guidelines for medical management of epileptic seizures · • commonly referred to as seizure...

Guidelines for medical management of epileptic

seizures

Department of Pharmacy Department of Pharmacy Department of Pharmacy Department of Pharmacy

ChiaChiaChiaChia----Yi Chang Gung Memorial HospitalYi Chang Gung Memorial HospitalYi Chang Gung Memorial HospitalYi Chang Gung Memorial Hospital

YaYaYaYa----JuJuJuJu, Ma, Ma, Ma, Ma

2017.01.112017.01.112017.01.112017.01.11

Outline

• Introduction • Pathophysiology• Classification• Symptoms• Mechanisms• Treatment• New antiepileptic drugs

Introduction

• Epilepsy is one of the most common neurological diseases.

• Seizures are assigned to one of two major categories: partial or generalized.

• Epilepsy cases can involve more than one type of seizure.

• Commonly referred to as seizure disorder, epilepsy is a disorder comprising a collection of seizures that differ in regard to cause, symptoms, severity, and treatment.

Introduction

• Drug therapy is based on type of seizure, age, gender, comorbidities, adverse-effect potential, drug interactions, and cost.

• In the last 20 years, the FDA has approved 15 new antiepileptic drugs (AEDs) , with many more currently in development.

• First-line treatment is the administration of AEDs .

• These are divided into first-, second-, and third-generation AEDs.

• About 60% of patients achieve adequate seizure control with monotherapy.

Diagnosis

• Electroencephalogram (EEG)• Computed tomography (CT)• Magnetic resonance imaging (MRI)

Pathophysiology

• Seizures occur when there is a disturbance in the balance of excitation and inhibition in the central nervous system (CNS) .

• These factors include changes in ion channel conduction, membrane receptor response, messenger systems, and gene transcription.

• Imbalances between excitatory (glutamate) and inhibitory (GABA) neurotransmitters, as well as excessive acetylcholine, norepinephrine, and serotonin levels, may also precipitate seizures.

ILAE Classification of Seizures

Unknown (4%)

Epileptic spasms

Seizures

Partial (60%) Generalized (36%)

Simple Partial

Complex Partial

Secondarily Generalized

Tonic-Clonic

Absence

Myoclonic

Clonic

Tonic

Atonic

Grand mal

Petit mal

Symptoms

• Depend on the type of seizure or epilepsy.

• Seizures involve abnormal electrical activity that can produce changes in consciousness, motor and sensory activity, and behavior.

• A number of patients can experience an aura or warning symptoms minutes to hours before partial seizures.

• Aura symptoms can differ significantly; examples include irritability, nausea, headache, and fear.

Symptoms

• Generalized seizures involve both hemispheres and typically include bilateral motor symptoms and loss of consciousness.

• The many different types of generalized seizures (tonic-clonic, absence, myoclonic, clonic, tonic, atonic) will vary in motor symptom characteristics.

Mechanisms

• Excitatory and inhibitory currents are primarily mediated by different channels including voltage- and ligand-gated channels.

• Voltage-gated channels include sodium and calcium channels.

• Ligand-gated channels include GABA and glutamate channels.

AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; GABA, γ-aminobutyric acid; GAT-1, sod. dependent and chloride dependent GABA transporter 1; SV2A, synaptic vesicle glycoprotein 2A.

Ref: BMJ.2014;348:g2546

Ref:Neurol Med Chir56,205-220,2016,review article,the new antiepipeptic

Drug Treatment

• First generation AEDs

Drug Approved use (FDA, EMA)Phenobarbital-PB(1912) Luminal ®

Partial and generalized convulsive seizures,sedation, anxiety disorders, sleep disorders

Phenytoin-PHT(1938) Dilantin®

Partial and generalizedconvulsive seizures

Primidone-PRM(1954)Tremsolin ®

Partial and generalizedconvulsive seizures

Ethosuximide(1958)Zarontin ®

Absence seizures

Drug Treatment

• Second generation AEDs

Drug Approved use (FDA, EMA)Carbamazepine-CBZ(1964) Tegretol ®

Partial and generalized convulsive seizures, trigeminal pain, bipolar disorder

Valproate -VPA(1967) Depakine ®

Partial and generalized convulsive seizures, absence seizures, migraine prophylaxis,bipolar disorder

