Epilepsy Flashcards
Drugs That Cause Seizures
Antimicrobials Anesthetics and analgesics Immunosuppressants Psychotropics Radiographic contrast agents Theophylline Sedative hypnotic drug withdrawal Drugs of abuse Flumazenil
First line drugs of choice for partial seizures (
Carb PLOT)
carbamazepine phenytoin lamotrigine oxcarbazepine topiramate
Second line drug of choice for partial seizures
gabapentin levetiracetam phenobarbital pregabalin primidone tiagabine valproic acid
Drugs of choice for generalized absence seizures
First line: ethosuximide, Lamotrigine, Valproic Acid
Second line: Clonazepam
Drugs of choice for generalized myoclonic, atonic seizures
First line: Valproic acid, lamotrigine
Second line: clonazepam, topiramate
Drugs of choice for generalized Tonic-clonic seizures
first line: valproic acid, carbamazepine, oxcarbazepine, lamotrigine
second line: levetiracetam, phenobarbital, phenytoin, topiramate
Phenytoin (Dilantin) MOA
Blocks voltage-gated Na+ channels —> reduces propagation of abnormal impulses in brain
Phenytoin (Dilantin) Indications
Simple and complex partial Sz
Generalized tonic-clonic Sz
Status epilepticus
Phenytoin (Dilantin) pharmacokinetics
Metabolism by P450 system
Potent non-specific inducer of many drug metabolizing enzymes (other drugs wont work as well bc theyre metabolized)
Highly protein bound (not good for other drugs)
Non-linear kinetics- hard to predict whats happening
Requires close therapeutic monitoring
Therapeutic range 10-20 mg/L
Phenytoin (Dilantin) administration
Enteral feeding reduces oral absorption
Oral suspension must be shaken vigorously
Intravenous formulation (some issues)
Basic pH…phlebitis and extravasation are concerns (can cause pain when its infused)
Hypotension: maximum infusion rate = 50mg/min (if you stay below 50, pt shouldn’t experience hypotension. Monitor for this)
No IM injection
What are the drugs that phenytoin induces?
carbamazepine, OCP, doxycycline, quinidine, cyclosporin, methadone, levodopa
What are the drugs that are inhibitors of phenytoin?
chloramphenicol, cimetidine, sulfonamide, isoniazid
ADRs of phenytoin
Dose related: nystagmus, ataxia, drowsiness, cognitive impairment
Non-dose related: gingival hyperplasia, hirsutism, acne, rash, hepatotoxicity
Phenytoin relationship of toxicity to serum concentrations
> 20 mcg/ml – nystagmus
30 mcg/ml – ataxia
40 mcg/ml – mental status changes (coma)
Which drug is Fetal Hydantoin Syndrome associated with?
Phenytoin. Very teratogenic.
Cleft lip and palate
Congenital heart disease
Slowed growth and mental deficiency
How does Carbamazepine (Tegretol) work?
Blocks Na+ channels
Indications of Carbamazepine (Tegretol)
first line for treatment of simple partial, complex partial, and generalized tonic-clonic
Metabolism of Carbamazepine (Tegretol)
Metabolism through autoinduction*
First 20-30 days of treatment
Autoinduction is dose dependent
After autoinduction is complete, steady state concentrations achieved after 3 days
Is Carbamazepine an inducer or inhibitor of other drugs?
Potent non-specific inducer of many drug metabolizing enzymes and transporters
Metabolism mostly through CYP 3A4
ADRs of Carbamazepine
Dose related: vertigo, ataxia, diplopia, drowsiness, nausea
CNS side effects: HA, paresthesias, confusion, psychosis
Non-specific: SIADH (makes you not pee), leukopenia, thrombocytopenia, Stevens-Johnson Syndrome
Indications of Phenobarbital (Luminal)
Generalized tonic clonic
Partial Sz
Neonatal Sz
Febrile Sz
Side effects of Phenobarbital (Luminal)
sedation, irritability, slowed thinking, ataxia, hyperactivity, rash
What is unique about Phenobarbital’s pharmacokinetics?
Half-life: 96 hours. Means huge amt of time before you reach steady state.
Time to steady state: 20-30 days
Metabolized by P450 system (potential for drug interactions)
Indications of Primidone (Mysoline)
Alternative choice in partial SZ and tonic-clonic SZ
Efficacy from metabolites (prodrug). Can’t pick. Pt will get both metabolites
Phenobarbital (tonic-clonic SZ and simple partial SZ)
Phenyethylmalonamide (complex partial SZ)
Well-absorbed orally (easier to get into the body); poor protein binding; same adverse effects as phenobarbital
How do the following drugs work? Valproic Acid (Depakene) & Sodium Valproate (Depakote)
Both meds work the same way.
