DaiStephens Epilepsy Pharmacology1123.ppt

Pharmacological Treatments of Epilepsy ** are the slides to focus on Dai Stephens/Julia Aram Department of Psychology/Neurology **What are the anti-epileptic drugs? (AEDs)  AEDs available today are actually not antiepileptic; that is, they do not prevent the development of epilepsy.  Most drug...

Pharmacological Treatments of Epilepsy ** are the slides to focus on Dai Stephens/Julia Aram Department of Psychology/Neurology **What are the anti-epileptic drugs? (AEDs)  AEDs available today are actually not antiepileptic; that is, they do not prevent the development of epilepsy.  Most drugs work to prevent the spread of epileptic discharges.  Thus, they control epilepsy’s major symptom: the seizure, not the cause. ** How do drugs work to prevent the spread of epileptic discharges? Increased activity in the brain may be attributable to:  Increased membrane excitability  Increased efficiency of excitatory synaptic transmission - glutamate  Decreased efficiency of inhibitory synaptic transmission – GABA  Treatments are be aimed at opposing these actions;  Sodium channel blockers and GABA enhancers were the first generation antiepileptic drugs ** Reducing membrane excitability: sodium channel blockers  Many of the drugs that are used against partial seizures are effective at blocking repetitive firing of neurons by acting at ion channels (especially sodium channels).  Drugs that have selective actions at the channel may control seizures without affecting normal transmission  Normal neuronal firing is not impaired, thus there should be minimal effect on baseline functioning. When neuronal activity increases (as in a seizure), it is inhibited by the drugs, thereby preventing seizure spread. Sodium channel blockers oldest to newest  Phenytoin  Carbamazepine (oxcarbazepine/ eslicarbazepine)  Lamotrigine  Zonisamide  Lacosamide enhances slow inactivation of sodium channels  More selective actions = less side-effects ** A Na+ channel blocker prevents epileptiform discharges without affecting ordinary action potential firing. Drug has greater effect at partially depolarised channel, as a result of facilitated binding Blockade increases with repetitive firing sequence of voltage-gated sodium channels (VGSC) Carbamazepine, oxcarbazepine and eslicarbazepine competitively inhibit the voltage gated sodium channel by binding with the receptor in its inactive state, prolonging the period between successive firings (prevents burst firing) ** Reducing efficiency of excitatory synaptic transmission - glutamate  Obvious target is glutamate receptors  Several experimental agents active in animal models of epilepsy are blockers of NMDA, AMPA or kainate subtypes of glutamate receptor  Problem of separating therapeutic effect from side effects – topiramate and perampanel  recently licensed antiepileptic drug – perampanel is an AMPA receptor antagonist Perampanel • non-competitive blockade of AMPA glutamate receptor • reduce spread / generalisation of seizure • well tolerated with improved alertness • role in LD with multiple seizure types not established for perampanel (or lacosamide) ** Reducing efficiency of excitatory synaptic transmission - glutamate Alternative is to reduce release of neurotransmitter ** Controlling transmitter release  Calcium channels are voltage-activated and require strong membrane depolarization for gating and are largely responsible for the regulation of calcium entry and neurotransmitter release from pre-synaptic nerve terminals.  Several anticonvulsant drugs (e.g. topiramate, gabapentin/pregabalin and probably lamotrigine/zonisamide) work this way. ** narrow vs broad spectrum More on calcium  T-type calcium channels involved in bursting  and intrinsic oscillations  Act at 1G subunits containing channels heavily     represented in thalamic neurones. Thalamic neurones from knockout mice missing 1G fail to fire in burst mode and are resistant to chemical induction of absence-like events. A rat model of “Absence” exhibits increased expression of T-type channels Inducing the same mutations in rodent T-type channels results in hyperexcitability of neurones Ethosuximide, which is highly effective in Absence epilepsy, but not other seizure types blocks T-channels in thalamus. Zonisamide also acts on T-type channels ** Increase efficiency of inhibitory synaptic transmission – GABA  Focal epilepsy characterised by intermittent high amplitude discharges at site of epileptic focus during inter-ictal (seizure) periods.  Two phases, - synchronous depolarisation (caused by strong excitatory inputs to the region of the focus), followed by a period of hyperpolarisation, reflecting activation of GABA inhibition.  Transition from inter-ictal discharges to full-blown seizure is a decrease in the hyper-polarisation phase (failure of inhibition to kick in). *Book chapter. Hyperpolarization blocks burst firing Action of drugs acting via GABA-ergic neurotransmission Mutations of GABAA receptor associated with human epilepsies ** Anticonvulsant drugs Facilitators of GABAergic transmission  tendency to drowsiness/ sedation  sodium valproate (sodium channels)  benzodiazepines (clobazam, lorazepam)  barbiturates/primidone  tiagabine (inhibits re-uptake)  vigabatrin (inhibits GABA -T)  ! not preGABAlin and GABApentin ! ** A word about levetiracetam  high-affinity synaptic vesicle protein-2A ligand  modulates neurotransmitter release  rapidly titrated and is effective  keeps patients alert but…  mood lowering/agitation side-effects Refractory epilepsy –relative rate of 50% partial (focal) onset seizures reduction vs placebo  Levetiracetam – 3.81 (2.78-5.22)  Topiramate – 3.32 (2.52-4.39)  Lamotrigine – 2.71 (1.87-3.91)  Oxcarbazepine – 2.51 (1.88-3.33)  Zonisamide – 2.35 (1.74-3.17)  