Anticonvulsive drugs (antiepileptics) 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 % Types of seizures Types of seizures 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 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 An Pediatr (Barc). 2019;91(6):415.e1-- -415.e10 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) ̶ 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 ̶ GABAergics may exacerbate absences GABA-ergic drugs An Pediatr (Barc). 2019;91(6):415.e1- --415.e10 ̶ Carbamazepine ̶ Lamotrigine ̶ Phenytoin ̶ Lacosamide ̶ Bind preferentially to incativated channels and lower the number of functional channels able to generate action potential Na+ channel inhibitors An Pediatr (Barc). 2019;91(6):415.e1- --415.e10 ̶ 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 An Pediatr (Barc). 2019;91(6):415.e1- --415.e10 ̶ 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 An Pediatr (Barc). 2019;91(6):415.e1- --415.e10 ̶ 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 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 All types of seizures ̶ All but absence ̶ Carbamazepine (oxcarbazepine, eslicarbazepine), phenytoin, phenobarbital (primidon) ̶ All ̶ Vigabatrin, lamotrigine, valproate 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 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 in between ̶ 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 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. 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) 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.