Newer antiepileptic drugs

NEWER ANTIEPILEPTIC DRUGS

DR. PIYUSH OJHADM RESIDENT

DEPARTMENT OF NEUROLOGYGOVT MEDICAL COLLEGE, KOTA

Ideal Properties for an Antiepileptic Drug :-

• Broad spectrum activity against all seizure types

• High Efficacy

• Good tolerability

• No risk of allergic or idiosyncratic reactions (including teratogenicity)

• Low interaction potential

• Favorable pharmacokinetics ( linear kinetics, half life compatible with once or twice daily dosage)

Ideal Properties for an Antiepileptic Drug :-

• No tolerance to antiepileptic effects

• No withdrawal seizures

• No need for intensive laboratory monitoring

• Availability of convenient formulations (pediatric and parenteral )

• Low cost

“Older” Anti-Epileptic drugs

Phenobarbital 1912

Phenytoin 1938

Primidone 1952

Ethosuximide 1960

Carbamazepine 1974

Valproate 1978

• Despite a broad range of AEDs currently available, about 30 % of patients with epilepsy are uncontrolled with available treatment and a further 25 % suffer from manifestation of drug toxicity.

An introduction to Antiepileptic drug. Epilepsia 2005; 46 (Suppl 4): 31-37

Newer Antiepileptic drugs

• Equally effective as older AEDs

• Better tolerated than older AEDs

• Most have fewer interactions with other medications than older AEDs

• Expensive compared to older drugs.

Newer Antiepileptic drugs

• Felbamate 1993

• Gabapentin 1993

• Lamotrigine 1994

• Topiramate 1996

• Tiagabine 1998

• Levetiracetam 1999

• Oxcarbazepine 2000

• Zonisamide 2000

• Pregabalin 2005

• Lacosamide 2008

• Eslicarbazepine 2009

• Retigabine 2011

FELBAMATE

FELBAMATE

• FDA approval on 30th July 1993.

• Mechanism of action – Sodium channel blockade, potentiation of GABA a mediated inhibition and antagonism of NMDA mediated responses.

• Primary Indications –

- Not indicated as a First line agent.

- Add-on treatment of Lennox-Gestaut Syndrome and

partial and secondary generalised seizure refractory to

other agents.

• Usual preparations – Tablet 400,600 mg; syrup 600mg/5ml

• Usual dosages –

Initial 1200mg/day (adults); 15mg/kg (children)

Maintenace : 1200-3600mg/day (adults);

15- 80mg/kg/day (children)

• Dosing frequency – 2-4 times/day

FELBAMATE

• Oral Bioavailability – 90 % (not affected by food)

• Time to Peak Levels – 1-6 hours

• Half life – 20 hours approx

• Reference range – 30-60 mg/L

• Significant drug interactions –

increases Phenytoin, valproate levels

lowers carbamazepine and steroid levels

valproate decreases rate of Felbamate elimination.

FELBAMATE

• Common/ important adverse effects –

Hepatotoxicity and Aplastic anemia are rare but serious

(due to Toxic Metabolite ATROPALDEHYDE).

others- insomnia, headache, weight loss, mood and

behavioural changes, ataxia, visual disturbances, Rash.

FELBAMATE

• Elimination - hydroxylation and then conjugation (60%) and

renal excretion in unchanged form (40%).

So dose modification is required in hepatic and renal

diseases.

• Comment – Highly effective in severe refractory cases, but

use limited by hepatic and haematological toxicity.

FELBAMATE

• Based on the 2006 expert panel consensus, Felbamate should be regarded as a highly efficacious AED in patients refractory to first line agents. Patients considered unsuitable for candidates for Felbamate therapy include those with new onset epilepsy, history of haematological or hepatic dysfunction or autoimmune diseases. They also concluded that it has a risk-benefit ratio profile that allows it to use in selected patients with refractory epilepsy.

• A similar opinion was also reached in 1999 by join AAN and American Epilepsy Society practice advisory.

FELBAMATE

Pelleck JM et al. Felbamate :consensus of current clinical experience. Epilepsy Res 2006;71:89-101

GABAPENTIN

GABAPENTIN

• FDA approval on 31ST December 1993.

• Mechanism of action – Modulates neurotransmitter release by binding to α2-δ subunit of voltage gated Ca channels. This closes N and P/Q pre-synaptic calcium channels, diminishing excessive neuronal activity and neurotransmitter release


- Adjunctive therapy or monotherapy of partial or

secondary generalized seizures.

