Antiseizure Medications PDF

Antiseizure Medications Type of Seizure S/Sx Tx (First Line) Jerking may begin in one area of the body, arm, leg, face, then move in steps (“Jacksonian March”...

Antiseizure Medications Type of Seizure S/Sx Tx (First Line) Jerking may begin in one area of the body, arm, leg, face, then move in steps (“Jacksonian March”) Focal Aware Seizures Patient stays awake and aware (NO IMPAIRMENT of consciousness) (aka Simple Partial Sometimes spreads to convulsive seizure Seizures) Partial sensory seizures: Patient experiences distorted environment → May see/hear things not there (SIMPLE HALLUCINATIONs) , unexplained fear sadness, anger, joy May have nausea, experience odd smells, “funny” feeling in carbamazepine (Tegretol®) stomach oxcarbazepine (Trileptal®) lamotrigine (Lamictal®) lacosamide (Vimpat®) Starts w/blank stare then by chewing, random activity levetiracetam Keppra®) Focal Seizures with Patient unaware of surroundings, dazed & mumbling phenytoin (Dilantin®) Impaired Awareness IMPAIRMENT of consciousnes) Unresponsive, w/ actions that are clumsy, not directed (aka Complex Partial Same set of actions occurs w/ ea. seizure after established Seizures or Temporal pattern lobe or Patient may also experience structured hallucinations Psychomotor Epilepsy Sudden cry, fall, rigidity, followed by rigidity and then synchronous muscle jerking, shallow/ temporarily suspended breathing, cyanosis, loss of bladder control LOSS of consciousness valproic acid (Depakote®) Generalized levetiracetam (Keppra®) Lasts a few minutes, then normal breathing begins again Tonic-Clonic lamotrigine (Lamictal®) Possible confusion, fatigue, followed by return to (Grand Mal) consciousness Tonic = sustained tonic extension (stiffening) of muscles, contraction of the diaphragm, arched back opisthotonus) Clonic = synchronous jerking Patient has blank stare for a few seconds Most common in children (50% will outgrow) May be accompanied by rapid blinking, chewing ethosuximide (Zarontin®) Absence valproic acid (Depakote®) movements (Petit Mal) Awareness returns after seizure ends (Brief ImPAIRMENT or LOSS of consciousness) May result in learning difficulties if not treated Child or adult suddenly collapses to floor valproic acid (Depakote®) After 10 seconds to 1 minute, recovers, regains levetiracetam (Keppra®) Atonic Seizures (Drop consciousness lamotrigine(Lamictal®) Attacks) *Very Difficult to treat* very difficult to treat Patient can stand and walk again Sudden brief, massive muscle jerks (Shocks → Jolts) valproic acid (Depakote®) Involve whole body or parts of body lamotrigine (Lamictal®) – used in Myoclonic Seizures May cause patient to spill what they are holding or fall off children chair adjunctive: levetiracetam Clusters of quick, sudden movements (very much ACTH, glucocorticosteroids, resembles a series of “startles” Vigabatrin Start between 3 mo → 2 years old Infantile Spasms (West If child sitting up, head will fall forward arms flex forward very difficult to treat especially if Syndrome) If lying down, knees drawn up, arms and head flexed mental retardation or brain damage is forward (jackknife) present Page 1  Mechanisms for Common Antiepileptic Drugs GABA-T Enzyme → INHIBITED by: vigabatrin, weakly by valproic acid (or its metabolite?) GABA reuptake → INHIBITED by: tiagabine Presynaptic Enhancement of glutamic acid decarboxylase → valproic acid, gabapentin Postsynaptic GABA-A Receptor → POTENTIATED by: topiramate, felbamate, benzodiazepines, barbiturates, Structures clobazam VOLTAGE-GATED Na+ CHANNEL (fast) → INHIBITED by: phenytoin, felbamate, carbamazepine, valproate oxcarbazepine, lamotrigine, topiramate, zonisamide (PFC. R.C. Pre and postsynaptic – VOLTZ) repetitive firing Slow Na+ channel → INHIBITED by lacosamide inhibited T-TYPE Ca++ CHANNEL → INHIBITED by: zonisamide, ethosuximide α2δ subunits of voltage-gated Ca2+ channels (N-type) INHIBITED by: gabapentin, pregabalin Postsynaptic GLUTAMATE AMPA Receptor → INHIBITED by: topiramate, phenobarbital, peramparel Structures GLUTAMATE NMDA Receptor → INHIBITED by felbamate Page 2  Oldest, non-sedative anti-epileptic introduced in 1938 1st/2nd line treatment for all focal and tonic-clonic seizures; acute use (IV) as an adjunct to the benzodiazepine used in status epilepticus (prevents return of seizure) → fosphenytoin used more often Do not use in Absence Seizures → worsens condition Kinetics: Michaelis-Menten o Elimination dose-dependent: Phenytoin o Low doses → 1st-order (Dilantin®) o Higher doses → 0-order o Patients loaded at minimum therapeutic dose and titrated to CSS o Typically increased at 25-30 mg at 5-7 day intervals Pharmacology o MOA → Blockade of inactive state of voltage-gated Na+ channels → inhibits repetitive firing of neurons o Does not produce CNS depression at normal doses o Selectively binds to inactivated Na+ channel keeping it in the inactivated state and preventing the channel from returning to resting state (prolongs duration of