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Newer antiepileptic

The document discusses newer antiepileptic drugs (AEDs) and their efficacy, prevalence of epilepsy, and considerations for selecting appropriate treatments. It highlights the challenges faced by 20-30% of patients who have uncontrolled seizures or side effects from existing medications, emphasizing the need for tailored approaches based on individual patient profiles. Additionally, it reviews the historical development of AEDs, their pharmacological properties, and the significance of considering drug interactions and pregnancy safety when prescribing these medications.

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NEWER ANTIEPILEPTIC DRUGS Dr Akhila Kumar Panda MD, DM, Consultant Neurologist
APASMAR 6000BC 1000BC ( CHARAK)
Prevalence • Prevalence- 1 % 0f the population • 50 million worldwide • Higher rates in developing countries • 10 million in India • Incidence – 0.7% • Incidence is highest in the young and elderly
Pediatric Seizure Types Adult Seizure Types Distribution of seizure type
Background and Justification: • Between 70 and 80% of individuals are successfully treated with one of the more than twenty AEDs now available. • 20-30% of patients have either intractable or uncontrolled seizures or suffer significant adverse side effects secondary to medication. • There is no class I evidence comparing the new AEDs to the old, or the new AEDs to each other in patients with refractory epilepsy. • Selection of the appropriate drug for a given individual must be based on understanding of each drug’s pharmacology, side effect profile, and risks.
11th May 1857
HISTORY OF AED • Phenobarbital- Alfred Hauptmann- 1912 • Phenytoin- Tracy Putnam - 1934 • Ethosuximide - Parke, Davis - 1958 • Carbamazepine - Schindler at Geigy - 1953 epilepsy- 1963 • VPA- Pierre Eymard- 1963 • Diazepam - Henry Gastaut - 1965
• BEGAN IN 1975 . • National Institute of Neurological Disorders and Stroke established the Anticonvulsant Drug Development Programme. • Screened more than 28,000 new chemical entities. MORDEN ERA OF AED
FELBAMET 1993 GABAPENTIN 1994 LAMOTRIGINE 1995
TOPIRAMATE 1996 TIAGABIN 1998 LEVITIRACETAM 1999
OXCARBAZEPINE 2000 ZONISAMIDE 2000 PREGABALINE 2005
DRUG RESPONSE 50% controlled on1st AED. 10%-20% with 2nd AED. 30% refractory epilepsy.
Characteristics of Older AEDs: Advantages  Broad familiarity  long-term experience  Known efficacy  Lower cost  What is old is not necessarily outdated
Characteristics of Older AEDs: • Disadvantages • Cause hepatic enzyme induction (PB, PHT,CBZ, Primidone) or inhibition (VPA) • Cause change in internal hormonal compounds (sex steroids, Vit D) • Produce interaction with commonly used medications (warfarin, oral contraceptives, Ca-channel antagonists, chemotherapy agents) • Pregnancy Category D
Advantages of Newer AEDs • Greater tolerability • Fewer side effects • Fewer drug interactions • Fewer idiosyncratic reactions • Minimal influence on metabolic pathways • Pregnancy category C
Selecting an Antiepileptic Drug Choose antiepileptic drug most suited to the individual patient based on  seizure/epilepsy type  side effects (anemia, hepatotoxicity, rash, etc.)  patient profile (comorbidity, sex, age, etc,)  ease of use  cost  Balance between efficacy, tolerability and safety  Epilepsy may be a lifelong diagnosis – minimize  chronic side effects from AEDs (cognitive, reproductive, neuropathy, bone and weight changes, etc.)
PHARMACORESISTANCE
Reasons for pseudoresistance Wrong diagnosis Syncope, cardiac arrythmia, PNES Wrong drug Inappropriate for seizure type, pharmacokinetic or pharmacodynamic interactions Wrong Dose Too low, side effects preventing drug increase Life style issue Poor compliance with medication, alcohol or drug abuse
PHARMACORESISTA NT The drug faces a modified target, Interacts less effectively . Missing the Real Targets Increased expression or function of multidrug transporter proteins Decreases availability of the AED at its target versus.
PHARMACODYNAMICS
Targets and mechanisim ANTIEPILEPTIC DRUGS Sodium channel actions 1. Blockade by stabilizing fast- inactivated state 2.slow-inactivated state Phenytoin, carbamazepine,lamotrigine, oxcarbazepine, Rufinamide, eslicarbazepine Lacosamide Calcium channel actions 1.Blockade of high voltage activated channel (P/Q type) 2.Blockade of low voltage-activated channel (T type) Gabapentin, pregabalin Ethosuximide GABA-related actions Activation of GABA-A receptor Blockade of GABA transporter Inhibition of GABA transaminase Phenobarbital, benzodiazepines Tiagabine Vigabatrin SV2A actions Modulation of SV2A Levetiracetam Multiple actions on multiple targets Valproic acid, felbamate,topiramate, zonisamide Potassium channel activity Opens Kv7 potassium channels Retigabine/ezogabine
PHARMACOKINETICS
Drug Bioava ilability % Protein binding % t1/2(h) Dosage Therapeutic drug mon Mg/dl Felbamate >90 22–36 14–23 adult -upto 3,600 mg/day Ch =15 -45mg/kg/d 30–100 Lamotrigine 98 55 24-31 mono 15(EI) 59( VPA) 2-15 Levetiracetam >95 0 6-8 Upto 3000 mg/d 20–60 Oxcarbazepine >95 40 8-12 Adult-upto 2400mg/d Ch-30-46mg/kg/d 10-35 Tiagabine 90 96 4-13 (mon) 2-5(EI) In-15 to 16 mg/day. EI-30-32mg/d Maint-30-32mg/d 50-56mg/d 5–70 Topiramate 81-95 9-17 20-30(mon) 8-15(EI) 25 to 700 mg/day. Ch- init-0.5 to 1 mg/kg/day..6- 9mg/kg/d 2-25