- also used in Neuropathic Pain, postherpetic neuralgia,

and diabetic neuropathy.

• Usual preparations – Tablet 100,300,400,600,800 mg;

Syrup 250mg/5ml


Initial 300-900 mg/day

Maintenace : 900-3600mg/day


GABAPENTIN

• Oral Bioavailability – <65 % (decreases with increasing dose)

(60% with 300mg dose, 40% with 600mg dose, and

about 35% at a steady state dose of 1600 mg TDS i.e.

non linear increase in serum levels with increasing dosage)

• Time to Peak Levels – 2-3hours

• Half life – approx 5 hours

• Reference range – 2-20mg/L

• Significant drug interactions –

No significant interaction btw Gabapentin and other AEDs

Antacid containing Aluminium or Magnesium hydroxide can reduce Gabapentin absorption by abt 20%.

GABAPENTIN


drowsiness (24.4%), dizziness (20.3%), ataxia (17%),

headache (15%), tremor, diplopia, nausea, vomiting,

non-pitting pedal edema, weight gain

GABAPENTIN

• Elimination – renal excretion in unchanged form.

• Comment –

Gabapentin is effective in focal epilepsy but may aggravate

generalized epilepsy.

Main advantage is good tolerability.

Main disadvantage is modest efficacy, particularly in

severe cases, and spectrum of efficacy restricted to partial

epilepsies

GABAPENTIN

GABAPENTIN

• In SANAD study in patients with partial epilepsy, Gabapentinwas inferior to Lamotrigine in time to treatment failure (defined as stopping the randomly assigned drug due to inadequate seizure control, intolerable side effects or the addition of other AEDs) and inferior to carbamazepine in time to 12 month remission.

The SANAD study of effectiveness of carbamazepine, gabapentin, Lamotrigine, oxcarbazepine or Topiramate for treatment of Partial epilepsy :an unblinded randomised controlled trial LANCET 2007;369;1000-1015

GABAPENTIN

• In another study comparing Gabapentin with carbamazepine, Carbamazepine demonstrated superior efficacy but at the cost of more frequent adverse effects.

A double blind trial of gabapentin monotherapy for newly diagnosed partial seizures. Chadwick et al . Neurology 1998;51;1282-1288

• Compared to Lamotrigine, Gabapentin may show decreased effectiveness but has advantage of lacking potential for any serious adverse effects.

Gabapentin vs Lamotrigine monotherapy ; a double blind trial in newly diagnosed epilepsy : EPILEPSIA 2002;43;993-1000

LAMOTRIGINE

LAMOTRIGINE

• Mechanism of action – blockade of voltage dependent sodium and calcium channels.


- Adjunctive therapy and monotherapy of partial

seizures (with or without secondary generalization)

and primary GTCS.

- also useful for other generalized epilepsy syndromes,

including Lennox-Gastaut Syndrome, mostly as

adjunctive therapy.

• Usual preparations – Tablet 25,50,100,150,200 mg;


Initial 100-200 mg/day (>12 yrs of age)


LAMOTRIGINE

• Oral Bioavailability – >95 %

• Time to Peak Levels – 1-3hours


• Reference range – 2.5-15mg/L

• Elimination – primary by conjugation with glucuronic acid in

Liver.


dizziness, diplopia,ataxia, blurred vision, somnolence,

insomnia, headache, nausea, asthenia, skin rash(5.9%)

(including serious cutaneous reactions )

lower with a low starting dose and with a slow dose

escalation.

LAMOTRIGINE

LAMOTRIGINE

• Lamotrigine associated rash is typically maculopapular or erythematous, pruritic and has the characteristics of delayed hypersensitivity reaction, appearing within first 4 weeks of initiating treatment and resolving rapidly within drug withdrawl. Rarely, rash may be more severe (erythemamultiforme) and progress to dsquamation with involvement of mucous membrane (Stevens-Johnson Syndrome)

LAMOTRIGINE

• Sporadic cases of multiorgan failure have also been reported attributed to lamotrigine.

Multisystem adverse reaction to Lamotrigine ; Shaub et al; Lancet 1994, 344;481

• Isolated cases of Pseudolymphoma, agranulocytosis,neutropenia and hepatotoxicity have also been reported.