inactive state by milliseconds) → use-dependent action o High frequency repetitive depolarization increases the proportion of Na+ channels in the inactivated state and b/c these are susceptible to blockade by phenytoin, the Na+ current is progressively reduced until it is eventually insufficient to evoke an action potential o Neuronal transmission at normal frequencies is relatively unaffected by phenytoin b/c a much smaller proportion of the Na+ channels are in the inactivated state o Overall effect is to decrease number of channel openings without affecting channel conductance or opening time Dose-related ADRs: (SAND): o Sedation, Ataxia, Nystagmus, Diplopia → SAND Phenytoin o Non-dose related ADRs: (cont’d) o Classical S/Sx ▪ Acne ▪ Coarsening of facial features, ▪ Gingival hyperplasia (from altered collagen metabolism; PHENYTOIN secreted in saliva) ▪ Hirsutism ▪ RASH → potential for Steven-Johnson’s Syndrome – Asians with HLA B*1502 may have an increased risk ▪ D/C phenytoin IMMEDIATELY if rash develops!!! o Purple Glove Syndrome → if administered IV ▪ Extravasation of phenytoin leads to necrotic chemical phlebitis ▪ Use Fosphenytoin instead to prevent Page 3  o CYP450 Inducer – (CYP’s 3A4, 2C9, 2C19)) o Many drug interactions (Ex: valproic acid displaces phenytoin from albumin and inhibits its metabolism) o Osteomalacia - PHT directly interferes w/ Ca2+ absorption from the GI tract and induces CYP24 that coverts 25 hydroxy vitamin D into inactive calcitriol acid. o GI disturbances - N/V/epigastric pain/anorexia Phenytoin (cont’d) o Endocrine effects - hyperglycemia, glycosuria (inhibits insulin release) o PHT Induces enzymes that Increase Vit. K catabolism - hemorrhage in infants at delivery o Peripheral neuropathy o Fetal hydantoin syndrome – oral cleft palate o Moderate intellectual impairment Rare ADR’s: o Blood dyscresias (megaloblastic anemia→ PHT interferes with Folate absorption from GI tract ) o Systemic Lupus Erythematosus o Fatal Hepatic Necrosis o An injectable prodrug phosphate ester of phenytoin (water soluble Fosphenytoin vehicle) (Cerebyx®) o Phosphatases cleave off phosphate group in vivo to produce active drug (phenytoin) o DOES NOT appear to produce purple glove syndrome Page 4  1st line treatment for focal onset and tonic-clonic seizures and secondarily-generalized focal onset seizures. Also a DOC to treat trigeminal neuralgia o TCA derivative also used in Bipolar Disorder for patients nonresponsive to lithium therapy o Do not use in Absence or Myoclonic Seizures → worsens Condition Kinetics: Rate of absorption is variable Carbamazepine (Tegretol®) o MOA → Inhibits voltage gated Na+ channels therefore, impairing sustained firing of neurons. Same MOA as phenytoin ADR’s Similar to phenytoin – diplopia (double vision), ataxia, nystagmus Mild leukopenia is common (10%) Stimulation of ADH release →causes water retention leading to dilutional hyponatremia Powerful Inducer of its own metabolism So dose of drug may need to be increased during the first month → Induction effect typically is maximal at 30 days Inducer of CYP’s 3A4, 2C9, 2C19, 1A2 (broad spectrum inducer) Hypersensitivity reactions (rash - Steven-Johnsons Syndrome → risk increased 10x in Asians with HLA-B*1502→test for this allele Black Box Warning: Aplastic anemia (1 in 200,000) & Agranulocytosis → risk 5-8 x greater than that of general public but the overall risk in the untreated general population is quite low Hepatic effects (hepatitis, hepatocellular jaundice) Initial drowsiness → tolerance develops → essentially non-sedating Less cognitive impairment than phenytoin, but still considered moderate impairment o Behavioral impairment in children; confusion & agitation in elderly Carcinogenic and teratogenic (due to epoxide metabolite?) in mice and rats o Pregnancy category D – cleft palate Page 5  Many drug interactions because of potent broad-spectrum CYP450 induction Broad-spectrum CYP450 inducers = PPP +C o Phenytoin o Phenobarbital o Primidone o Carbamazepine Used for treatment of focal onset seizures and secondarily generalized focal seizures Pharmacology o Prodrug → monohydroxy metabolite (MHD) is the active form Chemically similar to carbamazepine Oxcarbazepine MOA → blockade of voltage-sensitive Na+ channels by its active metabolite, (Trileptal®) MHD Lower incidence of ADR’s o Dilutional hyponatremia more common than that associated with carbamazepine → increases ADH release o Less CYP450 induction and less drug interactions than carbamazepine) o Neuropsychological assessment reveal NO measurable cognitive impairment in first year Metabolized by CYP2C19 and CYP3A4 (MHD) ADRs: somnolence, dizziness, diplopia, ataxia, N/V Cross-reactivity with carbamazepine hypersensitivity occurs in 20-30% of patients The S-stereoisomer of the active metabolite of oxcarbazepine Indications: Monotherapy of focal onset seizures, Adjunctive treatment of focal seizures MOA: same as carbamazepine and oxcarbazepine ADR’s: Eslicarbazepine Common: Nausea/Vomiting, Somnolence, Dizziness, acetate Headache, Diplopia/Blurred Vision, Ataxia, Tremor (Aptiom®) Serious SE’s: - Psychiatric: Suicidal thoughts - Ophthalmologic: Visual impairment - Metabolic: Hyponatremia - Hematologic Eosinophilia - Hepatic: Increased transaminases, Increased bilirubin - Immune: Anaphylaxis, Drug hypersensitivity syndrome/DRESS, Stevens-Johnson syndrome - Other: Angioedema Page 6  Adjunct treatment of Lennox Gastaut Syndrome (LGS) in patients at least 4 years of age Rufinamide MOA: Prolongs the inactive state of Na+ channels. However, this action (Banzal®) cannot explain the unique anti-seizure spectrum of rufinamide. Metabolized by carboxylesterase to inactive metabolites Weak inducer of CYP3A4 (may reduce effectiveness of contraceptives) Take with food to increase bioavailability ADR’s: o Somnolence, Headache, Abnormal vision, Nausea o Can shorten the Q-T interval in some patients (avoid other drugs that shorten Q-T interval such as digoxin or magnesium) Approved as adjunct treatment of focal onset seizures Enhances slow inactivation of voltage-gated Na+ channels Fast inactivation (millisecond time scale) is thought to contribute to action Lacosamide potential termination & regulation of the refractory period; fast inactivation is (Vimpat®) enhanced by PFC R.C. VOLTZ anti-epileptic drugs Slow inactivation (occurs over hundreds of milliseconds or more) and is thought to contribute to overall membrane excitability by increasing action potential thresholds by making the inactivation occur at less depolarized membrane potentials. Slow inactivation occurs during sustained membrane depolarization or prolonged bursts of neuronal discharge. This means that lacosamide only affects neurons which are depolarized or active for long periods of time, typical of neurons at an epileptic focus Binds to the collapsing-response mediator protein, CRMP-2, thereby blocking effect of neurotropic factors such as BDNF and NT5 on axonal and dendritic growth: prevents “abnormal” synaptic connections ADRs: ataxia, dizziness, headache, nausea/GI upset, depression, memory impairment Prolongs PR interval →caution in patients with AV block or cardiac disease Page 7  Exact MOA is unknown, but the following are believed to be responsible: (1) It enhances fast and slow sodium channel inactivation, inhibiting Cenobamate persistent sodium channel flux. (Xcorpi®) (2) Acts as a positive allosteric modulator of the GABA-A chloride channel Indicated for oral treatment of focal onset seizures Common ADRs: Dose-related somnolence, dizziness, headache, fatigue, and diplopia. Psychiatric ADR’s (similar to most AE’s): can increase the risk of suicidal thoughts or behavior; patients taking the drug should be monitored for new or worsening depression, suicidal thoughts or behavior, and unusual changes in mood or behavior. Can cause euphoria and feelings of drunkenness, particularly with high doses. Physical dependence may develop; withdrawal symptoms (insomnia, decreased appetite, depressed mood, tremor, and amnesia) may occur after stopping the drug. Schedule V controlled substance Inducer of CYP2B6, 2C8, and 3A4 and may reduce serum concentrations of drugs that are metabolized by these isozymes, including other ASMs and oral contraceptives. Moderate inhibitor of CYP2C19 (may increase plasma concentrations of 2C19 substrates. Page 8  Was once DOC for neonatal and febrile seizure seizures; now 3rd line agent for tonic-clonic seizures Diazepam (rectal) now preferred over phenobarbital for febrile seizure MOA → 1. Enhances GABAergic neurotransmission (at chloride ionophore complex = GABAA receptor), and: 2. Blocks postsynaptic excitatory AMPA (glutamate) receptors ▪ AMPA receptors normally mediate rapid depolarization of neurons when stimulated Phenobarbital ▪ Phenobarbital. selectively suppresses abnormal neurons ▪ At levels supra therapeutic doses, blocks Ca2+ influx into Oldest of the presynaptic terminals and thereby decreases NT release antiepileptic ADR’s o More sedation than phenytoin or carbamazepine drugs - since 1900’s o Paradoxical excitement and hyperactivity; behavioral changes in children including irritability, depression o Considerable cognitive impairment - loss of concentration, depression → one of the WORST! o Powerful CYP450 Inducer (less induction of its own metabolism) o Vit. K deficiency → infant hemorrhage (when mother treated) → phenytoin also has this effect if mother was treated during pregnancy o Older ASM’s (clonazepam, phenobarbital, primidone, phenytoin, fosphenytoin, carbamazepine, valproic acid) have known teratogenic effects. Newer ASM’s: less?? o Tolerance to anticonvulsive effects may occur Kinetics: Active by itself but also metabolized to Phenobarbital by oxidation and to PEMA by scission of heterocyclic ring (both are active Primidone metabolites). (Mysoline®) Also used to treat essential tremor ADR o Similar to Phenobarbital, but drowsiness occurs earlier o Said to produce LESS paradoxical