Pharmacokinetics and Mechanisms of Antiepileptic Drugs

Carbamazepine

Blocks sodium channels, inhibiting repetitive action potentials in the epileptic focus and preventing their spread. Effective for focal seizures, generalized tonic-clonic seizures, trigeminal neuralgia, and bipolar disorder.

Eslicarbazepine

A prodrug converted to the active metabolite S-licarbazepine by hydrolysis. It is a voltage-gated sodium channel blocker approved for partial-onset seizures in adults.

Ethosuximide

Reduces propagation of abnormal electrical activity in the brain by inhibiting T-type calcium channels. Effective only in treating absence seizures.

Ezogabine

Thought to open voltage-gated M-type potassium channels leading to stabilization of the resting membrane potential. Exhibits linear pharmacokinetics and unique side effects include urinary retention and blue skin discoloration.

Fosphenytoin

A prodrug of phenytoin with a high protein binding rate and a half-life of 12-60 hours.

Gabapentin

Used for epilepsy with a low protein binding rate and a half-life of 5-9 hours.

Lacosamide

Has a low protein binding rate and a half-life of 13 hours.

Lamotrigine

Has a low protein binding rate and a half-life of 25-32 hours.

Levetiracetam

Has a low protein binding rate and a half-life of 6-8 hours.

Oxcarbazepine

A prodrug with a low protein binding rate and a half-life of 5-13 hours.

Phenobarbital

Has a low protein binding rate and a half-life of 72-124 hours.

Phenytoin

Has a high protein binding rate and a half-life of 12-60 hours.

Primidone

Has a high protein binding rate and a half-life of 72-124 hours.

Perampanel

Has a high protein binding rate and a half-life of 105 hours.

Pregabalin

Has a low protein binding rate and a half-life of 5-6.5 hours.

Rufinamide

Has a low protein binding rate and a half-life of 6-10 hours.

Tiagabine

Has a low protein binding rate.

Topiramate

Has a low protein binding rate and a half-life of 21 hours.

Valproic Acid

Also known as Divalproex, has a moderate/high protein binding rate and a half-life of 6-18 hours.

Zonisamide

Has a low protein binding rate and a half-life of 63 hours.

Active Metabolite

A metabolite that has pharmacological effects similar to the parent drug.

Major Organ of Elimination

The primary organ responsible for the elimination of a drug from the body.

Half-Life

The time it takes for the concentration of a drug in the blood to reduce to half its initial value.

Protein Binding

The degree to which drugs attach to proteins in the blood, affecting their distribution and elimination.

Felbamate

Has a broad spectrum of anticonvulsant action with multiple proposed mechanisms including the blocking of voltage-dependent sodium channels, competing with the glycine coagonist binding site on the NMDA glutamate receptor, blocking of calcium channels, and potentiating GABA action.

Teratogenicity

The potential of a drug to cause developmental malformations in a fetus.

Gabapentin

An analog of GABA that is approved as adjunct therapy for focal seizures and treatment of postherpetic neuralgia, exhibiting nonlinear pharmacokinetics due to its uptake by a saturable transport system from the gut.

Lacosamide

In vitro affects voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing; approved for adjunctive treatment of focal seizures.

Lamotrigine

Blocks sodium channels and high voltage-dependent calcium channels, effective in a wide variety of seizure types, including focal, generalized, absence seizures, and Lennox-Gastaut syndrome.

Levetiracetam

Approved for adjunct therapy of focal onset, myoclonic, and primary generalized tonic-clonic seizures in adults and children; the exact mechanism of anticonvulsant action is unknown.

CYP2C19

An enzyme that metabolizes certain drugs, including Felbamate, which inhibits drugs metabolized by this enzyme.

CYP3A4

An enzyme that metabolizes a variety of drugs, including Carbamazepine and Clobazam.

CYP1A2

An enzyme involved in drug metabolism.

CYP2C8

An enzyme that metabolizes certain drugs.