Drug-induced pseudolymphoma secondary to Lamotrigine ; Pathak P et al ; Neurology 1998; 50;1509-1510

LAMOTRIGINE

Significant drug interactions –Serum Lamotrigine levels are reduced by enzyme inducingAEDs (Phenytoin, carbamazepine, phenobarbital).Absorption is not altered by presence of food.Serum Lamotrigine levels are increased by Valproic acid asValproate reduces rate of Lamotrigine elimination . (approxdoubled half life). It explains the increased incidence of rashseen after starting add-on Lamotrigine in patiets reveivingValproate. While the pharmacokinetics of other AEDs is not altered whenLamotrigine is added or withdrawn to the regimen.

• Comment –

- A very useful drug which can be used as 1st or 2nd line

monotherapy, or as adjunctive therapy in treatment of

partial seizures and occasionaly in generalised epilepsy

syndromes.

- safe in pregnancy.

- Main advantage is relative broad spectrum efficacy against

multiple seizure types and good tolerability, particularly

when used as monotherapy.

- Main disadvantage is need for slow-dose escalation. Highly

variable pharmacokinetics in relation to physiological

factors (pregnancy) and drug interactions.

LAMOTRIGINE

TOPIRAMATE

TOPIRAMATE• Mechanism of action

- blockade of voltage dependent Na and Ca channels

- potentiation of GABA mediated inhibition at GABA A receptors,

- reduction of excitatory action of Glutamate via AMPA receptors,

- inhibition of carbonic anhydrase.


- Adjunctive therapy or monotherapy of partial

and secondary GTCS.

- also useful for Lennox-Gastaut Syndrome and primary

generalised tonic clonic seizures.

• Usual preparations – Tablet 25,50,100,200 mg;


Initial - 25 mg/day

Maintenance - 100-500 mg/day (>12 yrs of age)

• Dosing frequency –2 times/day

TOPIRAMATE

• Oral Bioavailability – approx 100%.




• Elimination – partly by renal excretion and partly by oxidative

metabolism.


dizziness, ataxia, somnolence, paraesthesia, tremor,

somnolence, cognitive dysfunction, confusion, agitation,

amnesia, depression, headache, nausea, diarrhoea,

diplopia, weight loss.

TOPIRAMATE

TOPIRAMATE

Significant drug interactions –

Serum Topiramate levels are reduced by enzyme inducingAEDs (Phenytoin, carbamazepine, phenobarbital).

Topiramate may increase serum Phenytoin levels.

Ingestion with food delays absorption by approx 2 hours butmaximal plasma concentrations are unchanged for a given oraldose.

• Comment –

- A very useful drug with relatively broad spectrum efficacy.

- Safe in pregnancy.

- Main advantage is high responder rates.

- Main disadvantage is CNS adverse effects.

- Dose reduction required in renal diseases.

TOPIRAMATE

TIAGABINE

TIAGABINE

• Mechanism of action – Inhibition of GABA reuptake by

depressing GABA transporter GAT-1 which removes

synaptically released GABA into neurons and glial cells

and thus potentiates GABA mediated neuronal inhibition.


- Adjunctive therapy for partial seizures, with or

without secondary generalization.

• Usual preparations – Tablet 2.5,5,10 and 15 mg


Starting dose - 5 mg/day, which may be increased

by weekly increment of 5 mg/day

Maintenance - 15-30 mg/day


TIAGABINE


• Time to Peak Levels – 0.5- 2.3 hours


• Reference range – 0.02-0.2 mg/L

• Elimination – Primarily by oxidative metabolism mediated by

cytochrome CYP3A4.


dizziness, asthenia, nervousness, tremor,

attention/ concentration difficulties, depressed mood,

language problems (difficulty in finding words or inititating

speech) , seizure exacerbations (myoclonic and

absence seizures, Non-convulsive status epilepticus)

TIAGABINE

TIAGABINESignificant drug interactions –

Serum Topiramate levels are reduced by enzyme inducingAEDs by promoting its clearance.

Tiagabine does not affect metabolism of coadministered AED.

Food delays the absorption but does not change the totalamount absorbed.

The pharmacokinetics of Tiagabine is unaffected in patientswith renal impairment Patients with hepatic impairment have higher and moreprolonged concentrations of Tiagabine and more neurologicaladverse effects.

• Comment –

- A valuable drug for the adjunctive treatment of refractory

partial epilepsy with or without secondary generalization.

- Its use in unclassied epilepsy and generalized epilepsies is

to be avoided.

- Main advantage is that mechanism of action distinct from

that of other AEDs and clearly demonstrated efficacy in

partial seizures.

- Main disadvantage is short half life necessitating multiple

daily dosing, need for slow dose titration, CNS adverse

effects, and efficacy spectrum related to partial seizures.