hyperactivity than phenobarbital but behavioral disturbances are similar since phenobarbital is one of the metabolites o CYP450 Inducer o 3rd line agent Page 9  Exhibited great promise for the treatment of focal seizures with impaired awareness, and refractory seizures (e.g., Lennox Gastaut) (1) Major action may be blockade of the (glutaminergic) NMDA receptor - associated ion channel via blockade of the glycine binding site on the Felbamate channel (Felbatol®) (2) Also blocks voltage-gated Na+ -channel similar to phenytoin (3) Enhances GABA actions at the chloride ionophore complex (GABA-A) 3rd line treatment for focal onset seizures 3rd line treatment for tonic-clonic seizures Adjunct in Lennox-Gastaut syndrome Originally ‘wonder-drug’ of antiepileptic drug: Pulled from market after cases (1:3000-5000) of: ▪ Aplastic anemia → must monitor blood counts and serum iron ▪ Severe hepatitis → Liver failure - must monitor LFT’s o Reinstated, but only if patient signs informed consent o Others SE’s: Weight loss, N/V, insomnia; Inhibits CYP2C19 In the MOST FAVORABLE category with respect to cognitive effects 1st line treatment for focal onset seizures & as adjunct for tonic-clonic seizures in adults Alternative agent for absence seizures in children (but little, if any, block of T-type calcium channels): valproic acid and ethosuximide are superior drugs Lamotrigine Has been used to treat myoclonic seizures in children, but exacerbation (Lamictal®) has been reported→(valproic acid is DOC) Adjunct in Lennox-Gastaut; also useful in atonic seizures Useful in the treatment of bipolar depression Chemistry : Originally developed as an antifolate compound Pharmacology: o Prolongs inactive state of voltage-gated Na+ channels o Inhibits presynaptic release of excitatory glutamate o Blocks high voltage Ca2+ channels of P/Q, or R type ADR: Black box warning: Increased incidence of skin rash –up to 10% of patients- (including severe rashes)→ Can progress to SJS/TEN : Resolves after D/C (must start at low doses and titrate up) Higher frequency in children 1st four weeks of treatment Little cognitive impairment – in the “MOST FAVORABLE” profile category Black box warning for aseptic meningitis Metabolized by direct conjugation by UGT Major interaction with valproic acid since VA inhibits UGT→can increase lamotrigine levels greater than 2-fold → patient at increased risk for SJS Recent reports of serious cardiotoxicity Page 10  Has been jokingly referred to as ‘Dopamax’ b/c of its impairment of cognitive functioning (“doped up”) Topiramate Focal onset seizures in adults; primary generalized tonic-clonic seizures (Topamax®) adjunct for Lennox-Gastaut for those ≥ 2 years; also efficacy in atonic seizures in children ?? has been used as monotherapy for many seizure disorders also FDA-approved for migraine prophylaxis Unusual chemical structure: a sulfamate substituted sugar Weak inducer of CYP3A4 (caution contraceptives) and a weak inhibitor of CYP2C19) Minimal metabolism (70% of drug eliminated unchanged in the urine) Pharmacology – Primarily eliminated unchanged in urine, but enzyme inducers (carbamazepine or phenytoin) can lead to hydroxylation and conjugation of topiramate Combination of activities account for its effects (similar to Felbamate) (1) Enhancement of GABA-A receptor activity (at site other than BZD or BARB binding site) (2) Antagonist at the AMPA subtype of glutamate receptor (3) Prolongs inactive state of voltage-gated Na+ channels (4) Mild carbonic anhydrase inhibitor potential for kidney stones due to metabolic acidosis. This mild metabolic acidosis is due to the ability of carbonic anhydrase inhibitors to prevent the reabsorption of bicarbonate ion (HCO3-) from the proximal renal tubule. Urine becomes more alkaline. Most common ADRS are drowsiness, dizziness, headache, ataxia Cognitive Impairment – WORST 2nd generation ASM with this ADR. Manifests as: o Speech difficulties, confusion, difficulty in word finding & name recognition, impaired concentration, interference with memory Psychomotor slowing Kidney stones (nephrolithiasis) – due to inhibition of carbonic anhydrase activity which results in alkalinization of the urine and subsequent increased calcium oxalate formation → hydrate patient ! Flat affect > 70% Taste changes (especially carbonated beverages such as diet sodas) Oligohidrosis (hydrate patient): Avoid high temperatures or prolonged exposure to the sun Paresthesia Weight loss - induction of β-oxidation in liver ? (↓’s FA’s for hepatic TG synthesis) → topiriamte is marketed in a fixed dose combination with phentermine for chronic weight management (Qsymia®) Increased risk of autism/intellectual disability in infants whose mothers used topiramate during pregnancy Page 11  Both agents are approved as ADJUNCT therapy of focal onset seizures in adults and children > 3-4 y.o. A prodrug, gabapentin encarbil (Horizant®) is approved for restless legs syndrome (RLS) Gabapentin is also FDA-approved to treat postherpetic