053 antiepileptic medication principle of clinical use

Antiepileptic Medication Principles of clinical use

Youmans Chapter 53

Older epileptic drugPhenytoin Loading : Adult 18 mg/kg,Ped 20 mg/kg

Maintenance : Adult 200-500 mg/d (MDF=qD), 100 mg PO TID, Peds 4-7 mg/kg/d (MDF=BID)

Carbamazepine Oral doseAdult 600-2000 mg/dPeds 20-30 mg/kg/d

Valproate (Depakine) Dose (MDF = q d)Adult 600-3000 mg/dPed 15-60 mg/kg/d

Phenobarbital and Primidone

Adult : loading 20 mg/kg maintenance 30-250 mg/dPed : loading 15-20 mg/kg maintenance 30-250 mg/d

Older epileptic drug

• Phenytoin(Dilantin)• Carbamazepine• Valproate(Depakine)• Phenobarbital and Primidone

Phenytoin(Dilantin)• Dose

– Loading : Adult 18 mg/kg,Ped 20 mg/kg– Maintenance : Adult 200-500 mg/d (MDF = q D)– 100 mg PO TID, Peds 4-7 mg/kg/d (MDF = BID)

• First-order kinetic at low level• Zero-order kinetic at therapeutic range• Volume of distribution(Vd) : 0.75L/kg• A dose of 7.5 mg/kg given intravenously raises the level

by 10 mg/L• Adult : 15 mg/L, 5-6 mg/kg/day (350-450 mg/day)

– Common dose of 300 mg/day often result in levels of 10 mg/L

Phenytoin(Dilantin)• Potent enzyme inducer lower the level of many drug

– carbamazepine, valproate, felbamate, lamotrigine, topiramate, zonisamide, and tiagabine

– warfarin, oral contraceptives, and cyclosporine

• Use– partial seizures (simple or complex without or with secondary

generalization)– generalized convulsive seizures– status epilepticus– neonatal seizures

Phenytoin(Dilantin)• IV administration, 50 mg/min or 1 mg/kg/min

– bradyarrhythmia – hypotension– skin necrosis

• CNS side effect– Nystagmus– Ataxia– lethargy.

• Delayes adverse effect– gingival hyperplasia– Hirsutism– peripheral neuropathy– bone demineralization secondary to reduced vitamin D levels.

Carbamazepine• Dose oral route (MDF = BID)

• Adult 600-2000 mg/d• Peds 20-30 mg/kg/d

• First-order kinetic• Autoinduction : induce hepatic enzymes that result in

increased metabolism of itself• USE– Partial seizure without or with secondary generalized seizure– Generalized tonic-clonic seizures

Carbamazepine• Against partial and secondarily generalized seizures,

phenytoin, CBZ, phenobarbital, and primidone are about equally effective in terms of seizure control

• no parenteral preparation• Side effect

– Neutropenia– Aplastic anemia– Hyponatremia(SIADH like effect)– movement disorders– allergic rashes– hypersensitivity syndrome

Valproate (Depakine)• Dose (MDF = q d)

– Adult 600-3000 mg/d– Ped 15-60 mg/kg/d

• USE– Partial seizure– Absence seizure– GTC seizure– Myoclonic seizure– Infantile spasm– Lennox-Gastaut syndrome

• Prolong the elimination(and raise the level) of other drugs

Valproate(Depakine)• Side effect

– Drowsiness– Transient hair loss– Dose-relates tremor– Fatal hepatotoxicity (< 2 Yr and in combination with other drug)– Pancreatitis– Thrombocytopenia– VPA-mediated disturbance of hemostasis withdraw VPA

before elective surgery is recommend– Women of childbearing age : neural tube defect(1-2 %),

polycystic ovaries and metabolic and endocrine disturbance

Phenobarbital and Primidone• Dose

– Adult : loading 20 mg/kg, maintenance 30-250 mg/d– Peds : loading 15-20 mg/kg, maintenance 30-250 mg/d

• Use– Partial and secondary generalized

• Decline because their central nervous effect• More sedative than other AED• Side effect

– Cognitive impairment– Sedation– Allergic reaction– Libido(Primidone)

Newer epileptic drug

• Felbamate• Gabapentin• Lamotrigine• Topiramate• Tiagabine• Oxcarbazepine• Levetiracetam• Pregabalin

Newer epileptic drugFelbamate 1200 mg/d BID,TID,QID and reduced other AED by about a thirdincrease biweekly in 600 mg to usual dose of 1600-3600 mg/d

Gabapentin(Neurontin)

Adult 300 mg PO x 1 day; 300 mg PO BID day 2; 300 mg PO TID day 3; then increase rapidly up to usual dose of 800-1800 mg/day

Lamotrigine(Lamictal)

Receiveing enzyme-enzyme inducing AED (PHT,CBZ,Phenobarbital) : 50 mg PO q d x 2 wk,then 50 mg BID x 2 wk, then increase by 100 mg/d q wk unitl 200-700 mg/dVA : maintainace dose 100-200 mg/d

Topiramate Adult : start with 25-50 mg/d(0.5-1 mg/kg/d) and increase slowly up up to 200-400 mg/d(5-6 mg/kg/d)

Oxcarbazepine Adult : 300 mg twice daily, increase weekly, target 1200-1800 mgPed : 5-10 mg/kg per day in children, target 20-30 mg/kg

Levetiracetam(Keppra)

Adult : 250-500 mg twice dialy(500-1000 mg/day), maintenace dose 1000-3000 mg/dayPed : 20 mg/kg per day, maintenance 30-40 mg/kg per day

Pregabalin(Lyrica)

Adult : 150 mg/day the first week, 300 mg/day the second week, 450 mg/day the third week, and 600 mg/day thereafter