- Dose modification not needed in Renal diseases but to be

done in hepatic disorders.

TIAGABINE

LEVETIRACETAM

LEVETIRACETAM• First approved in USA in 1999 as adjunctive treatment in

patients with partial-onset seizures.

• A pyrrolidine derivative that differs from all other currently approved AED in its chemical structure, pharmacological profile and mechanism of action and as a consequence posses unique pharmacological properties.

• Mechanism of action – Binds to Synaptic Vesicle 2A (SV2A)

protein. Precise mechanism by which this binding acts is

unknown but is likely to involve inhibition of

neurotransmitter release from nerve end terminals.

Doesnot involve any of the three main AED mechanism (blockade of

sodium or T type Ca channels or enhancement of GABA ergicneurotransmission)

LEVETIRACETAM


- First- line and adjunctive therapy of partial-onset

seizures.

- Adjunctive and, possibly, first line therapy of GTCS and

Myoclonic seizures associated with idiopathic

generalized epilepsies.

• Usual preparations –

Immediate Release Tablets 250,500,750,1000 mg

Extended release tablets – 500,750 mg

oral solution- 100mg/ml

Intravenous Preparation – 500mg/ 5ml (given as 15-min infusion)


Adults :1000-3000 mg/day. T/t may be started with 500 or 1000

mg/day and increased to target dose by increments of 500 or 1000

mg every 1-2 weeks

Children : 20-60 mg/kg/day. T/t may be started with 10-20mg/kg/day

and adjusted according to response , by increments of 10-20

mg/kg/day every 2 weeks

• Dosing frequency –2 times/day

LEVETIRACETAM


• Time to Peak Levels – 0.5-2 hours

• Half life – approx 6-8 hours


• Elimination – Primarily by renal excretion in unchanged form

(66%).


dizziness, ataxia, somnolence (10%), asthenia, infection,

nervousness, irritability, behavioural and Psychiatric

disorders (12.9% vs 6.2% of placebo patients), suicidal

behaviour (0.5% versus 0%in placebo)

LEVETIRACETAM

A systematic review of behavioural effects of Levetiracetam in adults with Epilepsy : Epilepsy behav 2003; 4; 124-132

LEVETIRACETAM


Serum Levetiracetam levels are reduced by enzyme inducingAEDs (Phenytoin, carbamazepine, phenobarbital) by about 20-30 %.

Levetiracetam doesnot induce or inhibit drug metabolizingenzymes.

Administration with food doesnot reduce the extent butdecreases the rate of absorption.

LEVETIRACETAM

• Renal impairment reduces clearance of Levetiracetam and its metabolites.

• Compared to subjects with normal renal function, levetiracetam clearance is reduced on an average by 40% with a creatinine clearance (CLcr) of 50-80 ml/min, by 50% with Clcr of 30-50 ml/min, and by 60% with CLcr < 30%.

Clinical Pharacokinetics of Levetiracetam : Clin Pharmacokinet2004;43;707-724

LEVETIRACETAM

• Dose reduction in relation to degree to renal impairment are recommended as follows :

Renal function Creatinine Clearance (ml/min/1.73 sq m)

Dose administered twice daily (mg)

Normal 80 500-1500

Mild 50-80 500-100

Moderate 30-50 250-750

Severe <30 250-500


LEVETIRACETAM

• For a patient with renal failure on hemodialysis, a dose of 500-1000 mg/day is recommended, with a supplemental dose of 250-500 after a dialysis treatment


LEVETIRACETAM

• Hepatic impairment :

• Mild to moderate (Child-pugh class A or B) hepatic impairment donot alter the clearance and no dose alterations are required in these patients.

• However, Levetiracetam clearance is reduced in severe hepatic failure (Child-Pugh class C), most likely due to concomitant renal insufficiency.

• Adjustments in dose should be made on renal rather than hepatic function.

Pharacokinetics of Levetiracetam in patients with moderate to severe liver cirrhosis: Clin Pharmaco ther 2005;77;529-541

• Comment –

- A valuable antiepileptic drug for both first line use and

adjunctive therapy.

- Main advantage is Relatively broad spectrum activity, good

tolerability, and lack of clinically significant drug

interactions.

- Main disadvantage is efficacy in some generalized seizure

types and epilepsy syndrome unproven. Behavioural and

psychiatric adverse effects

- dose reduction required in renal diseases.

LEVETIRACETAM

OXCARBAZEPINE

OXCARBAZEPINE

• Mechanism of action – Blockade of voltage gated Na channels

and N and P type calcium channels.


