Medical Pharmacology Chapter 19: Drugs Used to Manage Seizure Disorders (Antiepileptics)

Seizure Types and Drug Classes

• Partial seizures

  • Simple partial:

    • Carbamazepine (Tegretol)

    • Phenytoin (Dilantin)

    • Phenobarbital (Luminal)

    • Primidone (Mysoline)

    • Valproic acid (Depakene, Depakote)

    • Gabapentin (Neurontin)

    • Lamotrigine (Lamictal)

  • Complex partial

    • Carbamazepine (Tegretol)

    • Phenobarbital (Luminal)

    • Phenytoin (Dilantin)

    • Primidone (Mysoline)

    • Valproic acid (Depakene, Depakote)

    • Lamotrigine (Lamictal)

  • Partial is secondarily generalized tonic-clonic seizures

    • Carbamazepine (Tegretol)

    • Phenobarbital (Luminal)

    • Phenytoin (Dilantin)

    • Primidone (Mysoline)

    • Valproic acid (Depakene, Depakote)

    • Gabapentin (Neurontin)

    • Lamotrigine (Lamictal)

     

•  Antiepileptic drugs side effect profiles

  • Most antiseizure medications tend to be sedating, with drowsiness observed.

  • Often sedative effect diminish over time.

  • Other common side effects are referable to the gastrointestinal tract.

  • For most antiseizure agents, there are low frequency, but serious side effects.

  • Primidone (Mysoline)/phenobarbital (Luminal) side effects:

    • Sedation

    • Vertigo, nausea, vomiting, ataxia, nystagmus, diplopia.  Feeling of intoxication immediately after ingestion.

    •  Serious adverse effects are uncommon but include rash, leukopenia, thrombocytopenia, lupus, and lymphadenopathy.

    • Megaloblastic anemia which response to folate

    • Osteomalacia (response to high dose vitamin D) 

    • Hypoprothrombinemia with hemorrhage in newborns of primidone (Mysoline)-treated mothers (vitamin K is effective for treatment or prophylaxis)

  • Carbamazepine (Tegretol):

    • Acute intoxication: stupor, coma, hyperirritability, convulsions, and respiratory depression

    • Long-term: drowsiness, vertigo, blurred vision

    •  Serious hematological toxicity: aplastic anemia, agranulocytosis

  • Ethosuximide (Zarontin):

    • The most common complaint is gastrointestinal upset, including nausea, vomiting and anorexia, and CNS effects including drowsiness, euphoria, headache and hiccough.  Some tolerance of these effects may develop.

    • Hematological disturbances include: leukopenia, thrombocytopenia and aplastic anemia.  Bone marrow depression may be fatal, although very infrequently so.

    •   Skin reactions, including Stevens-Johnson syndrome and exfoliative dermatitis have been reported

     

• Drug-Drug Interactions

  • Drug interactions: barbiturates (e.g. phenobarbital (Luminal), primidone (Mysoline))

    • Alcohol increases CNS depression barbiturates.

    • Phenobarbital (Luminal) increases metabolism of oral anticoagulants, corticosteroids, oral contraceptives, anti-epilepticus, and digitoxin (Crystodigin).

  • Drug interactions: carbamazepine (Tegretol)

    • Verapamil (Isoptin, Calan) erythromycin estolate (Ilosone) may increase carbamazepine (Tegretol) levels

    • Carbamazepine (Tegretol) increases estrogen metabolism, thus decreasing effectiveness of oral contraception

    • Serum levels of other anticonvulsants may decreased due to increased from metabolism activity.

    • Carbamazepine (Tegretol) may decrease effectiveness of oral anticoagulants.

  • Drug interactions: clonazepam (Klonopin)

    • Alcohol or other CNS depressants will be additive in effect.

    • Clonazepam (Klonopin) increase phenytoin (Dilantin) levels.

  •  Drug interactions: ethosuximide (Zarontin)

    • Carbamazepine (Tegretol) decreases ethosuximide (Zarontin) levels

    • Isoniazid (INH) increases significantly ethosuximide (Zarontin) levels.

    • Ethosuximide (Zarontin) may alter phenobarbital (Luminal) and ethosuximide (Zarontin)'s levels

  • Drug interactions: phenytoin (Dilantin)

    • Alcohol decreases phenytoin (Dilantin) efficacy.

    • Other anticonvulsants may alter phenytoin (Dilantin) serum levels

    • Phenytoin (Dilantin) increases metabolism of corticosteroids and oral contraceptives, thus using oral contraceptives effectiveness.

    • Amiodarone (Cordarone), omeprazole (Prilosec), and chloramphenicol (Chloromycetin) increase phenytoin (Dilantin) levels.

  • Drug interactions: valproic acid (Depakene, Depakote)

    • Valproic acid (Depakene, Depakote) can cause serum phenobarbital (Luminal) to increase by as much as 40%.

