Partial Seizures

• focal in origin, often localized around a lesion within the brain

• simple=no loss of consciousness, may be sensory or motor
• complex=impairment or loss of consciouness
• secondarily generalized=spreads to entire brain, often progresses to tonic-clonic

Generalized seizures

global in origin

neocortical electric discharges synchronize with those from the thalamus

more likely to be congenital than lesion-associated

Absence: briefly impaired conscioussness ("zoning out spells")

Myoclonic: shocklike muscle contractions

Tonic: abrupt loss of muscle tone

Tonic-Clonic: loss of muscle tone followed by spasms

Seizure vs. Epilepsy

Seizure: finite episode of brain dysfunction resulting from abnormal neuronal discharge (often synchronous)

Epilepsy: group of chronic syndromes involving recurrent seizures

General Principles of Antiseizure Pharmacology

1. Most patients respond positively to medications, but about 25% are refractory to pharmacologic aid

2.Type of seizure determines which drugs are potentially useful

3. Side effects are significant and additive, drug-drug interactions are common

4. All antiseizure medications block excessive neuronal firing, usually by blocking ion channels

5. Anticonvulsants stop convulsions (mostly older drugs) while antiepileptics prevent recurring seizures (many newer drugs)

6. generally good oral absorption and bioavailability followed by hepatic metabolism w/various CYP450s

7. multiple drugs may be needed to acheive seizure control

Phenytoin (Dilantin)

MOA: blocks voltage-gated Na+ channels

Indications: Partial seizures and gen. tonic-clonics, mood stabilization in bipolar disorder, migraine prophylaxis

Contraindicated: Absence seizures

Toxicity: nystagmus, diploplia, ataxia, rash, hirsutism, gingival hyperplasia, facial "coarsening", teratogenic, drug interactions, sedation, variable bioavailability, anemia and leukopenia, cardiotoxicity from propylene glycol used in IV formulation

Random: highly plasma protein bound, elimination shifts from first to zero order at high doses

older highly effective drug, but largely replaced by less-sedating Diphenylhaydantoin orally or more water-soluble Fosphenytoin IV (no cardiotox.)

Phenytoin (Dilantin) Teratogenicity

Fetal Hydantoin Syndrome

mental retardation

abnormal facies: broad flat nasal ridge, epicanthal folds, hypertelorism, wide mouth, prominent upper lip

hypoplastic distal phalanges

Carbamazepine (Tegretol, Carbatrol)

MOA: inhibits voltage-gated Na+ channels and potentiates GABA-A post-synaptic receptors

Indicated for: partial and tonic-clonic seizures, mood stabilization in biopolar disorder

Toxicity: diploplia, ataxia, rash, mild leukopenia, rare but potentially fatal aplastic anemia

Effects on liver: potent CYP450 inducer! increases its own metabolism & that of other drugs over time

Random: tricyclic antidepressant,  non-sedating, highly plasma protein bound

Valproate (Valproic Acid, Depakote, Depakene)

MOA: activates K+ channels to hyperpolarize membrane, inhibition of thalamic Ca2+ voltage-gated channels, inhibits Na+ channels and GABA transaminase  at high doses (usually too toxic to be useful)

Useful for: all generalized seizures, esp. myoclonic, also a mood stabilizer (for bipolar disorder) and migraine prophylactic

Toxicity: Nausea, epigastric distresss, hepatotoxicity rare but severe esp. if under 2 years old (monitor hepatic enzymes for first 4 months then sporadically), highly teratogenic

Random: carboxylic acid, highly plasma protein bound, hepatic biotransformation to toxic compound

Topiramate (Topamax)

MOA: voltage-gated Na+ channel inhibitor, binds and potentiates postsynaptic GABA receptors, may also block glutamate receptors, multipart MOA increases effectiveness of drug (newer drug)

Used for: partial seizures, tonic-clonic

Toxicity: parasthesias, fatigue, decreased mental acuity, anxiety, confusion, glaucoma (must discontinue if vision changes occur!)

