Newer Anticonvulsants: Targets and Toxicity. Laura Tormoehlen, MD Neurology and EM-Toxicology
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1 Newer Anticonvulsants: Targets and Toxicity Laura Tormoehlen, MD Neurology and EM-Toxicology
2 Disclosures No financial disclosures
3 DEFINITIONS
4 Objectives/Outline Mechanism of Action Specific Indications Toxicity Adverse Effects
5 LACOSAMIDE
6 Lacosamide Trade Names: Vimpat Dosage Forms: Oral, Intravenous Mechanism of Action: Functionalized Amino Acid, decreases hyperexcitability via: Enhancing slow inactivation of voltage-gated sodium channels CRMP-2 binding Indication: Partial seizure, monotherapy Partial seizure, adjunct
7 Lacosamide : Targets Beyreuther BK, et al. Lacosamide: A Review of Preclinical Properties. CNS Drug Reviews 2001: 13(1): 21-42
8 Lacosamide : Toxicity Cardiac Arrest 1 Fatal (Malissin 2013, PMID ) Ingestion of 7 grams of lacosamide Co-ingestion with lamotrigine, phenobarbital, and carbamazepine, plus Initial rhythm asystole, resuscitated, followed by shock and multi-organ failure 1 Survival (Chua-Tuan 2015, PMID ) Ingestion of 4.5 grams of lacosamide Co-ingestion of cyclobenzaprine and levetiracetam Initial rhythm pulseless ventricular tachycardia Coma and Seizures (Bauer 2008, PMID ) Ingestion of 12 grams of lacosamide Co-ingestion with gabapentin (56g), topiramate (2g), zonisamide (2.8g) Also had PR prolongation (265 ms) and hypotension (60/30 mmhg)
9 Lacosamide : Adverse Effects Common: Nausea/Vomiting, Somnolence, Memory Impairment, Dizziness/Vertigo, Headache, Diplopia, Ataxia, Tremor Worse with other VGSC blocking agents Serious CV Atrial fibrillation/flutter, PR interval prolongation, all degrees of AV block, bradycardia, syncope Immune Drug hypersensitivity Psych Suicidal thoughts/behavior, Depression, Hallucinations
10 LACOSAMIDE Another Parenteral Sodium Channel Blocker
11 RUFINAMIDE
12 Rufinamide Trade Names: Banzel Dosage Forms: Oral Mechanism of Action: Triazole Derivative Prolongs inactive state of sodium channels Indication: Lennox-Gastaut syndrome, seizure, adjunct Off Label: Partial seizure, adjunct
13 Rufinamide : Targets Johannessen-Landmark C and Johannessen SI. Pharmacological Management of Epilepsy. Drugs 2008; 68(14):
14 Rufinamide : Toxicity An adult received 7200 mg during a clinical trial without any adverse effects
15 Rufinamide : Adverse Effects Common: Nausea/Vomiting, Somnolence, Dizziness, Headache, Diplopia/Blurred Vision, Ataxia/Gait Disturbance, Shortened QT Interval Serious: Neurologic Status Epilepticus Psychiatric Suicidal behavior Hematologic Leukopenia Immune Drug hypersensitivity syndrome/dress, Stevens-Johnson syndrome
16 RUFINAMIDE Yet Another Sodium Channel Blocker, for Lennox-Gastaut
17 ESLICARBAZEPINE
18 Trade Names: Aptiom Dosage Forms: Oral Eslicarbazepine Mechanism of Action: Structurally related to carbamazepine and oxcarbazepine Inhibition of voltage-gated sodium channels Indication: Partial seizure, monotherapy Partial seizure, adjuct
19 Johannessen-Landmark C and Johannessen SI. Modifications of Antiepileptic Drugs for Improved Tolerability and Efficacy. Perspect Med Chem 2008; 2: 21-39
20 Eslicarbazepine : Targets Johannessen-Landmark C and Johannessen SI. Pharmacological Management of Epilepsy. Drugs 2008; 68(14):
21 Eslicarbazepine : Toxicity Oxcarbazepine
22 Eslicarbazepine : Adverse Effects Common: Nausea/Vomiting, Somnolence, Dizziness, Headache, Diplopia/Blurred Vision, Ataxia, Tremor Serious: 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
23 ESLICARBAZEPINE A Once-A-Day Oxcarbazepine
24 PERAMPANEL
25 Trade Names: Fycompa Dosage Forms: Oral Perampanel Mechanism of Action: Noncompetetive antagonism of AMPA receptors Indication: Partial seizure, adjunct Tonic-clonic seizure, adjunct Orphan drug status for Lennox-Gastaut
26 Perampanel : Targets Johannessen-Landmark C and Johannessen SI. Pharmacological Management of Epilepsy. Drugs 2008; 68(14):
27 Perampanel : Toxicity Case report: 34 year-old with tuberous sclerosis (Hoppner 2013, PMID ) Ingestion of 204 mg, initially estimated to be 264 mg Dysarthria and fatigue, followed by stupor, then misperception and disorientation Impaired consciousness lasted 2 days EEG without epileptiform discharges
