Antiepileptic Drugs PDF

9/27/2023 Dr. Maysaa Banay 1 Epilepsy is the sudden, excessive, and synchronous discharge of cerebral neurons. This abnormal electrical activity may result in...

9/27/2023 Dr. Maysaa Banay 1 Epilepsy is the sudden, excessive, and synchronous discharge of cerebral neurons. This abnormal electrical activity may result in loss of consciousness, abnormal movements, atypical or odd behavior, and distorted perceptions that are of limited duration but recur if untreated. 2 1  9/27/2023 Etiology of Seizures 1. Epilepsy can be due to an underlying genetic, structural, or metabolic cause or an unknown etiology. 2. Illicit drug use, tumor, head injury, hypoglycemia, meningeal infection, and the rapid withdrawal of alcohol from an alcoholic, can precipitate seizures. 3. In cases when the source of a seizure can be determined and corrected, medication may not be necessary. For example, a seizure that is caused by a drug reaction or fever is not epilepsy and does not require chronic therapy. 3 Classification of epilepsy 4 2  9/27/2023 1. Focal seizures involve only a portion of one hemisphere of the brain. Patients may lose consciousness or awareness. 2. Generalized: include abnormal electrical discharges throughout both hemispheres of the brain. May be convulsive or nonconvulsive, and the patient usually has an immediate loss of consciousness. 1. Tonic–clonic: loss of consciousness, followed by tonic (continuous contraction) and clonic (rapid contraction and relaxation) phases. 2. Absence: a brief, abrupt loss of consciousness. occurs in patients at 3 to 5 years of age and lasts until puberty. The patient exhibits rapid eye blinking lasts for 3 to 5 seconds. 3. Myoclonic: muscle contractions that may recur for several minutes. 4. Clonic: short episodes of muscle contractions that resemble myoclonic seizures. But consciousness is more impaired with clonic seizures. 5. Tonic: increased tone in the extension muscles, less than 60 seconds 6. Atonic sudden loss of muscle tone. 5 Mechanism of action of antiseizure 1. Blocking voltage-gated channels (Na + or Ca 2+ ), 2. Enhancing inhibitory γ-aminobutyric acid (GABA)ergic impulses and interfering with excitatory glutamate transmission. 3. Some antiseizure have multiple targets within CNS, and the mechanism of action for some agents is poorly defined. Note: Antiseizure medications suppress seizures but do not “cure” or “prevent” epilepsy. 6 3  9/27/2023 Therapeutic indications for the antiseizure agents. 7 8 4  9/27/2023 GABA 9 Benzodiazepines Benzodiazepines bind to GABA inhibitory receptors to reduce the firing rate. Reserved for emergency or acute seizure treatment due to tolerance. Clonazepam and clobazam may be prescribed as adjunctive therapy Diazepam is available for rectal administration to avoid generalized tonic–clonic seizures when oral administration is not possible. 10 5  9/27/2023 Phenobarbital and primidone Enhancement of the inhibitory effects of GABA-mediated neurons Primidone is metabolized to phenobarbital (major) and phenylethylmalonamide, both with anticonvulsant activity. Phenobarbital is used primarily in the treatment of status epilepticus when other agents fail 11 Gabapentin Is an analog of GABA. However, it does not act at GABA receptors, enhance GABA actions or convert to GABA. Binds to voltage-gated calcium channels It is approved as adjunct therapy for focal seizures and treatment of postherpetic neuralgia and diabetic neuropathy. Gabapentin does not bind to plasma proteins and is excreted unchanged through the kidneys…Reduced dosing is required in renal disease. Gabapentin is well tolerated by the elderly population with focal seizures due to its relatively mild adverse effects and few drug interactions. So it a good choice for the older patient 12 6  9/27/2023 Vigabatrin An irreversible inhibitor of GABA-T. GABA-T is the enzyme responsible for metabolism of GABA. Associated with visual field loss. 13 Pregabalin Binds to voltage-gated calcium channels in the CNS, inhibiting excitatory neurotransmitter release. Effects on focal-onset seizures, diabetic peripheral neuropathy, postherpetic neuralgia, and fibromyalgia. Few drug interactions. Dosage adjustment is needed in renal dysfunction 14 7  9/27/2023 Na or Ca channels 15 Carbamazepine Blocks sodium channels, inhibiting the generation of repetitive action potentials in the epileptic focus and preventing spread. Treatment of focal seizures, generalized tonic–clonic seizures, trigeminal neuralgia, and bipolar disorder. Carbamazepine is an inducer of the CYP enzymes. It induces its own metabolism, resulting in lower total carbamazepine blood concentrations at higher doses. Hyponatremia especially the elderly, may necessitate a change in medication. Carbamazepine should not be prescribed for patients with absence seizures. 