Elimination: hepatic and renal (both organs must be functional!)

newer drug

Lamotrigine (Lamictal)

MOA: inhibits voltage-gated Na+ channels and thalamic calcium channels

Indications: partial or tonic-clonic seizures (classified as broad spectrum in CNS notes) newer drug

Adverse: dizziness, headache

Toxicity: rashes, Stevens-Johnson syndrome/toxic epidermal necrolysis esp. in kids

Elimination: hepatic glucuronidation (not safe for neonates!)

Zonisamide (Zonegran)

MOA: inhibits voltage-gated sodium and calcium channels

Used as: adjunct tx for refractory partial seizures (classified as broad spectrum in CNS lecture)

Adverse: somnolence and fatigue common, depression and psychosis less common

Toxicity: severe skin rashes!, renal calculi

Antiseizure medications that block voltage-gated Na+ channels

Phenytoin

Carbamazepine

Valproate

Topiramate

Lamotrigine

Zonisamide

dependant on frequency of neuronal discharge, therefore most useful in rapid-fire neurons

Antiseizure meds. that increase GABA mediated Cl- flux

Phenobarbital

Primidone

Tigabine

Gabapentin

Carbamazepine

Valproate

Topiramate

Diazepam (and other benzodiazepines)

Phenobarbital (Luminal)

MOA: enhances GABA mediated Cl- flux duration

Used for: most seizure types, esp. good for partial and generalized

Adverse: sedative activity typical since it is a barbiturate, tolerance, dependence

Toxicity: respiratory depression, coma, death

(rarely used now according to CNS notes)

Random: one of the first antiseizure drugs

Primidone (mysoline)

metabolized by liver to Phenobarbital, a barbiturate (sedating, tolerance and dependence, respiratory depression)

very effective in infants with adequate liver function

Tigabine (Gabritril)

MOA: inhibits GABA transporter reuptake, increasing synaptic GABA levels

highly effecibe newer drug

Adverse: Sedation at high doses

Toxicity: generally well tolerated, tremor, anxiety, depression, psychosis (withdraw drug!)

Gabapentin (neurontin)

MOA: unclear--enchances presynaptic GABA concentrations, GABA analogue but doesn't activate receptors

Uses: refractory partial seizures, neuropathic pain esp. postherpetic neuralgia & trigeminal neuralgia, newer drug

Toxicity: well tolerated, sedation at high doses

Elimination: renal mostly in unchanged form--very little hepatic metabolism (safer for patients with liver compromise but more dangerous for those with kidney failure)

Antiseizures meds. that block thalamic calcium channels

Ethosuximide

Valproate

Lamotrigine

Zonisamide

Ethosuximide

MOA: blockage of thalamic calcium channels

used ONLY for uncomplicated Absence seizures

highly effective and well tolerated

Adverse: gastric distress (N/V and anorexia), rash that starts like an insect bite but spreads esp. on face, blood dyscrasias

low clearance rates, relatively inactive metabolites

Levetiracetam (Keppra)

adjunct against partial seizures MOA unknown (this is widely used as a first line broad-spectrum antiseizure drug according to CNS notes)

Adverse: sedation and dizziness

Felbamate (Felbatrol)

MOA: blocks glutamate NMDA receptors

newer drug, adjunct for refractory partial seizures

Toxicity: aplastic anemia, hepatitis

Drugs used to treat Simple Partial Seizures 

(focal jerking/paresthesia/psychic symptoms/autonomic disfunction, no impairment of consciousness)

newer: Levetiracetam, Tiagabine, and Zonisamide 

Gabapentin, Lamotrigine Topiramate

older: Carbamazepine, Phenytoin, Valproate

low doses often effective

Drugs used to treat Complex Partial Seizures

(impaired consciouness and focal signs)

newer: Gabapentin, Lamotrigine, Levetriacetam, Tigavine, Topiramate, Zonisamide

older: Carbamazepine, Phenytoin, Valproate

Drugs used to treat Partial seizures with Secondary Generalization

newer: Lamotrigine (limited by hepatotoxicity), Topiramate and Gabapentin (adjuntive drugs for refractory cases), Vigabatrin (alternative)

older: Carbamazipine, Phenytoin, and Valproate rapid first line drugs

Phenobarbital and Primidone alternative drugs in adults

Primidone is first line in infants

Drugs used to treat Absence Seizures

(staring spells, automatisms, subtype of generalized)

newer: Lamotrigine

older: Ethosuximide and Valproate preferred due to low sedation (valproate if concomitant tonic-clonic or myoclonic seizures present)