neuralgia A number of off-label uses for Gabapentin had been reported, including bipolar disorder (BPD); diabetic neuropathy; complex regional pain syndrome; attention deficit disorder; trigeminal neuralgia; periodic limb movement disorders (PLMDs) of sleep; premenstrual syndrome, migraine headache; and drug and alcohol withdrawal seizures Pregabalin is FDA-approved for neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, fibromyalgia, and neuropathic pain associated with spinal cord injury. Pregabalin is approved in Europe for treatment of generalized anxiety disorder :Designed as GABA receptor agonists, but neither acts as one Gabapentin Kinetics: (Neurontin®) o Both drugs are excreted renally as intact drug (not metabolized). Pregabalin o NO major drug interactions with other ASM’s (Lyrica®) Pharmacology: o Do not bind to the GABA receptor → gabapentin and pregabalin may increase the activity of glutamic acid decarboxylase (GAD) which increases the synthesis of GABA o May modify the synaptic or non-synaptic release of GABA o An increase in brain GABA concentration is seen with gabapentin o One study found that these agents act to inhibit new synapse formation o Limit Na+ dependent action potentials o Act at a different portion of Na+ channel than other drugs Bind to α2δ subunits of voltage-gated Ca2+ channels → Decreases Ca2+ entry with a predominant effect on presynaptic N-type channels; this decreases the synaptic release of glutamate and provides the anti-seizure effect ADR’s: Dizziness, drowsiness, ataxia, edema, weight gain Pregabalin is Schedule V due to reports of euphoria Serious, life-threatening, and fatal respiratory depression has been reported with the use of gabapentin and pregabalin. Most cases occurred in association with co-administered central nervous system (CNS) depressants, especially opioids, in the setting of underlying respiratory impairment, or in the elderly. Page 12  Restricted use in USA: Monotherapy for infantile seizures!! or add-on therapy for focal onset seizures with impaired awareness Vigabatrin in adults who are refractory to several ASMs (Sabril®) Irreversible inhibitor of GABA-transaminase (GABA-T) o GABA-T = Enzyme that degrades GABA Black box warning: Long-term use associated with concentrically constricted visual fields in up to 1/3 patients. May be irreversible. Patients must undergo visual field testing: o The 30-Hz flicker ERG provides assessment of VGB retinal damage in infants o Visual field impairment occurs in 52% of adults and 34% of children treated with vigabatrin Intramyelinic edema in 20% of children < 3 years old (but no clear clinical correlates of these changes) Can lower serum concentrations of phenytoin by inducing CYP2C9/19 REMS requirement for dispensing ADR’s: Common: Somnolence, Dizziness/Vertigo, Headache, Agitation Serious: - Ophthalmologic: Permanent vision loss - Neurologic: Coma, Seizures - Psychologic: Psychosis, depression, agitation - Respiratory: Respiratory depression - Cardiovascular: Hypotension, bradycardia Inhibits neuronal and glial reuptake of GABA→ Tiagabine resulting prolongation of GABA’s actions decreases (Gabitril®) seizures Cognitive impairment - confusion, difficulty in concentration, abnormal thinking, depression Most common side effects are dizziness, somnolence, and tremor Adjunct for focal onset seizures Page 13  1st line treatment of focal and tonic-clonic seizures; effective as add- on therapy for refractory myoclonic seizures; 2nd line for absence Levetiracetam seizures; may be useful in children with Lennox-Gastaut (Keppra®) Kinetics Major metabolic pathway is hydrolysis : o Amide → Carboxylic acid derivative o Metabolism independent of CYP450 so NO drug interactions MOA: Unique, No effect on usual receptors or ion-channels of other AED’s Binds specifically to the SV2A protein on synaptic vesicles (this protein is involved in exocytosis of NT’s) Inhibits rectifying K+ channels to inhibit repetitive firing of neurons ? ADRs: somnolence, asthenia, dizziness, headache, coordination difficulty, psychiatric symptoms, worsening of depression, anxiety, and PTSD; (irritability and aggression = Keppra rage), SJS has been reported Binds selectively to SV2A to modulate neurotransmitter release (same mechanism of action as levetiracetam) Brivaracetam It is also a partial antagonist of voltage-gated Na+ channels (Briviact®) Has 10-30 fold higher affinity for SV2A than levetiracetam Higher brain permeability and more rapid onset of action than levetiracetam Indication: FDA approved for treatment of partial-onset seizures in patients > 16 years old Like levetiracetam it may be effective against myoclonic and primary generalized seizures ADRs: somnolence & sedation, dizziness, fatigue, N/V Psychiatric ADRs (13%): mainly anxiety and depression, but some cases of psychosis and aggression ( lesser incidence than levetiracetam) Metabolism: inactivated primarily by hydrolysis; some metabolism (hydroxylation) by CYP2C19 Co-administration