Exam 3 - Lecture 23 and 25, Anticonvulsants

Greek “to be seized” A group of syndromes characterized by recurrent, unprovoked seizures

Latin “to take possession of”. An abnormal, excessive hyper synchronous discharge of a population of (cortical) neurons Focal = partial

Sudden, irregular, involuntary muscle contraction

The process by which a “normal” brain becomes epileptic

Epilepsy remains uncontrolled following prescription of 2 different drugs. Also called intractable or pharmacoresistant

Results from a known/ suspected CNS disorder

No known cause, possibly genetic

The disease etiology is unknown

(classic seizure phenotype) ~20-30% of patients Tonic Phase -> Clonic Phase -> Post-ictal confusional Fatigue

The seizure

State of altered consciousness after a seizure. Lasts 5 - 30 min, characterized by drowsiness, confusion, nausea, hypertension, headache or migraine and other disorienting symptoms

~ 10 to 15% of patients Auditory - Hiss or ringing in ears Visual - See flashes of light, blurring etc Somatosensory - Tingling of face, side of body Focal Motor - Tonic-clonic movements of upper/lower limb Autonomic - Sweating, flushing Grimacing Head and eyes turned opposite sides

~20 - 50% of patients “Grand Mal” Dysphasia Olfactory Hallucinations Formed visual hallucinations - seeing a tree that’s not there Formed auditory hallucinations - hearing music etc Dreamy state, blank face Psychomotor phenomena - chewing movement, wetting lips Impairment of consciousness - cognitive, affective symptoms

SUDEP Defined as the sudden and unexpected, non-traumatic and non-growing death of a person with epilepsy, without a toxicological or anatomical cause of death detected during the post-mortem examination

Males, mostly younger because don’t survive to older age Severe refractory seizures Poor compliance Young age and early age of seizures onset Biologically male Being asleep during seizure

Seizure in brain causes a chain reaction, causing issues with heart rate and breathing. Causes apnea (stop breathing), Arrhythmia and Asystole (No contraction) of heart

Anti-convulsant/seizure/epileptic drugs Surgery - specific focal lesions vs corpus callostomy Ketogenic diet - no carbs, burn fat release ketones Implanted device - Vagus nerve or deep brain stimulator

Highly effective, low incidence of toxicity Effective against more than one seizure type Long lasting, long half life Non-sedating Inexpensive No tolerance, particularly to anticonvulsant effect

SV40 binders Ion channel ligands Barbiturate Benzodiazepines Novel AEDs

MoA: Sodium Channel Blocker, state dependent Low efficacy inhibitor of 5HT reuptake FDA approved for: Partial seizures, Generalized tonic-clonic seizures, Mixed seizures, Trigeminal neuralgia, Mania in bipolar disorder Side effects: DRESS syndrome (Drug reaction with eosinophilia and systemic systems) or DIHS (drug-induced hypersensitivity syndrome). Suicidal tendency, hyponatremia, Spina bifida

MoA: Sodium channel blocker, state dependent binds when channel is moving between closed-open-inactive Indications: Focal seizures, Tonic-clonic seizures, Lennox Gastaut syndrome, Recurrent depressive episodes in bipolar disorder Side effects: in >10% of patients, Nav1.7 channels activate nerves, leading to a rash. Arrhythmias rare but possible in case of OD. Long list of side effects

MoA: Enhances Na channel inactivation (state dependent, likes to hold in inactive state), Low efficacy block of Cav3 channels, No effect on GABAA receptor function Side effects: Frequent GI (16%), anorexia, nausea, vomiting CNS: sedation, ataxia, tremor (not common) Toxicity: Rare, fulminant hepatits (liver death) often fatal Combo with clonazepam has caused absence status epileptics (rare) Effective in many seizure models and clinical seizure types

MoA: Enhances Na inactivation, state dependent…likes to hold in inactive state. Binds to collapse-in response mediator protein 2 (crmp-2) Approved for: adjunct partial onset seizures in 17yr + Patients with diabetic neuropathic pain oral or injectable dosage forms effective as add on in refractory partial seizures Side effects: headache, drowsiness, blurred vision and tremor

Novel MoA: Binds Vesicle protein SV2A, stereoselective Pyrrolidine s-enantiomer of a protest nootropic agent FDA approved for: Partial-onset seizure, Myclonic seizure, Tonic-clonic seizure Side effects: Psychosis, Suicidal ideation, somnolence (drowsiness), Asthenia (lack of strength), Dizziness….low incidence of side effects Dose not interact metabolically with other AEDs