Newer antiepileptic drugs

Newer antiepileptic drugs
by By Dr Piyush Ojha , DM Resident, GMC Kota
under guidance of Prof. Dr Vijay Sardana (HOD,Neurology)

1. NEWER ANTIEPILEPTIC DRUGS DR. PIYUSH OJHA DM RESIDENT DEPARTMENT OF NEUROLOGY GOVT MEDICAL COLLEGE, KOTA

2. 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)

3. 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

4. “Older” Anti-Epileptic drugs Phenobarbital 1912 Phenytoin 1938 Primidone 1952 Ethosuximide 1960 Carbamazepine 1974 Valproate 1978

5. 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

6. 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.

7. 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

8. FELBAMATE

9. FELBAMATE FDA approval on 30 th 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.

10. 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

11. 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

12. 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

13. 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

14. 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

15. GABAPENTIN

16. GABAPENTIN FDA approval on 31 ST December 1993. Mechanism of action – Modulates neurotransmitter release by binding to α 2- δ subunit of voltage gated Ca channels. This closes N and P/Q pre-synaptic calcium channels, diminishing excessive neuronal activity and neurotransmitter release Primary Indications – - Adjunctive therapy or monotherapy of partial or secondary generalized seizures. - also used in Neuropathic Pain, postherpetic neuralgia, and diabetic neuropathy.

17. Usual preparations – Tablet 100,300,400,600,800 mg; Syrup 250mg/5ml Usual dosages – Initial 300-900 mg/day Maintenace : 900-3600mg/day Dosing frequency – 2-3 times/day GABAPENTIN

18. 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

19. Common/ important adverse effects – drowsiness (24.4%), dizziness (20.3%), ataxia (17%), headache (15%), tremor, diplopia , nausea, vomiting, non-pitting pedal edema , weight gain GABAPENTIN

20. 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

21. GABAPENTIN In SANAD study in patients with partial epilepsy, Gabapentin was 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

22. 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

23. LAMOTRIGINE

24. LAMOTRIGINE Mechanism of action – blockade of voltage dependent sodium and calcium channels. Primary Indications – - 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.

25. Usual preparations – Tablet 25,50,100,150,200 mg; Usual dosages – Initial 100-200 mg/day (>12 yrs of age) Dosing frequency – 1-2 times/day LAMOTRIGINE

26. Oral Bioavailability – >95 % Time to Peak Levels – 1-3hours Half life – approx 5 hours Reference range – 2.5-15mg/L Elimination – primary by conjugation with glucuronic acid in Liver. Common/ important adverse effects – 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

27. 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 ( erythema multiforme ) and progress to dsquamation with involvement of mucous membrane (Stevens-Johnson Syndrome)

28. 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

29. LAMOTRIGINE Significant drug interactions – Serum Lamotrigine levels are reduced by enzyme inducing AEDs ( Phenytoin , carbamazepine , phenobarbital ). Absorption is not altered by presence of food. Serum Lamotrigine levels are increased by Valproic acid as Valproate reduces rate of Lamotrigine elimination . (approx doubled half life). It explains the increased incidence of rash seen after starting add-on Lamotrigine in patiets reveiving Valproate . While the pharmacokinetics of other AEDs is not altered when Lamotrigine is added or withdrawn to the regimen.

30. Comment – - A very useful drug which can be used as 1 st or 2 nd 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

31. TOPIRAMATE

32. 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 . Primary Indications – - Adjunctive therapy or monotherapy of partial and secondary GTCS. - also useful for Lennox- Gastaut Syndrome and primary generalised tonic clonic seizures.

33. Usual preparations – Tablet 25,50,100,200 mg; Usual dosages – Initial - 25 mg/day Maintenance - 100-500 mg/day (>12 yrs of age) Dosing frequency –2 times/day TOPIRAMATE

34. Oral Bioavailability – approx 100%. Time to Peak Levels – 2-4 hours Half life – approx 5 hours Reference range – 5-20mg/L Elimination – partly by renal excretion and partly by oxidative metabolism. Common/ important adverse effects – dizziness, ataxia, somnolence, paraesthesia , tremor, somnolence, cognitive dysfunction, confusion, agitation, amnesia, depression, headache, nausea, diarrhoea , diplopia , weight loss . TOPIRAMATE

35. TOPIRAMATE Significant drug interactions – Serum Topiramate levels are reduced by enzyme inducing AEDs ( Phenytoin , carbamazepine , phenobarbital ). Topiramate may increase serum Phenytoin levels. Ingestion with food delays absorption by approx 2 hours but maximal plasma concentrations are unchanged for a given oral dose.

36. 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

37. TIAGABINE

38. 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. Primary Indications – - Adjunctive therapy for partial seizures, with or without secondary generalization.