Lamotrigine , titration As add-on therapy Concomitant antiepileptic drugs Adult Valproate others Weeks 1 and 2 Weeks 3 and 4 Maintenance 12.5 mg daily 25 mg daily 50–100 mg twice daily 50 mg daily 50 mg twice daily 100–200 mg twice daily Children Weeks 1 and 2 Weeks 3 and 4 Maintenance 0.15 mg/kg 0.3mg/kg 1-5mg/kg 0.6mg/kg 1.2mg/kg 5-15mg/kg As monotherapy Adults children Weeks 1 and 2 Weeks 3 and 4 Maintenance 25 mg daily 25 mg twice daily 50–100 mg twice daily 0.5 mg/kg 1 mg/kg 2–8 mg/kg
Drug Bioavailability % Protein binding % t1/2 (h) Dosage Therapeuti drug mon Mg/dl Vigabatrin 60-80 0 5-8 Adult-2 and 4 g/day. Infant-100- 150mg/kg/d No range; indirect effect Zonisamide Complete 40-60 50-60 (mon) 27-38(EI) Init- 100 -200 mg/d(ch1-2mg/kg/d) Maint-200-400mg/d (ch 2-4mg/kg/d) 15–30 Gabapentin 35-60 0 5-7 Adult-1800 mg/d Chi- 25-35mg/kg/d 4-16
CLINICALUSE
Drugs Indication Contra indication Minimal titration period for add- on therapy Considerations partial generalised Felbamate Intractable partial sz (add –on therapy) LGS when primary therapy failed Absolute: hematologic, autoimmun ds Relative- renal 1 day Hematologic & LFT Gabapentin Add-on None Relative- renal 1 wk TDS , may combine with CBZ , well tolerated Lamotrigine Mono,add- on All sz type when 1st line failed Absolute-SME, rel- rash, with PHT,CBZ, liver ds >6wk Long titration may combine with VPA, well tolerated Levetiracetam Add-on GTCS Relative: renal dis 1wk
Drugs Indication Contra indication Minimal titration period for add- on therapy Considerations partial generalised Oxcarbazepine monother/ Add-on Tonic-clonic When 1st line failed Absol: absence or myoclonic relat- renal ds, hyponatrmic drug ( lithium ,diuretics ) 2wk Fewer SE than CBZ Tiagabine Add-on None Abso- absence, myoclonic , Relat- liver ds, depression > 6wk Long titration , TDS/QID dosing Topiramate Add-on All sz except absence sz Rela- psych illness, renal ds f/h renal calculi > 6wk Long titration relatively sever neurotoxic effect
Drugs Indication Contra indication Minimal titration period for add- on therapy Considerations partial generalised Vigabatrin Add-on therapy in adult West syndrome in tuberous sclerosis Absolute: absence/myo clonic sz Rela- psy illness ,renal ds 1 day Visual field testing at regular interval Zonisamide Add-on All seizure types when 1st line failed Rela – psy illness,renal ds , h/o renal calculi 2wk Experience is still limited
SAFTY & TOLERABILITY
Antiepileptics in pregnancy
WHICH DRUG IS THE SAFEST IN PREGNANCY ? NONE…
AED TERATOGENICITY Phenytoin Facial cleft, Diaphragmatic hernias, Hip dysplasias, heart abnormalities Carbamazepine Hypertelorism, Spina bifida, Cardiac malformations Sodium valproate Neural tube defects, Intellectual decline Lamotrigine Gastrointestinal, Urinal,cardiac Topiramate Animal studies Levericetam Animal studies, Syndactyl, Fallot’s Gabapentin No data
• AED exposure – 0.4 – 0.6 % of all pregnancies • Major malformation – 2-3 % general population • Epileptic women – 4 – 8% of major malformation, 6 – 20% of minor malformation • Still births -1.3% - 14.0 % controls – 1.2 – 7.8 % • Perinatal death rates – 1.3% -7.8%, controls -1-3.9%
CONGENITAL Malformations MAJOR • Neural tube defects • Cong. heart disease • Orofacial clefts • Intestinal atresia • Congenital defects MINOR • Cranio-facial dysmorphism • Distal digit / nail = hypoplasia • Umbilical / inguinal hernias • Some improve / disappear later
The FDA has categorized AED medications into 2 classes, D and C. Category C drugs have demonstrated teratogenicity in animals, but human risk is not known. The newer AEDs are classified as Category C. Phenytoin, carbamazepine and valproic acid are category D. Category D drugs are those drugs for which related to teratogenicity in both animal and human pregnancies. In both categories, the recommendation remains the same: selection of AED in pregnancy should be decided upon risk –benefit ratio to seizure control.
IS Lamotrigine THE antiepileptic in pregnancy ? Epilepsia 2007 Among 802 exposures the frequency of major Birth defects was 2.7% No effect of dose upto 400 mg/day
• Epileptic women with difficult to treat seizure disorder requiring more than 2 antiepileptics BEST POLYTHERAPY – CARBAMAZEPINE WITH LAMOTRIGINE
Where do we go from here????
Newly licensed for the treatment of epilepsy
LACOSAMIDE Add-on therapy for adults with partial-onset seizures with or without secondary generalization Approved in patients ≥16 years by the European Commission (August 2008) In patients ≥17 years by the U.S. Food and Drug Administration (October 2008) Mechanisim 1. Enhancing sodium channel slow inactivation Normalization of activation thresholds Reduced pathophysiological hyperresponsiveness. 2. Binding to collapsin-response mediator protein 2 (Crmp-2). Neuronal protection from excitotoxicity and apoptosis Downregulation of NMDA receptor subunit NR2B
PHARMACOKINETIS  Almost completely and rapidly absorbed from the GI tract.  Peak plasma conc 4 hours.  The elimination half-life is around 13 hours  minimally bound to plasma proteins (<15%).  Renal excretion  Dosage adjustments are recommended for pt with mild or moderate hepatic impairment or severe renal impairment.  Use in severe hepatic impairment patients is not recommended DRUG INTERACTIONS • Does not induce or inhibit hepatic enzymes. • No effect on the plasma concentrations of other AEDS.