16 8  9/27/2023 Oxcarbazepine Is a prodrug that is rapidly reduced to the 10-monohydroxy (MHD) metabolite responsible for its anticonvulsant activity. MHD blocks sodium channels and modulate calcium channels. Use in adults and children with focal seizures. Oxcarbazepine is a less potent inducer of CYP3A4 than carbamazepine. The adverse effect of hyponatremia limits its use in the elderly. 17 Phenytoin and fosphenytoin Blocks voltage-gated sodium channels. Treatment of focal and generalized tonic–clonic seizures and in the treatment of status epilepticus. Phenytoin induces CYP2C and CYP3A families Phenytoin exhibits saturable enzyme metabolism resulting in nonlinear pharmacokinetic properties (small increases in the daily dose can produce large increases in plasma concentration, resulting in drug-induced toxicity). Depression of the CNS causing nystagmus and ataxia. The elderly are highly susceptible to this effect. Gingival hyperplasia may cause the gums to grow over the teeth (Figure). Long-term use may lead to peripheral neuropathies and osteoporosis. Fosphyenytoin is a water soluble phenytoin prodrug, given I.V 18 9  9/27/2023 Gingival hyperplasia in patient treated with phenytoin 19 Lacosamide Affects voltage-gated sodium channels, resulting in stabilization of neuronal membranes and inhibition of repetitive neuronal firing. Lacosamide is approved for adjunctive treatment of focal seizures. 20 10  9/27/2023 Lamotrigine Blocks sodium channels and voltage–dependent calcium channels. Lamotrigine is effective in focal, generalized, absence seizures. also treat bipolar disorder. Lamotrigine dosages should be reduced when adding valproate to therapy due to risk of rash, which may progress to a serious, life- threatening reaction. 21 Topiramate It blocks voltage-dependent sodium channels, reduces voltage calcium currents (L type), is a carbonic anhydrase inhibitor, and may act at glutamate (NMDA) sites. Use in focal and primary generalized epilepsy, prevention of migraine. It inhibits CYP2C19 and coadministration with phenytoin and carbamazepine may reduce serum concentrations of topiramate. Adverse effects include somnolence, weight loss, and paresthesias. Renal stones, glaucoma, oligohidrosis (decreased sweating), and hyperthermia. 22 11  9/27/2023 Ethosuximide Reduces propagation of abnormal electrical activity in the brain, most likely by inhibiting T-type calcium channels. Effective in treating absence seizures. L-type: long lasting T-type: transient 23 Others 24 12  9/27/2023 Brivaracetam For treatment of focal-onset seizures in adults. It demonstrates high and selective affinity for a synaptic vesicle protein (SV2A); however, the exact mechanism is unknown. Comedication with strong CYP-inducing medications may lead to lower plasma concentrations. Brivaracetam is a moderate inhibitor of epoxide hydrolase (enzyme detoxified metabolite), resulting in increased levels of the active metabolite of carbamazepine when the drugs are coadministered. 25 Levetiracetam For adjunct therapy of focal-onset, myoclonic, and primary generalized tonic–clonic seizures in adults and children. It demonstrates high affinity for a synaptic vesicle protein (SV2A). The drug is well absorbed after oral administration and is excreted in urine mostly unchanged, resulting in few to no drug interactions. Levetiracetam can cause mood alterations that may require a dose reduction or a change of medication. 26 13  9/27/2023 Valproic acid and divalproex Sodium channel blockade, blockade of GABA transaminase (GABA-T), and action at the T-type calcium channels. These varied mechanisms provide a broad spectrum of activity against seizures. Treatment of focal and primary generalized epilepsies. Divalproex sodium is a combination of sodium valproate and valproic acid that is converted to valproate ion in the gastrointestinal tract. It was developed to improve gastrointestinal tolerance of valproic acid. Valproate inhibits metabolism of the CYP2C9 Rare hepatotoxicity may cause a rise in liver enzymes Use in children under age 2 and women should be avoided if possible (risk of birth defect and PCO in girls) 27 Felbamate has a broad spectrum of anticonvulsant action with multiple mechanisms including: ❑ the blocking of voltage-dependent sodium channels ❑ competing with the glycine-binding site on the N- methyl-D-aspartate (NMDA) glutamate receptor ❑ blocking of calcium channels ❑ potentiating GABA action It is reserved for use in refractory epilepsies!! Why? because of the risk of aplastic anemia and hepatic failure. 28 14  9/27/2023 Status Epilepticus In status epilepticus, two or more seizures occur without recovery of full consciousness in between episodes. These may be focal or generalized, convulsive or nonconvulsive. Status epilepticus is life threatening and requires emergency treatment usually consisting of parenteral administration of a fast-acting medication such as a benzodiazepine, followed by a slower- acting medication such as phenytoin, fosphenytoin, divalproex, or levetiracetam. 29 Adverse effects of antiseizure medications 30 15