NEWER ANTIEPILEPTIC DRUGS

OVERVIEWDr.Subhashis Sharma

Moderator

Dr.Anurag Jhanjee

Asst.Professor[Pschiatry]

OVERVIEW

Seizures are sudden episodes of neurological dysfunction caused by abnormal electrical activity of the brain

Seizures are common

10% of the population will have a seizure during their lifetime (about half are seizures with fever in infancy)

Epilepsy: recurrent, unprovoked seizures

SEIZURE TYPES

Primary Generalized Tonic-clonic (“grand mal”) Absence (“petit mal”) Myoclonic Tonic Atonic (“drop attacks”)

Partial Simple Complex Secondary generalized

“OLDER” AEDS

Phenobarbital 1912

Phenytoin 1938

Primidone 1952

Ethosuximide 1960

Carbamazepine 1974

Valproate 1978

Ethosuximide 1980

NEWER AEDS

Felbamate 1993

gabapentin 1994

Lamotrigine 1995

Topiramate 1996

Tiagabine 1998

Levetiracetam 1999

Oxcarbazepine 2000

Zonisamide 2000

Rufinamide 2004

Pregabalin 2005

Lacosamide 2008

Eslicarbazepine 2009

Retigabine 2011

MECHANISM OF ACTION OF DIFFERENT AEDS

CARBAMAZEPINE

First line drug for partial szs for years

Two long-acting forms now avail (2X/day)

Side effects at just above therapeutic range

Not effective for some seizure types

Must start slowly due to side effects

No IV form

Lots of interactions

PHENYTOIN

First line for partial seizures for years

Once a day

IV form

Side effects at just avove therapeutic range

Not effective for some seizure types

Side effects: imbalance, sedation, cognitive, gum problems, osteoporosis

Many interactions

VALPROATE

Works for all seizure types

Around for decades

Rare allergic reactions

Helps prevent migraines

New IV form

New long-acting form

Side effects, esp. weight gain & tremor

Menstrual irregularities

Not best for pregnancy

Significant drug interactions

BARBITURATES (PRIMIDONE AND PHENOBARBITAL)

Effective

Once a day (phenobarbital)

cheap

IV form (phenobarbital)

Sedation and cognitive effects

Withdrawal

OTHER OLD MEDICATIONS

Acetazolamide

Conazepam & lorazepam

Ethosuximide

Ketogenic diet

ACTH/steroids

NEWER AEDS

Equally effective as older AEDs

Most better tolerated than older AEDs

Most have fewer interactions with other medications than older AEDs

All expensive

GABAPENTIN

Binds to the α2-δ protein subunit of voltage-gated

calcium channels

This closes N and P/Q presynaptic calcium channels,

diminishing excessive neuronal activity

and neurotransmitter release

GABAPENTIN

Generic name: Gabapentin

Available as: Gabapentin: tablets 600mg, 800mg, capsules 100mg, 300mg, 400mg.

Average total daily dose: 900mg – 3600mg daily divided into 3 doses, up to 4800mg daily

Doses per day: 3

Treatment: Monotherapy and add-on therapy for focal seizures with or without secondary generalisation (where other treatment has not worked). May make myoclonic and absence seizures worse.

Most common possible side effects include the following:Rash. Diarrhoea, nausea, vomiting, dry mouth, appetite change, weight gain, high blood pressure, fluid retention, confusion, depression, sleep disturbance, headache, dizziness, anxiety, tremor, unsteadiness, flu-like symptoms, incontinence, impotence, and double vision.

GABAPENTIN

ADVANTAGES:.No interaction with other drugs

.Eextremely rare allergic reactions

.Can be started quickly

.Well tolerated

.Treats pain,anxiety,restless leg syndrome,pain due to diabetic neuropathy,post herpetic neuralgia,prophylactic for migraine.

DISADVANTAGES:.Three times a day dosing.