Current therapy + Placebo (n=359) Current therapy + Lacosamide 400 mg/day (n=359) Lacosamide + 1st generation AEDs Lacosamide + 2nd generation AEDs 50% responder rate from baseline with lacosamide vs placebo Effective regardless of concomitant AED used
TRIALS US multicenter RCT (Ben-Menachem E Epilepsia 2007) 418 patients European trial Halasz P (Epilepsia 2009) 485 patients SP754 Study Group Chung SS(Epilepsia 2010) 405 patients Seizure frequency 26% with 200 mg/day, 39% with 400mg/day 40% with 600mg/day, 35.5% with 200 mg/day (p = 0.02) 36.4% with 400 mg/day (p = 0.03) > 50% reduction with lacosamide 400 and 600 mg/day
Safety and Tolerability Common adverse effects • Dizziness, headache, nausea and vomiting. • Fatigue, ataxia, visual disturbance, diplopia and somnolence also occurred. • Rare reports of cardiac events with the drug. (PR prolongation, AF/Afl) Dosage and Administration • starting dose is 50 mg twice daily increased at weekly intervals by 100 mg/day maintenance dosage of 200 or 400 mg/day • Recent data suggest intravenous loading doses of lacosamide 200 and 300 mg over 15 minutes were best tolerated.
Dosageand Administration Twice daily oral administration Starting dosage 100 mg/day Maintenance dosage 200– 400 mg/day
RUFINAMIDE Triazole derivatives Mechanisim • prolongs the inactive state of voltage dependent sodium channels • limits sustained repetitive firing of neuronal sodium-dependent action potentials
PHARMACOKINETICS • Following oral administration 85% absorbed • • peak plasma concentrations reached in 5–6 hours • 23–34% bound to plasma proteins. • t 1/2 - 8 to 12 hours. • undergoes extensive hepatic metabolism
DRUG INTERACTION • Weak inhibitor of CYP2E1 • weakly induces the CYP3A4 isoenzyme. • metabolized by carboxylesterases. • Carbamazepine clearance was increased by 7.9–15.4%, lamotrigine by 7.7–15.6%. • phenobarbital and phenytoin clearance decreased by 7.1–11.7% and 6.5–17.5%, respectively. • 42% rise in rufinamide concentrations in children, and an 11% rise in adults with sodium valproate. • no change with topiramate or lamotrigine. • Clearance of rufinamide was increased by carbamazepine , phenytoin , phenobarbital and primidone.
First study • seizure frequency 41% in pt taking rufinamide 400–1600 mg/day compared with a 52% in those taking placebo (p = 0.04). ( Palhagan S, Epilepsy Res 2001; 43: 115-24) Second study 84-day period, with adjunctive rufinamide being administered to 74 patients with treatment-resistant Lennox-Gastaut syndrome(including drop attacks and atypical absence attacks) (Glauser T, Ann Neurol 2008; 70: 1950-8)
SEIZURE TYPE RUFINAMIDE PLACEBO TOTAL SEIZURE 32.7% 11.5% TONIC-ATONIC 42.5% 1.4% ATYPICAL ABSENCE & ATONIC Decreased
THIRD TRIAL • By Brodie and colleagues in 313 adults and adolescents with partial- onset seizures, • rufinamide 1600mg twice daily • significant median reduction of 20.4% in partial seizure frequency relative to an increase of 1.6%(p = 0.05). (Brodie MJ, Epilepsia 2009; 50: 1899-909) FOURTH TRIAL • In a retrospective open-label study of rufinamide in 60 patients with refractory epilepsy of any type, 8.3%became seizure free over 12 weeks. 46.7% had a 50% reduction in seizure frequency. (Kluger G et al.. Epilepsy Behav 2009; 14: 491-5)
Safety and Tolerability • somnolence, nausea, vomiting, • anorexia, dizziness, diplopia and ataxia Dosage and Administration • available in 100, 200 and 400 mg tablets. • initially at a dose of 200 mg twice daily. • increasing in 200 mg twice-daily increments at intervals of not less than 2 days . • maximum daily dose of 3200 mg.
Eslicarbazepine Acetate Recently licensed in Europe as adjunctive treatment for partial seizures with or without Secondary generalization in adults. In 2010, the licensing application for the AED was not approved by the US FDA.
Mechanisms of Action  competitively interacts with the inactivated state of the voltage-gated sodium channel. Pharmacokinetics  not metabolized to carbamazepine 10,11-epoxide, it is therefore not susceptible to enzyme induction or autoinduction.  half-life is 13–20 hours,  steady-state concentrations being reached within 4–5 days of once- daily dosing
Pharmacokinetics  <40% protein bound.  Inactive by glucuronidation, or excreted unchanged, mainly by renal elimination.  Not affected by age, sex, food consumption or moderate hepatic impairment  Dosage reduction may be required if cr cl <60ml/minute.
DRUG INTERACTION • Except with phynetoin ,no pharmacokinetic interactions have been reported with other AEDs. • Accelerates the clearance of both hormonal components of the oral contraceptive pill • Coadministration with warfarin had no effect on coagulation.
EFFICACY • Seizure reduction varied between 33% and 45% with eslicarbazepine acetate1200 mg/day, • Responder rates (>50% seizure reduction vs baseline) ranged between 38% and 43%). • Only a few patients in each trial remained seizure free throughout. Safty and tolerability • Dizziness and somnolence. • Headache, abnormal coordination, disturbed attention, diplopia, blurred vision, vertigo, nausea, vomiting, diarrhoea and rash.