Clonazepam

Drugs used to treat Myoclonic Seizures

(electric appearing muscle twitches, subtype of generalized)

newer: Topiramate

Levetiracetam, Lamotrigine, Zonisamide as back-up drugs

Felbamate as adjunct (hematotoxic and hepatotoxic)

older: Valproate (first line), Clonazepam (limited by sedation)

Drugs used to treat Tonic-Clonic Seizures

(collapse in tonic phase then twitching clonic phase, "grand mal" subtype of generalized)

newer: Lamotrigine (limited by hepatotoxicity), Topiramate and Gabapentin (adjuntive drugs for refractory cases)

older: Carbamazipine, Phenytoin, and Valproate rapid first line drugs

Phenobarbital and Primidone alternative drugs in adults

Primidone is first line in infants

Treatment of Status Epilepticus

(sustained seizure, most often tonic-clonic, >30 minute duration untreated, 30% mortality, severe muscle and brain damage possible)

respiratory, cardiovascular, and metabolic supportive care

IV diazepam/lorazepam to terminate seizure, rectal diazepam (Diastat) is also used 

followed by IV phenytoin (despite renal and cardiac toxicity due to propylene glycol in IV phenytoin) for long-term therapy (less sedating than benzodiazepines)

IV fosphenytoin (Cerebyx) is safter since it is formulated with water not propylene glycol

Phenobarbital may be used in children 

General anesthesia as last resort in refractory cases

Benzodiazepines used to treat seizures

Diazepam, Clonazepam, Clorazepate, Lorazepam, Nitrazepam

MOA: binds GABA A receptors and increases frequency of Cl- ion flux

used for absence, myoclonic and tonic-clonic seizures, IV or rectal forms (diazepam only) used to terminate status epilepticus 

sedating, tolerance and dependence inducing, use limited by respiratory depression

Barbiturate and Benzodiazepine Overdose/Toxicity

life-threatening respiratory depression

Phenobarbital, Primidone, Diazepam, Clonazepam, Clorazepate, Lorazepam, Nitrazepam

supportive ventilatory care and flumazenil to treat

Drug-drug interactions that increase antiseizure med. plasma levels

cause increased toxicity

drugs that inhibit hepatic metabolism of the antiseizure meds. (H2 inhibitors and PPIs tend to do this)

drugs that displace plasma protein bound antiseizure meds. (like phenytoin) from albumin and other proteins

Drug-drug interactions that lower plasma levels of antiseizure meds.

cause increases in seizure frequency and severity

drugs that induce hepatic metabolism (like rifampin)

Important Phenytoin Interactions

phenobarbital, rifampin, and carbamazepine decrease plasma levels by inducing CYP450s

sulfonamides and valproic acid, increase levels by competing for plasma protein sites

cimetidine, proton pump inhibitors, and isoniazid increase levels by inhibiting hepatic metabolism

Safer IV alternative to Phenytoin for status epilepticus

Fosphenytoin

metabolized to phenytoin but formulated without cardiotoxic propylene glycol

Important Carbamazepine interactions

carbamazepine is a self-inducer (dose must be raised as hepatic metabolism is upregulated)

propoxyphene and valproic acid increase levels by inhibiting hepatic metabolism

Important Valproic Acid Interactions

competes with phenytoin for albumin binding sites (increases free plasma levels of both)

metabolism inhibited by phenytoin, phenobarbital, lamotrigine

increases ethosuximide levels 

Vigabatrin

 MOA: irreversible inhibitor of GABA transaminase (enzyme important in terminating GABA action)

newer antiseizure drug, very effective

Elimination: renal mostly in unchanged form--very little hepatic metabolism (safer for patients with liver compromise but more dangerous for those with kidney failure)

Drugs that prolong Na+ channel inactivation at high, usually toxic, doses

Phenobarbital

Valproic Acid

Treatment of Infantile Spasms

Corticotropin and cortiocsteroids-->Cushingoid effects

Benzodiazepines and other anticonvulsants (limited efficacy)

Valproic Acid (Valproate) Teratogenicity

neural tube defects

big problem

drug contraindicated in women with child-bearing potential unless no other medications effective in controlling seizures