Felbamate• Dose

– 1200 mg/d BID,TID,QID and reduced other AED by about a third– increase biweekly in 600 mg to usual dose of 1600-3600 mg/d

• Use– Partial seizure(complex and secondary generalized)

• Not to be used in 1st line drug• Side effect

– Aplastic anemia– Hepatic failure– Insomnia– Anorexia– N/V– H/A

Gabapentin(Neurontin)• Dose :

– Adult 300 mg PO x 1 day; 300 mg PO BID day 2; 300 mg PO TID day 3; then increase rapidly up to usual dose of 800-1800 mg/day

• Eliminated entirely by the kidneys no pharmacokinetic interaction

• Side effect– Somnolence– Dizziness– Ataxia– Fatigue– Nystagmus– Increase appetite

Lamotrigine(Lamictal)• Dose

– Receiveing enzyme-enzyme inducing AED (PHT,CBZ,Phenobarbital) : 50 mg PO q d x 2 wk,then 50 mg BID x 2 wk, then increase by 100 mg/d q wk unitl 200-700 mg/d

– VA : maintainace dose 100-200 mg/d– Ped : not indicated for use in patients < 16 Yr

• Use– Partial seizure– Lennox-Gastaut syndrome

• Side effect– Somnolence,dizziness,diplopia– Steven-Johnson symdrome,TEN

Topiramate• Dose

– Adult : start with 25-50 mg/d(0.5-1 mg/kg/d) and increase slowly up up to 200-400 mg/d(5-6 mg/kg/d)

• Use– GTC– Lennox-Gastaut syndrome

• Side effect– Somnolence– Impaired concentration– Confusion– Abnormal thinking– Impaired verbal memory

Tiagabine• Not found widely use• Use

– Partial seizure without or with secondary generalized

• Side effect– Dizziness– Tremor– Difficulty with concentration– Nervousness– Emotional lability

Oxcarbazepine• Dose

– Adult : 300 mg twice daily, increase weekly, target 1200-1800 mg– Ped : 5-10 mg/kg per day in children, target 20-30 mg/kg

• Derivative of carbamazepine• Enzyme inducer• Use

– Partial seizure– Secondary generalized seizure

• Side effect– Somnolence,Dizziness– hyponatremia– Ataxia– Diplopia and blurred vision

Levetiracetam(Keppra)• Dose

– Adult : 250-500 mg twice dialy(500-1000 mg/day), maintenace dose 1000-3000 mg/day

– Ped : 20 mg/kg per day, maintenance 30-40 mg/kg per day

• No drug-drug interaction,protein binding is low• No level monitoring need• Side effect

– somnolence, asthenia, dizziness, emotional lability, depression, and psychosis

– Behavioral problems are particularly common in children and include agitation, hostility, oppositional behavior, anxiety, and aggression

– Allergic reactions, liver failure, and bone marrow suppression are exceedingly rare.

Levetiracetam(Keppra)• Use, broad spectrum AED

– partial and secondarily generalized seizures– primarily generalized tonic-clonic seizures in idiopathic general

epilepsies– myoclonic seizures in juvenile myoclonic epilepsy– absence seizures– severe myoclonic epilepsy in infancy– progressive myoclonic epilepsy (Unverricht-Lundborg)– rolandic epilepsy– posthypoxic and postencephalitic myoclonus

Pregabalin(Lyrica)• Dose

– Adult : 150 mg/day the first week, 300 mg/day the second week, 450 mg/day the third week, and 600 mg/day thereafter

• Use,narrow spectrum activity– Focal onset seizure– Secondarily generalized seizure

• Side effect– Dizziness,somnolence– dry mouth– peripheral edema– blurred vision– excessive weight gain– difficulty with concentration

Principle of treatment• Decision to initiate antiepileptic drug therapy

– risk for recurrence seizure, potential risk associated with seizure recurrence, chronic AED therapy associated

– Not indicated routine treatment,patient own preference– Risk factor for recurrence

• Remote symptomatic seizure• Focal onset seizure• History of previous acute symptomatic seizures• Epileptiform abnormalities on electroencephalography (EEG)• First seizure manifested as status epilepticus• First seizure followed by Todd’s paralysis

– Low risk for recurrence• idiopathic generalized tonic-clonic seizure• absence of epileptiform abnormalities on EEG

Principle of treatment• Antiepileptic Drug Selection by Seizure Type or Epilepsy

Syndrome– AED is based first on the seizure type or on the epileptic

syndrome– Adverse effect, Patient’s age, gender and preference

Principle of treatment• Basic Principles of Antiepileptic Drug Use

– Initial target dose– Further increase in dose, seizure control, side effect by the drug– Children higher clearance,Elderly lower clearance– The drug not fail,if maximal tolerated dose has been reached– If the first drug fail to control the seizure at maximal tolerated

dose second drug– When a therapeutic dose or level of the second drug has been

reached, the first drug should be tapered

Principle of treatment• Discontinuation of Antiepileptic Drug Therapy

– Risk versus benefit analysis– Factor for seizure recurrence after stopping AED

• known remote cause• seizure onset after the age of 12 years• a family history of epilepsy in patients with idiopathic epilepsy• focal or generalized slowing on EEG before discontinuation• a history of atypical febrile seizures• IQ of less than 50

– The 2-year risk for recurrence after drug discontinuation may vary from about 10% in patients with none of these risk factors to about 80% in patients with remote symptomatic seizures and three risk factors

Principle of treatment• Discontinuation of Antiepileptic Drug Therapy

– decision to discontinue an AED is made after 2 years without seizures,taper slowy over at least 3 month

– In patient who have become free of seizures after epilepsy surgery : reduce the number of AED after 1 year and to discontinue all drug after 2 years