Adobe Systems Anticonvulsive drugs (antiepileptics) Adobe Systems Epilepsy ̶brain disorder characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological, and social consequences of this condition ̶ ̶Seizures ̶manifestation of abnormal hypersynchronous or hyperexcitable discharges of cortical neurons ̶many causes, including a genetic predisposition for certain types of seizures, head trauma, stroke, brain tumors, alcohol or drug withdrawal, repeated episodes of metabolic insults, such as hypoglycemia ̶ ̶Prevalence 0,5–1 % ̶ Adobe Systems Factors lowering seizure threshold ̶Sleep deprivation ̶Alcohol withdrawal ̶Television flicker ̶Epileptogenic drugs ̶Systemic infection ̶Head trauma ̶Recreational drugs ̶Non-compliance ̶Menstruation ̶Dehydration ̶Barbiturate withdrawal ̶Benzodiazepine withdrawal ̶Hyperventilation ̶Flashing lights ̶Diet and missed meals ̶Stress ̶Intense exercise ̶ Adobe Systems Pharmacotherapy ̶The goal to achieve a seizure-free status without adverse effects ̶Monotherapy is desirable - avoids drug interactions ̶Many of the older anticonvulsant agents have hepatic enzyme–inducing properties ̶ ̶Main mechanism - to stabilize membrane of neuron and to decrease the excitability ̶ ̶ Adobe Systems An Pediatr (Barc). 2019;91(6):415.e1---415.e10 Adobe Systems Mechanisms of action ̶Classical ̶Enhancement of GABA mainly via GABA-A rc ̶Inhibition of sodium channel function ̶Inhibition of calcium channel function ̶ ̶Mechanisms of newer drugs ̶Inhibition of glutamate release ̶Inhibition of GABA uptake ̶AMPA receptor antagonism ̶Synaptic vesicle protein SV2A ̶ ̶(multiple mechanisms) Adobe Systems ̶barbiturates (phenobarbital), BZD ̶vigabatrin – irreversible inhibition of GABA transaminase ̶tiagabine – inhibitor of GABA transporter (increases extracellular GABA) ̶stiripentol ̶increases GABA effect similarly as barbiturates and inhibits lactate dehydrogenase, which may reduce metabolic energy prodcution requiered to mainain the seizure, used as adjunctive treatment in children ̶GABA-ergics may exacerbate absences ̶ GABA-ergic drugs Adobe Systems An Pediatr (Barc). 2019;91(6):415.e1---415.e10 Adobe Systems ̶carbamazepine ̶lamotrigine ̶phenytoin ̶lacosamide ̶ ̶Bind preferentially to inactivated channels and lower the number of functional channels able to generate action potential ̶ Na+ channel inhibitors Adobe Systems An Pediatr (Barc). 2019;91(6):415.e1---415.e10 Adobe Systems ̶ethosuximide, valproate ̶Act primarily on T type channels in the thalamus, which are responsible for absences ̶ ̶gabapentin, pregabalin ̶GABA analogues, act primarily on P/Q type channels ̶Lower trafficking of the channels to the membrane - reduce the calcium entry to the cell – reduce neurotransmitter release ̶ Ca2+ channel inhibitors Adobe Systems An Pediatr (Barc). 2019;91(6):415.e1---415.e10 Adobe Systems ̶levetiracetam, brivaracetam ̶Bind to SV2A protein and probably have also other mechanisms ̶perampanel, topiramate (multiple mechanisms) ̶AMPA antagonism ̶rufinamide ̶Inhibition of GABA reuptake ̶retigabine ̶ Opens KCNQ/Kv7 potassium channels Other mechanisms Adobe Systems An Pediatr (Barc). 2019;91(6):415.e1---415.e10 Adobe Systems ̶valproate ̶Inhibition of both sodium and calcium channels (T type), GABA transaminase ̶All types of seizures ̶felbamate ̶Inhibition of both sodium and calcium channels, GABA-A and NMDA rc ̶Lennox-Gastaut sy ̶topiramate ̶Inhibition of both sodium and calcium channels, GABA-A and AMPA rc ̶Lennox-Gastaut sy ̶zonisamide ̶Inhibition of both sodium and calcium channels, GABA-A rc ̶Partial seizures ̶ Multiple mechanisms Adobe Systems Cannabidiol ̶for adjuvant treatment of seizures associated with Lennox-Gastaut syndrome (LGS) or with Dravet’s syndrome (DS) in use together with clobazam in patients of the age 2 years and older ̶for adjuvant treatment of attacks associated with tuberous sclerosis complex (TSC) in patients of the age 2 years and older Adobe Systems Choice of anticonvulsant agent ̶https://pathways.nice.org.uk/pathways/epilepsy#path=view%3A/pathways/epilepsy/anti-epileptic-drugs -to-offer-based-on-presenting-epilepsy-seizure-types.xml&content=view-node%3Anodes-absence-seizures Adobe Systems All types of seizures ̶All but absence ̶carbamazepine (oxcarbazepine, eslicarbazepine), phenytoin, phenobarbital (primidon) ̶ ̶ ̶All ̶vigabatrin, lamotrigine, valproate ̶ Adobe Systems Treatment of specific types of seizures ̶Absence ̶ethosuximide or valproate ̶lamotrigine ̶Partial (focal) seizures ̶carbamazepine or lamotrigine ̶valproate, levetiracetam, clobazam, gabapentin, topiramate ̶Generalised tonic–clonic seizures ̶valproate, carbamazepine or lamotrigine ̶topiramate, levetiracetam ̶Myoclonic seizures ̶valproate, topiramate, levetiracetam ̶ ̶ Adobe Systems Status epilepticus ̶Critical, life threatening condition, one seizure comes after another without recovery, lasts at