CYP2C9

An enzyme that metabolizes certain drugs.

UDP-glucuronosyltransferase

An enzyme involved in the metabolism of drugs like Lamotrigine.

Aplastic anemia

A serious side effect associated with Felbamate, occurring at a risk of about 1 in 4000.

Hepatic failure

A serious risk associated with Felbamate use.

Nonlinear pharmacokinetics

A characteristic of Gabapentin due to its uptake by a saturable transport system from the gut.

Renal disease

Condition requiring reduced dosing of Gabapentin.

Dizziness

A common adverse event associated with Lacosamide treatment.

Headache

A common adverse event associated with Lacosamide treatment.

Fatigue

A common adverse event associated with Lacosamide treatment.

Bipolar disorder

A condition for which Lamotrigine is also used as a treatment.

Slow titration

Necessary with Lamotrigine to reduce the risk of rash, which may progress to a serious, life-threatening reaction.

Divalproex

A drug that significantly decreases lamotrigine clearance, leading to higher lamotrigine concentrations.

Levetiracetam

A drug with unknown anticonvulsant action that demonstrates high affinity for a synaptic vesicle protein (SV2A), well absorbed orally, excreted mostly unchanged in urine, and can cause mood alterations.

Oxcarbazepine

A prodrug rapidly reduced to the 10-monohydroxy (MHD) metabolite responsible for anticonvulsant activity, blocking sodium channels and modulating calcium channels, approved for use in adults and children with partial-onset seizures.

MHD

The metabolite of oxcarbazepine responsible for its anticonvulsant activity, blocking sodium channels.

Antiepilepsy Medications

A category of drugs used to prevent seizures in individuals with epilepsy.

Perampanel

A selective α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonist that reduces excitatory activity, has a long half-life for once-daily dosing, and is approved for adjunctive treatment of partial-onset seizures in patients 12 years or older.

Phenobarbital

A drug that enhances the inhibitory effects of GABA-mediated neurons, primarily used in the treatment of status epilepticus when other agents fail.

Primidone

A drug metabolized to phenobarbital and phenylethylmalonamide, both with anticonvulsant activity.

Phenytoin

A drug that blocks voltage-gated sodium channels, effective for focal and generalized tonic-clonic seizures and status epilepticus, inducing drugs metabolized by CYP2C and CYP3A families.

Fosphenytoin

A prodrug rapidly converted to phenytoin in the blood, can be administered intramuscularly, and is the drug of choice for IV and IM administration of phenytoin.

Saturable enzyme metabolism

A phenomenon where small increases in phenytoin dosage can produce large increases in plasma concentration, leading to drug-induced toxicity.

CNS depression

A side effect of phenytoin that occurs particularly in the cerebellum and vestibular system, causing nystagmus and ataxia.

Gingival hyperplasia

A condition where the gums grow over the teeth, which can occur as a side effect of long-term phenytoin use.

Peripheral neuropathies

A potential long-term effect of phenytoin use that may develop over time.

Osteoporosis

A potential long-term effect of phenytoin use that may develop over time.

CYP3A4

An enzyme that is less potently induced by oxcarbazepine compared to carbamazepine.

UGT

An enzyme system that is less potently induced by oxcarbazepine compared to carbamazepine.

Hyponatremia

An adverse effect of oxcarbazepine that limits its use in the elderly.

Adjunctive treatment

A therapy used in conjunction with other treatments, such as perampanel for partial-onset seizures.

Half-life

The time it takes for the plasma concentration of a drug to reduce to half its initial value, relevant for dosing schedules.

Voltage-gated sodium channels

Channels that phenytoin blocks by selectively binding to them in the inactive state, affecting seizure activity.

Tonic-clonic seizures

A type of seizure that phenytoin is effective in treating.

Status epilepticus

A medical emergency condition where seizures are prolonged or occur consecutively, treated primarily with phenobarbital.

