Anticonvulsant Pharmacology

• Anticonvulsant pharmacology covers the use of medications to manage seizures and epilepsy.

Lecture Objectives

• Define epilepsy and distinguish between different types of seizures.
• Discuss the pathophysiology of epilepsy.
• Explain the mechanisms of action of anticonvulsant drugs, including their effects on sodium channels, calcium channels, and GABAergic activity.
• Categorize anticonvulsant drugs based on chemical structure and action mechanisms.
• Identify major anticonvulsants and their specific uses for different seizure types.
• Describe the absorption, distribution, metabolism, and excretion of anticonvulsant drugs.
• Discuss the pharmacodynamic properties and therapeutic targets of anticonvulsants.
• Outline goals for anticonvulsant therapy.
• Discuss side effects, adverse reactions, and contraindications of anticonvulsant medications.
• Highlight important drug interactions and patient management considerations.

Epilepsy

• Epilepsy is a chronic brain disorder characterized by recurrent, unprovoked seizures.
• Seizures involve abnormal electrical discharges leading to loss of consciousness, unusual movements, altered behavior, and distorted perceptions.
• Symptom specifics depend on where the abnormal firing originates.
• Epilepsy can be idiopathic or caused by brain disorders like malformations, strokes, and tumors, leading to symptomatic epilepsy.
• Epileptic seizures start in a group of neurons (the epileptogenic focus) that are hyperexcitable and discharge periodically.

Seizure Types

• Generalized seizures involve aberrant electrical discharge diffusely affecting the entire cortex of both hemispheres from onset, usually causing loss of consciousness.
• Generalized seizures often result from metabolic or genetic disorders.
• Generalized seizures include infantile spasms, absence, tonic-clonic, atonic, and myoclonic seizures.
• Focal (partial) seizures involve excess neuronal discharge in one cerebral cortex.
• Focal seizures are often due to structural abnormalities.
• Focal seizures can be simple (no impairment of consciousness) or complex (reduced but incomplete loss of consciousness).
• Focal seizures may be followed by a generalized seizure.
• Focal seizures may be preceded by an aura involving sensory, autonomic, or psychic sensations, and typically end spontaneously in 1-2 minutes.
• Absence seizures manifest as staring spells.

Status Epilepticus

• Status epilepticus involves at least one of the following:
• Tonic-clonic seizure activity lasting longer than 5 minutes
• Two or more seizures occur between which the patient does not fully regain consciousness.
• Initial treatment for status epilepticus (5-20 minutes) includes IV lorazepam (Ativan).
• when IV access isn't available, administer IM midazolam.
• If no hospital access is available, administer diazepam rectally.
• Phase 2 treatment (20-40 minutes) may involve IV fosphenytoin, valproic acid, levetiracetam, or phenobarbitone.

Treatment Goals & Principles

• Treatment goals are to keep patients seizure-free without dose-dependent toxicity.
• If possible, monotherapy is the preferred long-term treatment strategy.
• If seizures aren't controlled with the maximum dose of a single drug, replace it with another, gradually decreasing the dose of the old drug while introducing the new one.
• Abrupt withdrawal of anticonvulsants can cause status epilepticus.

Anti-Epileptic Drugs (AEDs)

• AEDs control seizures but do not cure epilepsy and are usually taken for life.
• Drug selection depends on the acceptability of side effects and the number of doses influencing lifestyle.
• Sodium channel blockers include phenytoin, fosphenytoin, carbamazepine, and oxcarbazepine.
• T-type calcium channel blockers include ethosuximide.
• GABA enhancers include phenobarbitone and benzodiazepines. - GABA analogues include gabapentin and pregabalin.
  • Miscellaneous AEDs include valproic acid, levetiracetam, lamotrigine, tiagabine, ezogabine, acetazolamide, and vigabatrin.

Sodium Channel Blockers

• Phenytoin, Fosphenytoin, Carbamazepine, Oxcarbazepine, and Lacosamide are sodium channel blockers.

Phenytoin

• Phenytoin prodrug is Fosphenytoin
• Mechanism of action: Blocks voltage-gated sodium channels.
• Indication: focal and generalized tonic-clonic seizures, excluding absence seizures, and status epilepticus.
• The dose is 200-600 mg daily, with a maximum of 400 mg at night.
• Pharmacokinetics: non-linear.
• Drug interactions: hepatic enzyme inducer exhibiting zero-order kinetics.
• Contraindications: HLA-B*1502 test needed for Asians.
• Adverse effects: nausea, vomiting, headache, disorientation, megaloblastic anemia, gingival hyperplasia, hirsutism, and loss of bone density.
• At increased doses can cause nystagmus, ataxia, lethargy, idiosyncratic rash, and exfoliative dermatitis.
• Note that Fosphenytoin is always dosed in Phenytoin equivalents, where 1 mg PE of Fosphenytoin = 1 mg of Phenytoin.
• IV Phenytoin should not exceed 50 mg/min, and IV Fospheytoin should not exceed 150 mg/min.

