Pharmacological Treatment of Epilepsy (Princess Nourah bint Abdulrahman University)

Pharmacological treatment of epilepsy Summarised for final exam Lecture 4 1446 H Psychopharmacology (CPY 490) Lecture objective By the end of this lecture, you will be able to: Explain medications used for seizures and status epilepticus. Describe mec...

Pharmacological treatment of epilepsy Summarised for final exam Lecture 4 1446 H Psychopharmacology (CPY 490) Lecture objective By the end of this lecture, you will be able to: Explain medications used for seizures and status epilepticus. Describe mechanism of action, therapeutic uses, adverse effects, drug interactions of antiseizure medications. Status epilepticus A seizure lasting beyond five minutes because the normal mechanisms that terminate seizures are not working. Life-threatening >> need emergency treatment. Established anti-seizure New anti-seizure medications medications Phenobarbital Lamotrigine Phenytoin Gabapentin Ethosuximide Topiramate Carbamazepine Sodium valproate Levetiracetam Clonazepam Pregabalin Mechanism of action ASMs decrease abnormal electrical activity in the brain (CNS depressants) by: Blocking sodium channels Blocking calcium channels GABA Glutamate Other mechanisms include: modulation of synaptic proteins. Some antiseizure medications (ASMs) have multiple mechanisms of action Blockage of sodium channel Voltage-gated sodium channels control the action potential by controlling the passage of sodium ions across the neuronal membrane. Many antiseizure medications act by blocking the sodium channel. Blockage of calcium channel Voltage dependent calcium channels subtypes: High voltage calcium channels Low voltage calcium channels (T-type). High voltage calcium channels: Control the neurotransmitter release by controlling calcium influx across. Gabapentin and pregabalin block these channel. Calcium channel blockers Low-voltage calcium channel (T-type): Plays a pathological role in the absence seizure. Ethosuximide blocks of this channel > drug of choice for children with absence seizures. GABA potentiation GABA: Most important inhibitory neurotransmitter in the brain. Three types of GABA receptors (A, B, and C). GABA-A >> generation of fast inhibitory postsynaptic potentials >> controlling seizure activity. Ligand-gated chloride channels, activation of GABA-A receptors >> increase CL- Influx >> hyperpolarisation. GABA potentiation After GABA is released to the synapse, it is taken back into presynaptic neuronal cells and into glia cells, where it is metabolised by GABA aminotransferase. Phenobarbital and benzodiazepines (such as clonazepam) >> activate the GABA-A receptors. Other antiseizure medications act by inhibiting GABA aminotransferase or blocking GABA reuptake. Glutamate inhibition Glutamate: Main excitatory neurotransmitter in CNS. Glutamate inotropic receptors: NMDA, AMPA, and Kainate receptors. These receptors have ion channel that controls the calcium and sodium ions influx >> depolarisation. Antiseizure medications act by inhibiting these receptors. Other mechanism Modulate synaptic vesicle protein 2A >> exocytosis of neurotransmitters, particularly glutamate. Levetiracetam binds selectively to the synaptic vesicle protein 2A. Mechanism of action Levetiracetam Brivaracetam Extra information Status epilepticus management IV lorazepam (IV unavailable: IM midazolam or rectal diazepam), if seizure persists: IV infusion fosphenytoin, valproic acid, levetiracetam. Other indications of ASMs Some ASMs have specific other indications: Psychatirc diorders >bipolar and anxiety Migraine headache and neuropathic pain Adverse drug reactions of ASMs CNS Idiosyncratic Chronic symptoms reactions reactions Drug Teratogenicity interactions CNS adverse reactions Common (due to decreased neuronal excitability): Sedative effects (e.g. tiredness, drowsiness). Coordination disturbances (e.g. dizziness, ataxia, tremor, diplopia) Cognitive dysfunction (e.g. memory problem) >> highest with topiramate (word-finding difficulty). Psychiatric effects CNS adverse reactions Psychiatric effects of ASMs: Some ASMs have negative psychotropic effects: Mood disorders, irritability, aggressiveness, psychosis. Different rate and type among ASMs. Examples: levetiracetam. Some ASMs have positive psychotropic properties: Can be used to treat psychiatric disorders. Examples carbamazepine, valproate, lamotrigine, pregabalin, and gabapentin. Idiosyncratic reactions Rare (in general), reported with specific ASMs Dermatological reactions: Range from mild skin rash to rare severe reactions (Stevens-Johnson syndrome, SJS). Hematological reactions (e.g. aplastic anemia). Hepatotoxicity. Chronic adverse reactions Weight gain/loss Osteoporosis and reproductive dysfunction Hair-loss Chronic dysmorphic symptoms >> phenytoin Phenytoin induced gingival hyperplasia Improvement after 3 months of phenytoin discontinuation. Teratogenicity Including birth defect and other adverse effects on fetus. Highest risk with valproate (should be avoided in young women) Lowest risk lamotrigine, levetiracetam Drug interactions Clinically important aspect of ASMs Drug interaction Enzyme inhibitor >> valproate: Enzyme inducer >>several specific ASMs are enzyme inducers. Some ASMs have no potential for drug interactions such as levetiracetam.