.Does not treat all types of seizures

LAMOTRIGINE

Carbamazepine like action profile

Prolongation of Na+ channel inactivation

And suppression of high frequency firing

In addition it may directly block voltage

sensitive Na+ channels thus stabilizing the

presynaptic membrane

And preventing release of excitatory neurotransmitters mainly glutamate and mainly glutamate & aspartate

This may account for broad spectrum of antiseizure

efficacy

LAMOTRIGINE

Generic name: Lamotrigine

Available as:tablets 25mg, 50mg, 100mg, 200mg, dispersible tablets 5mg, 25mg, 100mg.

Average total daily dose: Used alone: 100 – 200mg daily divided into 1 – 2 doses, up to 500mg.With sodium valproate: 100 – 200mg daily divided into 1 – 2 doses.With enzyme-inducing AEDs and without sodium valproate: 200 – 400mg daily divided into 1 – 2 doses, up to 700mg.Without enzyme-inducing AEDs and without sodium valproate: 100 – 200mg daily divided into 1 – 2 doses.

Doses per day: 1 – 2 Treatment: Monotherapy and add-on therapy for focal and generalised seizures. Also used for

seizures associated with Lennox-Gastaut syndrome.

Most common possible side effects include the following:Serious skin rash and hypersensitivity. Risk minimised with slow introduction. Nausea, vomiting, diarrhoea, dry mouth, aggression, agitation, headache, drowsiness, dizziness, tremor, difficulty sleeping, unsteadiness, back pain, joint pain, eye movements, double vision, and blurred vision.

LAMOTRIGINE

ADVANTAGES:

Minimal effect on other medications

Works for al types of Seizures

Very well Tolerated

Minimal sedation

Safe in pregnancy

Monotherapy

DISADVANTAGES:

Rashes if started quickly.Must start slowly

TOPIRAMATE

It appears to act by multiple mechanisms

Phenytoin like prolongation of Na+ channel inactivation

GABA potentiation by a postsynaptic effect and antagonism of certain glutamate receptors

TOPIRAMATE

Generic name: Topiramate

Available as:tablets 25mg, 50mg, 100mg, 200mg, capsules 15mg, 25mg, 50mg.

AVERAGE DAILY DOSE: Taken alone: 100mg daily (up to 18 years) or 100 – 200mg daily (over 18 years). Taken with other AEDs: 5 – 9mg/kg daily (up to 18 years) or 200 – 400mg daily (over 18 years). All divided into 2 doses.

Doses per day: 2 Treatment: Used for focal seizures with or without secondary generalisation and

tonic clonic seizures, where other treatment has not worked. Topiramate has a licence for monotherapy but is not widely used as a first line drug

Most common possible side effects include the following:Rash. Nausea, diarrhoea, vomiting, constipation, indigestion, abdominal pain, dry mouth, appetite changes, impaired attention, cognition and coordination, movement problems, tremor, drowsiness, dizziness, anxiety, confusion, mood changes, depression, irritability, and anaemia.

TOPIRAMATE

ADVANTAGES:

Minimal interaction

Probably works for all seizure types

Sprinkle form

Approved for monotherapy

Weight loss

Approved for migraine prevention

DISADVANTAGES: Cognitive side effects

½% renal stone

Tingling/pins & needles

Can decreases the efficacy of OCP

TIAGABINE

Potentiates GABA mediated neuronal inhibition

by depressing GABA transporter GAT-1

which removes synaptically released GABA

into neurons and glial cells

TIAGABINE

Generic name: Tiagabine

Available as:tablets 5mg, 10mg, 15mg.

Average total daily dose: With enzyme-inducing AEDs: 30 – 45mg daily divided into 2 – 3 doses. Without enzyme-inducing AEDs: 15 – 30mg daily divided into 2 – 3 doses.

Doses per day: 1 – 3

Treatment: Add-on therapy for focal seizures with or without secondary generalisation where other treatment has not worked. May make myoclonic seizures worse.

Most common possible side effects include the following. Report severe reactions, such as a skin rash, to your doctor.Diarrhoea, dizziness, tiredness, nervousness, tremor, concentration problems, emotional reactions, and speech impairment.