- Adjunctive therapy or monotherapy for partial and

secondary generalized seizures.

- Also useful to treat primary generalized tonic clonic

seizures not associated with absence and myoclonic

seizures.

-

• Usual preparations – Tablet 150,300, 600 mg

oral suspension – 60mg/ml


Starting dose - 300 mg/day (5mg/kg/day), which may

be increased by weekly increment of

300 mg/week

Maintenance - 900-1800 mg/day (20-45 mg/kg/day)

• Dosing frequency – 2 times/day

OXCARBAZEPINE

• Oral Bioavailability – > 95 %.

• Time to Peak Levels – 4- 6 hours

• Half life – approx 5 hours (of MHD)


• Elimination – Ketoreduction to MHD (monohydroxycarbazepine) ,

which is then cleared in urine in unchanged form and

as a glucuronide conjugate. Toxic effects due to

epoxide etabolite (as with Carbamazepine) are

hence avoided.


Dizziness, diplopia, ataxia, somnolence, headache, fatigue,

rash, hyponatremia, gastrointestinal disturbances

OXCARBAZEPINE

OXCARBAZEPINESignificant drug interactions –

Serum Oxcarbazepine levels are reduced by enzyme inducingAEDs by promoting its clearance.

Oxcarbazepine may increase the levels of phenytoin andPhenobarbital.

oral bioavailability is not affected by food intake.

Drug interactions and auto induction of own metabolism areless marked because it is a weak enzyme inducer

• Comment –

- A useful drug for the treatment of partial and secondary

generalized seizures, with some advantages over

Carbamzepine.

- Main advantage is that it is better tolerated and has fewer

interactions than carbamazepine. Risk of hepatotoxicity is

estimated to be lower than carbamazepine.

- Main disadvantage is efficacy spectrum restricted to

partial epilepsies. Higher incidence of hyponatremia

compared with carbamazepine.

- Not indicated for absence, myoclonic and other types of

generalized seizures other than tonic-clonic seizures and

indeed may exacerbate them.

OXCARBAZEPINE

ZONISAMIDE

ZONISAMIDE• Was approved in USA (2000) and Europe(2005).

• Mechanism of action – Multiple including blockade of voltage

gated Na channels, blockade of T-type calcium channels,

potentiation of GABAergic transmission and inhibition of

Carbonic anhydrase.


- Adjunctive therapy for partial and secondary

generalized seizures.

- May also be used as adjunctive therapy in primary

generalized seizures.

- Myoclonic Epilepsies (Uncontrolled studies)

• Usual preparations – Capsules 25,50, 100 mg


Starting dose - 50 mg/day initially, increased to 100

mg/day after 1 week and 200mg/day after a further 2

weeks. Further dose increments by 100mg/day may be

indicated at intervals of 1-2 weeks, according to clinical

response.



ZONISAMIDE

• Oral Bioavailability – ~ 100%.

• Time to Peak Levels – 2- 6 hours



• Elimination – partly by renal excretion, partly by metabolism

mediated by CYP3A4, N-Acetyltransferase and glucuronyl

transferase.

ZONISAMIDE

ZONISAMIDE

Significant drug interactions –Serum Zonisamide levels are reduced by enzyme inducingAEDs.

Administration with food doesnot reduce the extent butdecreases the rate of absorption.

Zonisamide doesnot induce or inhibit drug metabolizingenzymes.

• Since both Zonisamide and Topiramate exhibit carbonic anhydrase inhibitory activity, possibility of an increase in the incidence of renal stones has been raised.

• No renal calculi were identified in 59 patients exposed to both Zonisamide and Topiramate for upto 135 weeks in the US and European clinical trials, while one case of Nephrolithiasis was reported during postmarketing surveillance in the USA.

Zonisamide and renal calculi in patients with Epilepsy : how big an issue? Wroe S. : Curr MedRes Opin 2007;23;1765-1773

ZONISAMIDE


Dizziness, somnolence (18% vs placebo), diplopia, ataxia, headache, attention and concentration difficulties, memory impairment, agitation, irritability, confusion, depression, anorexia, Weight loss, Nephrolithiasis (1.2-1.4%), skin rashes (including Stevens Jonhnson Syndrome), blood dyscrasias and hypersensitivity reaction.