Na+ blockade and enhancement of GABAergic transmission
Indications of Valproic Acid (Depakene) & Sodium Valproate (Depakote)
Generalized Seizures
myoclonic, tonic, atonic, absence
Metabolism of Valproic Acid
hepatic metabolism but doesn’t induce P450
inhibits metabolism of phenobarbital, carbamazepine, ethosuximide
Side effects of Valproic Acid
Dose related: N,V, abdominal pain, diarrhea, sedation, tremor, unsteadiness
Non-dose related: acute hepatic failure, acute pancreatitis
Monitor for jaundice and LFTs
How does Ethosuximide (Zarontin) work?
Inhibits Calcium channels
Indications for Ethosuximide (Zarontin)
DOC for generalized absence seizures
Side effects of Ethosuximide (Zarontin)
Dose related- GI, lethargy; HA, dizziness, anxiety
What are the Second Generation AEDs?
Gabapentin (Neurontin) Oxcarbamazepine (Trileptal) Tiagapine (Gabitril) Felbamate (Felbatol) Lamotrigine (Lamictal) Zonisamide (Zonegran) Levetiracetam (Keppra) Pregabalin (Lyrica)
How does Oxcarbazepine (Trileptal) work?
Active metabolite blocks NA+ channels
Indications of Oxcarbazepine (Trileptal)
partial Sz with or without secondary generalization (can be used first line)
Name one analog of Carbamazepine
Oxcarbazepine (Trileptal) (Demonstrated equal efficacy and fewer side effects when compared with carbamazepine and phenytoin)
ADRs of Oxcarbazepine (Trileptal)
Dizziness, ataxia, fatigue, GI, hyponatremia (2.5%), rash
NOTE: 30% cross reactivity for rash with CBZ (remember rash for CBZ is steven johnson)
What are the benefits of using Oxcarbazepine (Trileptal) rather than Carbamazepine?
Benefit!: No PK monitoring; no autoinduction
MOA for Gabapentin (Neurontin)
Analog of GABA. MOA unknown
Indication for Gabapentin (Neurontin)
Adjunct to partial and GTC seizures
Treatment of peripheral neuropathy
Pharmacokinetics of Gabapentin (Neurontin)
Favorable PK profile: dose-dependent oral absorption (means easy to predict, easy to dose) not protein bound excreted unchanged via kidneys no serum level monitoring
Side effects of Gabapentin
Side effect profile: Somnolence, dizziness, ataxia, nystagmus
How does Tiagabine (Gabitril) work?
Competitive inhibitor of GABA transporter in neurons and glia (inhibits re-uptake)
Indications for Tiagabine (Gabitril)
adjunctive treatment of partial seizures
Pharmacokinetics of Tiagabine (Gabitril)
Quickly and completely absorbed
Increased clearance in Pediatrics; with enzyme inducers
Serum concentrations unnecessary
Side effects of Tiagabine (Gabitril)
Dose related: dizziness, fatigue, nervousness, difficulty concentrating
How does Lamotrigine (Lamictal) work?
Blocks Na+ and Ca++ channels
Pharmacokinetics of Lamotrigine (Lamictal)
100% oral absorption; metabolized via Phase II (conjugate step in metabolism. Less effect on other drugs (vs phase I-p450))
Side effects of Lamotrigine (Lamictal)
Rash (10%), confusion, depression, N,V, diplopia, Severe idiosyncratic (skin, blood)
Indications for Lamotrigine (Lamictal)
GTC, Partial seizures, absence
How does Topiramate (Topamax) work?
Blocks Na+ channels and binds GABA thus opening Cl- channels
Indications for Topiramate (Topamax)
treatment for partial and generalized seizures in pediatrics and adults
Pharmacokinetics of Topiramate (Topamax)
2C19 substrate and inhibitor p450
70% renal elimination- dose adj in pt w/ renal compromise
1st order kinetics- easy to dose
Clearance increased with enzyme inducers
ADRs of Topiramate (Topamax)
Dose related: drowsiness, parasthesias, psychomotor slowing, weight loss, renal calculi (Maintain adequate fluids to decrease risk of renal calculi)
How does Felbamate (Felbtol) work?