Clobazam-CLB(1975) Frisium ®

Lennox-Gastaut syndrome,anxiety disorders

Drug Treatment • Third generation AEDs

Drug Approved use (FDA, EMA)Vigabatrin-VGB(1989)Sabril ®

Infantile spasms, complex partial seizures (currently for adjunctive use only)

Lamotrigine-LTG(1990)Lamictal ®

Partial and generalized convulsive seizures, Lennox-Gastaut syndrome,bipolar disorder

Oxcarbazepine-OXC(1990) Trileptal ®

Partial seizures

Gabapentin-GBP(1993)Neurontin ®

Partial and generalized convulsive seizures, postherpetic and diabetic neuralgia, restless leg syndrome


Drug Approved use (FDA, EMA)Topiramate-TPM(1995) Topamax ®

Partial and generalized convulsive seizures, Lennox-Gastaut syndrome,migraine prophylaxis

Tiagabine-TGB

(1997)Gabitril®Partial seizures

Levetiracetam-LEV(2000)Keppra ®

Partial and generalized convulsive seizures, partial seizures, GTCS, juvenile myoclonicepilepsy

Zonisamide-ZNS(2000)Zonegran®

Partial seizures

Pregabalin-PGB(2004)Lyricar ®

Partial seizures, neuropathic pain,generalizedanxiety disorder,fibromyalgia


Drug Approved use (FDA, EMA)Rufinamide-RFN(2004) Banzel ®

Lennox-Gastaut syndrome

Lacosamide-LCM(2008) Vimpat ®

Partial seizures

Eslicarbazepineacetate (2009) Aptiom ®

Partial seizures

Perampanel-PER(2012) Fycompa ®

Partial seizures

Indications for the new antiepileptic drugs

DrugsFocal

seizure

Generalized seizure

Epilepticspasms

Induced aggravation of seizure type /epilepsy syndrome

PrimaryGTC

Absence Myoclonic Lennox-Gastaut

Gabapentin + ABS, MCS, LGS

Topiramate + + + + + +

Lamotrigine + + + (+) + + MCS, JME, LGS, BECTS, Dravet syndrome

Levetiracetam + + (+) + (+) (+) ABS

Rufinamide + + + Little information

Vigabatrin + + ABS, MCS, LGS, Dravetsyndrome

Oxcarbazepine + ABS, MCS, JME, LGS

Perampanel + + Little information

Lacosamide + Little information

ABS: absence seizure, BECTS: benign epilepsy with centro-temporal spikes, GTC: generalized tonic-clonic, JME: juvenilemyoclonic epilepsy, LGS: Lennox-Gastaut syndrome, MCS: myoclonic seizure, +: effective, (+): most likely effective.

Ref:Neurol Med Chir

Drugfrequency of dosing(total mg/day; frequency of dosing)

Carbamazepine 600-1200 ; bid or tid

Clobazam 10-60 mg ; bid or qd

Eslicarbazepine 800-1200 ; qd

Felbamate 2400-3600 ; bid, tid

Gabapentin 900-3600 ; bid, tid

Lacosamide 400-600 ; bid

Lamotrigine 100-400 ; qd, bid

Levetiracetam 1000-3000 ; bid

Oxcarbazepine 800-1800 ; bid, tid

Phenobarbital 50-200 ; qd, bid

Phenytoin 200-300 ; bid, tid

Perampanel 8-12 ; qd

Pregabalin 150-600 ; bid, tid

Primidone 500-750 ; bid, tid

Retigabine 900-1200 ; bid, tid

Tiagabine 36-60 ; bid, tid

Topiramate 100-400 ; bid, tid

Vigabatrin 500-3000 ; bid

Valproate 600-1500 ; bid slow release

Zonisamide 200-600 ; bid, tid Ref:BMJ.2014;348:g2546

Pharmacokinetic characteristics of Pharmacokinetic characteristics of AEDsAEDsAEDs T ½ (hr) Protein

binding(%)Bioavailability(%) Metabolism and clearance

Carbamazepine 9 75 89 CYP3A4 (major)Dose adjustment in severe renal impairment

Oxcarbazepine 9 40 100 Liver/ urine excretion

Phenytoin 9- >42 (dose dependent )

