Antiepileptics PDF

Antiepileptics Seizures are episodes of abnormal electrical activity in the brain that cause involuntary movements, sensations, or thoughts ○ Results from head trauma, CVA, brian tumors, hypoxia, hypoglycemia, fever, EtOH withdrawal, and other conditions that alt...

Antiepileptics Seizures are episodes of abnormal electrical activity in the brain that cause involuntary movements, sensations, or thoughts ○ Results from head trauma, CVA, brian tumors, hypoxia, hypoglycemia, fever, EtOH withdrawal, and other conditions that alter neuronal function ○ Recurrent seizures that cannot be attributed to any proximal cause are seen in patients with epilepsy Classification ○ Partial (focal) seizures Originates in one cerebral hemisphere No LOC ○ Generalized seizures Arises in both cerebral hemispheres LOC Partial seizures ○ EEG abnormalities are seen in one or more lobes of cerebral hemisphere → patient may experience motor, sensory and autonomic symptoms Simple partial seizures → consciousness not altered Complex partial seizures → altered consciousness and exhibit automatisms (repetitive behaviors) ○ About 60% of epileptic seizures are partial seizures. ○ Simple partial seizure → no alteration of consciousness ○ Complex partial seizure → altered consciousness, automatisms and behavioral changes ○ Secondary generalized seizures → focal seizure becomes generalized and is accompanied by LOC Generalized seizures ○ Tonic clonic seizures (formerly grand mal seizures) Brief tonic phase followed by a clonic phase with muscle spasms lasting 3-5 minutes Followed by post-ictal period (drowsiness, confusion, glazed eyes) ○ Status epilepticus occurs when patients experience recurrent tonic clonic seizures without regaining consciousness or normal muscle movement between episodes. ○ Absence seizures (formerly petit mal seizures) Abrupt LOC and decreased muscle tone lasting about 15 seconds Can include mild clonic component, automatisms and autonomic effects Characteristic synchronous 3-Hz spike and dome pattern on EEG Classification ○ Tonic clonic seizure → increased muscle tone followed by spasms of muscle contraction +  ○ Tonic seizure → increase muscle tone ○ Clonic seizure → spasms of muscle contraction and relaxation ○ Myoclonic seizure → rhythmic, jerking spasms ○ Atonic seizure → sudden loss of all muscle tone ○ Absence seizure → brief loss of consciousness with minor muscle twitches and eye blinking Antiepileptic drugs ○ Antiepileptic drugs suppress the formation or spread of abnormal electrical discharges in the brian via 3 mechanisms: Inhibition of sodium or calcium influx responsible for neuronal depolarization Augmentation of GABA neurotransmission (which inhibits seizures) Inhibition of excitatory glutamate neurotransmission Ion channels ○ Normally voltage sensitive Na channels rapidly open when voltage read their threshold → depolarization occurs, causing release of neurotransmitter → inactivation gate is closed (and must be open again before the next action potential can occur) ○ Many drugs (e.g., carbamazepine, lamotrigine, phenytoin, topiramate) prolong the time the inactivation gate remains closed, delaying the formation of the next action potential GABAergic systems ○ Antiepileptic drugs facilitate GABA neurotransmission by various means Benzodiazepines (e.g., clonazepam), barbiturates (e.g., phenobarbital), and topiramate enhance GABA activation of the GABAa receptor-chloride ion channels Gabapentin increases GABA release while vigabatrin inhibits GABA degradation Glutaminergic systems ○ A few anti epileptics (e.g., felbamate, topiramate, and valproate) inhibit glutamate neurotransmission ○ Affects the formation of a seizure focus and terminates a seizure at an early stage of its own development Treating seizure disorders ○ Some drugs are only active against one or two types of seizure while others have a broad spectrum of activity covering most seizures ○ Newer agents (e.g., lamotrigine, topiramate, tiagabine, levetiracetam,) are considered adjunct agents and are primarily used in combi with older drugs for treating partial seizures  ○ Newer agents are useful because complex partial seizures are more resistant to treatment than other types of seizures Partial and generalized tonic-clonic ○ First line drugs for partial seizures and generalized tonic-clonic seizures: Carbamazepine and phenytoin → have similar MOA, induces CYP450 and increases metabolism Valproate → different MOA, inhibits CYP450 Mechanisms ○ Both block voltage-sensitive sodium channels in neuronal cell membranes ○ Additional MOA (e.g., blocks adenosine receptors; blocks norepi reuptake like TCAs) are present but their contribution to its antiepileptic effects are unknown. ○ TCA-like activity probably responsible for mood elevating effects Interactions ○ Potent inducer of CYP450 enzymes that metabolize many drugs ○ Even accelerates its own metabolism and that other drugs like lamotrigine, phenytoin, topiramate and valproate → decreased serum levels and efficacy of these drugs ○ Increases lithium toxicity Indications ○ Used to treat partial seizures and generalized tonic-clonic seizures ○ Drug of choice for treating trigeminal neuralgia ○ Also effective as an alternative to lithium for treatment of bipolar disorder Phenytoin, fosphenytoin ○ Phenytoin (dilantin) ○ Fosphenytoin (cerebyx) Phenytoin is a hydantoin derivative that poorly soluble in water Different pharmaceutical formulations may have different bioavailability (so avoid switching and monitor labs if you musT) Pharmacokinetics ○ Phenytoin is converted to an inactive hydroxylated metabolite by CYP450 enzymes ○ Exhibits genetic polymorphism → considerable patient variation in plasma drug conc produced by a given dose (so monitor serum levels) Mechanisms and adverse effects ○ Blocks voltage-sensitive sodium channels like carbamazepine ○ Interferes with folate metabolism which can cause megaloblastic anemia and birth defects (e.g., fetal hydantoin syndrome) ○ Impairs cerebellar function → ataxia, diplopia, nystagmus and slurred speech ○ Interferes with vitamin D metabolism and decreases Ca absorption from gut → osteomalacia  ○ Adversely affects collagen metabolism and contributes to gingival hyperplasia ○ Also can cause hirsutism ○ Phenytoin is avoiding in children Valproate ○ Valproic acid (Depakene) ○ Divalproex sodium (depakote) Many formulations available, including free acid form (depakene) and 1:1 mixture of valproic acid and valproate sodium (depakote) Divalproex sodium is more slowly absorbed, less GI and CNS adverse events Mechanisms ○ Valproate has several mechanisms of action that contribute to its broad spectrum of antiepileptic effects Inhibits voltage- sensitive sodium channels and T type calcium channels Increases GABA synthesis and decreases GABA degradation Decreased glutamate synthesis Indications ○ Valproate has the broadest spectrum of activity compared to all other antiepileptics Effective in the treatment of partial seizures and all forms of generalized seizures and can be given in combo with other drugs when a single drug does not adequately control seizures Also used as an alternative to lithium to treat mania in bipolar disorder for the ppx of migraines Phenobarbital, primidone ○ Phenobarbital (luminal) ○ Primidone (Mysoline) Both are second line drugs for partial seizures and generalized tonic-clonic seizures Phenobarbital is the oldest of the currently used antiepileptics Mechanisms and usage ○ Phenobarbital enhances GABA-mediated chloride flux that causes membrane hyperpolarization ○ Primidone does the same (via phenobarbital metabolite) plus blocks sodium channels and prevents depolarization ○ Both can cause ataxia, dizziness, drowsiness, and cognitive impairment ○ Can cause respiratory distress in excessive dosage Felbamate ○ Fembamate (Felbatol)  Was a promising new drug for treating partial seizures until cases of fatal aplastic anemia and acute hepatic failure were reported Since 1994, limited to treatment of partial seizures refractory to other drugs Unique MOA that blocks glycine coactivation of NDMA receptors Gabapentin ○ Gabapentin (neurontin) GABA analog that works by increasing release of GABA from central neurons Relatively short-half life, so must be given several times a day Effective when used in combo with other drugs to treat all forms of partial seizures (for many patients, may even be effective alone) Levetiracetam, brivaracetam ○ Levetiracetam (keppra) ○ Brivaracetam (briviact) Mechanisms unclear but does bind to synaptic vesicle protein which reduces vesicular packaging of GABA and impedes neurotransmission across synapses Levetiracetam effective as adjunct in treating partial seizures in children Brivaractam has the same indication Ethosuximide ○ Ethosuximide (Zarontin) Most effective and least toxic of several succinimide derivatives used to treat epilepsy for >50 years Well absorbed from gut, widely distributed and metabolized to inactive metabolites excreted in urine Long half life of 30 horus in kids and 55 hours in adults Management ○ Drugs of choice are diazepam (Valium®) or lorazepam (Ativan®), both benzodiazepines, via slow IV injection q10-15 min until seizures are controlled or until max dose ○ After benzodiazepines are used, phenytoin (Dilantin®) or fosphenytoin (Cerebyx®) is often given IV to provide a longer duration of control ○ Large doses of phenobarbital may be used if either fail to control seizures ○ On occasion, general anesthesia is sometimes required to control seizures First line drugs ○ For partial seizures and generalized tonic-clonic seizures, carbamazepine, phenytoin, and valproate are first line drugs while phenobarbital and primidone are second-line drugs ○ For generalized absence seizures, ethosuximide is the first choice in treating children while valproate is more effective for adults with absence seizures ○ For generalized myoclonic and atonic seizures,valproate is the drug of choice