Antiepileptics PDF

ANTIEPILEPTICS Seizure is a paroxysmal derangement of cerebral function caused by an abnormal excessive and hyper synchronous electrical discharge of groups of neurons in the brain. It can be traced to insults such as head trauma, high fever or alcohol withdrawal. Epilepsy is a clin...

ANTIEPILEPTICS Seizure is a paroxysmal derangement of cerebral function caused by an abnormal excessive and hyper synchronous electrical discharge of groups of neurons in the brain. It can be traced to insults such as head trauma, high fever or alcohol withdrawal. Epilepsy is a clinical syndrome that involves recurrent unprovoked seizures that cannot be explained by a medical condition. A single seizure doesn't mean epilepsy. OCCURRENCES OF SEIZURES Neuronal activity is normally Asynchronous i.e while some are firing AP, others are hyperpolarized. It is noticeable on EEG as wave forms. They maintain balance, posture and fine motor control. Abnormal synchronized activity often arises from an area in the brain i.e seizure focus Seizures are noticeable on EEG as spike wave forms. Manifesting as abnormalities in movement, sensations or consciousness, confusion. CAUSES OF SEIZURES Primary (idiopathic) : Genetic abnormalities Secondary: Toxins, autobodies, acquired lesions. Unclassified: Neonatal seizures, Infantile spasms FACTORS THAT PREVENT REPETITIVE SYNCHRONOUS FIRING ∆ Cellular level ∆ Network level Cellular: In a healthy neuronal circuit Depolarizing inwards Na and Ca ionic currents are activated by excitatory glutamate receptors. Followed by repolarising outward K current activated by inhibitory GABA B receptors Influx of Cl ion produced by excitatory GABA A receptor repolarises the cell and inhibit impulse generation Note: Anti epileptic drugs produce effect by blocking depolarizing ion channels or enhancing inhibitory actions of GABA Network: Surround inhibition; a process that normally prevents the activation of neurons adjacent to a focus. Essential in normal functioning of Nervous system by amplifying local signals, providing insulation and protecting against synchronicity in surrounding areas Focal seizures occurs as a result loss of surround inhibition. Drug that increase surround inhibition are effective in treatment. TYPES OF SEIZURES 1. PARTIAL: Seizures involving part of the brain.  Seizures that involve brain regions that serve a basic function(motor, movement or sensation) it's referred to as focal seizure without altered awareness. Seizures that involve brain regions serving complex functions (language,memory and emotions) It's referred to as focal seizures with altered awareness. 2. Generalized: Seizures that involve both hemisphere of the brain. It could be primary generalized seizure; this results from abnormal synchronization between thalamic and cortical cells that involve both hemispheres. These seizures do not necessarily begin with an aura(a conscious warning of the spread of seizures) or secondary generalized seizure which begins in a focus (partial) and spreads to subcortical areas. Synchronize spread of activity to both hemispheres. Comes with an aura. Divided into Tonic- clonic: Initial rigid extensor spasm, respiration stops, defecation, micturition and salivation (Tonic phase). Violent synchronous jerks (Clonic phase). Absence: Abrupt loss of awareness of surroundings. Atonic: Loss of muscle tone Myoclonic: Seizures of muscles CLASSIFICATION OF AEDs Drugs that block Sodium channel: PCOLL-V; These drugs help to increase Na channel inactivation thereby enhancing inhibition at the single cell level. They have little effect on Absence seizures. PHENYTOIN: $ Oldest $ MOA:Slows rate of recovery from inactivated state to resting state by doing this it increases the threshold for AP and prevents repetitive firing. It also prevents the rapid spread of seizure activity to other neurons. $ Major drug of choice for Focal seizures and tonic clonic seizures. $ 95% protein bound $ ADVERSE EFFECTS No longer 1st line agent CONCENTRATION-DEPENDENTCerebellar symptoms: Dysarthria, Ataxia, Nystagmus, Intention tremors. GIT: Anorexia, nausea OTHERS: Chorea, peripheral neuropathy, seizures. LONG TERM Cosmetic side effects: Acne, coarse facials, hirsutism, gingival hyperplasia. OTHERS : Drug induces SLE, Osteomalacia, Megaloblastic anaemia, Dupuytrens contracture, Aplastic anaemia, Fetal hydantoin syndrome $ Parenteral formulation: 1st line therapy in status epileptic us. Administered as IV only. Strongly Alkaline. Avoid rapid administration it causes depression of CVS and CNS. Rate should not exceed 50mg/min.  $ Other uses: Anti arrhythmic, trigeminal neuralgia. $ Contraindications: Porphyria and heart block $ Fosphentoin: Pro drug, can be administered rapidly, administered IV and IM. CARBAMAZEPINE: $ Similar MOA to that of phenytoin $ It metabolite, 10,11-epoxycarbamazepine acts to slow down sodium channel recovery. $ Drug of choice for partial seizures $ Less protein bound $ t½ 10-20 hrs $ Induces it's metabolism $ Completely metabolized by CYP3A4 $ Contraindications: Porphyria, Cardiac conduction defects, Bone marrow suppression, MAOIs, Myoclonic and Absence seizures $ Other Uses: Trigeminal neuralgias, prophylaxis for mood swings in manic- depressive episodes, Diabetes insipidus. $ Adverse effects: Rash, depression of CNS and CVS, leucopenia, aplastic anemia, SIADH, cleft lip and palate, spinal bifida. OXCARBAZEPINE $ A pro drug $ t½ 1-2hrs $ Rapidly converts to an active metabolite, eslicarbazepine. $ Less risk of rash $ Drawback; Higher risk of dilutional