90-95 20-90 Dose adjustment is needed in severe renal or hepati c insufficiency

Phenobarbital 75-110 55 80-100 Dose adjustment is needed in severe renal or hepati c impairment

Valproate 7-16 80-95 90 Liver/ urine excretion

Gabapentin 5-7 <5 60 urine excretion

Lacosamide 15-23 <15 100 Hepatic metabolism (CYP2C19)

Urine excretion (95%)

Lamotrigine 25-33 55 60 Hepatic metabolism


Perampanel 36-42 95 Good PO absorption

hepatic metabolism (CYP3A4/CYP3A5)Feces excretion (48%)

Pregabalin 6 <5 >90 Not extensively metabolized


Topiramate 21 9-17 80 Minimal hepatic metabolismUrine excretion (70%)

Vigabatrin 10.5 0 100 Not extensively metabolizedUrine excretion (95%)

Zonisamide 63 50 no significant effect

Liver metabolism (CYP450)Urine excretion (62%)

Treatment considerations

• Although most AEDs can cause common CNS side effects (dizziness and drowsiness)

• Impaired cognition is one major concern for many patients and family members.

• In general, newer agents like gabapentin and levetiracetam appear to have the least effects on cognition and may be better options.

Renal dysfunction

• Should have dosage adjustment performed for topiramate, oxcarbazepine,gabapentin, levetiracetam, pregabalin, vigabatrin andlacosamide to avoid accumulation of the drug or its metabolites.

Drug Clcr ( ml/min ) Dosage (mg)

Topiramate <70 50% of the usual adult dosage

Oxcarbazepine <30 300 QD

Lacosamide <30 or ESRD 300 mg/day

Gabapentin

Clcr ( ml/min ) Dosage (mg)

>60 400 tid

30~60 300 bid

15~30 300 qd

<15 300 qod

Levetiracetam


>80 500~1500 Q12H

50~79 500~1000 Q12H

30~49 250~750 Q12H

<30 250~500 Q12H

End stage 500~1000 QD

Pregabalin


30~60 75~300 bid~tid

15~30 25~150 qd

<15 25~75 qd

Vigabatrin


50~80 ↓dose by 25%

30~50 ↓dose by 50%

10~30 ↓dose by 75%

Liver dysfunction

• A number of agents can affect the liver. Carbamazepine, phenytoin, and valproicacid can cause elevations in liver enzymes and thus should be avoided in patients with liver disease.

• Although these agents have also been known to cause hepatotoxicity, more severe liver problems are rare.

Dermatologic reactions

• Rare, fatal skin reactions like Stevens-Johnson syndrome (SJS) 、 toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms(DRESS) have been reported.

• More common with carbamazepine, valproic acid, phenytoin, phenobarbital, and lamotrigine.

Dermatologic reactions

• In Taiwan , it seems that aromatic AEDs is the main cause for SJS and TEN, and is a secondary reason for DRESS occurred.

• Among those AEDs, carbamazepine is the most common drug to cause SJS/TEN.

• DERSS usually caused by phenytoin.

• The study found that the AEDs (carbamazepine) caused of SJS / TEN and the Asians human leukocyte antigen gene Type HLA-B * 1502 has a strong correlation.

Adverse effects of new antiepileptic drugsAdverse events GBP TPM LTG LEV RFN VGB OXC PER LCM

CNS effects

Somnolence + ++ + + + + ++

Insomnia +

Sedation/psychomotor slowing (+)

Depression (+) +

Behavioral problems ++ + + ++

Psychotic episodes + + + ++ +

Cognitive impairment + +

Ataxia + +

Dizziness + ++ + + + + ++ ++ ++

Encephalopathy ++

General issues

Hypersensitivity + + +

Rash + +

Fatigue + + +

Weight gain + + +

Weight loss + +

Seizure aggravation + (+) ++ +

Splanchnic and humoral system

Leukopoenia (+)

Hyponatremia +

Gastrointestinal (+) (+) +

Pancreatitis (+)

Nephrolithiasis (+)

GBP: gabapentin, LCM: lacosamide, LEV: levetiracetam, LTG: lamotrigine, OXC: oxcarbazepine, PER: perampanel, RFM:rufinamide,TPM: topiramate, VGB: vigabatrin, ++: high risk, +: moderate risk, (+): minimal risk. Ref:Neurol Med Chir

Interactions

• Many AEDs are metabolized through the CYP450 system in the liver and can be either enzyme inducers or enzyme inhibitors.