Carbamazepine

• Mechanism of action: Blocks sodium channels, inhibiting the generation of repetitive action potentials in the epileptic focus and preventing their spread.
• Indication: Is a first-line monotherapy for generalized tonic-clonic and partial (focal) seizures, trigeminal neuralgia, and bipolar disorder.
• The dose is 200 mg twice daily, then 300 mg with a maximum of 900 mg twice daily.
• Drug interactions: Induces hepatic enzymes, increasing the toxicity of MAOIs like tranylcypromine; MAOIs must be discontinued 14 days before starting carbamazepine.
• Adverse effects: ataxia, dizziness, sedation, Nausea, Vomiting, rashes including Stevens-Johnson syndrome, jaundice, dry mouth, aplastic anemia, leukopenia, and hyponatremia, especially in the elderly.
• Contraindications: MAO inhibitors, nefazodone, and NNRTIs.

Oxcarbazepine

• Mechanism of action: Blocks voltage-gated sodium channels, stabilizes hyper-excited neural membranes, suppresses repetitive neuronal firing, and reduces propagation of synaptic impulses.
• Indications: First-line monotherapy for generalized tonic-clonic and partial (focal) seizures; also used for trigeminal neuralgia.
• Adverse effects: Nausea and Vomiting as well as somnolence, dizziness, visual disturbances (double vision), drowsiness, tiredness, tremors, rash, balance and coordination problems.
• HLA-B*1502 test (Asians) and hyponatremia are a warning.
• Is better tolerated than carbamazepine.

Lacosamide

• Works by binding to collapsin response mediator protein-2 (CRMP-2), a phosphoprotein involved in neuronal differentiation and control of axonal outgrowth
• Sodium channel blocker that slowly inactivates voltage-gated Na+ channels
• Monotherapy in partial-onset seizures; adjunctive therapy in partial-onset and primary GTC seizures
• Contraindicated with amiodarone, beta-blockers, CCBs, and alcohol, can induce depression and cardiovascular disease, hepatic impairment, and renal impairment
• AE: N/V, diplopia, blurred vision
• BBW: prolong PR-interval, ↑arrhythmias

T-Type Calcium Channel Blockers

• Ethosuximide blocks T-type calcium channels, reducing the propagation of abnormal electrical activity in the brain.
• It's a first-line monotherapy for typical absence seizures.
• Common adverse effects: Fatigue, Gl disturbances (gastric pain), Headache, Itching, skin rashes (e.g. SJS), nausea, vomiting, sedation, ataxia, dizziness, euphoria, bone marrow suppression, weight loss, hiccups, etc.

GABA Enhancers

• Include Phenobarbitone, Benzodiazepines (Diazepam, Clonazepam)

Phenobarbitone

• Phenobarbitone treats all forms of epilepsy except absence seizures and is a first-line treatment in neonates.
• The dose ranges from 60-180 mg/day orally in 1-2 divided doses.
• Drug interactions: It is a hepatic enzyme inducer, increasing the metabolism of other AEDs, estrogens, progestogens, ARVs, alcohol, or other CNS depressants, leading to additive CNS depression.
• Common adverse effects include physiological dependence, tolerance, hangover, ataxia, sedation, nystagmus; paradoxical stimulation, behavioural and learning problems (in children); megaloblastic anaemia, and idiosyncratic rash.

Bezodiazepines

• Clonazepam, clobazam, diazepam, and lorazepam are benzodiazepines.
• They bind to GABA inhibitory receptors, reducing the firing rate.
• Reserved for emergencies or seizure attacks (status epilepticus).
• Clonazepam and clobazam serve as adjunctive therapy for particular types of seizures.
• Diazepam is available for rectal administration in children and can avoid or interrupt prolonged generalized tonic-clonic seizures.

GABA Analogs

• Gabapentin and Pregabalin

Gabapentin

• Gabapentin is an analogue of GABA, where it increases GABA release into nerve synapses and blocks N-Type Calcium Channels.
• It's used for focal seizures,( post-herpetic neuralgia, chronic pain, migraines, bipolar disorder)
• Dosage should be adjusted in renal disease and is well-tolerated by the elderly population with partial seizures, with fewer drug interactions.
• Interacts with antacids, morphine, fluoxetine, antipsychotics, cannabis, heroin, and naproxen.
• Common adverse effects: peripheral edema, weight gain, mild euphoria, fatigue, dizziness, drowsiness, and ataxia.

Pregabalin

• Binds to the auxiliary subunit of voltage-gated calcium channels.
• Affects focal-onset seizures, diabetic peripheral neuropathy, post-herpetic neuralgia, and fibromyalgia.
• Requires dosage adjustments in renal disease.
• Interacts with opioids, BDZs, antihistamines, and alcohol.
• Adverse effects: weight gain, impaired memory, peripheral oedema, and mild euphoria.

Miscellaneous AEDs

• Valproic acid, Levetiracetam, Lamotrigine, Topiramate, Tiagabine, Ezogabine, Acetazolamide, and Vigabatrin do not perfectly fit other categories; include drugs falling into more than one.