Teratogenicity has been reported in animal studies. (cardiovascular defects, skeletal abnormalities and fetal death)

Reproduction studies of Zonisamide in animals ; Terada Y et al; JpnPharmaco Ther; 1987; 15; 4399-4416

• Comment –

- A useful AED drug with a probable broad spectrum of

efficacy

- Main advantage is long term clinical experience

(Japan) and suggestive evidence of broad spectrum

efficacy.

- Main disadvantage is CNS adverse effects.

- No proven safety in Pregnancy, so should be avoided.

ZONISAMIDE

PREGABALIN

PREGABALIN• Was approved by Eurpean Medicines Agency (EMEA) in July

2004 and US FDA in June 2005.

• Mechanism of action –Binds to the α2- δ subunit of voltage gated calcium channels, causing decreased calcium influx at nerve terminals and reduced excitatory neurotransmitter release . No effect on GABA pathways.


- Adjunctive therapy for partial seizure with or without

secondary generalization.

- also used in Neuropathic pain, Fibromyalgia and

generalized anxiety disorders.

• Usual preparations – Capsules 50, 75,100,150,200,300 mg


Starting dose - 150 mg/day



PREGABALIN



• Half life – 5-7 hours

• Elimination –Renal excretion in unchanged form.

So dose should be reduced by 50% in patients with CLcrbetween 30-60 ml/min compared to those with CLcr > 60ml/min . And a further reduction of dose by 50 % for each additional 50 % decrease in Clcr.

PREGABALIN

PREGABALIN


Pregabalin may potentiate the effects of other CNSdepressants on cognition and motor coordination.

Pregabalin is devoid of any enzyme-inducing or inhibiting activity on drug metabolizing enzymes and is not itselfsignificantly metabolized. So drug interactions are unlikely.

PREGABALIN


Dizziness (28.9%) , somnolence (20.8%), ataxia, asthenia,

weight gain (10.4% vs 1.4% in placebo),

visual disturbances, attention and concentration

difficulties, tremor and peripheral edema

• Comment –

- A useful AED drug for management of Refractory Partial

onset seizures.

- Main advantage is robust efficacy, predictable

pharmacokinetics, lack of drug interactions and activity in

neuropathic pain, Fibromyalgia and Generalized Anxiety

Disorders.

- Main disadvantage is spectrum of efficacy limited to

partial eplipsies, CNS adverse effects and propensity to

cause weight gain.

- No data on Pregabalin adminstration in Pregnancy.

- Studies in Generalized epilepsies are under way.

PREGABALIN

LACOSAMIDE

LACOSAMIDE• Recently been licensed for clinical use (2008).

• Mechanism of action – Enhances slow inactivation of

voltage- gated sodium channels resulting in stabilization of

hyperexcitable neuronal membranes ; may interact with

Collapsin response mediated protein 2 (CRMP-2)

(involved in signal transduction of Neurotrophic factors ---under research)


- Adjunctive therapy for refractory partial-onset seizure

with or without secondary generalization in adults

with epilepsy.


Tablets - 50, 100,150,200 mg

Syrup – 15 mg/ml

Intravenous solution – 10 mg/ml


Starting dose - 100 mg/day



LACOSAMIDE


• Time to Peak Levels – 0.5-4 hours following oral dose.


• Elimination – Partly by Renal excretion in unchanged form in

urine (40%) and partly by metabolism

(primarily demethylation) follwed by excretion.

No dose reduction required in Mild to Moderate Renal or

Hepatic dysfunction but dose reduction required in severe cases

LACOSAMIDE

LACOSAMIDE


Enzyme inducing AEDs reduce serum Lacosamide levels byapprox 25 %.

No significant effect of food intake on Pharmacokinetics ofLacosamide.

Lacosamide doesnot alter metabolism of coadministered AEDs.

LACOSAMIDE


Dizziness , headache, nausea, diplopia, Tremor, nausea,

vomiting

Initial concerns were regarding QTc prolongation – but found to have no effect on QTc at 800mg/day.

Lacosamide demonstrated no potential for QTc prolongationEpilepsia 2007;48 (suppl 7)

Asymptomatic PR prolongation has been observed but no 2nd

or 3rd degree Heart block has been observed.

Lacosamide in diabetic neuropathic pain trials ; Euro J Neurol 2008; 15 (Suppl 3)

• Comment –

- A potentially valuable AED as an adjunctive therapy in the

management of Partial-onset seizures with or without

secondary generalization in adults with epilepsy.

- Main advantage is well documented efficacy, lack of

clinically important drug interactions and availability of

Intravenous formulation.

- Main disadvantage is limited clinical experience, CNS

and gastrointestinal adverse effects.