    • Alcohol can potentiates CNS depression caused by antiepileptic agents.

    • Aspirin, dipyridamole (Persantine), or warfarin (Coumadin) administration together with valproic acid (Depakene, Depakote) can result in decreased clotting or spontaneous leading.

    • Salicylates can increase valproic acid (Depakene, Depakote) levels.

     

• Drugs Used to Treat Grand Mal, Status Epilepticus, and Partial Seizures

  • Phenytoin (Dilantin)

    • Phenytoin is effective in treating all types of partial and tonic-clonic seizures but NOT absence seizures.

    • It is one of the most widely used agents.

  • Benzodiazepines: Drug of choice by IV for termination of status epilepticus

    •  Diazepam (Valium)  Adverse Effects:

      • By injection: shock, coma, acute alcohol intoxication, infants < 30 days old

      • By tabet: children less than 6 months; acute narrow angle glaucoma, untreated open angle glaucoma, during or within 14 days of MAO inhibitor therapy; safe use in pregnancy not established

    • Clonazepam (Klonopin)

      • Clonazepam is useful in treating myoclonic seizures in children and absence seizures.

      • Clonazepam may also be used (sometimes in combination with other drugs) to treat:

        •  Akinetic seizures

        •  Lennox-Gastaut syndrome

        •  Absence seizures refractory to succinimides or valproic acid (Depakene, Depakote)

        •  Infantile spasms

        •  Restless legs.

      • Adverse effects:

        • The most common side effect with long-term clonazepam use is lethargy and drowsiness.

  • Barbiturates:

    • Phenobarbital (Luminal):

      • Phenobarbital is effective in treating generalized tonic-clonic seizures and partial seizures.

      • It is one of the most widely used agents because of its efficacy, low toxicity and low cost.

    • Primidone (Mysoline):

      • Primidone is effective against tonic-clonic and partial seizures.

      • Primidone's antiseizure efficacy is due both to the drug itself and to its active metabolites, especially phenobarbital.

      • Adverse effects:

        • Sedation

        • Vertigo, nausea, vomiting, ataxia, nystagmus, diplopia. feeling of intoxication immediately after ingestion

  • Valproic acid (Depakene, Depakote)

    • Valproic acid (Depakene, Depakote) is effective in partial and generalized seizures

    •  Valproic acid (Depakene, Depakote) is also effective in treatment of absence seizures.

• Absence seizures

  • Absence seizure is a seizure type and epileptic syndrome

  • characterized by a very brief, sudden onset, period of altered consciousness, often with minimal warning.

  • Post-ictal symptoms are lacking.

  • Absence seizures occur with automatisms (chewing, lip smacking, etc), clonic movements (eyelid flutter), atonic and tonic symptoms and myoclonus.

    • Tran, T.A., Seizures, In, Medicine for the Practicing Physician, (Hurst, J.W., editor-in-chief) Appleton and Lange, 1996, p. 1801.

  • Management of absence seizures

    • Ethosuximide and valproic acid:

      • These agents equally effective in treating absence (petit mal) seizures.

      • Using these agents, between 50% and 75% of newly diagnosed patients become seizure free.

    • If tonic-clonic seizures are also present or emerge during treatment, valproic acid would be preferred.

    • Clonzepam is also effective; however, tolerance to antiseizure properties of clonazepam in treating absence seizure make ethosuximide or valproic acid preferable.

      • McNamara, J.O. Drugs Effective in the Therapy of the Epilepsies In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.483

  • Ethosuximide (Zarontin)

    • Ethosuximide (Zarontin) is a central agent in treating absence seizures

    • Ethosuximide is more effective in managing absence seizures than trimethadione (Tridione) with fewer serious side effects.

  • Valproic acid (Depakene, Depakote)

    • Valproic acid (Depakene, Depakote) is effective in partial and generalized seizures

    • Valproic acid (Depakene, Depakote) is also effective in treatment of absence seizures.

    • The drug is well absorbed after oral administration, extensively protein bound and extensively metabolized--mostly conjugated (glucuronidation).

• Some Antiepileptic Drugs

  • Grand mal (tonic-clonic seizures)

    • Carbamazepine (Tegretol)

    • Clonazepam (Klonopin)

    • Diazepam (Valium);(status epilepticus)

    • Phenobarbital (Luminal)

    • Phenytoin (Dilantin)

    • Primidone (Mysoline)

    • Valproic acid (Depakene, Depakote)

  • Petit mal (absence seizures)

    • Acetazolamide (Diamox)

    • Ethosuximide (Zarontin)

    • Trimethadione (Tridione)

    • Valproic acid (Depakene, Depakote)

  • Partial Seizures

    • Carbamazepine (Tegretol)

    • Phenytoin (Dilantin)

    • Vigabratrin

     

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