CHOOSING THE RIGHT MEDICAL TREATMENT AND - PowerPoint Presentation

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CHOOSING THE RIGHT MEDICAL TREATMENT AND RECENT ADVANCES

NEELIMA THAKUR, MD.

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Epilepsy Burden

The lifetime likelihood of Experiencing at least 1 seizure is ~ 9%. Receiving a diagnosis of epilepsy is ~3%. Approximately 200,000 new cases of seizures and epilepsy occur each year.Epilepsy and seizures affect nearly 3 million Americans of all ages, at an estimated annual cost of $17.6 billion in direct and indirect costs.

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Seizures are defined as abnormal discharge of electrical activity from brain neurons resulting in transient loss of motor, sensory or mental function.

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Provoked seizuresAcute symptomatic.Often a reversible cause.By definition, these are not epilepsy.Unprovoked seizures2 unprovoked seizures 24hrs apart is considered epilepsy.

Seizure types

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First unprovoked seizure – risk of seizure recurrence.

24-74 %

in first 5 years.

Normal EEG and imaging studies –

24%

Abnormal EEG and imaging studies-

74%

After 2

nd

unprovoked seizure –

80%

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First unprovoked seizure

Risk factors for seizure recurrence Family historyAbnormal EEG Abnormal neuroimaging.Seizure in sleep.

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First unprovoked seizure

50 % seizures recur in the first year80% with in two years.

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First unprovoked seizure

Current GuidelinesNo antiepileptic drugs (AEDs) if There are no other risk factors Normal EEG.

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Anti epileptic Drugs

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Antiepileptic drugs

1

st drug- 47 % seizure free2nd drug- 13% seizure free3rd / multi drugs - 4% seizure free

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Epilepsy outcome at >7 years.

Seizure free

>7years

-

59 %

Seizure free >1 year and relapses-

16 %

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Which AED to choose?

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Anti epileptic Drugs

1850 : Bromides1910: Phenobarbital1940: Phenytoin1950: Ethosuximide1958: ACTH1954: Primidone1968: Carbamazepine1975: Clonazepam1978: Depakote

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1990s: Newer AEDs were developed.lamotrigine (Lamictal) felbamate (Felbatol) levetiracetam (Keppra)topiramate (Topamax)oxcarbazepine (Trileptal)zonisamide (Zonegran)pregabalin (Lyrica)lacosamide (Vimpat)rufinamide (Banzel)vigabatrin (Sabril)clobazam (Onfi)ezogabine (Potiga)perampanel (Fycompa)eslicarbazepine (Aptiom)

Good efficacy,Fewer toxic effects, Better tolerability

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Following criteria may be helpfulType of epilepsyComorbiditiesSide effect profilePharmacokineticsDrug-drug interactionsSingle dose-ComplianceWomenElderly

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Type of epilepsy

Primarily generalized epilepsies.ethosuximide ( Absence seizures)valproatetopiramatezonisamidelamotriginelevetiracetamrufinamaideclobazamvigabatrin.

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Primarily generalized epilepsies

Avoid carbamazepine, gabapentin, Phenytoin.

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Efficacy Primarily generalized epilepsy

Absence seizures ethosuximide, valproate are effective than lamotrigine.Atonic seizures : clobazam.Primarily generalized epilepsies: valproate>topamax and leviteracetam.

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Type of epilepsy

Partial EpilepsiesAll AEDs except ethosuximide.

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Efficacy-Partial seizures

Not possible to compare efficacy as there are no major head to head trials.The study population, inclusion and exclusion criteria are different. ‘

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Mechanism of action

Rational polypharmacy.

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Comorbidities

Bipolar disorder/depression/anxiety: valproate, lamotrigine, carbamazepine, oxcarbazepine.Migraines: valproate, topiramate, zonisamide.Obesity: topiramate, zonisamideNeuropathy: gabapentin, lyrica, carbamazepine, oxcarbazepine.

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ComorbiditiesAEDs to avoid

Psychiatric/behavorial problems: levetiracetam.Osteoporosis: phenobarbital, phenytoin, valproate, carbamazepine.Renal stones : topamax, zonegran.Obesity: valproate, pregabalin, gabapentin.Diabetes: valproate.

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Liver dysfunction

Drugs of choiceleviteracetamlacosamidepregabalingabapentin

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Renal dysfunction

Decrease drug doses that are cleared primarily by kidneyslevetiracetamlacosamidepregabalingabapentin

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Hemodialysis

Risk of drug removal is high for non protein bound drugs Doses need to be adjusted accordingly.High risk levetiracetam lacosamide phenobarbital topiramate.Low risk phenytoin valproate lamotrigine. carbamazepine

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Drug interactions

Liver enzyme(CYP 450 & UGT) inducersphenytoin, phenobarbital, carbamazepine, oxcarbazepine, topiramate, felbamate, rufinamide.Liver enzyme inhibitorsvalproate, felbamate.

