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TRAVIS LAFFOON, DNP, APRN, CRNA MINNEAPOLIS SCHOOL OF ANESTHESIA NEURO DRUGS METROPOLITAN STATE UNIVERSITY ANTIEPILEPTICS  ANTIEPILEPTIC DRUGS Epilepsy refers to a group of chronic central nervous system disorders characteriz...

TRAVIS LAFFOON, DNP, APRN, CRNA MINNEAPOLIS SCHOOL OF ANESTHESIA NEURO DRUGS METROPOLITAN STATE UNIVERSITY ANTIEPILEPTICS  ANTIEPILEPTIC DRUGS Epilepsy refers to a group of chronic central nervous system disorders characterized by sudden disturbance of sensory, motor, autonomic, or psychic origin Seizures are caused by transient synchronous discharge of groups of neurons in the brain with symptoms depending on the location of discharge and duration Changes in factors such as blood glucose, electrolyte balance, PaO2, pH, stress, or fatigue may facilitate spread of epileptogenic foci into “normal” areas of the brain that previously inhibited seizure foci spread Status epilepticus is continuous seizure activity or more than one seizure occurring in succession without return to consciousness between  ANTIEPILEPTIC DRUGS Seizures are grossly classified based on two factors: loss of consciousness and regions of the brain affected Simple seizure: no loss of consciousness Complex seizure: altered levels of consciousness Partial seizure: originate from limited neurons in a single hemisphere Generalized seizure: activation of neurons in both hemispheres Seizures are treated with antiepileptics initially and combination therapy may be considered if monotherapy fails Goal is to control seizure activity with minimal medication side effects For seizures refractory to medication, surgical intervention may be required (vagal nerve stimulator, laser ablation, neurosurgical resection, etc.)  PHARMACOKINETICS Antiepileptic drugs typically rely upon liver metabolism and hepatic excretion and therefore may need dosage adjustments based on baseline liver and kidney function Several of the drugs are highly protein bound to albumin and can be displaced or affected by various factors (other highly protein bound drugs or hypoalbuminemia) Many of these agents induced metabolizing enzymes therefore lowering the efficacy of other drugs metabolized by the same factors (oral contraceptives and many anesthetics) Phenytoin is unique in that it exhibits non-linear saturation dose kinetics and therefore routine monitoring for plasma concentration is required 10-20 mcg/mL therapeutic plasma concentration  PHARMACODYNAMICS MOA of these drugs is not completed understood but generally accepted that seizure control is the result of decreased neuronal excitability through alterations in ion currents and/or enhanced inhibition of neurotransmitters Primarily sodium and calcium balance, but sometimes potassium Benzodiazepines (diazepam, lorazepam, and midazolam) provide acute seizure treatment by increasing GABA channel opening Barbiturates increase the duration of GABA channel opening Tiagabine delays the reuptake of GABA, thus prolonging its action Seizure control during pregnancy is important because they can result in significant morbidity and mortality, however, teratogenicity of many of the agents complicate drug management Folate supplementation has been shown to lower the risk of teratogenicity during pregnancy  CARBAMAZEPINE Use: partial and generalized seizure, trigeminal and glossopharyngeal neuralgia Pharmacokinetics: oral only, peak 2-6 hrs, protein binding 80%, half-time 8-24 hours, hepatic metabolism to some active metabolites Notes: Induces its own metabolism and therefore may need a dosage increase 2-4 weeks after starting therapy Also induces metabolism of oral contraceptives, valproic acid, corticosteroids, anticoagulants, and antipsychotics Drugs inhibiting metabolism of carbamazepine: cimetidine, propoxyphene, diltiazem, verapamil, isoniazid, and erythromycin Side effects: most common include sedation, vertigo, diplopia, N/V Rare: aplastic anemia, thrombocytopenia, neutropenia, jaundice, oliguria, hypertension, cardiac dysrhythmia,  ESLICARBAMAZEPINE Use: partial-onset seizures Pharmacokinetics: oral administration, peak 2-4 hrs, 40% protein bound, 90% renal excretion Side effects: most common include N/V, diarrhea, fatigue, dizziness