synaptic vesicle glycoprotein 2A (SV2A) with higher affinity than levetiracetam. Also inhibits sodium channels. Perampanel Treatment for partial-onset seizures with or without secondarily generalized seizures. Non-competitive AMPA glutamate receptor antagonist. Inhibits AMPA receptors, preventing repetitive neuronal firing. Rufinamide Adjunctive therapy for seizures associated with Lennox-Gastaut Syndrome (LGS). Prolongs the inactive state of voltage-gated sodium channels, stabilizing neuronal membranes and blocking the spread of partial seizure activity. Also inhibits mGluR5 subtype receptors. Common adverse effects include headache, dizziness, and fatigue.

17. Stiripentol is an aromatic alcohol that is structurally different from other ASDs. It gained orphan drug status for treating Dravet syndrome in 2008, but it has not been approved by the FDA . While its antiseizure mechanism is not fully understood, stiripentol might raise CNS levels of inhibitory GABA. Its absorption is rapid, with nonlinear elimination kinetics. It interacts with various drugs, inhibiting CYPs 3A4, 1A2, and 2C19. Used with clobazam and valproate to treat refractory seizures, particularly in patients with Dravet syndrome. Common side effects include anorexia, weight loss, and drowsiness. Tiagabine is a derivative of nipecotic acid, approved for focal seizures in adults. It inhibits the GABA transporter GAT-1. Topiramate , a sulfamate -substituted monosaccharide, is FDA-approved for various seizure types and migraines. It works by reducing Na+ currents, enhancing postsynaptic GABAA receptor currents, and inhibiting certain glutamate receptors.

18. Valproate , discovered by chance, inhibits seizures through complex mechanisms and interactions. It is broadly used for various seizure types. The common side effects of valproate include GI symptoms, sedation, and alopecia. Vigabatrin , approved for refractory focal seizures in adults, is considered for infantile spasms. It irreversibly inhibits GABA transaminase. However, it can cause vision loss, weight gain, and seizures. Zonisamide is particularly effective as an adjunct therapy for focal seizures and inhibits the firing of spinal cord neurons by various mechanisms. Its common side effects include somnolence, dizziness, and cognitive impairment, while serious issues like renal calculi and metabolic acidosis are rare but possible.

19. REFERENCE   1. Laurence L. Brunton , PhD,Randa Hilal-Dandan , PhD,Björn C. Knollmann , MD, PhD,THE Pharmacological basis of therapeutics,13 th ed. Mc Graw Hill Education, Newyork,2017,303-326. 2.Tripathi.K.D,Essentials of Medical Pharmacology. 7 th Edition. Jaypee Brothers Medical Publishers (P) Ltd., New Delhi,2013,412-421. 3.https:// en.m.wikipedia.org /wiki/Convulsion 4.https:// www.happiesthealth.com /articles/neurology/difference-between-seizure-and-epilepsy 5.https:// en.m.wikipedia.org /wiki/Anticonvulsant 6.https:// pubmed.ncbi.nlm.nih.gov /8719918/#:~:text=Depending%20on%20their%20mechanism%20of,mechanism%20of%20action%20is%20unresolved. 7.https:// www.erdemdemirkan.av.tr /?g=the-pharmacology-and-clinical-efficacy-of-antiseizure-medications-from-uu-52zzzKIN 8.https:// link.springer.com /article/10.1007/s40263-021-00827-8 9.https:// www.cancer.gov /publications/dictionaries/cancer-terms/ def /anticonvulsant