- May also be used in Neuropathic Pain at doses of

400mg/day.

LACOSAMIDE

Lacosamide safety and efficacy in painful distal diabetic neuropathy ; Neurology ; 66:( Suppl 2 ) 318-319

ESLICARBAZEPINE ACETATE

ESLICARBAZEPINE ACETATE• One of the latest AED to be licensed for clinical use (2009).

• Mechanism of action –

Blockade of voltage gated sodium channels resulting in

stabilization of hyper-excitable neuronal membranes.


- Adjunctive therapy for partial seizures.

(potential additional indications are under assessment)


Tablets – 400, 600 and 800 mg

Syrup – 50 mg/ml


800 – 1200mg/day (tentative dose range)

• Dosing frequency – once daily



• Time to Peak Levels – 2-3 hours following oral dose.


• Elimination – Hydrolyzed rapidly to Eslicarbazepine, which is

excreted in urine in free and conjugated form. Minor

metabolites include (R)-licarbazepine, oxcarbazepine and

their conjugates.




Enzyme inducing AEDs reduce serum Eslicarbazepine levels.

Eslicarbazepine acetate decreases the levels of OCPs.



Dizziness , blurred vision, headache, nausea, diplopia,

nausea, vomiting, visual disturbances

• Comment –

- Potentially a useful AED, but more data are needed to

establish its place in the current therapy.

- Main advantage is usually well tolerated, once daily dosing

- Main disadvantage is limited clinical experience, efficacy

spectrum probably restricted to partial epilepsies.


RETIGABINE

RETIGABINE• Recently been approved by FDA (2011).

• Mechanism of action – Activation of voltage gated neuronal

Potassium channels [KCNQ (kv7)], resulting in enhanced

M-current, and thereby stabilization of resting membrane

potential. (under research)


- Adjunctive therapy for refractory partial-onset seizure.


Tablets - 50, 100,200,300 and 400 mg


600-1200 mg/day. Treatment started at 300mg/day and increased at weekly intervals by 150mg/day upto desired target dose.


RETIGABINE


• Time to Peak Levels – 0.6-1.5 hours.


• Elimination – Partly by Renal excretion in unchanged form in

urine (20-30%) and partly by metabolism

(50-65% ) followed by excretion.

No dose reduction required in Mild to Moderate Renal or

Hepatic dysfunction but dose reduction required in severe cases

RETIGABINE

RETIGABINE

Significant drug interactions –Retigabine increases Lamotrigine levels by about 20%.

Enzyme inducing AEDs reduce serum Lacosamide levels byapprox 30 %.

No significant effect of food intake on Pharmacokinetics ofLacosamide.

RETIGABINE


Dizziness , somnolence, fatigue, confusion, dysarthria, confusion, tremor, urinary hesitancy/retention.

• Comment –

- A potentially valuable AED as an adjunctive therapy in the

management of refractory Partial-onset seizures.

- Studies are required to assess potential efficacy in other

seizure types.

- Main advantage is clearly defined dose related efficacy,

low interaction potential.

- Main disadvantage is need for gradual titration and for

frequent dosing, CNS adverse effects and limited clinical

experience.

RETIGABINE

ANTIEPLILEPTIC DRUGS IN EARLY CLINICAL DEVELOPMENT

2-DEOXY-D-GLUCOSE

• Differs from normal Glucose by lacking an Oxygen atom at 2 position.

• MOA- intake into cells is not followed by metabolism-leading to inhibition of Glycolysis – supposed to decrease epileptogenesis.

• Effective in various animal models.

• Drug interaction, efficacy and adverse effects are presently unknown.

Fructose-1,6-Bisphosphate Has Anticonvulsant Activity in Models of Acute Seizures in Adult Rats :Xiao-Yuan Lian, Firdous A. Khan, and Janet L. Stringer The Journal of Neuroscience, 31 October 2007, 27(44): 12007-12011; doi: 10.1523/JNEUROSCI.3163-07.2007

FLUOROFELBAMATE• Analogue of Felbamate, devoid of toxic metabolite

(Atropaldehyde).

• So designed to emulate clinical efficacy of Felbamate without its safety concerns ( aplastic anemia and hepatotoxicity)

• Exact MOA is unknown, but appears to decrease responses to GABA, kainate and NMDA and to decrease voltage dependent sodium currents.