Blocks Na+ channels, competes for NMDA receptor, prevents AMPA receptor stimulation, blocks Ca++ channels
Indications for Felbamate (Felbtol)
Partial Sz and Lennox-Gastaut syndrome
Use restricted to refractory Lennox-Gastaut syndrome
Active metabolite covalently (irriversibly) binds liver and bone marrow proteins and DNA
Aplastic anemia and liver failure
ADRs of Felbamate (Felbtol)
Dose related – anorexia, N/V, insomnia, HA
Non-dose related – aplastic anemia, hepatic failure
Indications for Levetiracetam (Keppra)
treatment of generalized Sz
Pharmacokinetics of Levetiracetam (Keppra)
Almost completely absorbed
Metabolism not dependent on P450 system
Minimal protein binding
Minimal drug interactions
ADRs of Levetiracetam (Keppra)
sedation, behavioral abnormalities
How does Zonisamide (Zonegran) work?
Sulfonamide derivative (don’t use if pt has sulfa allergy); blocks Na+ and Ca++ channels and enhances GABA-receptor function
Indications for Zonisamide (Zonegran)
adjunctive therapy for partial Sz
Pharmacokinetics of Zonisamide (Zonegran)
Good oral absorption
Both Renally and hepatically eliminated
ADRs of Zonisamide (Zonegran)
Dose related: sedation, dizziness, cognitive impairment, nausea
Non-dose related: rash, oligohydrosis, kidney stones (so adivise pt to maintain adequate volume)
Indications of Pregabalin (Lyrica)
Adjunctive treatment for partial onset Sz
Peripheral neuropathy (also Gabapentin)
Postherpetic neuralgia
Fibromyalgia syndrome
ADRs of Pregabalin (Lyrica)
dizziness, somnolence, dry mouth, peripheral edema, blurred vision, weight gain
When is it ok to discontinue AED medication regime?
Seizure free for 2-5 years an AED
Pt should have single type of partial or primarily generalized tonic-clonic Sz
Pt should have a normal neuro-exam and normal IQ
Patient’s EEG should have normalized with AED treatment
First choice drugs for Status Epilepticus
Benzodiazepines
DOA Lorazepam > Diazepam
Respiratory depression
2nd line drugs for Status Epilepticus
Hydantoins: Fosphenytoin or phenytoin
3rd choice for Status Epilepticus
Barbituates: Phenobarbital
How do Benzodiazepines work
Act as positive allosteric modulators (bind at separate site) by enhancing channel gating in presence of GABA.
1st line of therapy to terminate sz in status epilepticus
ADRs for Benzos
Infusion rate related arrhythmias and hypotension
Respiratory depression
Impairment of consciousness
Lorazepam (Ativan)
DOC for patient with IV access
Dose 0.1 mg/kg over 30 sec. May repeat q5 minutes (max dose usually 4mg)
Onset of action: 3-5 minutes
Can cause vein irritation…dilute dose with equal volume D5W, NS, SWI
Lorazepam (Ativan) vs Diazepam (Valium)
Lorazepam preferred over diazepam secondary to duration of action
Diazepam highly lipophilic and quickly redistributes out of brain to other fat stores in body
Diazepam DOA: 15 min to 2 hr
Lorazepam DOA: 12-24 hr
Midazolam (Versed)
A type of Benzo. Unique bc it can be administered Buccal, intranasal, IM routes.
Give by continuous infusion for refractory SE
Hydantoins
fosphenytoin and phenytoin
Second-line (loading dose) if Sz continue after 2-3 doses of Benzos
Less CNS and respiratory depression than benzodiazepines and barbituates
Administration of Phenytoin in the tx of status epilepticus
Erratic absorption and pain with IM injection
Dilute to <5 mg/ml with NS
Contains propylene glycol (antifreeze)
Arrhythmias, hypotension, metabolic acidosis with repeated doses
Fosphenytoin (Cerebyx)
H2O soluble prodrug of phenytoin converted by plasma esterases. Preferred over phenytoin.
Doses expressed as phenytoin equivalents (PE)
Compatible with most IV solutions with less phlebitis
Doesn’t contain propylene glycol!!
Paresthesias and pruritis more frequent than with phenytoin
Phenobarbital use in status epilepticus
3rd line agent: If Sz persists despite 2-3 doses of benzos and loading dose of hydantoin
2nd line agent: If Sz continues after 2-3 doses of benzos and hydantoins contraindicated
Pediatrics
ADRs of Phenobarbital
More CNS and respiratory depression than hydantoins
Contains propylene glycol