 Available in 800 mg tablets.  Initial recommended dose is 400 mg  Once daily, increasing after 1–2 weeks to 800 mg once daily.  The drug can be titrated thereafter to a maximum tolerated daily dose of 1200 mg according to efficacy and tolerability.
RETIGABIN submitted applications to the FDA European Medicines Agency to have the drug licensed as an adjunctive treatment for patients with partial-onset seizures. Mechanisms of Action opening of neuronal voltage-gated potassium channels, enhancing the M-type potassium current. repolarising the membrane back towards resting potential and suppressing repetitive firing.
Pharmacokinetics Rapidly absorbed following oral administration Bioavailability 60%. Peak plasma conc within 60–90 minutes. Protein binding is <80%. Half-life 8 hours. With modest or severe hepatic impairment, clr is decreased by 30–50%.
• No interactions between retigabine and enzyme-inducing or non- inducing agents. • Five studies (3 phase II and 2 phase III studies) demonstrating the efficacy and safety of retigabine in pt with partial-onset seizures. • Median percentage reduction in monthly total partial seizure frequency from baseline was 23% for 600 mg/day, 29% for 900 mg/day and 35% for 1200 mg/day (p = 0.047)
PHASE III TRIAL RESTORE I RESTORE II DOSAGE 1200mg/d 600,900mg/d SEIZURE FREQUENCY 44% 28% (600),40% (900) SIGNIFICANCE P<0.001 P<0.01
Retigabine Efficacy and Safety Trials for Partial Onset Epilepsy
Safety and Tolerability • somnolence, confusion, dizziness, tremor, amnesia, abnormal thinking, vertigo, speech disorders and asthenia. • Urinary hesitancy, dysuria and dis colouration
BRIVARACETAM N-propyl analogue of levetiracetam. Has a 10-fold higher affinity for SV2A than levetiracetam. inhibits neuronal voltage-gated sodium channels
PHARMACOKINETICS half-life of 7–8 hour Protein binding is <20%. Metabolic pathways include hydrolysis of the acetamide group hepatic CYP2C8-mediated hydrolysis. Renal clearance is approximately 3mL/minute through substantial tubular reabsorption
DRUG INTERACTIONS • reduces plasma concentrations of CBZ and PHT. • Decreases the estrogen and progestin concentrations of low dose OCP. SAFETY AND TOLERABILITY • Dizziness, headache and somnolence. • Neutropenia
TRIALS STUDY 1 (Neurology® 2010;75:519–525) STUDY 2 (27th International Epilepsy Congress; 2007 Jul) SEIZURE FREQUENCY 32% 44.2% 55.8% 5mg/d 20mg/d 50mg/d P<0.047 P<0.002 P<0.001 18.9% 38.2% 30.0% placebo 50mg/d 150 mg/day (p = 0.017) (p = 0.113)
PERAMPANEL selective noncompetitive (allosteric) AMPA-type glutamate receptor antagonist
PHARMACOKINETICS • Rapid absorption, • Peak conc. achieved 1-hour post-dose. • Long half-life of around 52–129 hours following a single dose (0.2– 8mg) • 66–90 hours with multiple dosing. • Pharmacokinetic profile supports once-daily dosing. • Steady state concentrations are usually reached by day 14.
PERAMPANEL FIRST STUDY (Krauss G, Epilepsia 2008) SECOND STUDY ( Eisai Co. Ltd. Status of the E2007 (perampanel) Development Program) 206 PATIENTS 4mg/d 31% decreased seizure 22% in placebo 208 patient 40% decreased seizure 2% increased in pla arm
GANAXOLONE Novel class of neurosteroids called epalons.  Chemically related to progesterone Devoid of any hormonal activity  potent antiepileptic, anxiolytic, sedative and hypnotic properties
MECHANISM OF ACTION • specifically modulate GABA receptors containing the d- subunit in the CNS. • Efficacy in a new, spontaneous model of perimenstrual catamenial epilepsy.
Pharmacokinetics • partially absorbed following oral administration. • steady-state plasma concentrations occurred after around 7 days of dosing • Safety and Tolerability • dizziness and somnolence. • Nervousness, headache, malaise, diarrhoea, constipation and vomiting.
Efficacy • Phase II studies are being performed to assess the efficacy and safety of ganaxolone in adult patients with uncontrolled partial-onset seizures, and in children with infantile spasms. ( Bialer M,Epilepsy Res 2009; 83: 1-43) • In a randomized,double-blind study, ganaxolone, in dosages up to 1875 mg/day, had significant efficacy for refractory partial-onset seizures in 52 patients who had other AEDs withdrawn during epilepsy surgery assessment. ( Laxer K, Epilepsia 2000; 41: 1187-94)
STIRIPENTOL • Granted in the european union in january 2007. • Use adjunctively to clobazam and valproate in the treatment of refractory generalized tonic–clonic seizures in patients with severe myoclonic epilepsy in infancy (SMEI, dravet’s syndrome). • Acts as a positive allosteric modulator at GABA- A receptors.
traditional AEDs seizure reduction 15% + stiripentol 61% sz
Principles of Management • Combination Therapy • pharmacomechanistic approach based on differing modes of action Latest Developments in Drug Therapy Nondrug Therapy surgical treatment vagus-nerve stimulation ketogenic diet modified Atkins diet
New and Emerging Theapies • intracranial and extracranial treatment systems of electrotherapy or pharmacotherapy • delivers scheduled electrical stimulation bilaterally to the anterior nucleus of the thalamus. (class I evidence) • “closed-loop system”: • when the device detects epileptiform activity, it also delivers electrical stimulation to the site of this activity
We are nearing the end of an era. The new one must provide answers to at least some of these questions. ‘‘Hope springs eternal in the human breast’’, but groundbreaking science would also help!
Newer antiepileptic

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Newer antiepileptic

  • 1.
    NEWER ANTIEPILEPTIC DRUGS DrAkhila Kumar Panda MD, DM, Consultant Neurologist
  • 2.
