Anticonvulsants (Antiseizure Drugs) — Classification and
Side Effects
Definitions and Classification of Seizures
Epilepsy is a group of neurological disorders characterized by
the recurrence of seizures. A seizure is a brief surge of
uncontrolled, abnormal electrical activity in the brain which
may produce a physical convulsion in some individuals or
minor physical signs in others. Yet other people may suffer
thought disturbances or a combination of symptoms. Many
structures and processes are involved in the development of a
seizure, including neurons, ion channels, receptors, glia, and
inhibitory and excitatory synapses.
Epilepsy is defined by any of the following:
1. At least two unprovoked (or reflex) seizures
occurring greater than 24 hours apart
2. One unprovoked (or reflex) seizure and a probability
of further seizures similar to the general recurrence
risk (at least 60 %) after two unprovoked seizures,
occurring over the next 10 years
3. Diagnosis of an epilepsy syndrome
Anti-seizure or antiepileptic drugs, therefore, are targeted to
inhibit neurotransmission. This can be achieved via blocking
sodium or calcium excitatory channels/currents, enhancing the
inhibitory activity of gamma-aminobutyric acid (GABA), or
by blocking glutamate receptors.
Seizures can be primary (idiopathic) or secondary to a specific
cause such as trauma or a tumor. Most antiseizure drugs
require dose adjustment in patients with liver and/or kidney
failure, and some have considerable drug-drug interactions.
Seizures are clinically classified as partial or generalized:
Partial seizures
 Simple partial seizures, in which consciousness is not
impaired.
 Complex partial seizures, in which consciousness is
impaired.
 Both types of partial seizures can spread, resulting
in secondarily generalized tonic-clonic seizures.
Generalized seizures
Generalized seizures are those in which the first clinical
changes indicate that both hemispheres are initially involved.
Consciousness usually is impaired during generalized seizures,
although some seizures, such as the myoclonic type, may be so
brief that impairment of consciousness cannot be assessed.
 Generalized tonic-clonic seizures, aka grand mal or
GTC
 Absence seizures, aka petit mal seizures
 Tonic seizures
 Atonic seizures
 Clonic seizures
 Myoclonic seizures
 Infantile spasms
The meanings of some of the terms involved are as follows:
 Simple: no loss of consciousness
 Complex: accompanied by loss of consciousness
 Partial: a part of the body is involved
 Complete: the whole body is involved, e.g., status
epilepticus
 Absence: no epileptic movements, but there is
impaired consciousness
Relevant Pathophysiology of Seizure Types
Focal
 Decreased inhibition—defective activation of
GABA neurons, defective GABA-A/ -B inhibition,  a
defect in intracellular calcium regulation
 Increased excitation—increased activation of
glutamate N-methyl-D-aspartate (NDMA) receptors,
increased synchrony or activation of neurons
Generalized
 Altered thalamocortical rhythms (regulated by the
T-type calcium channels/currents)
Antiseizure Drugs (Anticonvulsants)
As already mentioned, the main effect of antiseizure drugs is
to suppress the abnormal electrical activity at the epileptic
foci in the brain. This is achieved by many different
mechanisms.

Sodiu
m channel blockade: phenytoin and phenobarbital and
valproic acid at high doses
The block of voltage-gated sodium channels in neuronal
membranes prevents Na+ influx, which results in
decreased axonal conductance by increasing the refractory
period of the neuron.
Promotion of GABA-related inhibition:
 Increase the frequency of chloride ion channel
opening—benzodiazepines
 Increase the duration of chloride ion channel
opening—barbiturates, such as phenobarbital