TIGABINE

ADVANTAGES: Minimal effect on other medications

DISADVANTAGE

.Dose is dependent on concurrent AEDs.

Anxiety.

Occasionally makes some seizure types Worse

LEVETIRACETAM

Binds to synaptic vesicle protein SV2A

which is involved in synaptic vesicle exocytosis

LEVITIRACETAM

Generic name: Levetiracetam

Available as: Desitrend: granules 250mg, 500mg, 1000mg.Keppra: tablets 250mg, 500mg, 750mg, 1000mg, oral solution 100mg/ml. Levetiracetam: tablets 250mg, 500mg, 750mg, 1000mg, oral solution 100mg/ml.

Average total daily dose: Up to 1500mg twice daily.

Doses per day: 2

Treatment: Monotherapy and add-on therapy for focal seizures with or without secondary generalisation. Add-on therapy for myoclonic seizures in Juvenile Myoclonic Epilepsy.

Most common possible side effects include the following:Anorexia, weight changes, abdominal pain, nausea, vomiting, diarrhoea, drowsiness, unsteadiness, dizziness, headache, tremor, amnesia, aggression, agitation, depression, anxiety, and double or blurred vision.

LEVETIRACETAM

ADVANTAGES: No interactions

Minimal liver metabolism

Works for most seizure types

Can start Quickly

Well tolerated

Liquid formulation

DISADVANTAGES: Behavioral/psych side effects

Twice per day

OXCARBAZEPINE

Oxcarbazepine is a prodrug which is activated to eslicarbazepine in the liver.

Same mechanism as carbamazepine – sodium channel inhibition and is generally used to treat the same conditions.

reduce the impact on the liver of metabolizing the drug, and also prevents the serious forms of anemia or agranulocytosis occasionally associated with carbamazepine

OXCARBAZEPINE

Generic name: Oxcarbazepine

Available as:tablets 150mg, 300mg, 600mg, oral suspension 60mg/ml.

Average total daily dose: Up to 18 years: 30mg/kg daily divided into 2 or 3 doses, up to 46mg/kg. From 18 years: 600mg – 2400mg daily divided into 2 or 3 doses.

Doses per day: 2 – 3

Treatment: Effective for focal seizures, tonic clonic seizures and secondarily generalised tonic clonic seizures.

Most common possible side effects include the following. Skin rash. Nausea, vomiting, constipation, diarrhoea, abdominal pain, dizziness, headache, drowsiness, agitation, amnesia, hair loss, weakness, unsteadiness, confusion, depression, and tremor.

OXCARBAZEPINE

ADVANTAGES:

As effective and better tolerated than Carbamazepine

Fewer interactions than Carbamazepine

Approved for children > 4

Approved for first-line monotherapy

DISADVANTAGES:

Not for all seizure types

Low sodium, esp if on diuretics also

Lessens effectiveness of birth control pill

ZONISAMIDE

Weak carbonic anhydrase inhibitory action

Prolongation of Na+ channel inactivation

resulting in suppression of repetitive neuronal

firing has been observed

ZONISAMIDE

Generic name: Zonisamide

Available as:capsules 25mg, 50mg, 100mg.

Average total daily dose: From 18 years: 300mg – 500mg daily divided into 1 or 2 doses.

Doses per day: 1 – 2

Treatment: Add-on therapy for focal seizures with or without secondary generalisation.

Most common possible side effects include the following:Skin rash. Nausea, diarrhoea, abdominal pain, constipation, indigestion, anorexia, weight loss, drowsiness, dizziness, confusion, agitation, irritability, depression, psychosis, and unsteadiness

ZONISAMIDE

ADVANTAGES: Used in Japan for many years

Works for all seizure types

Approved for children

Once daily

Weight loss

Recent addition of 25 mg capsules

DISADVANTAGES: 1-2% kidney stones

Occasional psychiatric or sedative side effects

PREGABALIN

Binds to the α2-δ protein subunit of

voltage-gated calcium channels

This closes N and P/Q presynaptic calcium channels,

diminishing excessive neuronal activity and

neurotransmitter release

PREGABALIN

Generic Name:Pregabalin

Available as:tablet

Average total daily dose: 150–600 mg/DAY

Doses: Start treatment with 50 mg/day in two divided doses

Treatment: Adjunctive treatment of partial seizures with or without secondary generalization in adults