39. Usual preparations – Tablet 2.5,5,10 and 15 mg Usual dosages – Starting dose - 5 mg/day, which may be increased by weekly increment of 5 mg/day Maintenance - 15-30 mg/day Dosing frequency – 2-4 times/day TIAGABINE

40. Oral Bioavailability – approx 100%. Time to Peak Levels – 0.5- 2.3 hours Half life – approx 5 hours Reference range – 0.02-0.2 mg/L Elimination – Primarily by oxidative metabolism mediated by cytochrome CYP3A4. Common/ important adverse effects – 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

41. TIAGABINE Significant drug interactions – Serum Topiramate levels are reduced by enzyme inducing AEDs by promoting its clearance. Tiagabine does not affect metabolism of coadministered AED. Food delays the absorption but does not change the total amount absorbed. The pharmacokinetics of Tiagabine is unaffected in patients with renal impairment Patients with hepatic impairment have higher and more prolonged concentrations of Tiagabine and more neurological adverse effects.

42. 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

43. LEVETIRACETAM

44. 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 ergic neurotransmission)

45. LEVETIRACETAM Primary Indications – - 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.

46. 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) Usual dosages – 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

47. Oral Bioavailability – approx 100%. Time to Peak Levels – 0.5-2 hours Half life – approx 6-8 hours Reference range – 12-46mg/L Elimination – Primarily by renal excretion in unchanged form (66%). Common/ important adverse effects – 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

48. LEVETIRACETAM Significant drug interactions – Serum Levetiracetam levels are reduced by enzyme inducing AEDs ( Phenytoin , carbamazepine , phenobarbital ) by about 20-30 %. Levetiracetam doesnot induce or inhibit drug metabolizing enzymes. Administration with food doesnot reduce the extent but decreases the rate of absorption.

49. 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 Pharmacokinet 2004;43;707-724

50. 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 Clinical Pharacokinetics of Levetiracetam : Clin Pharmacokinet 2004;43;707-724

51. 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 Clinical Pharacokinetics of Levetiracetam : Clin Pharmacokinet 2004;43;707-724

52. 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

53. 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

54. OXCARBAZEPINE

55. OXCARBAZEPINE Mechanism of action – Blockade of voltage gated Na channels and N and P type calcium channels. Primary Indications – - 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. -

56. Usual preparations – Tablet 150,300, 600 mg oral suspension – 60mg/ml Usual dosages – 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

57. Oral Bioavailability – > 95 %. Time to Peak Levels – 4- 6 hours Half life – approx 5 hours (of MHD) Reference range – 3-35 mg/L 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. Common/ important adverse effects – Dizziness, diplopia , ataxia, somnolence, headache, fatigue, rash, hyponatremia , gastrointestinal disturbances OXCARBAZEPINE

58. OXCARBAZEPINE Significant drug interactions – Serum Oxcarbazepine levels are reduced by enzyme inducing AEDs by promoting its clearance. Oxcarbazepine may increase the levels of phenytoin and Phenobarbital. oral bioavailability is not affected by food intake. Drug interactions and auto induction of own metabolism are less marked because it is a weak enzyme inducer

59. 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

60. ZONISAMIDE

61. 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 . Primary Indications – - Adjunctive therapy for partial and secondary generalized seizures. - May also be used as adjunctive therapy in primary generalized seizures. - Myoclonic Epilepsies (Uncontrolled studies)

62. Usual preparations – Capsules 25,50, 100 mg Usual dosages – 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. Maintenance - 200-600 mg/day Dosing frequency – 1-2 times/day ZONISAMIDE

63. Oral Bioavailability – ~ 100%. Time to Peak Levels – 2- 6 hours Half life – approx 5 hours Reference range – 10-40 mg/L Elimination – partly by renal excretion, partly by metabolism mediated by CYP3A4, N- Acetyltransferase and glucuronyl transferase . ZONISAMIDE

64. ZONISAMIDE Significant drug interactions – Serum Zonisamide levels are reduced by enzyme inducing AEDs. Administration with food doesnot reduce the extent but decreases the rate of absorption. Zonisamide doesnot induce or inhibit drug metabolizing enzymes.

65. 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

66. ZONISAMIDE Common/ important adverse effects – 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; Jpn Pharmaco Ther ; 1987; 15; 4399-4416

67. 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

68. PREGABALIN

69. PREGABALIN Was approved by Eurpean Medicines Agency (EMEA) in July 2004 and US FDA in June 2005. Mechanism of action –Binds to the α 2- δ subunit of voltage gated calcium channels, causing decreased calcium influx at nerve terminals and reduced excitatory neurotransmitter release . No effect on GABA pathways. Primary Indications – - Adjunctive therapy for partial seizure with or without secondary generalization. - also used in Neuropathic pain, Fibromyalgia and generalized anxiety disorders.

70. Usual preparations – Capsules 50, 75,100,150,200,300 mg Usual dosages – Starting dose - 150 mg/day Maintenance - 150-600 mg/day Dosing frequency – 2-3 times/day PREGABALIN

71. Oral Bioavailability – ~ 90%. Time to Peak Levels – 1-2 hours Half life – 5-7 hours Elimination –Renal excretion in unchanged form. So dose should be reduced by 50% in patients with CLcr between 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

72. PREGABALIN Significant drug interactions – Pregabalin may potentiate the effects of other CNS depressants on cognition and motor coordination. Pregabalin is devoid of any enzyme-inducing or inhibiting activity on drug metabolizing enzymes and is not itself significantly metabolized. So drug interactions are unlikely.