Ir
reversible inactivation of GABA amino
transaminase (which terminates the activity of
GABA)—vigabatrin and at high doses valproic
acid
 Inhibition of a GABA transporter (GAT-1), thereby
prolonging GABA action—tiagabine
 Structural analog of GABA—gabapentin
Glutamate NMDA receptor blockade: decreased glutamic
acid excitability—felbamate
Calci
um channel blockade: inhibition of the T-type
Ca+ currents, especially in thalamic neurons, and decreased
Ca+ influx in presynaptic vesicles. E.g., ethosuximide and
valproic acid.
General pharmacokinetics
 Good absorption from the gut, with a bioavailability
of 80–100%
 They usually do not have high plasma protein binding
(exceptions: valproic acid, phenytoin, and tiagabine).
 Mainly metabolized by the liver
 Some are excreted unchanged in the urine, and these
have minimal drug-drug interaction.
 Usually, medium-to-long acting because of relatively
low plasma clearance; longer half-lives
 Phenytoin and gabapentin can exhibit nonlinear
pharmacokinetics.
Important Antiseizure Drugs
Phenytoin
Image: “2D structure of anticonvulsive drug phenytoin” by
Harbin – Own work. License: Public Domain
 Most widely used antiepileptic drug
 Fosphenytoin is a water-soluble prodrug; it can be
used parenterally (intravenous and intramuscular).
 Highly bound to plasma proteins
Mechanism of action: sodium channel blockade
Use:
 Status epilepticus
 GTC seizures (primary or secondary)
 Focal seizures
Notable adverse effects: Notable adverse effects: hyponatremia (partly due to
 Nystagmus and ataxia (because of cerebellar
depression), gingival hyperplasia, hirsutism, increased responsiveness of collecting tubules in the kidney to
diplopia, folic acid deficiency (manifested as
depression, apathy, psychomotor retardation, and ADH), dizziness, drowsiness, and nausea.
cognitive decline) Important points:
 Long-term use mild peripheral  It induces its own metabolism.
neuropathy, osteomalacia (due to vitamin D
 Inducer of CYP1A2, CYP2C, CYP3A, and UDP
metabolism abnormalities)
glucuronosyltransferase
 Fosphenytoin’s adverse effects (not found with
 Severe, even fatal, dermatological reactions may
phenytoin) include perineal paresthesias and
rarely occur—toxic epidermal
rash/itching, and these are concentration-dependent.
necrolysis and Stevens-Johnson syndrome.
 Stevens-Johnson syndrome and toxic epidermal
 Contraindicated in pregnancy due to the risk of fetal
necrolysis may occur.
carbamazepine syndrome
Important points:  Contraindicated in patients with a history of bone
 Zero order (non-linear) marrow suppression and administration of
 Requires dose adjustment in patients with renal monoamine oxidase (MAO) inhibitors in the past 14
failure. days.
 Slow-/extended-release formulation available, which Oxcarbazepine
can be administered once daily.
 Calcium and vitamin D supplements required in This is a prodrug and converted to active monohydroxy
long-term use to prevent osteomalacia.
derivative (MHD) metabolite. It shows fewer drug
Drug-drug interactions of phenytoin:
interactions than carbamazepine because it is a less potent
Drug Effect
inducer of CYP3A and UDP glucuronosyltransferase.
Lamotrigine Increased metabolism of lamotrigine (glucuronidation
Hyponatremia is a significant adverse effect (probably higher
induction)
than that in carbamazepine).
Oxcarbazepine Possible phenytoin toxicity with higher doses of
oxcarbazepine Valproic acid

Tiagabine Increased tiagabine metabolism (CYP3A4)

Topiramate Possible phenytoin toxicity with higher doses of

topiramate

Valproic acid Increased valproic acid metabolism à increased the

formation of a toxic metabolite. Thus, decreased
efficiency and increased toxicity Image: “2D structure of anticonvulsant valproic acid
(Depakote)” by Harbin – Own work. License: Public
Domain
Zonisamide Decreased zonisamide metabolism (CYP3A4)
 Highly bound to plasma proteins

Mechanism of action: sodium channel and calcium T-type

Carbamazepine
current blockade
Mechanism of action: sodium channel blockade
Inhibits GABA transaminase
Use:
Use:
 Focal seizures
 Complex partial seizures as monotherapy and/or
 GTC seizures
adjuvant
 Trigeminal neuralgia
 Simple and complex absence seizures
 Bipolar disorder
 Myoclonic seizures
 Not in absence seizures (may increase them)
 Migraine prophylaxis
 Bipolar mania.
 high syndro Stev
Notable adverse effects: weight gain, pancreatitis, volt me, ens-
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Important points: bloc
 Being a teratogenic drug it can cause spina bifida if kade

given during pregnancy.