Most common possible side effects include the following: Somnolence, dizziness,Ataxia, tremor, dysarthria, paresthesia,Impaired attention, euphoric mood, irritability, Vomiting, dry mouth, constipation

PREGABALIN

ADVANTAGES

Peripheral and central neuropathic pain

Generalized anxiety disorders

Management of pain associated with diabetic peripheral neuropathy

Management of postherpetic neuralgia

Management of fibromyalgia

DISADVANTAGES

Blurred vision, diplopia,Peripheral edema Rare- neutropenia,

hypoglycemia,

atrioventricular block

and congestive heart failure

LACOSAMIDE

Acts by enhancing slow inactivation of

voltage-gated sodium channels

resulting in stabilization of hyperexcitable

neuronal membranes

LACOSAMIDE

Generic name: Lacosamide

Available as: Tablets 50mg, 100mg, 150mg, 200mg, syrup 10mg/ml.

Average total daily dose: From 16 years: 200mg twice a day.

Doses per day: 2

Treatment: Add-on therapy for focal seizures with or without secondary generalisation.

Most common possible side effects include the following.Nausea, vomiting, constipation, wind, dizziness, headache, impaired coordination, drowsiness, tremor, depression, fatigue, abnormal walking, blurred vision, abnormal eye movements, and itching.

LACOSAMIDE

ADVANTAGES: Recently been licensed for clinical use.

Adjunctive treatment of partial onset seizure.

In patients with epilepsy aged 16 years & older.

DISADVANTAGES: Dizziness, headache, balance disorder, abnormal coordination

memory impairment, somnolence, tremor, nystagmus

Diplopia

Nausea, vomiting, constipation

Pruritus

Increases PR interval

ESLICARBAZEPINE ACETATE

Acts as a use-dependent blocker of

voltage-sensitive sodium channels

resulting in stabilization of hyperexcitable

neuronal membranes

ESLICARBAZEPINE ACETATE

Generic name: Eslicarbazepine acetate

Available as:tablets 800mg.

Average total daily dose: From 18 years: 800mg once a day, up to 1200mg.

Doses per day: 1

Treatment: Effective as an add-on therapy for focal seizures, tonic clonic and secondarily generalised tonic clonic seizures.

Most common possible side effects include the following.Skin rash. Nausea, vomiting, diarrhoea, dizziness, drowsiness, headache, impaired coordination, tremor, visual problems, and fatigue.

ESLICARBAZEPINE ACETATE

ADVANTAGES:

Adjunctive treatment of partial onset seizures with or without secondary generalization

in patients with epilepsy aged 16 years and older

. Oral bioavailability: >90%

Dosing schedule is once per day

Dose adjustment is not necessary in Hepatic impairment

DISADVANTAGES:

Increases PR interval

Increased risk of suicidal ideation

Stevens-Johnson syndrome

Severe renal impairment (CrCL <30 mL/min) results in a 90% decrease in clearance so is not recommended for these patients

RUFINAMIDE

 While the exact mechanism of rufinamide is still unknown, it is thought to act through modulation of sodium channels resulting in membrane stabilization.

Rufinamide administration slows recovery after a prolonged prepulse in cortical neurons and limits sustained repetitive firing of sodium-dependent action potentials.

RUFINAMIDE

Generic name: Rufinamide

Available as):tablets 100mg, 200mg, 400mg, oral suspension 40mg/ml.

Average total daily dose: 900mg – 1600mg (depending on body weight and whether also taking sodium valproate) twice daily.

Doses per day: 2

Treatment: Add-on therapy for Lennox-Gastaut syndrome

Most common possible side effects include the following.Hypersensitivity syndrome (possibly including rash and fever) – if concerned seek immediate medical attention. Nausea, vomiting, diarrhoea, constipation, indigestion, abdominal pain, weight loss, anorexia, runny nose, nosebleeds, dizziness, headache, drowsiness, insomnia, anxiety, tiredness, flu-like symptoms, and blurred or double vision.