least 30 min, fatal in 5-10% patients ̶Shall be distinguished from a series of seizures with recovery inbetween ̶ ̶Causes – frontal lobe lesion (including stroke), head trauma, anticonvulsant discontinuation, alcohol withdrawal, metabolic disturbances, pregnancy ̶Requires inpatient treatment – energetically demanding condition, hypoglycaemia, lung edema, hyperthermia, excitotoxicity, ... ̶ ̶lorazepam IV or midazolam IM or diazepam rectally ̶ Adobe Systems Epilepsy resistant to monotherapy ̶Consider combination therapy when: ̶Treatment with two first line AEDs has failed ̶The first well-tolerated drug substantially improves seizure control, but fails to produce seizure freedom at maximal dosage. ̶The choice of drugs in combination should be matched to the patient’s seizure type(s) and should be limited to two or at most three AEDs. ̶ ̶gabapentin, lacosamide, lamotrigine, levetiracetam, pregabalin, topiramate, zonisamide (alphabetical order) may be considered as adjunctive therapy dependent on patient and seizure type. ̶ ̶ ‹#› •ILAE - DRE non-satisfactory compensation of attacks after trying of two well-tolerated, correctly chosen and dosed antiepileptic drugs (anti-seizure medication; ASM) in the form of monotherapy or combined treatment.1 • DRUG RESISTENT EPILEPSY (DRE) About 40 % of patients with epilepsy after treatment with two AE drugs do not achieve permanent and full control of attacks and therefore it belon to DRE defined by ILAE1 ILAE, Mezinárodní liga proti epilepsii. 1. Kwan P, et al. Epilepsia 2010;51:1069–1077; 2. Chen Z, et al. JAMA Neurol 2018;75:279–286. ‹#› Combinations ● suitable combination (with respect to MoA) ● less suitable combination (with respect to MoA) ● non-suitable combination (with respect to risk of nephrolithiasis) ● significant or potentially significant interactions (check SmPC) Adobe Systems Other uses on antiepileptic drugs ̶Bipolar disorder (valproate, carbamazepine, oxcarbazepine, lamotrigine, topiramate) ̶ ̶Prophylaxis of migraine (valproate, gabapentin, topiramate) ̶ ̶Anxiety disorders (gabapentin, pregabalin) ̶ ̶Neuropathic pain (gabapentin, pregabalin, carbamazepine, lamotrigine) Adobe Systems Drug-drug interactions ̶Drug-drug interactions are common among anticonvulsants as well as between anticonvulsants and other drugs ̶Mostly pharmacokinetic Adobe Systems Interactions of anticonvulsant drugs Adobe Systems Anticonvulsants in specific populations ̶Neonates, children, elderly patients ̶Slowed hepatic metabolism ̶Decreased renal clearance ̶Decreased volumes of distribution ̶Women on contraceptive agents ̶Pregnant women - folic acid, at least 0.4mg/day, TDM, many drugs are teratogenic ̶Patients with hepatic or renal insufficiency ̶Gabapentin, pregabalin, levetiracetam, and lacosamide excreted mostly renal clearance - their doses can be adjusted for renal insufficiency ; useful in patients with hepatic failure ̶Lamotrigine metabolized by glucuronidation - also might be used in hepatic insufficiency. ̶ ̶ Adobe Systems Generic substitution ̶Changing the formulation or brand of AED is NOT recommended because different preparations may vary in bioavailability or have different pharmacokinetic profiles and, thus, increased potential for reduced effect or excessive side effects. ̶ ̶ Adobe Systems Exam questions ̶gabapentin – GABA analogue, without affinity to GABA rcp., without effects on metabolism of GABA ̶bonding to voltage gated Ca2+ channels ̶used for therapy of partial attacks ̶way of application: p.o. ̶low interaction potential ̶relatively safe, few AE ̶other use: peripheral neuropathic pain (diabetic neuropathy, postherpetic neuralgia), preemptive analgesia Adobe Systems ̶carbamazepine – inhibition of Na+ channels ̶used for therapy of generalized attacks, mixed attacks, ineffective in absences ̶way of administration: p.o. (both conventional tbl. and tbl. with prolonged effect) ̶teratogenic! ̶risk of severe skin toxicity (mainly in people of Chinese or Thai origin – pharmacogenetic background) ̶high interaction potential (with inhibitors of CYP3A4 ® AE) ̶other use: mania and prophylactic treatment of bipolar affective disorder, treatment of neuropathic pain and neuralgias (neuralgia of trigeminal nerve, diabetic neuropathy, treatment of abstinence syndrome in alcoholics Exam questions Adobe Systems ̶valproate (valproic acid) – inhibition of sodium and calcium channels of T type, GABA transaminase ̶suitable for therapy of many types of attacks (epilepsy in children, adolescents; affects both tonic-clonic seizures and absences), suitable for therapy of pharmaco-resistant epilepsy ̶non-sedative ̶way of administration: p.o. (with prolonged effect), injections ̶high interaction potential ̶high teratogenic!!! ̶about 10% of patients – hair impairment, hepatotoxic ̶other possible use: bipolar affective disorder, prophylaxis of migraine Exam questions