  • 3.
    Prevalence • Prevalence- 1% 0f the population • 50 million worldwide • Higher rates in developing countries • 10 million in India • Incidence – 0.7% • Incidence is highest in the young and elderly
  • 5.
    Pediatric Seizure TypesAdult Seizure Types Distribution of seizure type
  • 6.
    Background and Justification: •Between 70 and 80% of individuals are successfully treated with one of the more than twenty AEDs now available. • 20-30% of patients have either intractable or uncontrolled seizures or suffer significant adverse side effects secondary to medication. • There is no class I evidence comparing the new AEDs to the old, or the new AEDs to each other in patients with refractory epilepsy. • Selection of the appropriate drug for a given individual must be based on understanding of each drug’s pharmacology, side effect profile, and risks.
  • 7.
  • 9.
    HISTORY OF AED •Phenobarbital- Alfred Hauptmann- 1912 • Phenytoin- Tracy Putnam - 1934 • Ethosuximide - Parke, Davis - 1958 • Carbamazepine - Schindler at Geigy - 1953 epilepsy- 1963 • VPA- Pierre Eymard- 1963 • Diazepam - Henry Gastaut - 1965
  • 10.
    • BEGAN IN1975 . • National Institute of Neurological Disorders and Stroke established the Anticonvulsant Drug Development Programme. • Screened more than 28,000 new chemical entities. MORDEN ERA OF AED
  • 11.
  • 12.
  • 13.
  • 16.
  • 17.
    Characteristics of OlderAEDs: Advantages  Broad familiarity  long-term experience  Known efficacy  Lower cost  What is old is not necessarily outdated
  • 18.
    Characteristics of OlderAEDs: • Disadvantages • Cause hepatic enzyme induction (PB, PHT,CBZ, Primidone) or inhibition (VPA) • Cause change in internal hormonal compounds (sex steroids, Vit D) • Produce interaction with commonly used medications (warfarin, oral contraceptives, Ca-channel antagonists, chemotherapy agents) • Pregnancy Category D
  • 19.
    Advantages of NewerAEDs • Greater tolerability • Fewer side effects • Fewer drug interactions • Fewer idiosyncratic reactions • Minimal influence on metabolic pathways • Pregnancy category C
  • 20.
    Selecting an AntiepilepticDrug Choose antiepileptic drug most suited to the individual patient based on  seizure/epilepsy type  side effects (anemia, hepatotoxicity, rash, etc.)  patient profile (comorbidity, sex, age, etc,)  ease of use  cost  Balance between efficacy, tolerability and safety  Epilepsy may be a lifelong diagnosis – minimize  chronic side effects from AEDs (cognitive, reproductive, neuropathy, bone and weight changes, etc.)
  • 21.
  • 22.
    Reasons for pseudoresistance Wrongdiagnosis Syncope, cardiac arrythmia, PNES Wrong drug Inappropriate for seizure type, pharmacokinetic or pharmacodynamic interactions Wrong Dose Too low, side effects preventing drug increase Life style issue Poor compliance with medication, alcohol or drug abuse
  • 23.
    PHARMACORESISTA NT The drug facesa modified target, Interacts less effectively . Missing the Real Targets Increased expression or function of multidrug transporter proteins Decreases availability of the AED at its target versus.
  • 25.
  • 26.
    Targets and mechanisimANTIEPILEPTIC DRUGS Sodium channel actions 1. Blockade by stabilizing fast- inactivated state 2.slow-inactivated state Phenytoin, carbamazepine,lamotrigine, oxcarbazepine, Rufinamide, eslicarbazepine Lacosamide Calcium channel actions 1.Blockade of high voltage activated channel (P/Q type) 2.Blockade of low voltage-activated channel (T type) Gabapentin, pregabalin Ethosuximide GABA-related actions Activation of GABA-A receptor Blockade of GABA transporter Inhibition of GABA transaminase Phenobarbital, benzodiazepines Tiagabine Vigabatrin SV2A actions Modulation of SV2A Levetiracetam Multiple actions on multiple targets Valproic acid, felbamate,topiramate, zonisamide Potassium channel activity Opens Kv7 potassium channels Retigabine/ezogabine
  • 27.
  • 28.
    Drug Bioava ilability % Protein binding % t1/2(h) DosageTherapeutic drug mon Mg/dl Felbamate >90 22–36 14–23 adult -upto 3,600 mg/day Ch =15 -45mg/kg/d 30–100 Lamotrigine 98 55 24-31 mono 15(EI) 59( VPA) 2-15 Levetiracetam >95 0 6-8 Upto 3000 mg/d 20–60 Oxcarbazepine >95 40 8-12 Adult-upto 2400mg/d Ch-30-46mg/kg/d 10-35 Tiagabine 90 96 4-13 (mon) 2-5(EI) In-15 to 16 mg/day. EI-30-32mg/d Maint-30-32mg/d 50-56mg/d 5–70 Topiramate 81-95 9-17 20-30(mon) 8-15(EI) 25 to 700 mg/day. Ch- init-0.5 to 1 mg/kg/day..6- 9mg/kg/d 2-25
  • 29.
    Lamotrigine , titrationAs add-on therapy Concomitant antiepileptic drugs Adult Valproate others Weeks 1 and 2 Weeks 3 and 4 Maintenance 12.5 mg daily 25 mg daily 50–100 mg twice daily 50 mg daily 50 mg twice daily 100–200 mg twice daily Children Weeks 1 and 2 Weeks 3 and 4 Maintenance 0.15 mg/kg 0.3mg/kg 1-5mg/kg 0.6mg/kg 1.2mg/kg 5-15mg/kg As monotherapy Adults children Weeks 1 and 2 Weeks 3 and 4 Maintenance 25 mg daily 25 mg twice daily 50–100 mg twice daily 0.5 mg/kg 1 mg/kg 2–8 mg/kg
  • 30.