with rifampin decreases plasma conc. of brivaracetam by 45% Page 14  MOA: Blocks voltage gated Na+ channels and T-Type Ca2+ channels (the latter allows efficacy against absence seizures) → broad spectrum agent FDA- approved as adjunct for focal onset seizures in adults but there is considerable experience worldwide for other seizure types in children: has been used to treat myoclonic, infantile spasms, generalized tonic-clonic, and atypical absence seizures, mixed seizure types of Lennox-Gastaut ADR’s : - Most common side effects are dizziness and somnolence, ataxia, Zonisamide anorexia, confusion, abnormal thinking, nervousness, fatigue (Zonegran®) -Cognitive and psychiatric side effects (including depression, psychosis, and aggression) -Nephrolithiasis (kidney stones) → related to weak carbonic anhydrase inhibition (same side effect is associated with topiramate and acetazolamide) → all 3 are carbonic anhydrase inhibitors -Weight loss, fatigue, somnolence - Rare side effects include: o Oligohidrosis (can’t sweat) in children o Hyperthermia/ Heat stroke in children → avoid high temperature /prolonged exposure to the sun o Contraindicated in patients with sulfonamide hypersensitivity! Metabolized in liver by CYP3A4: concomitant use of drugs that inhibit or induce this isoenzyme may alter zonisamide’s metabolism Page 15  DOC treatment for absence seizures - especially in children (valproic acid is also a DOC for tx of absence seizures) Ethosuximide Pharmacology o Selectively antagonizes T-Type Ca2+ channels in (Zarontin®) thalamic neurons (potent block) ▪ T-type channels – in absence-seziures these channels produce pacemaker current in thalamic neurons which, in turn, produces rhythmic discharge of cortical neurons ADR: 40% patients report gastric distress - pain, N/V avoided by slowly elevating dose Other ADR’s: N/V, drowsiness, ataxia, rash (SJS), lupus-like reaction, hepatotoxicity, blood dyscrasia, DRESS Numerous low incidence adverse effects including acute psychotic reactions and EPS syndromes Page 16  2nd line treatment for absence, atypical absence, myoclonic & atonic Benzodiazepines seizures MOA → same as benzo’s o Allosterically enhances the binding of GABA at the chloride ionophore complex and hence, frequency of Cl_ channel opening Clonazepam One of the more potent and long-T1/2 benzodiazepines (Klonopin®) Metabolism: reduction of the nitro group to the primary amine followed by N-acetylation ADR’s o Sedation o Rapid tolerance to its anti-seizure activity may occur after 1-6 mo) o Paradoxical hyperactivity & behavioral disturbances (in children mostly – aggressiveness, irritability, agitation, hyperkinesis, loss of concentration, euphoria transitioning to dysphoria Often used to treat panic attacks and the anxiety associated with major depression “Less sedating” benzodiazepine analog MOA: Binds to benzodiazepine site of GABA-A receptor to potentiate GABA-ergic neurotransmission Indications: Clobazam – Adjunctive treatment of Lennox Gastaut (Onfi ®) – Off Label: SGE, Adjunctive treatment of focal onset seizure Not labeled for EtOH withdrawal or anxiety ADRs: Common: Somnolence/Sedation, Ataxia, Dysarthria, Cough, Fever, Dependence, Constipation, Drooling, Insomnia Serious: Dermatologic: SJS, TEN Psychiatric: Suicidal behavior/Ideation, Aggressive behavior Typically used to treat tonic-clonic seizures of status epilepticus Not for chronic treatment! Diazepam Given IV for status epilepticus (a medical emergency → (Valium®) hypoxia/neurological defects/mental retardation/coma/death) Highly lipophilic , but brain concentration quickly decreases due to redistribution to adipose tissue (fat) Concomitant IV infusion of diazepam + fosphenytoin (or phenytoin or phenobarbital) prevents return of status epilepticus after diazepam CNS levels decline Problem: CNS concentration of diazepam is reduced quickly due to redistribution from CNS to fat and muscle → seizure may return a DOC for treatment of acute febrile seizures in infants and children (rectal) and administered intermittently (orally) if seizure is prolonged or recurrent Diazepam and midazolam are now available in a nasal spray formulation IV Lorazepam Used more often than diazepam for status epilepticus emergency b/c their & actions are prolonged compared to diazepam due to the fact that they are IV or IM less lipophilic and therefore their actions are not terminated by redistribution Midazolam as quickly as that of diazepam Page 17  1st line treatment for atonic, myoclonic, absences, generalized tonic- clonic; can also be used for focal seizures but less effective than carbamazepine → broad-spectrum agent DOC when absence seizures are co-expressed w/ any other seizure type!! Effective in treatment of bipolar disorder in patients refractory to lithium (often more effective than lithium in patients who are rapid-cyclers or with mixed symptoms) Approved for migraine prophylaxis Serendipitously discovered as anticonvulsant o Originally used as a solvent for