Notes: contraindicated in patients with 2nd and 3rd degree AV block Carbamazepine and phenytoin reduce its plasma concentration through enzyme induction  ETHOSUXIMIDE Use: drug of choice for absence (petit mal) epilepsy without tonic-clonic seizure Pharmacokinetics: oral administration, peak 1-7 hours, 25% excreted unchanged in urine with remainder metabolized by liver, half time 20-60 hours Side effects: N/V, lethargy, dizziness, ataxia, photophobia, hyponatremia, and bone marrow suppression (rare) Notes: Works by decreasing calcium conductance in thalamic nuclei  FELBAMATE Use: intractable epilepsy Pharmacokinetics: mostly excreted unchanged by the kidneys, half life 20 hours, 25% protein binding Major side effects: aplastic anemia, hepatotoxicity Notes: requires monitoring of blood counts and liver function, carbamazepine and phenytoin decrease its plasma concentration, felbamate is a potent inhibitor of P450 enzymes and can slow metabolism of phenytoin, phenobarbital, and valproic acid  GABAPENTIN Use: seizures (limited efficacy), anxiety, panic, and major depression Pharmacokinetics: half life 6 hours, 0% protein binding Side effects: sedation and GI disturbances Notes: analog of GABA but does not bind to GABA receptors, probably works by inhibition of calcium channels  LACOSAMIDE Use: partial onset seizures Pharmacokinetics: peak 2-5 hours, almost 100% bioavailability, 20% plasma protein binding Side effects: N/V, diarrhea, headaches, itching, postural hypotension, dysrhythmias Notes: inhibits voltage gated sodium channels and stabilizes hyperexcitable neurons  LAMOTRIGINE Use: partial onset and generalized seizures Pharmacokinetics: half life 25 hours, 50% protein binding Side effects: Headache, N/V, diplopia, ataxia, tremor, Steven-Johnson’s syndrome (rare) Notes: stabilizes voltage gated sodium channels, phenytoin, phenobarbital, and carbamazepine decrease its half life by 50%, valproic acid increases it half life to 60 hours  LEVETIRACETAM Use: juvenile myoclonic epilepsy, partial and general convulsive seizures, tonic-clonic seizures Pharmacokinetics: no hepatic metabolism and minimal protein binding Side effects: sedation, anxiety, headache Notes: binds to calcium channels and reduces release of neurotransmitters  PERAMPANEL Use: partial onset and generalized tonic-clonic seizures Pharmacokinetics: 95% protein bound, elimination half-life 110 hrs, primarily metabolized by liver and excreted 70% in feces and 30% in urine Side effects: Black box warning for suicide or homicidal thoughts, vertigo, slurred speech, irritability, aggression, fatigue, and euphoria Notes: works by selective noncompetitive antagonism of alpha-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid receptors  PHENOBARBITAL Use: long-acting barbiturate effective against all seizure types except non- convulsive generalized seizures Pharmacokinetics: oral absorption is nearly 100% with peak 12-18 hrs, protein binding 50%, 25% elimination by pH dependent renal excretion and 75% hepatic Side effects: sedation, irritability, hyperactivity, depression, confusion, rash, megaloblastic anemia, osteomalacia, nystagmus, ataxia, abnormal collagen deposits manifesting as Dupuytren’s contracture, congenital malformations when given during pregnancy Notes: postsynaptic potentiation of GABA and inhibition of glutamate thus prolonging duration of chloride channel opening, 2nd line drug due to cognitive and behavioral side effects, induces hepatic enzymes thus speeding metabolism of many lipid soluble drugs  PHENYTOIN Use: partial and generalized seizures Pharmacokinetics: available oral and IV (therapeutic concentration of 10-20 mcg/mL within 20 min), high therapeutic index with minimal sedation, 90% protein bound, 9-40 hr half life, 98% metabolism by the liver, first order elimination at plasma concentrations 10 mcg/mL Side effects: nystagmus, ataxia, diplopia, vertigo, peripheral neuropathy, gingival hyperplasia, acne, hirsutism, fetal hydantoin syndrome if given during pregnancy, rash, hyperglycemia and glycosuria from inhibition of insulin secretion, megaloblastic anemia, hepatic toxicity, Notes: regulates sodium and calcium transport thus decreasing neuronal excitability, precipitates in solutions with pH