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Single daily dose

Improves Patient compliance.XR formulations may have lesser side effects. Q day AEDs Phenytoin, Phenobarbital and zonegran.XR formulation Depakote ER, Lamictal XR, Keppra XR, Oxtellar XR and Trokendi XR.

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Epilepsy in Elderly

The prevalence and incidence of epilepsy are highest in later life!!Approximately 7% of seniors have epilepsy.25% of new cases occur in elderly

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AEDs : Elderly

Older people with a first unprovoked seizure are more likely to develop recurring seizures than are younger adults.Starting AEDs after a single unprovoked seizure may be appropriate in some cases.

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AEDs: Elderly

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AEDs - Elderly

TREAT CAUTIOUSLY!Elderly are more susceptible to the adverse effects of drugs than their younger patients.Pharmacokinetics and pharmacodynamics of AEDs differ in old age . Drug-drug interactions

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AEDs- Elderly Treatment Challenges

Comorbidities complicate the treatment options.Polypharmacy make them susceptible to drug interactions.Adherence may not be as good in elderly patients with epilepsy.

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AEDs - Elderly

Pharmacokinetic Albumin results in free fraction phenytoin, carbamazepine and valproate.Drug metabolism is affected by decreased liver enzymes.Drug excretion is affected by decreased renal clearance.

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AEDs - Elderly

In general the preferred drugs arelevetiracetamlamotriginegabapentin

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AEDs-Pregnancy

Concerns Effect of AEDs on Fetus and infant duringPregnancyBreast feeding.AED pharmacokinetics affecting levels duringPregnancyPostpartum

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AEDs - Pregnancy

Teratogenic risks mono vs polytherapy.Single AED 3.1 %Two AEDs 5.8 %Three AEDs 8.3%

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AEDs - Pregnancy

Major malformations with monotherapyvalproate 9.3%phenobarbital 5.5 %topiramate 4.2 %carbamazepine 3%phenytoin 2.9%levetiracetam 2.4%lamotrigine 2.0%

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AEDs - Pregnancy

Pharmacokineticslamotrigine & levetiracetam clearance during pregnancy level up to 50% of baseline.Postpartum- clearance returns to baseline and drug levels.Check monthly levels and adjust dose.

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AEDs - Pregnancy

In general, levetiracetam, lamotrigine, oxcarbazepine and carbamazepine are considered relatively safe.

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Newer AEDs

Ezogabine (Potiga)Perampanel (Fycompa)Eslicarbazepine (Aptiom)

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Ezogabine (Potiga)2011

Mechanism of action: Potassium ChannelApproved for add on treatment for Partial epilepsy. It is the first neuronal potassium channel opener developed for the treatment of epilepsy .

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Ezogabine (Potiga)

Mechanism of action: Potassium ChannelApproved as add on treatment for Partial epilepsy. First neuronal potassium channel opener developed for the treatment of epilepsy .

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Ezogabine (Potiga)

Absorption and Metabolism:Well absorbed. Food has no influence.Not known whether excreted in human milk. Metabolized in liver. Dosage adjustment is required in patients with moderate and greater renal or hepatic impairment .*urine bilirubin can show falsely elevated readings

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Ezogabine (Potiga)

Drug interactionsCarbamazepine, phenytoin may Potiga levels. Potiga has no effect on other AED levels. POTIGA may digoxin serum concentrations. Alcohol systemic exposure to POTIGA

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Ezogabine (Potiga)

Adverse reactionsFDA warning blue skin discoloration and eye abnormalities characterized by pigment changes in the retinaInitial and periodic eye exams are recommended. Urinary retentionNeuropsychiatric symptoms- confusion, psychosisQT interval prolongation

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Perampanel (Fycompa)2012

Mechanism of action: AMPA glutamate receptor noncompetitive antagonist. Approved as add on treatment for Partial epilepsy.

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Perampanel (Fycompa)

Absorption and Metabolism:Well absorbed. Food has no influence.Not known whether excreted in human milk. Metabolized in liver. Dosage adjustment is required in patients with moderate and greater renal or hepatic impairment .

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Perampanel(Fycompa)

Drug interactionsDoes not effect other AEDs.Enzyme inducers perampanel levels.

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Perampanel (Fycompa)

Adverse reactionsNeuro-psychiatric symptoms ( black box warning for aggression and hostility).Dizziness , Somnolence fatigue, blurred vision.Pregnancy category C

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Eslicarbazepine (Aptiom)2013

Mechanism of action: Na channel blocker. the prodrug metabolizes to eslicarbazepine.. Approved as add on treatment for Partial epilepsy.

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Eslicarbazepine (Aptiom)

Absorption and Metabolism:Well absorbed. Food has no influence.Metabolized in liver and kidneys.Drug interactions and Side effectsSimilar but more tolerable than oxcarbazepine

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Thank you