other antiepileptics Valproic acid Chemistry: Branched fatty-acid (Depakote®, Kinetics: Metabolized by β-oxidation of side chains Depakene®) MOA – Unknown, but it does: (1) Reduce fast and transient inward Na+ currents acting at a site on voltage-gated Na+ channels different from other ASM’s. This interferes with the mechanism of sustained and prolonged firing. (2) Appears to increase GABA turnover: Is valproic acid or a metabolite the active specie? : o Inhibits GABA-T → raises GABA levels o Stimulates glutamic acid decarboxylase (the enzyme which synthesizes GABA from glutamate) → raises GABA levels o Produces reductions in Ca2+ influx through T-type Ca channels ?? (very weak or not observed in in vitro experiments) ADR’s N/V, GI distress ▪ Less common with enteric-coated version = divalproex sodium DEPAKOTE® o BBW: Severe idiosyncratic hepatotoxicity - Monitor LFT’s - Risk greatest for those 12 years of age MOA: selectively antagonizes glutaminergic AMPA receptors by binding Perampanel to an allosteric site on the AMPA receptor-associated Na+/K+ channel. (Fycompa®) This prevents discharge of neurons ADR’s: Dizziness, somnolence, vertigo, ataxia, anger, irritability, aggression, blurred vision, dysarthria, fatigue, falls in the elderly, and weight gain Boxed warning recommends monitoring patients for serious or life- threating psychiatric and behavioral reactions including homicidal ideation and threats Can be euphoric. Schedule III controlled substance Metabolized (oxidation) by CYP3A4 followed by glucuronidation Elimination 48% feces; 22% urine Indications: Adjunct therapy for seizures associated with Dravet Stiripentol syndrome in patients two years of age and older who are taking clobazam (Diacomit®) Mechanism of action: (1) Allosteric modulator of the gamma-aminobutyric acid A (GABA-A) receptor with direct activating effects. Has a barbiturate-like effect in that it increases the duration of the opening of the chloride channel. Relatively selective for those channels with an α-3 subunit (2) Also inhibits the reuptake of GABA and inhibits GABA metabolism (3) It has been shown to inhibit lactate dehydrogenase, which is an important enzyme involved in the energy metabolism of neurons. Inhibition of this enzyme can make neurons less prone to fire action potentials, likely due to prolonging the open state of ATP-sensitive potassium channels which allows K+ to exit neurons thereby hyperpolarizing them (Note: ATP usually closes ATP-sensitive K+ channels → less ATP produced in you inhibit lactate dehydrogenase) Page 19 Stiripentol A moderate inhibitor of both CYP1A2 and CYP2C19 thereby increasing (cont’d) blood levels of some antiseizure drugs, especially clobazam. ADR’s: somnolence, decreased appetite, agitation, ataxia, weight loss, hypotonia, nausea, tremor, dysarthria, and insomnia Metabolism: CYP2C19 & CYP3A4 (major) ; CYPA12 (minor) Cannabidiol (CBD) is a cannabinoid constituent of the marijuana plant (Cannabis sativa). FDA-approved for the treatment of Dravet Syndrome or in Lennox-Gastaut patients > 2 years of age MOA by which cannabidiol exerts its anticonvulsant effect is unknown Cannabidiol oral Unlike tetrahydrocannabinol (THC), it does not cause intoxication or solution euphoria: (Epidiolex®) →Has a low binding affinity for cannabinoid CB1 and CB2 receptors, which might explain the absence of euphoria. Metabolized by CYP3A4 and 2C19 to an active metabolite or conjugated using certain UGT isoenzymes Peak plasma level in 2.5- hours. Half-life = 55-60 hours. Eliminated in the feces ADR’s: Dose-related somnolence (25%), decreased appetite (22%), diarrhea (20%), and elevated LFT’s (16%). Hepatic transaminase and total bilirubin levels should be monitored before and during treatment. Decreases in hemoglobin and hematocrit levels and increases in serum creatinine levels have also been reported Oral fenfluramine solution is FDA approved for the treatment of Dravet syndrome: a significantly greater proportion of patients who were taking fenfluramine (vs placebo) experienced a clinically meaningful (≥50%) or profound (≥75%) reduction in monthly convulsive seizure frequency. Use: Adjunctive treatment in patients 2-18 years old with Dravet syndrome who do not have an adequate response to their current Fenfluramine antiseizure drug regimen (Fintepla®) MOA: The exact mechanism for its antiseizure effect is unknown: Fenfluramine causes the release of 5-HT by disrupting vesicular storage of the neurotransmitter and reversing serotonin transporter (SERT) function. To a lesser extent, the drug also acts as a NE releasing agent, particularly via its active metabolite norfenfluramine. At high concentrations, norfenfluramine, though not fenfluramine, also acts as a DA releasing agent. While fenfluramine binds only very weakly to the serotonin 5-HT2 receptors, norfenfluramine binds to and activates 5-HT2B and 5- HT2C receptors with high affinity and the 5-HT2A receptor with moderate affinity. Fenfluramine has activity at neuronal