Fosphenytoin

The trade name of fosphenytoin is Cerebyx®, which is easily confused with Celebrex®, the cyclooxygenase-2 inhibitor, and Celexa®, the antidepressant.

Pregabalin

Pregabalin [pree-GA-ba-lin] binds to the α2-δ site, an auxiliary subunit of voltage-gated calcium channels in the CNS, inhibiting excitatory neurotransmitter release.

Focal-onset seizures

Pregabalin has proven effects on focal-onset seizures.

Diabetic peripheral neuropathy

Pregabalin has proven effects on diabetic peripheral neuropathy.

Postherpetic neuralgia

Pregabalin has proven effects on postherpetic neuralgia.

Fibromyalgia

Pregabalin has proven effects on fibromyalgia.

Renal elimination of Pregabalin

More than 90% of pregabalin is eliminated renally.

Rufinamide

Rufinamide [roo-FIN-a-mide] acts at sodium channels and is approved for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in children over age 4 years and in adults.

CYP2E1 and CYP3A4

Rufinamide is a weak inhibitor of CYP2E1 and a weak inducer of CYP3A4 enzymes.

Food interaction with Rufinamide

Food increases absorption and peak serum concentrations of rufinamide.

QT intervals and Rufinamide

Adverse effects of Rufinamide include the potential for shortened QT intervals.

Tiagabine

Tiagabine [ty-AG-a-been] blocks GABA uptake into presynaptic neurons permitting more GABA to be available for receptor binding, enhancing inhibitory activity.

Adjunctive treatment in epilepsy

Tiagabine is effective as adjunctive treatment in partial-onset seizures.

Topiramate

Topiramate [toe-PEER-a-mate] has multiple mechanisms of action including blocking voltage-dependent sodium channels and reducing high-voltage calcium currents.

Migraine prevention

Topiramate is also approved for prevention of migraine.

Valproic acid and divalproex

Possible mechanisms of action include sodium channel blockade, blockade of GABA transaminase, and action at the T-type calcium channels.

Valproic acid

Valproic acid [val-PRO-ik A-sid] is available as a free acid.

Divalproex sodium

Divalproex [dye-val-PRO-ex] sodium is a combination of sodium valproate and valproic acid that is converted to valproate when it reaches the gastrointestinal tract.

Medication errors with Valproate

The risk for medication errors is high with valproate, and it is essential to be familiar with all preparations.

CYP2C9, UGT, and epoxide hydrolase

Valproate inhibits metabolism of the CYP2C9, UGT, and epoxide hydrolase systems.

Vigabatrin

Acts as an irreversible inhibitor of γ-aminobutyric acid transaminase (GABA-T), responsible for metabolism of GABA; associated with visual field loss in 30% or more of patients.

Zonisamide

A sulfonamide derivative with a broad spectrum of action, blocking voltage-gated sodium channels and T-type calcium currents; approved for focal epilepsy and may cause kidney stones.

Status Epilepticus

A condition where two or more seizures occur without recovery of full consciousness in between; life-threatening and requires emergency treatment.

Mean IQ at age 3 years

Cognitive function measurement indicating the average IQ of children exposed to antiepileptic drugs in utero.

Valproate

Associated with an increased risk of impaired cognitive function at 3 years of age; should be avoided in women of childbearing potential.

Folic Acid

Recommended in high doses (1 to 5 mg) for women considering pregnancy to prevent birth defects.

Antiepilepsy Medications

Medications that may increase the metabolism of hormonal contraceptives, potentially rendering them ineffective.

Pregnancy Planning

Vital for women with epilepsy as many antiepilepsy medications can affect fetal development.

Cognitive Function

Refers to the mental processes involved in gaining knowledge and comprehension, particularly in children exposed to antiepileptic drugs.

Neural Tube Defects

Birth defects that may occur due to certain antiepileptic medications during pregnancy.

SHARE Program

A restricted distribution program through which Vigabatrin is available.

Oligohidrosis

A condition where there is decreased sweating, which may occur with Zonisamide.