Valproic Acid

• Blocks sodium channels, GABA transaminase, and T-type calcium channels.
• Treats focal and primary generalized tonic-clonic seizures and all forms of epilepsy
• The first choice for patients on ART.
• The dose ranges from 500 mg twice daily to a max of 2500 mg daily.
• Drug interactions: induces hepatic enzymes.
• Contraindications: hyperammonemia and thrombocytopenia.
• Adverse effects: weight gain, Nausea, anorexia/ increased appetite, ataxia, sedation, alopecia, oedema, and PCOS.
• Can also cause hepatic failure, teratogenicity, and neural tube defects.

Levetiracetam

• Modulates transmission by binding to synaptic vesicle protein 2A (SV2A)- ↑affinity; partially inhibits N-type calcium currents → ↓calcium release from stores.
• It doesn't exhibit the same actions as classical anticonvulsants by inhibiting voltage-dependent Na+ channels or affecting GABAergic transmission.
• Used on focal, myoclonic, and generalized tonic-clonic seizures, as well as perioperative neurosurgery.
• Drug interactions: methotrexate, carbamazepine, sertraline, duloxetine, warfarin, and alcohol.
• Common adverse effects: mood alterations, ataxia, somnolence, dizziness, agitation, and weakness.

Lamotrigine

• Lamotrigine works by blocking Sodium Channels as well as HV-dependent calcium channels.
• Helps with focal, generalized, and absence seizures, Lennox-Gastaut syndrome, and bipolar disorder
• Slow dose titration is essential to minimize the risk of serious and life-threatening skin reactions (Stevens-Johnson syndrome); Decrease the Lamotrigine dosage if adding VPA
• Can interact with ARVs, sertraline, and fluoxetine, alcohol.
• Adverse reactions: ataxia, somnolence, dizziness, blurred vision, rash, and nausea/ vomiting.
• Black Box Warning is serious skin reactions (SJS/TEN).

Topiramate

• Topiramate blocks voltage-dependent sodium channels, reduces high-voltage calcium currents, and targets glutamate (NMDA) sites.
• Treats partial and primary generalized seizures, migraine prophylaxis, and obesity.
• Interacts with sodium valproate, zonisamide, hormonal contraceptives, CNS depressants, and alcohol.
• Common side effects include drowsiness, fatigue, weight loss, nervousness, renal stones, glaucoma, hyperthermia, and paraesthesia.
• Black box warning: metabolic acidosis, oligohydrosis (less sweating), nephrolithiasis, hyperammonaemia, and foetal harm.

Vigabatrin

• Irreversibly inhibits ꝩ-aminobutyric acid transaminase (GABA-T) enzyme, an enzyme responsible for the metabolism of GABA
• Helps with resistant partial seizures with or without secondary generalisation and infantile spasms (west syndrome)
• Can interact with amphetamine, dexamphetamine, levetiracetam, and topiramate
• Contraindications: vision loss and suicidal ideation, neurotoxicity, as well as peripheral neuropathy
• Adverse effects can be dizziness, drowsiness, weight gain, mental confusion, and psychosis
• Black Box Warning is permanent vision loss

Choice of AED Treatment

• AED treatment should be selected based on classification of the seizures, patient-specific variables like age, co-morbidities, and lifestyle, and drug characteristics such as drug interactions and cost.
• Drug selection depends on the drug toxicities profiles of agents and patient characteristics.
• Successful treatment relies on awareness and consideration of antiepileptics' MOA, pharmacokinetics, potential drug interactions, and adverse effects.

Conditions Lowering Seizure Threshold

• Anti-Psychotics, Anti-Virals, Buproprion, Carbapenems (e.g. Imipenem), Cephalosporins which are drugs and alcohol (ethanol) Withdrawal, Lithium, Lindane, Mefloquine are conditions that lower seizure threshold.
• Other drugs and conditions that lower seizure threshold include Meperidine, Metoclopramide, Penicillins and Fluoroquinolones, infection & fever, Theophylline, Tramadol, and Varenicline.

Summary of AEDs

• Selection of AED is patient-specific, considering seizure type, age, pregnancy, and side effects.
• All AEDs cause CNS depression.
• Consider other formulations for children with difficulty swallowing.
• All AEDs can cause bone loss and increase fracture risk.
• Supplement patients with Calcium and Vitamin D.
• AEDs have many drug interactions.
• Many AEDs are teratogenic and decrease oral contraceptive efficacy.
• Non-hormonal contraceptives should be used in patients taking AEDs.
• Dosage adjustment is required to maintain therapeutic levels and safety.
• ALL AEDs require MEDGUIDE information regarding suicide, teratogenicity, and Stevens-Johnson syndrome (SJS)/Toxic Epidermal Necrolysis (TEN).
• For chronic seizure management, avoid medications that lower the seizure threshold.
• Never stop AEDs abruptly.
• AEDs with the most drug interactions include carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbitone, primidone, topiramate, and valproic acid.