sigma-1 receptors that may contribute to its antiseizure effect Black Box warning: valvular heart disease (VHD) and pulmonary arterial hypertension (PAH) → patients must have cardiac monitoring using echocardiograms performed before treatment, every 6 months during treatment, and once 3 to 6 months after treatment is discontinued. Page 20  The most common adverse effects include decreased appetite, fever, fatigue, drowsiness/ sedation & lethargy, and diarrhea; no patient developed valvular heart disease or pulmonary hypertension. Fenfluramine Less common adverse effects were constipation, ataxia, balance (cont’d) disorder, gait disturbance, increased blood pressure; salivary hypersecretion & drooling, upper respiratory tract infection, vomiting; decreased weight, risk of falls, and status epilepticus. Schedule IV: REMS program requirement for prescribers and dispensers Tmax = 4-5 hours Half-life = 20 hours Eliminated in urine (>90%); feces (5%) Metabolism: Primarily CYP1A2, 2B6, 2D6 to norfenfluramine Increased risk of serotonin syndrome with SSRI/SNRI’s, bupropion, SJW dextromethorphan; contraindicated within 14 days of an MAOI Can be used as treatment of many seizure types, but perhaps of practical use only for seizures that occur in women during Acetazolamide menses (catamenial seizures) (Acetazolam®) More commonly used for treatment of glaucoma (inhibits synthesis of bicarbonate needed for aqueous humor formation) & as prophylaxis of altitude sickness (used a few days before person plans to ascend to higher altitudes) Carbonic anhydrase inhibitor → in glial and neuronal cells CA catalyzes hydration of CO2 → carbonic acid CO2 + H2O → H2CO3 → H+ + HCO3- Inhibition of the enzyme CA produces acidemia by inhibiting the reabsorption of HCO3- from the kidney. Acute effects of acid-base disturbances on K+ redistribution have long been known. In general, metabolic acidosis with acidemia causes a net shift of K+ from the intracellular to the extracellular space. This K+ shift in neurons results in hyperpolarization and an increase in seizure threshold of the cells. Rapid tolerance develops → limited effectiveness (not used long term) Valproic acid, topiramate, felbamate, lamotrigine, rufinamide, clobazam and cannabidiol are FDA- approved for treatment of Lennox-Gastaut syndrome Off-label pharmacologic treatment of Dravet syndrome has included valproic acid, clobazam, topiramate, and levetiracetam. The FDA has recently approved cannabidiol oral solution for treatment of seizures associated with Dravet syndrome. Stiripentol in combination with clobazam or fenfluramine is also FDA approved. The FDA requires makers of ALL anti-seizure medications to add a warning about increased risk of suicidal thoughts and behaviors to the products' prescribing information or labeling. The warning is not a "black box" warning, but applies to all antiepileptic medications, including those used to treat psychiatric disorders, migraines, and other conditions, as well as epilepsy Page 21 AED CYP Induction Main Route of CYP CYP UGT UGT UGT Elimination Degradation Inhibition Degradation Induction Inhibition Carbamazepine Oxidation Yes, CYP3A4, No No Yes No 2C9, 1A2 Yes, 3A4, and epoxide hydrolase (metabolite) Clobazam Oxidation Yes, CYP3A4 No No No No No Page 22 AED CYP Induction Main Route of CYP CYP UGT UGT UGT Elimination Degradation Inhibition Degradation Induction Inhibition Clonazepam Reduction/acetylation No No No No No No Eslicarbazepine Glucuronidation No Yes, CYP3A4 No No No acetate Yes, but isoenzymes not identified Ethosuximide Oxidation Yes, CYP3A4 No No No No No Felbamate Yes, CYP CYP3A4* CYP2C19 No No No 3A4, 2E1 Oxidations (>50 %), renal excretion (50 %), renal excretion (>30 No, arylketone %) reductase Phenobarbital Yes, CYP3A4, No Yes No No 2C9, 1A2 Yes, Oxidation/conjugation CYP2C9, (75 %), renal excretion (25 %) 2C19, 2E1 Phenytoin Oxidation Yes, No Yes No CYP2C9 Yes, Yes, CYP2C9, CYP3A4,2C9, 2C19 1A2 Pregabalin Renal excretion No No No No No No Page 25 Rufinamide Yes, CYP3A4 No Yes No No No, carboxyl Hydrolysis, glucuronidation esterases Stiripentol No, carboxyl No Yes, CYP No No No? esterases 1A2, 3A4, 2C19, 2D6 Oxidation, hydroxylation,Omethylation, glucuronidation Tiagabine Oxidation Yes, CYP3A4 No No No No No AED CYP Induction Main Route of CYP CYP UGT UGT UGT Elimination Degradation Inhibition Degradation Induction Inhibition Topiramate Yes, No No No CYP2C19* Yes, Oxidation (20%), renal Yes, but excretion: unchanged isoenzymes CYP3A4* (70 %) not identified (>200 mg/day) Page 26 Valproic Acid Oxidation (>50 %), Yes, 2A6, No Yes, No Yes conjugation (30-40 2C9, 2C19, UGT1A3, 2B6 and (30-40 %) mitochondrial 2B7 oxidases Yes, CYP2C9, CYP3A4?, and epoxide hydrolase Vigabatrin Renal excretion No No No No No No Zonisamide Oxidation, reduction, No No No acetylation (>50 %), renal excretion (30 %) Yes, CYP3A4, and N-acetyl transferase No No * Weak induction or inhibition. 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