RETIGABINE

Opens KCNQ2/3 (Kv7.2/7.3) voltage-gated potassium channels on neurons and activates M-current, which regulates neuronal excitability and suppresses epileptic activity.

RETIGABINE

Generic name: Retigabine

Available as:tablets 50mg, 100mg, 200mg, 300mg, 400mg.

Retigabine is not widely prescribed due to possible side effects.

Average total daily dose: From 18 years: 600mg – 1200mg daily divided into 3 doses.

Doses per day: 3

Treatment: Add-on therapy for focal seizures with or without secondary generalisation. 

Most common possible side effects include the following.skin rashDizziness, sleepiness, fatigue, weight gain, confusion, anxiety, tremor, double or blurred vision, nausea, constipation, and problems urinating. Retigabine can cause problems with heart rhythm

INTRANASAL OR BUCCAL MIDAZOLAM

Safe and effective (studies in UK, Israel): 5-10 mg in adults

Easy to use

Less social stigma

Not approved in US for this usage

Not easy to obtain (controlled substance) in a convenient form

Shorter acting than Diastat

CONSIDERATIONS IN CHOOSING AN AED

Side effect profile

Efficacy and correct seizure/syndrome diagnosis

Convenience (doses/day, etc) Once/day

Cost

Drug interactions/potential for future problems

Non-epileptic indications for AEDs Pain Headaches Psychiatric

Concurrent medical problems

DRUGS THAT DECREASE EFFICACY OF ORAL CONTRACEPTIVES

Phenytoin

Carbamazepine

Phenobarbital

Primidone

Topiramate at higher doses

Oxcarbazepine

WEIGHT ISSUES

Risk of weight gain Valproate Gabapentin and Pregabalin

“Risk” of weight loss Topiramate Zonisamide Felbamate

LIFESTYLE CHANGES TO MINIMIZE SEIZURES

Avoid sleep deprivation

Avoid alcohol

Treat fevers quickly

Occasional patients should avoid specific factors such as strobe lights, etc

Pill boxes/reminders

SPECIAL CASES

Contraception:

Lamotrigine and oxcarbazepine have little interaction, and sodium valproate has no interaction with oral contraception.

Pregnancy :

Epilepsy presents specific management problems during pregnancy. With the exception of gabapentin, treatment with almost all anticonvulsant drugs is associated with an increased incidence of fetal congenital abnormalities such as cleft lip, spina bifida and cardiac defects

GUIDELINES FOR ANTICONVULSANT THERAPY

Start with one first-line drug

Start at a low dose; gradually increase dose until effective control of seizures is achieved or side-effects develop (drug levels may be helpful)

Optimise compliance (use minimum number of doses per day)

If first drug fails (seizures continue or side-effects develop), start second first-line drug whilst gradually withdrawing first

If second drug fails (seizures continue or side-effects develop), start second-line drug in combination with preferred first-line drug at maximum tolerated dose (beware interactions)

If this combination fails (seizures continue or side-effects develop), replace second-line drug with alternative second-line drug

If this combination fails, check compliance and reconsider diagnosis (is there an occult structural or metabolic lesion or are seizures truly epileptic?)

If this combination fails, consider alternative, non-drug treatments (e.g. epilepsy surgery, vagal nerve stimulation)

Do not use more than two drugs in combination at any one time

CONCLUSION

The guideline is intended to act as a working model for managing patients with epilepsy. Every medical practitioner needs to combine guidelines with his/her own skill, knowledge and experience keeping in mind the needs of individual patients. With so many new AEDs in the market, a physician might be tempted in trying them out but the first-line AEDs still remain the most preferred agents in India considering their wide availability, known long-term toxicity profile, wide experience with these agents and cheap price. Since a patient has to take these drugs for a long time and ensuring drug compliance is a key issue, appropriate choice of the drug is important.

THANK YOU