• Enzyme inducing AEDs- phenytoin, phenobarbital, carbamazepine, and primidone.

• Enzyme inhibiting AEDs- valproic acid.

Interactions

• Enzyme inducers can enhance the metabolism of warfarin, oral contraceptives, antibiotics, and antidepressants resulting, in decreased serum concentrations and effects.

• Valproic acid can decrease the metabolism of warfarin, statins, and tricyclic antidepressants, resulting in increased serum concentrations and effects.

Ref:US Pharmacist Published January 23, 2013Epilepsy: Treatment and Management

enzyme inhibitor

LTG＋VPA：decrease LTG dose by 50%

TPM＋enzy inducer：TPM clearance ↑2X

Preferable indications for the administration of new antiepileptic drugs

Entity Ponderable new AEDs

Background

History of rush, allergy LEV, GBP, TPM

Obesity TPM,LTG,LEV,OXC

Elderly group LEV,LTG,GBP

Comorbidity

Depression LTG,OXC

Cognitive impairment LTG,GBP

Brain tumor LEV,GBP

Migraine TPM

Neuropathic pain GBP,LTG,LCM

Hyperlipidemia no-enzyme inducing AEDs

Co-medications no-enzyme inducing AEDs

LEV,LTG,GBP,PGB,VGB

Therapeutic Drug Monitoring

Drug Target plasma concentration

Ethosuximide 40-100 ug/ml

Phenobarbital 15-40 ug/ml

Phenytoin 10-20 ug/ml

Primidone 5-12 ug/ml

Valproic acid 50-100 ug/ml

TDM is performed when a clear clinical problem occurs

• For the initial diagnosis of partial and major seizures –CBZ, PHT ,PB , OXC and VPA can be considered as the first line .partial seizure-CBZ and PHTgrand mal-CBZ、LTG、OXC、PB、PHT、TPM and VPA

• Adjunctive treatment –focal epilepsy-CBZ, GBP, LCM,LTG,LEV,OXC,PER,PGB

,TPM, VPA and ZNS generalised epilepsy-LTG,LEV, Ethosuximide, VPA and

TPM

• The choice of drugs in combinationshould be matched to the patient's seizure type(s) and should, where possible, be limited to two or at most three AEDs.

• When the type of epileptic seizure is uncertain, or when a grand mal-Valproate,lamotrigine.

Diagonsis of epilepsyDiagonsis of epilepsy

MonotherapyBegin treatmentwith one AED

MonotherapyBegin treatmentwith one AED

Seizure free?Seizure free?

Intolerable side effects?


↓↓↓↓AED dose↓↓↓↓AED doseOptimal QOLOptimal QOL

Continue current treatment


Explore QOL issues?Explore QOL issues?

↑↑↑↑ AED dose↑↑↑↑ AED dose

↓↓↓↓dose of 1st AEDAdd 2nd AED↓↓↓↓dose of 1st AED

Add 2nd AED


Consider removing 1st

Consider removing 1st



Yes

Yes

Yes

Yes

Yes

No

NoNo

No

No



Algorithm for the treatment of epilepsy.Algorithm for the treatment of epilepsy.

Ref:Pharmacotherapy: A Pathophysiologic Approach, 9e



↑↑↑↑Dose of 2nd AED check for DIC

↑↑↑↑Dose of 2nd AED check for DIC

Remove least effective AED add Another 2nd

AED

Remove least effective AED add Another 2nd

AED




Reconfirm diagnosisConsider surgery

Reconfirm diagnosisConsider surgery

Yes

No

NoYes

Ref:Pharmacotherapy: A Pathophysiologic Approach, 9e

Summary

• Recommend initiating an AED in monotherapy who are at hight risk of recurrent seizures.

• If the first AED trial is unsuccessful，a second AED trial is recommended.

• Drug therapy is individualized.

• Each drugs have their advantages and disadvantages.

• Controlling seizures，avoiding treatment side effects，and maintaining or quality of life.

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guidelines for medical management of epileptic seizures · • commonly referred to as seizure...

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