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 Many of these drugs can cause drowsiness, sedation,
te mood/ behavior changes (particularly depression).
seizures)
.  Withdrawal of antiseizure drugs should be gradual;
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Status epilepticus

Notes: Status epilepticus is a series of epileptic episodes

Drug excreted unchanged through the kidneys requires dose (usually tonic-clonic) without recovery of consciousness

reduction in renal disease. between attacks. It is a life-threatening emergency.

Newer antiseizure drugs have somewhat fewer neurotoxic and Management of status epilepticus:
 Securing airway, breathing, and circulation
systemic side effects than the older/standard ones.  Start IV benzodiazepine (diazepam or lorazepam) for
immediate control
Other points on toxicity:
 Maintenance by phenytoin (fosphenytoin)
 Most antiseizure drugs are CNS depressants.
 If seizures continue, a loading dose of phenobarbital
Therefore, overdosage can depress the respiration
 If seizures still continue, intubate and
center.
administer general anesthesia.
 Respiratory depression is managed using
conservative treatment.
Infantile spasms 1. A 37-year-old female with a BMI of 29.6 is diagnosed

Infantile spasms are an epileptic syndrome characterized with absence seizures. Which of the following is the most

by myoclonic jerks; however, the manifestation varies. suitable drug? 

 Reported association with A. Carbamazepine
infection, kernicterus, tuberous sclerosis, B. Valproic acid
and hypoglycemia C. Lamotrigine
 Patients usually have cognitive deficiency, and D. Felbamate
therapy may not alleviate this. E. Phenytoin

Management of infantile spasms: 2. A 17-year-old male presented to the emergency

 Intramuscular corticotropin or oral prednisolone; if
seizures recur, repeat the course. department with fever, vomiting, facial edema, and an
 Benzodiazepines—clonazepam or nitrazepam (as erythematous rash over his face, neck, chest, and back. He
effective as corticosteroids)
 Vigabatrin (sometimes considered the drug of choice) had been diagnosed with juvenile myoclonic epilepsy two
Nonepileptic Uses of Antiseizure Drugs
weeks ago and had been started on an antiepileptic drug.

Which of the following drugs could be responsible?

A. Phenytoin
B. Lamotrigine
C. Clonazepam
D. Carbamazepine
E. Ethosuximide
Image: “Trigeminal Neuralgia.” by BruceBlaus – Own work.
License: CC BY-SA 4.0 3. A 68-year-old woman was newly diagnosed with
 Phenytoin is a group 1B antiarrhythmic agent.
 Several drugs, especially carbamazepine and epilepsy. Considering the adverse effect profile, especially
lamotrigine, are useful for bipolar disorder.
in an elderly person, which of the following drugs should
 Gabapentin is useful in postherpetic neuralgia.
 Carbamazepine is the drug of choice of trigeminal be prescribed?
neuralgia. A. Carbamazepine
 Many drugs are useful in migraine, e.g., phenytoin, B. Phenytoin
gabapentin, topiramate. C. Phenobarbital
D. Valproic acid
High-yield points to remember regarding antiseizure drugs E. Lamotrigine
High drug-drug interactions Phenytoin, carbamazepine,
valproic acid

Dose adjustment/cessation required in Gabapentin, levetiracetam,

renal insufficiency/failure topiramate,vigabatrin

Preferred in the elderly Gabapentin

Increase weight Carbamazepine, valproic acid

Decrease weight felbamate, topiramate
Weight neutral Lamotrigine, levetiracetam,
phenytoin

Can exacerbate seizures Carbamazepine—absence,

  atonic, or myoclonic seizures
Phenytoin, vigabatrin—
generalized seizures
Gabapentin—myoclonic jerks

Review Questions

The correct answers can be found below the references.