73. PREGABALIN Common/ important adverse effects – 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

74. 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

75. LACOSAMIDE

76. 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 ) Primary Indications – - Adjunctive therapy for refractory partial-onset seizure with or without secondary generalization in adults with epilepsy.

77. Usual preparations – Tablets - 50, 100,150,200 mg Syrup – 15 mg/ml Intravenous solution – 10 mg/ml Usual dosages – Starting dose - 100 mg/day Maintenance - 200-400 mg/day Dosing frequency – 2 times/day LACOSAMIDE

78. Oral Bioavailability – ~ 100%. Time to Peak Levels – 0.5-4 hours following oral dose. Half life – 12-16 hours 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

79. LACOSAMIDE Significant drug interactions – Enzyme inducing AEDs reduce serum Lacosamide levels by approx 25 %. No significant effect of food intake on Pharmacokinetics of Lacosamide . Lacosamide doesnot alter metabolism of coadministered AEDs.

80. LACOSAMIDE Common/ important adverse effects – 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 prolongation Epilepsia 2007;48 ( suppl 7) Asymptomatic PR prolongation has been observed but no 2 nd or 3 rd degree Heart block has been observed. Lacosamide in diabetic neuropathic pain trials ; Euro J Neurol 2008; 15 ( Suppl 3)

81. 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

82. ESLICARBAZEPINE ACETATE

83. 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. Primary Indications – - Adjunctive therapy for partial seizures. (potential additional indications are under assessment)

84. Usual preparations – Tablets – 400, 600 and 800 mg Syrup – 50 mg/ml Usual dosages – 800 – 1200mg/day (tentative dose range) Dosing frequency – once daily ESLICARBAZEPINE ACETATE

85. Oral Bioavailability – ~ 100%. Time to Peak Levels – 2-3 hours following oral dose. Half life – 13-20 hours Elimination – Hydrolyzed rapidly to Eslicarbazepine , which is excreted in urine in free and conjugated form. Minor metabolites include (R)- licarbazepine , oxcarbazepine and their conjugates. ESLICARBAZEPINE ACETATE

86. ESLICARBAZEPINE ACETATE Significant drug interactions – Enzyme inducing AEDs reduce serum Eslicarbazepine levels. Eslicarbazepine acetate decreases the levels of OCPs.

87. ESLICARBAZEPINE ACETATE Common/ important adverse effects – Dizziness , blurred vision, headache, nausea, diplopia , nausea, vomiting, visual disturbances

88. 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. ESLICARBAZEPINE ACETATE

89. RETIGABINE

90. 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 ) Primary Indications – - Adjunctive therapy for refractory partial-onset seizure.

91. Usual preparations – Tablets - 50, 100,200,300 and 400 mg Usual dosages – 600-1200 mg/day. Treatment started at 300mg/day and increased at weekly intervals by 150mg/day upto desired target dose. Dosing frequency – 3 times/day RETIGABINE

92. Oral Bioavailability – ~ 60%. Time to Peak Levels – 0.6-1.5 hours. Half life – 8-10 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

93. RETIGABINE Significant drug interactions – Retigabine increases Lamotrigine levels by about 20%. Enzyme inducing AEDs reduce serum Lacosamide levels by approx 30 %. No significant effect of food intake on Pharmacokinetics of Lacosamide .

94. RETIGABINE Common/ important adverse effects – Dizziness , somnolence, fatigue, confusion, dysarthria , confusion, tremor, urinary hesitancy/retention.

95. 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

96. ANTIEPLILEPTIC DRUGS IN EARLY CLINICAL DEVELOPMENT

97. 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

98. 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 Drug interaction, efficacy and adverse effects are presently unknown. Seizure. 2002 Oct;11(7):423-30.Anticonvulsant and antiepileptogenic effects of fluorofelbamate in experimental status epilepticus.Mazarati AM, Sofia RD,  Wasterlain CG

99. 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.Pieribone VA, Tsai J,  Soufflet C, Rey E, Shaw K,  Giller E,  Dulac O

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

101. 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)

102. YKP3089 A novel compound with broad spectrum anticonvulsant activity. MOA is unknown Effective in all kinds of experimental models. Drug interaction, efficacy and adverse effects are presently unknown. 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,  Johannessen SI,  Kupferberg HJ, Levy RH,  Perucca E,  Tomson T.

103. THANK YOU

104. REFERENCES The treatment of Epilepsy 3 rd 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

105. 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 Eigth Eilat Conference (EILAT VIII). Bialer M,  Johannessen SI,  Kupferberg HJ, Levy RH,  Perucca E,  Tomson T.

106. 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 randomised controlled 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