    Drug Bioavailability % Protein binding % t1/2 (h) Dosage Therapeuti drugmon Mg/dl Vigabatrin 60-80 0 5-8 Adult-2 and 4 g/day. Infant-100- 150mg/kg/d No range; indirect effect Zonisamide Complete 40-60 50-60 (mon) 27-38(EI) Init- 100 -200 mg/d(ch1-2mg/kg/d) Maint-200-400mg/d (ch 2-4mg/kg/d) 15–30 Gabapentin 35-60 0 5-7 Adult-1800 mg/d Chi- 25-35mg/kg/d 4-16
  • 31.
  • 32.
    Drugs Indication Contra indication Minimal titration periodfor add- on therapy Considerations partial generalised Felbamate Intractable partial sz (add –on therapy) LGS when primary therapy failed Absolute: hematologic, autoimmun ds Relative- renal 1 day Hematologic & LFT Gabapentin Add-on None Relative- renal 1 wk TDS , may combine with CBZ , well tolerated Lamotrigine Mono,add- on All sz type when 1st line failed Absolute-SME, rel- rash, with PHT,CBZ, liver ds >6wk Long titration may combine with VPA, well tolerated Levetiracetam Add-on GTCS Relative: renal dis 1wk
  • 33.
    Drugs Indication Contra indication Minimal titration periodfor add- on therapy Considerations partial generalised Oxcarbazepine monother/ Add-on Tonic-clonic When 1st line failed Absol: absence or myoclonic relat- renal ds, hyponatrmic drug ( lithium ,diuretics ) 2wk Fewer SE than CBZ Tiagabine Add-on None Abso- absence, myoclonic , Relat- liver ds, depression > 6wk Long titration , TDS/QID dosing Topiramate Add-on All sz except absence sz Rela- psych illness, renal ds f/h renal calculi > 6wk Long titration relatively sever neurotoxic effect
  • 34.
    Drugs Indication Contra indication Minimal titration periodfor add- on therapy Considerations partial generalised Vigabatrin Add-on therapy in adult West syndrome in tuberous sclerosis Absolute: absence/myo clonic sz Rela- psy illness ,renal ds 1 day Visual field testing at regular interval Zonisamide Add-on All seizure types when 1st line failed Rela – psy illness,renal ds , h/o renal calculi 2wk Experience is still limited
  • 35.
  • 38.
  • 39.
    WHICH DRUG ISTHE SAFEST IN PREGNANCY ? NONE…
  • 40.
    AED TERATOGENICITY Phenytoin Facialcleft, Diaphragmatic hernias, Hip dysplasias, heart abnormalities Carbamazepine Hypertelorism, Spina bifida, Cardiac malformations Sodium valproate Neural tube defects, Intellectual decline Lamotrigine Gastrointestinal, Urinal,cardiac Topiramate Animal studies Levericetam Animal studies, Syndactyl, Fallot’s Gabapentin No data
  • 41.
    • AED exposure– 0.4 – 0.6 % of all pregnancies • Major malformation – 2-3 % general population • Epileptic women – 4 – 8% of major malformation, 6 – 20% of minor malformation • Still births -1.3% - 14.0 % controls – 1.2 – 7.8 % • Perinatal death rates – 1.3% -7.8%, controls -1-3.9%
  • 42.
    CONGENITAL Malformations MAJOR • Neuraltube defects • Cong. heart disease • Orofacial clefts • Intestinal atresia • Congenital defects MINOR • Cranio-facial dysmorphism • Distal digit / nail = hypoplasia • Umbilical / inguinal hernias • Some improve / disappear later
  • 43.
    The FDA hascategorized AED medications into 2 classes, D and C. Category C drugs have demonstrated teratogenicity in animals, but human risk is not known. The newer AEDs are classified as Category C. Phenytoin, carbamazepine and valproic acid are category D. Category D drugs are those drugs for which related to teratogenicity in both animal and human pregnancies. In both categories, the recommendation remains the same: selection of AED in pregnancy should be decided upon risk –benefit ratio to seizure control.
  • 45.
    IS Lamotrigine THEantiepileptic in pregnancy ? Epilepsia 2007 Among 802 exposures the frequency of major Birth defects was 2.7% No effect of dose upto 400 mg/day
  • 46.
    • Epileptic womenwith difficult to treat seizure disorder requiring more than 2 antiepileptics BEST POLYTHERAPY – CARBAMAZEPINE WITH LAMOTRIGINE
  • 48.
    Where do wego from here????
  • 49.
    Newly licensed forthe treatment of epilepsy
  • 50.
    LACOSAMIDE Add-on therapy foradults with partial-onset seizures with or without secondary generalization Approved in patients ≥16 years by the European Commission (August 2008) In patients ≥17 years by the U.S. Food and Drug Administration (October 2008) Mechanisim 1. Enhancing sodium channel slow inactivation Normalization of activation thresholds Reduced pathophysiological hyperresponsiveness. 2. Binding to collapsin-response mediator protein 2 (Crmp-2). Neuronal protection from excitotoxicity and apoptosis Downregulation of NMDA receptor subunit NR2B
  • 51.
    PHARMACOKINETIS  Almost completelyand rapidly absorbed from the GI tract.  Peak plasma conc 4 hours.  The elimination half-life is around 13 hours  minimally bound to plasma proteins (<15%).  Renal excretion  Dosage adjustments are recommended for pt with mild or moderate hepatic impairment or severe renal impairment.  Use in severe hepatic impairment patients is not recommended DRUG INTERACTIONS • Does not induce or inhibit hepatic enzymes. • No effect on the plasma concentrations of other AEDS.
  • 52.
    Current therapy + Placebo (n=359) Currenttherapy + Lacosamide 400 mg/day (n=359) Lacosamide + 1st generation AEDs Lacosamide + 2nd generation AEDs 50% responder rate from baseline with lacosamide vs placebo Effective regardless of concomitant AED used
  • 53.