• Shown to have greater potency than Felbamate in experimental models


Seizure. 2002 Oct;11(7):423-30.Anticonvulsant and antiepileptogenic effects of fluorofelbamate in experimental status epilepticus.Mazarati AM, Sofia RD, Wasterlain CG

GANAXOLONE

• A neurosteroid, synthetic analogue of allopregnalone, a metabolite of Progesterone.

• Potent positive modulator of GABA-A receptors.

• Effective in various experimental Models

• Preliminary trials have not shown any significant drug interactions.

• Might be useful in Generalized as well as partial epilepsy and also in Infantile Spasms.

• Adverse effects – sedation, dizziness, headache, GI disturbances , fatigue

Epilepsia. 2007 Oct;48(10):1870-4. Epub 2007 Jul 18.Clinical evaluation of ganaxolone in pediatric and adolescent patients with refractory epilepsy.PieriboneVA, Tsai J, Soufflet C, Rey E, Shaw K, Giller E, Dulac O

JZP-4

• Structural analogue of Lamotrigine with better pharmacokinetic and safety profiles compared to Lamotrigine.

• Potent sodium and high voltage calcium channel blocker.

• Co adminstration of valproic acid did not result in any significant change in JZP-4 pharmacokinetics.


Pharmacol Biochem Behav. 2008 Jun;89(4):523-34 In vivo pharmacological effects of JZP-4, a novel anticonvulsant, in models for anticonvulsant, antimania and antidepressant activity. Foreman MM et al

SELETRACETEM• An analogue of Levetiracetam.

• Is approximately 10 fold more potent than Levetiracetam in some experimental models.

• Drug interaction, efficacy are presently unknown.

• Well tolerated

• Most frequently encountered adverse effect is somnolence, dizziness, euphoria and nausea.

J Neuro Sci 2005;238 : Matagne et al : Seletracetam (UCB 44212)

YKP3089

• A novel compound with broad spectrum anticonvulsant activity.

• MOA is unknown

• Effective in all kinds of experimental models.


Epilepsy Res. 2007 Jan;73(1):1-52. Progress report on new antiepileptic drugs: a summary of the Eigth Eilat Conference (EILAT VIII). Bialer M, JohannessenSI, Kupferberg HJ, Levy RH, Perucca E, Tomson T.

THANK YOU

REFERENCES

• The treatment of Epilepsy 3rd Edition : Simon Shorovon, Emilio Perucca & Jerome Engel Jr

• Fructose-1,6-Bisphosphate Has Anticonvulsant Activity in Models of Acute Seizures in Adult Rats :Xiao-Yuan Lian, Firdous A. Khan, and Janet L. Stringer The Journal of Neuroscience, 31 October 2007, 27(44): 12007-12011; doi: 10.1523/JNEUROSCI.3163-07.2007

• Seizure. 2002 Oct;11(7):423-30.Anticonvulsant and antiepileptogenic effects of fluorofelbamate in experimental status epilepticus.Mazarati AM, Sofia RD, Wasterlain CG

• Epilepsia. 2007 Oct;48(10):1870-4. Epub 2007 Jul 18.Clinical evaluation of ganaxolone in pediatric and adolescent patients with refractory epilepsy.Pieribone VA, Tsai J, Soufflet C, Rey E, Shaw K, Giller E, Dulac O

• Pharmacol Biochem Behav. 2008 Jun;89(4):523-34 In vivo pharmacological effects of JZP-4, a novel anticonvulsant, in models for anticonvulsant, antimania and antidepressant activity. Foreman MM et al

• J Neuro Sci 2005;238 : Matagne et al : Seletracetam (UCB 44212)

• Epilepsy Res. 2007 Jan;73(1):1-52. Epub 2006 Dec 8.Progress report on new antiepileptic drugs: a summary of the EigthEilat Conference (EILAT VIII).Bialer M, JohannessenSI, Kupferberg HJ, Levy RH, Perucca E, Tomson T.

• Pelleck JM et al. Felbamate :consensus of current clinical experience. Epilepsy Res 2006;71:89-101

• The SANAD study of effectiveness of carbamazepine, gabapentin, Lamotrigine, oxcarbazepine or Topiramate for treatment of Partial epilepsy :an unblinded randomisedcontrolled trial ;LANCET 2007;369;1000-1015

• A double blind trial of gabapentin monotherapy for newly diagnosed partial seizures. Chadwick et al . Neurology 1998;51;1282-1288

• Gabapentin vs Lamotrigine monotherapy ; a double blind trial in newly diagnosed epilepsy : EPILEPSIA 2002;43;993-1000

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Newer antiepileptic drugs