Antiepileptics 20-21 PDF

http://bgr.com/2016/01/21/brain-memory-capacity-petabyte/ Antiepileptics DR SARAH TRINDER [email protected] http://www.cvr.org.au/ Outline Overview of epilepsy Types of brain imaging Pre-clinical models Antiepileptic drugs ◦ Enhance GABA action ◦ Inhibit Na+ channels ◦ Inhibit Ca2+ channels Epi...

http://bgr.com/2016/01/21/brain-memory-capacity-petabyte/ Antiepileptics DR SARAH TRINDER [email protected] http://www.cvr.org.au/ Outline Overview of epilepsy Types of brain imaging Pre-clinical models Antiepileptic drugs ◦ Enhance GABA action ◦ Inhibit Na+ channels ◦ Inhibit Ca2+ channels Epilepsy Common disorder characterised by seizures ◦ Episodic neuronal discharges 0.5-1% of population affected Often no recognisable cause ◦ Brain damage – trauma, stroke, infection, tumour ◦ Inherited neurological syndromes webmd.com Epilepsy Neurological disorders, exhibit periodic seizure Seizures – episodic high-frequency discharge of impulses by a group of neurons (focus) Can start as local discharge, may spread Symptoms – depends on area of brain affected and it’s function Imaging Electroencephalography (EEG) ◦ Detects electrical activity ◦ Recordings made from electrodes ◦ Type of seizure recognised by nature & distribution of the abnormal discharge http://www.hopkinsmedicine.org/ Rang & Dale Pharmacology 8th Ed Imaging Magnetic resonance imaging (MRI) Positron emission tomography (PET) Intermountain Medical Imaging, Boise, Idaho Rang & Dale Pharmacology 8th Ed Types of epilepsy Seizure Classification Partial Conscious/unconscious Generalised Unconscious Partial Seizures Jacksonian epilepsy ◦ Focus in motor cortex – repetitive involuntary jerking of a muscle group ◦ Begins one side of body – thumb, big toe, angle of mouth – spreads Psychomotor epilepsy ◦ Consists of purposed movements ◦ Lasts a few mins ◦ Patient recovers with no recollection Generalised seizures Tonic-clonic ◦ Two phases ◦ Initial strong contraction of whole musculature – tonic phase ◦ Series of violent, synchronous jerks – clonic ◦ Injury can occur during convulsions Absence seizure ◦ Abruptly stops activity, stares vacantly for a few secs ◦ Recover abruptly with no after effects Lennox-Gastaut ◦ Severe, associated with progressive mental retardation ◦ Due to excitotoxic neurodegeneration? Rang & Dale Pharmacology 8th Ed Epilepsy & genetics 1/3 of epilepsy – familial & involve genetic mutations ◦ Mostly multiple mutations but some single ◦ Encode neuronal ion channels – control action potential generation ◦ Voltage gated Na+/K+ channels, GABAA, nACh Aetiology of epilepsy Underlying neuronal abnormality – poorly understood Excitation if unimpeded will spread throughout neuronal network ◦ Normally prevented by inhibitory mechanisms Epilepsy due to – ◦ Enhanced excitatory transmission ◦ Reduced inhibitory transmission Pre-clinical models Transgenic mouse strains ◦ Spontaneous seizures ◦ Knock-out (KO) – ion channels or other synaptic proteins Kainate model – single injection of kainic acid in amygdaloidal nucleus of rat ◦ Spontaneous seizures occur 2-4 weeks later Electrically induced seizures ◦ Electrically stimulate regions of limbic system repeatedly ◦ Prevented by NMDA antagonists Antiepileptics Mechanism of action Antiepileptic drugs Optimal drug therapy, completely controls 75% of all patients epilepsy ◦ 10% patients have seizure every month or more frequently Required to take drugs continuously for many years/indefinitely ◦ Low side effect profile - beneficial Mechanisms of action Aim – prevent proximal discharge without affecting normal transmission Inhibit abnormal discharge – do not correct underlying cause Main mechanisms ◦ Enhance GABA action ◦ Inhibit Na+ channel function ◦ Inhibit Ca2+ channel function Enhance gaba action Benzodiazepines – enhance activation of GABAA ◦ Acute seizures in children & status epilepticus ◦ Acts rapidly but sedation, dependence Cl- BDZ – opens channel Vigabatrin – irreversibly inhibits GABA transaminase (GABA-T) ◦ All types of epilepsy ◦ Peripheral visual field defect, depression Tiagabine – inhibits GAT1 ◦ Partial seizures (add on therapy) ◦ Drowsiness, confusion, fatigue Inhibition of + Na channel function Voltage-gated Na+ channel blockers ◦ “Use-dependent” ◦ 3 states for Na+ channels – resting, active (open), inactive ◦ Drugs bind inactive channels ◦ Carbamazepine - all types of epilepsy except absence seizures ◦ Drowsiness, severe motor & mental disturbances Inhibition of 2+ Ca channels T-type Ca2+ channel inhibition 2+ Caneurons ◦ Important in determining rhythmic discharge of thalamic – absence seizures ◦ Ethosuximide – nausea & anorexia Ethosuximide – blocks channel P/Q-type Ca2+ channel inhibition ◦ Galapentin binds a channel subunit (α2δ1) – prevents trafficking to plasma membrane ◦ ↓ Ca2+ channels with α2δ1 subunit = ↓ Ca2+ entry = ↓ NT release ◦ Effective in partial seizures ◦ Less severe side effects – sleepiness, dizziness, weight gain Valproate Used in all types of epilepsy ◦ Especially effective in infantile epilepsy – low toxicity & sedation Several mechanisms of action ◦ ↑[GABA], weak inhibitor of GABA-T ◦ GABA agonist? ◦ Inhibits T-type Ca2+ channels – effective in absence seizures ◦ Inhibits voltage-gated Na+ channels Side effects – well tolerated – nausea, hair loss Other drugs Derived on basis of efficacy in animal models Levetiracetam- binds synaptic vesicle protein 2A (SV2A) ◦ Interferes with NT release? Topiramate – ‘Jack of all trades’ ◦ Blocks Na+ & Ca2+ channels, enhances GABA action, blocks AMPA ◦ Add on therapy in partial & generalised seizures Many others! NMDA antagonists? Would prevent Glu-dependent Na+ & Ca2+ entry Too narrow therapeutic window ◦ Effectiveness vs motor co-ordination side effects From Rang and Dale’s Pharmacology Learning outcomes To describe and explain the main types of epilepsy To describe and explain pre-clinical models of epilepsy Discuss the 3 major antiepileptic drug categories ◦ Enhance GABA action ◦ Inhibit Na+ channels ◦ Inhibit Ca2+ channels