    TRIALS US multicenter RCT (Ben-Menachem E Epilepsia2007) 418 patients European trial Halasz P (Epilepsia 2009) 485 patients SP754 Study Group Chung SS(Epilepsia 2010) 405 patients Seizure frequency 26% with 200 mg/day, 39% with 400mg/day 40% with 600mg/day, 35.5% with 200 mg/day (p = 0.02) 36.4% with 400 mg/day (p = 0.03) > 50% reduction with lacosamide 400 and 600 mg/day
  • 54.
    Safety and Tolerability Commonadverse effects • Dizziness, headache, nausea and vomiting. • Fatigue, ataxia, visual disturbance, diplopia and somnolence also occurred. • Rare reports of cardiac events with the drug. (PR prolongation, AF/Afl) Dosage and Administration • starting dose is 50 mg twice daily increased at weekly intervals by 100 mg/day maintenance dosage of 200 or 400 mg/day • Recent data suggest intravenous loading doses of lacosamide 200 and 300 mg over 15 minutes were best tolerated.
  • 55.
    Dosageand Administration Twice daily oral administration Startingdosage 100 mg/day Maintenance dosage 200– 400 mg/day
  • 56.
    RUFINAMIDE Triazole derivatives Mechanisim • prolongsthe inactive state of voltage dependent sodium channels • limits sustained repetitive firing of neuronal sodium-dependent action potentials
  • 57.
    PHARMACOKINETICS • Following oraladministration 85% absorbed • • peak plasma concentrations reached in 5–6 hours • 23–34% bound to plasma proteins. • t 1/2 - 8 to 12 hours. • undergoes extensive hepatic metabolism
  • 58.
    DRUG INTERACTION • Weakinhibitor of CYP2E1 • weakly induces the CYP3A4 isoenzyme. • metabolized by carboxylesterases. • Carbamazepine clearance was increased by 7.9–15.4%, lamotrigine by 7.7–15.6%. • phenobarbital and phenytoin clearance decreased by 7.1–11.7% and 6.5–17.5%, respectively. • 42% rise in rufinamide concentrations in children, and an 11% rise in adults with sodium valproate. • no change with topiramate or lamotrigine. • Clearance of rufinamide was increased by carbamazepine , phenytoin , phenobarbital and primidone.
  • 59.
    First study • seizurefrequency 41% in pt taking rufinamide 400–1600 mg/day compared with a 52% in those taking placebo (p = 0.04). ( Palhagan S, Epilepsy Res 2001; 43: 115-24) Second study 84-day period, with adjunctive rufinamide being administered to 74 patients with treatment-resistant Lennox-Gastaut syndrome(including drop attacks and atypical absence attacks) (Glauser T, Ann Neurol 2008; 70: 1950-8)
  • 60.
    SEIZURE TYPE RUFINAMIDEPLACEBO TOTAL SEIZURE 32.7% 11.5% TONIC-ATONIC 42.5% 1.4% ATYPICAL ABSENCE & ATONIC Decreased
  • 61.
    THIRD TRIAL • ByBrodie and colleagues in 313 adults and adolescents with partial- onset seizures, • rufinamide 1600mg twice daily • significant median reduction of 20.4% in partial seizure frequency relative to an increase of 1.6%(p = 0.05). (Brodie MJ, Epilepsia 2009; 50: 1899-909) FOURTH TRIAL • In a retrospective open-label study of rufinamide in 60 patients with refractory epilepsy of any type, 8.3%became seizure free over 12 weeks. 46.7% had a 50% reduction in seizure frequency. (Kluger G et al.. Epilepsy Behav 2009; 14: 491-5)
  • 62.
    Safety and Tolerability •somnolence, nausea, vomiting, • anorexia, dizziness, diplopia and ataxia Dosage and Administration • available in 100, 200 and 400 mg tablets. • initially at a dose of 200 mg twice daily. • increasing in 200 mg twice-daily increments at intervals of not less than 2 days . • maximum daily dose of 3200 mg.
  • 63.
    Eslicarbazepine Acetate Recently licensedin Europe as adjunctive treatment for partial seizures with or without Secondary generalization in adults. In 2010, the licensing application for the AED was not approved by the US FDA.
  • 64.
    Mechanisms of Action competitively interacts with the inactivated state of the voltage-gated sodium channel. Pharmacokinetics  not metabolized to carbamazepine 10,11-epoxide, it is therefore not susceptible to enzyme induction or autoinduction.  half-life is 13–20 hours,  steady-state concentrations being reached within 4–5 days of once- daily dosing
  • 65.
    Pharmacokinetics  <40% proteinbound.  Inactive by glucuronidation, or excreted unchanged, mainly by renal elimination.  Not affected by age, sex, food consumption or moderate hepatic impairment  Dosage reduction may be required if cr cl <60ml/minute.
  • 66.
    DRUG INTERACTION • Exceptwith phynetoin ,no pharmacokinetic interactions have been reported with other AEDs. • Accelerates the clearance of both hormonal components of the oral contraceptive pill • Coadministration with warfarin had no effect on coagulation.
  • 67.
    EFFICACY • Seizure reductionvaried between 33% and 45% with eslicarbazepine acetate1200 mg/day, • Responder rates (>50% seizure reduction vs baseline) ranged between 38% and 43%). • Only a few patients in each trial remained seizure free throughout. Safty and tolerability • Dizziness and somnolence. • Headache, abnormal coordination, disturbed attention, diplopia, blurred vision, vertigo, nausea, vomiting, diarrhoea and rash.
  • 68.
     Available in800 mg tablets.  Initial recommended dose is 400 mg  Once daily, increasing after 1–2 weeks to 800 mg once daily.  The drug can be titrated thereafter to a maximum tolerated daily dose of 1200 mg according to efficacy and tolerability.