28 Perampanel : Adverse Effects Common: Somnolence, Dizziness, Headache, Ataxia/Abnormal Gait/Falls, Dysarthria, Irritability, Mood Disorder Serious: Psychiatric Aggressive behavior, Homicidal thoughts, Suicidal thoughts Dermatologic Drug hypersensitivity syndrome
29 PERAMPANEL AMPA antagonist, limited use due to SI/HI
30 CLOBAZAM
31 Trade Names: Onfi Dosage Forms: Oral Clobazam Mechanism of Action: Benzodiazepine Binds to benzodiazepine site of GABA(A) and potentiate neurotransmission Indication: Lennox-Gastaut, seizure, adjunct Off Label: SGE, Partial seizure, adjunct Not labeled for EtOH withdrawal or anxiety
32 Clobazam : Targets Johannessen-Landmark C and Johannessen SI. Pharmacological Management of Epilepsy. Drugs 2008; 68(14):
33 Clobazam : Toxicity It s a Benzodiazepine
34 Clobazam : Adverse Effects Common: Somnolence/Sedation, Ataxia, Dysarthria, Cough, Fever, Dependence, Constipation, Drooling, Insomnia Serious: Dermatologic Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis Psychiatric Suicidal Behavior/Ideation, Aggressive Behavior
35 CLOBAZAM Less Sedating Benzodiazepine
36 VIGABATRIN
37 Trade names: Sabril Dosage Forms: Oral Mechanism of Action: Vigabatrin Irreversibly inhibits GABA Transaminase May also stimulate GABA release Indication: Partial seizure, adjunct Infantile spasms Restricted distribution, black box warning for vision loss
38 Vigabatrin : Targets Johannessen-Landmark C and Johannessen SI. Pharmacological Management of Epilepsy. Drugs 2008; 68(14):
39 Case reports Vigabatrin : Toxicity Adult ingested 8-12 grams Psychosis 25 year-old woman ingested 60 grams Severe delirium Davie MB, Cook MJ, Ng C. Vigabatrin Overdose. Med J Aust 1996; 165: 403.
40 Vigabatrin : Adverse Effects Common: Somnolence, Dizziness/Vertigo, Headache, Agitation Serious: Ophthalmologic: Permanent vision loss Neurologic: Coma, Seizures Psychologic: Psychosis Respiratory: Respiratory depression Cardiovascular: Hypotension, Bradycardia
41 VIGABATRIN Novel agent, VERY limited use due to visual impairment
42 EZOGABINE/RETIGABINE
43 Ezogabine Trade names: Potiga (US), Trobalt (Europe) Dosage Forms: Oral Mechanism of Action: Opens voltage-gated potassium channels (KCNQ2/3) resulting in hyperpolarization Indication: Partial seizure, in patients with inadequate response to several alternatives, adjunct Benign familial neonatal convulsions (loss of function of KCNQ2/3) Black box warning for retinopathy
44 Ezogabine : Targets Johannessen-Landmark C and Johannessen SI. Pharmacological Management of Epilepsy. Drugs 2008; 68(14):
45 Ezogabine : Toxicity Moderate: agitation, aggressive behavior, irritability (doses greater than 2500 mg) Severe: Cardiac dysrhythmias (asystole or ventricular tachycardia) within 3 hours of single 900-mg dose in 2 volunteers. QT prolongation known, TdP possible but not yet reported Product Information: Potiga oral tablets, ezogabine oral tablets. GlaxoSmithKline (per FDA), Research Triangle Park, NC, 2015
46 Ezogabine : Adverse Effects Common: Fatigue, Memory Impairment, Vertigo, Diplopia/Blurred Vision, Tremor, Incoordination/Abnormal gait, Aphasia/Dysarthria Serious: Neurologic Dizziness, Somnolence, Confusion Ophthalmologic Retinal disorder, Pigment change Psychiatric Hallucinations/Psychosis, Suicidal thoughts Cardiovascular Prolonged QT interval Renal Urinary retention Dermatologic Skin pigmentation (blue, grey, brown)
47 Zaugg BE, et al. Ezogabine maculopathy. Retinal Cases & Brief Reports 2016; 0: 1-6.
48 EZOGABINE Niche drug, limited use due to retinal/skin pigment changes and urinary retention
49 GANAXOLONE
50 Johannessen-Landmark C and Johannessen SI. Modifications of Antiepileptic Drugs for Improved Tolerability and Efficacy. Perspect Med Chem 2008; 2: 21-39
51 Ganaxolone : Targets Johannessen-Landmark C and Johannessen SI. Pharmacological Management of Epilepsy. Drugs 2008; 68(14):
52 SIRIPENTOL
53 Stiripentol : Targets Johannessen-Landmark C and Johannessen SI. Pharmacological Management of Epilepsy. Drugs 2008; 68(14):
54 BRIVARACETAM
55 Brivaracetam : Targets Johannessen-Landmark C and Johannessen SI. Pharmacological Management of Epilepsy. Drugs 2008; 68(14):
56 QUESTIONS? emedicine.medscape.com
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