Antiepileptic Drugs and Epilepsy

What is a Seizure?

• A seizure is a brief episode of abnormal electrical activity in the nerve cells of the brain.
• It may or may not lead to a convulsion.

What is Epilepsy?

• Epilepsy is a chronic, recurrent pattern of seizures.
• It results from excessive electrical activity of neurons located in the superficial area of the brain (cerebral cortex).
• It is the most common chronic neurologic illness.

Types of Epilepsy

• Primary (idiopathic) epilepsy: Epilepsy without an identifiable cause.
• Secondary epilepsy: Epilepsy has a distinct cause, such as trauma, infection, cerebrovascular disorder, or other illness.

Febrile Seizure

• Occurs in children aged 6 months to 5 years.
• Caused by fever.
• Children usually outgrow the tendency to have such seizures.
• Does not constitute a chronic illness.

Status Epilepticus

• Two or more seizures occur without recovery of full consciousness in between episodes.
• May be focal or primary generalized, convulsive or nonconvulsive.
• Life-threatening and requires emergency treatment.
• Therapy involves administering fast-acting medication, typically diazepam (the drug of choice).
• Once status epilepticus is controlled, long-term drug therapy is begun with other drugs, such as phenytoin, for the prevention of future seizures.

Antiepileptic Drugs

• Goal: to control or prevent seizures while maintaining a reasonable quality of life.
• In most cases, the therapeutic goal is to maximally reduce the incidence of seizures while minimizing drug-induced toxicity.
• Sometimes, a combination of drugs must be given to control the disorder.
• Single-drug therapy must fail before two-drug or multidrug therapy is attempted.
• Antiepileptic drugs should never be stopped abruptly unless a severe adverse effect occurs.
• Therapeutic drug monitoring of serum drug concentrations provides a useful guideline in assessing the effectiveness of therapy.
• Each patient should be monitored individually, and the dosages adjusted based on the individual case.

Mechanism of Action

• The exact mechanism of action of antiepileptic drugs is not known with certainty.
• Strong evidence indicates that they alter the movement of sodium, potassium, calcium, and magnesium.
• Regardless of mechanism, the overall effect is that antiepileptics stabilize neurons and keep them from becoming hyperexcited and generating excessive nerve impulses to adjacent neurons.

Indications

• Antiepileptic drugs are chiefly used for the long-term maintenance treatment of epilepsy.
• They are also useful for the acute treatment of convulsions and status epilepticus.

Drug Profiles

A. Benzodiazepines

• Bind to GABA inhibitory receptors to reduce firing rate.
• Most benzodiazepines are reserved for emergency or acute seizure treatment due to tolerance.
• Clonazepam and clobazam may be prescribed as adjunctive therapy for types of seizures.
• Diazepam is also available for rectal administration when oral administration is not possible.

B. Carbamazepine (Tegretol)

• Marketed in the late 1960s for the treatment of epilepsy in adults after its efficacy and safety for the treatment of trigeminal neuralgia were proved.
• Blocks sodium channels, thereby inhibiting the generation of repetitive action potentials in the epileptic focus and preventing their spread.
• Effective for treatment of focal seizures and, additionally, generalized tonic–clonic seizures, trigeminal neuralgia, and bipolar disorder.
• Associated with autoinduction of hepatic enzymes.
• Hyponatremia may be noted in some patients, especially the elderly, and may necessitate a change in medication.

C. Gabapentin

• Chemical analogue of GABA.
• Precise mechanism of action is not known.
• Indicated as an adjunct drug for the treatment of partial seizures and for prophylaxis of partial seizures.
• Effective as a single-drug therapy for the new-onset epilepsy.
• Also commonly used to treat neuropathic pain.
• Adverse effects include CNS and GI symptoms.

D. Phenobarbital

• Used primarily in the treatment of status epilepticus when other agents fail.
• Effective prophylactic drug for the control of febrile seizures.
• In developing countries, oral phenobarbital is often the drug of choice for routine seizure prophylaxis because of its lower cost compared with the newer drugs.
• Associated with physical dependence and withdrawal syndrome.
• Interacts with many drugs because it is a major liver enzyme inducer.
• Available in oral and injectable forms.
• Most common adverse effect is sedation.
• Contraindications include:
  • Known drug allergy
  • Liver or kidney impairment
  • Respiratory illness

E. Phenytoin

• Primarily indicated for the management of tonic-clonic and partial seizures.
• Most often taken orally or given intravenously if needed.
• Contraindications include:
  • Known drug allergy
  • Heart conditions that involve bradycardia
• Most common adverse effects are:
  • Lethargy
  • Abnormal movements
  • Mental confusion
• Long-term phenytoin therapy can cause:
  • Gingival hyperplasia
  • Acne
  • Hirsutism
• Can interact with other medications for two reasons:
  • First, it is highly bound to plasma proteins and competes with other highly protein-bound medications for binding sites.
  • Second, it induces hepatic enzymes.
• Generally well tolerated, highly effective, and relatively inexpensive.

F. Valproic acid

• Used primarily in the treatment of generalized seizures.
• Also shown to be effective in controlling partial seizures.
• Main reason for drug interactions is protein binding and liver metabolism.
• Available in both oral and injectable forms.
• Most serious adverse effects are:
  • Hepatotoxicity
  • Pancreatitis
• Contraindications include:
  • Known drug allergy
  • Liver impairment
  • Urea cycle disorders
• Common adverse effects include:
  • Drowsiness
  • GI disturbances (nausea, vomiting)
  • Tremor
  • Weight gain
  • Transient hair loss