  • 69.
    RETIGABIN submitted applications tothe FDA European Medicines Agency to have the drug licensed as an adjunctive treatment for patients with partial-onset seizures. Mechanisms of Action opening of neuronal voltage-gated potassium channels, enhancing the M-type potassium current. repolarising the membrane back towards resting potential and suppressing repetitive firing.
  • 70.
    Pharmacokinetics Rapidly absorbed followingoral administration Bioavailability 60%. Peak plasma conc within 60–90 minutes. Protein binding is <80%. Half-life 8 hours. With modest or severe hepatic impairment, clr is decreased by 30–50%.
  • 71.
    • No interactionsbetween retigabine and enzyme-inducing or non- inducing agents. • Five studies (3 phase II and 2 phase III studies) demonstrating the efficacy and safety of retigabine in pt with partial-onset seizures. • Median percentage reduction in monthly total partial seizure frequency from baseline was 23% for 600 mg/day, 29% for 900 mg/day and 35% for 1200 mg/day (p = 0.047)
  • 72.
    PHASE III TRIALRESTORE I RESTORE II DOSAGE 1200mg/d 600,900mg/d SEIZURE FREQUENCY 44% 28% (600),40% (900) SIGNIFICANCE P<0.001 P<0.01
  • 73.
    Retigabine Efficacy andSafety Trials for Partial Onset Epilepsy
  • 74.
    Safety and Tolerability •somnolence, confusion, dizziness, tremor, amnesia, abnormal thinking, vertigo, speech disorders and asthenia. • Urinary hesitancy, dysuria and dis colouration
  • 75.
    BRIVARACETAM N-propyl analogue oflevetiracetam. Has a 10-fold higher affinity for SV2A than levetiracetam. inhibits neuronal voltage-gated sodium channels
  • 76.
    PHARMACOKINETICS half-life of 7–8hour Protein binding is <20%. Metabolic pathways include hydrolysis of the acetamide group hepatic CYP2C8-mediated hydrolysis. Renal clearance is approximately 3mL/minute through substantial tubular reabsorption
  • 77.
    DRUG INTERACTIONS • reducesplasma concentrations of CBZ and PHT. • Decreases the estrogen and progestin concentrations of low dose OCP. SAFETY AND TOLERABILITY • Dizziness, headache and somnolence. • Neutropenia
  • 79.
    TRIALS STUDY 1 (Neurology®2010;75:519–525) STUDY 2 (27th International Epilepsy Congress; 2007 Jul) SEIZURE FREQUENCY 32% 44.2% 55.8% 5mg/d 20mg/d 50mg/d P<0.047 P<0.002 P<0.001 18.9% 38.2% 30.0% placebo 50mg/d 150 mg/day (p = 0.017) (p = 0.113)
  • 80.
    PERAMPANEL selective noncompetitive (allosteric)AMPA-type glutamate receptor antagonist
  • 81.
    PHARMACOKINETICS • Rapid absorption, •Peak conc. achieved 1-hour post-dose. • Long half-life of around 52–129 hours following a single dose (0.2– 8mg) • 66–90 hours with multiple dosing. • Pharmacokinetic profile supports once-daily dosing. • Steady state concentrations are usually reached by day 14.
  • 82.
    PERAMPANEL FIRST STUDY (Krauss G,Epilepsia 2008) SECOND STUDY ( Eisai Co. Ltd. Status of the E2007 (perampanel) Development Program) 206 PATIENTS 4mg/d 31% decreased seizure 22% in placebo 208 patient 40% decreased seizure 2% increased in pla arm
  • 84.
    GANAXOLONE Novel class ofneurosteroids called epalons.  Chemically related to progesterone Devoid of any hormonal activity  potent antiepileptic, anxiolytic, sedative and hypnotic properties
  • 85.
    MECHANISM OF ACTION •specifically modulate GABA receptors containing the d- subunit in the CNS. • Efficacy in a new, spontaneous model of perimenstrual catamenial epilepsy.
  • 86.
    Pharmacokinetics • partially absorbedfollowing oral administration. • steady-state plasma concentrations occurred after around 7 days of dosing • Safety and Tolerability • dizziness and somnolence. • Nervousness, headache, malaise, diarrhoea, constipation and vomiting.
  • 87.
    Efficacy • Phase IIstudies are being performed to assess the efficacy and safety of ganaxolone in adult patients with uncontrolled partial-onset seizures, and in children with infantile spasms. ( Bialer M,Epilepsy Res 2009; 83: 1-43) • In a randomized,double-blind study, ganaxolone, in dosages up to 1875 mg/day, had significant efficacy for refractory partial-onset seizures in 52 patients who had other AEDs withdrawn during epilepsy surgery assessment. ( Laxer K, Epilepsia 2000; 41: 1187-94)
  • 88.
    STIRIPENTOL • Granted inthe european union in january 2007. • Use adjunctively to clobazam and valproate in the treatment of refractory generalized tonic–clonic seizures in patients with severe myoclonic epilepsy in infancy (SMEI, dravet’s syndrome). • Acts as a positive allosteric modulator at GABA- A receptors.
  • 90.
  • 91.
    Principles of Management •Combination Therapy • pharmacomechanistic approach based on differing modes of action Latest Developments in Drug Therapy Nondrug Therapy surgical treatment vagus-nerve stimulation ketogenic diet modified Atkins diet
  • 92.
    New and EmergingTheapies • intracranial and extracranial treatment systems of electrotherapy or pharmacotherapy • delivers scheduled electrical stimulation bilaterally to the anterior nucleus of the thalamus. (class I evidence) • “closed-loop system”: • when the device detects epileptiform activity, it also delivers electrical stimulation to the site of this activity
  • 93.
    We are nearingthe end of an era. The new one must provide answers to at least some of these questions. ‘‘Hope springs eternal in the human breast’’, but groundbreaking science would also help!