Gabapentin – 1.93 (1.37-2.71)  No data for pregabalin, lacosamide, or eslicarbazepine  Cochrane database So how do we choose the right drug for the patient? Which drug? The ideal antiepileptic agent  good efficacy, easy and rapid to titrate  no drug-drug interactions/liver enzyme induction  no cognitive side-effects/low sodium  no bone marrow suppression  no affective (mood)/drowsy side-effects  different routes of administration  cost effective Which drug? General statements  established  single mode of action  less selective effects  modern  act in broad spectrum  more selective actions  more side effects in cognition,  less sedating side effects but sedation  more drug interactions  kinetics/narrow therapeutic range  much cheaper     many have psychiatric/ behavioural effects less long term toxicity fewer or no drug interactions easier titration 10 X expensive ** Matching the drug to the patient ** Classification of seizures/ epilepsy syndromes  primary generalized epilepsy  sodium valproate, lamotrigine first line  (also levetiracetam, topiramate, zonisamide)  broad spectrum antiepileptic drugs  partial (focal onset) epilepsy  carbamazepine, lamotrigine first line  all other antiepileptic drugs have efficacy (all new antiepileptic drugs are tested first in partial epilepsy) Some drugs exacerbate generalized seizure types such as myoclonus and absences - phenytoin - carbamazepine - gabapentin/pregabalin consider this if patients worsen on treatment ** Have we available the ideal anti-epileptic drug ?  not yet  But some AEDs  mood stabilising effects  benefit migraine  benefit neuropathic pain  side effect weight loss/ weight gain Refractory (to treatment) epilepsy  Non-responders (relapse)  Idiopathic (primary) – 27%  Cryptogenic partial onset– 43%  Symptomatic– 39%  Juvenile Myoclonic Epilepsy – 20%  Hippocampal sclerosis - 42%  Mohanraj R, Eur J neurol 2006, 13, 277-82 Problems of therapies  “It would be unusual for a patient suffering from epilepsy not to have at some time suffered from the medication needed to control it” Porter, 1986 ** Some side effects – older drugs Benzodiazepines Phenytoin Dose related - (acute) Drowsiness Ataxia Hyperactivity Personality Change Cognitive impairment Dose related - (acute) - long term Tolerance/dependence Ataxia Diplopia Nystagmus long term Gingival hyperplasia Osteomalacia Cerebellar atrophy Sodium Valproate Dose related - (acute) sedation nausea and vomiting tremor long term Hair thinning Weight gain Menstrual irregularities Encephalopathy ** Teratogenicity  most anticonvulsants implicated in congenital  birth defects - less data for newer agents  ** sodium valproate –affects cognitive development; reduced IQ in infant by 9-10 points, and has a higher rate (8-10%% vs 2% of major congenital malformations - dose related). Commoner in mums with an intellectual disability  epilepsy pregnancy register – voluntary, not randomised or controlled. Risk increased > 1 AED Variability of response to therapeutic agents  Although various forms of epilepsy respond well to AEDs, 30- 40% of patients remain refractory to pharmacological treatment.  Some of this variability is attributable to genetic differences among patients, an area of investigation called pharmacogenomics.  Candidate genes whose variation might be associated with variability in pharmacological success might include drug targets (e.g. sodium channels), or on genetic variation in proteins involved in drug pharmacokinetics (e.g. drug metabolising enzymes, membrane transporters). ** Drug-drug interactions  CYP450 liver enzymes most implicated  remember treatment is often long term  but not the only story! Check BNF; some antiepileptic drug blood levels can be measured  consider current and future co-morbidities; digoxin, theophylline, warfarin, OCP, rifampicin (TB), erythromycin, chemotherapy  ** bones, heart Enzyme induction - matters  phenobarbitone/primidone  carbamazepine broad spectrum  phenytoin  oxcarbazepine  (topiramate)  eslicarbazepine  zonisamide  rufinamide  perampanel at maximum dose  Note valproate is an enzyme inhibitor CYP3A4 Recommended reading  Michael Rogawski and Wolfgang Loscher. The Neurobiology of antiepileptic drugs. Nature Reviews: Neuroscience 5: 553-564 (2004)  ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Chadwick D, Guerreiro C, Kalviainen R, Mattson R, Perucca E, Tomson T. Epilepsia. 2006 Jul; 47(7):1094120  NICE guidelines, 2012 Summary  A perfect antiepileptic drug is probably not achievable  We have more choices  And less toxic drugs to use  Important in elderly and patients with ID  The future looks brighter for our patients Questions on pharmacology 1. 2. 3. 4. What are the ideal properties of an antiepileptic drug? What are the outstanding problems with all antiepileptic agents? Why do antiepileptic agents have so many side effects? What issues particularly face women starting epilepsy treatment? References 1. Flores et al. Clinical experience with oral lacosamide as adjunctive therapy in adult patients with uncontrolled epilepsy; A multicenter study in epilepsy clinics in the UK, Seizure, 2012, 21;512-517 retrospective study 13 IGE 2. Rastogi RG and Ny Y-T. Lacosamide in refractory mixed paediatric epilepsy: A prospective add-on study. J Child Neurol. 2102 27; 492-495 4 with LGS; 2 good response >90% reduction in seizure frequency; 2 no respsonse small numbers, not randomised, phase II trial in process 3. Franco et al. Perspective on the use of perampanel and intravenous carbamazepine for generalized seizures. Expert Opin Pharmacother. 2014 Apr;15(5):637-44. 4. Steinhoff et al. Efficacy and safety of adjunctive perampanel for the treatment of refractory partial seizures: a pooled analysis of three phase III studies. Epilepsia. 2013 Aug;54(8):1481-9.