hyponatraemia LACOSAMIDE $ t½ 13 hrs. $ Reserved for Refractory partial seizures. $ Adverse effects: Dizziness, nausea and headache, Prolongation of PR interval. LAMOTRIGINE $ MOA: Slows sodium channel recovery, inhibits T type Ca channels, Glutamate receptor blocker. $ Uses: Focal, Tonic-clonic (First line), Absence seizures, Bipolar disorders. $ t½: 24hr $ Metabolism inhibited by valproic acid $ Adverse effect: Rash, May progress to sjoren syndrome, or angioedema Drugs that enhance Potassium channel conductance: leads to hyper polarization of the cell membrane and reduces neuronal firing. Example is Retigabin $ Requires 3 times a day dosing $ Metabolised through glucuronidation $Adverse effects: Urinary retention, blue skin discoloration and retina abnormalities  Drugs that inhibit Ca-Channel: There are two types of Ca channel; T-Type(low voltage): Provides for rhythmic firing of thalamic neurones.Used in treatment of Absence seizures N-Type(High voltage): They control calcium entry into the pre-synaptic terminal and control release of neurotransmitters. Used in focal seizures and primary generalized seizures. ETHOSUXIMIDE $ Drug of choice in absence also useful in myoclonic $ MOA: Reduce transient current $ Side effects: Nausea, gastrointestinal irritation, drowsiness, anorexia, ataxia, lethargy, psychoses, allergic runs and drug-induced SLE VALPROIC ACID $ Administered as Na-Valporate converted to valproic acid in small intestine for absorption. $ MOA:Slows rate of Na channel recovery. Limits activity of T-channels. Increases GABA mediated inhibition. $ Uses: Generalized seizures because of its many potential sites of action. Treatment of absence seizures that doesn’t respond to ETHOSUXIMIDE. Alternative to phenytoin and carbamazepine for focal seizures. Drug of choice for myoclonic seizures, bipolar disorder and migraine prophylaxis. $ Adverse effects: Congenital malformation, elevation of liver enzymes and blood ammonia levels, fetal hepatitis, (Weight gain, POS, hair loss) in women, impaired glucose intolerance GABAPENTIN $ In vitro: Increases the content of GABA in neurons and glial cells. $ In Vivo: do not bind to or affect GABA metabolism or reuptake. Primarily inhibits HVA- Ca channels $ Has low interactions with other drugs $ Not metabolized, excreted unchanged $ Uses: Partial seizures +/- generalized seizures, Neuropathic pain and anxiety $ Adverse effects: Dizziness, Somnolence, Ataxia, Weight gain. PREGABALIN $ MOA: Inhibition of N-Type calcium channel thereby reducing neurotransmitters including glutamate and norepinephrine, Substance P and calcitonin $ Useful in patients with hepatic dysfunction. $ Has no drug interactions $ Similar Use and adverse effects with Gabapentin Drugs that enhance GABA-mediated inhibition: Vi,Ti,B,B; BENZODIAZEPINES $ MOA: Increase affinity of GABA for GABA A receptors. Enhance GABA A channel opening in the presence of GABA thereby increasing Chlorine influx This action has dual effect: I) Increase threshold of membrane AP II) Strengthen surround inhibition $ Uses: Diazepam, lorazepam and midazolam are well suited for treatment of focal and tonic-clonic seizures, first line in status epileptics $ Adverse effects: Drowsiness, tiredness, Ataxia forgetfulness, confusion, tolerance and addiction $ Clonazepam: Inhibit T-Type Ca channel currents, 4th drug of choice for absence seizures also useful in myoclonic seizures. $ Clobazam: Used as an adjunctive treatment for Lennox-Gastaut syndrome. Asssociated with increased risk of skin reactions. Contraindicated in Narrow angle gaucoma BARBITURATES $ Phenobarbital: Mode of action; Increase duration of GABA- activated Cl channel opening, Agonist activity at GABA A receptor. Useful in partial and tonic clonic seizures $ Primidone: Pro drug of phenobarbital. Both used in status epilepticus VIGABATRIN $ MOA: Irreversibly inhibits GABA transaminase thereby reducing GABA metabolism $ Drawback: Causes severe irreversible peripheral visual field defects and psychiatric disorders $ Uses: Infantile spasms and refractry partial seizures $ Contraindicated in absence and myoclonic seizures $ Associated with Alopecia and weight gain TIAGABINE $ MOA: Blocks reuptake of GABA into neurons and glia by inhibiting GABA transporters thereby increasing GABA in synaptic cleft. $ USES: Partial complex seizures, panic disorder $ Side effect: Confusion, difficulty speaking, clearly stuttering and mild sedation Drugs that block Glutamate receptors: NMDA & AMPA blockers. e.g felbamate, perampanel, lamotrigine FELBAMATE $ MOA: NMDA receptor blocker also blocks, Na channels, Ca channels and potentiate GABA actions $ Side effects: aplastic anaemia and liver failure $ USES: Refractory epilepsy and Lennox Gastaut syndrome PERAMPANEL $ MOA: A non-competitive antagonist at AMPA receptor $ Adverse effects: Increase risk of psychiatric symptoms Carbonic anhydrase inhibitors: TOPIRAMATE $ MOA:Na channel inhibitor Glutamate receptor blocker Enhances GABA activity Carbonic anhydrase inhibitor $ USES: Tonic clonic seizures and partial complex seizures. Also used as migraine prophylaxis. $ ADVERSE EFFECTS; Weight loss, Increased IOP, renal stones, high incidence of CNS related side effects. ZONISAMIDE $ MOA: Carbonic anhydrase inhibitor Na Channel blocker T type Ca channel $ USES: Same as Topira hmmmate. $ Adverse Effects: Same as Topiramate Levetiracetam $ MOA: Unknown $ USES: Partial and generalize seizures $ Not approved for children below 4 yrs $ Adverse effects: Cause sedation and behavioral adverse effects, including irritability.