Seizures Flashcards
Definitions
Seizures: excessive electrical discharge of cortical neurons resulting in disruption of brain fxn and change in behavior-> 10% of gen pop will have atleast one seizure in their lifetime
Epilepsy: two or more unprovoked seizures-> 125,000 new cases per yr-> affect ~2 mill pple in US
Mechanisms of seizures
- Abnormal firing of neurons-> increased excitability, ion channels (Na, Ca)
- Increased excitatory amino acids-> Glutamate, aspartate
- Decreased inhibitory process-> GABA
- Interference w/ metabolic processes
Classification of seizures
- Focal seizures: Old classification= partial
- Generalized seizures: involve both hemispheres of the brain from the beginning of seizure
- Unknown onset: newer term from International League Against Epilepsy (ILAE)-> includes: tonic-clonic, atonic, and epileptic spasms
Exitatory vs Inhibitory factors
Excitatory:
-Glutamatergic neurons
-Mod of the release of excitatory nt glutamate
-Na channels
-AMPA receptors and Kainate receptors (coupled to K+ and Ca 2+ channels)
Inhibitory:
GABAergic neurons
GABAa receptors
GABA
Focal vs Generalized seizures - summary
good summary
MOA targets of antiseizure drugs
- Voltage-gated ion channels
- Inhibition of GABA
- Synaptic release components
- Ionotropic glutamate receptors
- Disease specific targets
- mixed/unknown
Anticonvulsant MOA
“spectrum” of antiseizure drug activity
Narrow spectrum: designed for specific seizure types-> approp if seizures occur in one specific part of the brain on a regular basis
Broad spectrum: designed to prevent seizures in more than one part of the brain-> tx more than one seizure subtype
Tx of epilepsy- principles
must be individualized
establish the diagnosis (type of seizure)
select apprp drug for seizure type-> efficacy and SE
Establish therapeutic goals
Strive for monotherapy in seizure control
Anticipate age-related changes in drug response
-pharmacokinetic differences
-pharmacodynamic differences
tx of epilepsy choosing AED
Antiepileptic drug:
Efficacy
safety
cost (generic formulations of older drugs)
drug interactions
dosing frequency
dosage form
-ease of swallowing
-liquid forms
-mixing w/ food
HIGH MED INTERACTIONS + DIZZY+ GI ISSUES + DROWSY
tx of epilepsy monitoring
Monitoring: important for management of most AED
Start at initiation and in early stages of tx
DRUG LEVELS ARE A THERAPEUTIC GUIDELINE-> NOT A HARD AND FAST RULE-> may see response @ concentrations “below” or “above” the therapeutic range-> always combine w/ clinical assessment-> expensive and may not be necessary in all pts
Blood
LFTs
CBC
Problems w/ some traditional 1st gen AEDs
poor water solubility
extensive protein-binding
autoinduction of cytochrome p450 system (carbamazepine)
many drug-drug interactions (all)
Phenobarbital- schedule lV drug
AE of antiseizure meds
GI (N/V)
Sedation
Ataxia
Rash
Hyponatremia
weight gain or loss
teratogenicity
osteoporosis
summary= DIZZINESS, DROWSINESS, GI
Pharmacokinetics of AEDs
gray= 1st gen higher protein binding
blue= 2nd gen mod
green= 3rd gen Low protein binding
Phenobarbital (PB)
brand name: Luminal (1912)
low cost and effective
barbiturate w/ sedative, hypnotic, anticonvulsant properties
Indications:
focal, generalized tonic-clonic seizures, status epilepticus
MOA: enhances the inhibitory actions of GABA neurons
SE: CNS (impaired cognition, sedation, confusion, memory problems, ataxia, hyperactivity in children, CNS depression), blood dyscrasias, osteomalacia, stevens johnson syndrome (SJS), can be abused
Drug interactions: alot of other meds effecting dosing
Primidone (Mysoline)
Indications: tonic-clonic seizures, focal, psychomotor (temporal lobe) seizures
MOA: Initially blocks Na channels but is converted to phenobarbital-> GABA EFFECTS
SE and AE: very sedating like phenobarbital
Monitor: Blood counts and LFTs
Special notes: supplement w/ folic acid
not used much
Benzodiazepines
used for acute/short term use: Generalized anxiety disorder, seizure cessation, alcohol withdrawal, muscle spasms, insomnia
MOA: increase frequency of GABA receptor opening- development of tolerance limits THEIR USE IN CHRONIC TX of EPILEPSY
Lorazepam, diazepam, midazolam= RESCUE MEDICATIONS FOR ACUTE REPETITIVE SEIZURES OR STATUS EPILEPTICUS-> USUALLY REQUIRES TAPERING TO DC IF USED FOR >4 WEEKS
Warnings: sedation, tolerance, hypnosis/amnesia, respiratory depression
PREGNANCY CATEGORY D= AVOID
LIVER DISEASE = AVOID
drug interactions: sedatives and opioids
ANTIDOTE (BENZODIAZEPINE REVERSAL AGENT)-> FLUMAZENIL= can cause withdrawal and seizures
Clonazepam (Klonopin)
Indications: Lennox-Gastaut syndrome, myoclonic seizures, refractory abscence seizures, infantile spasms
SE/AE: salivation, blood dyscrasias
Drug interactions: other seizure meds (may need dose adjustment), other sedatives/hypnotics
Monitoring: CBC, LFTS, renal fxn with long term therapy
MAY PRECIPITATE TONIC-CLONIC SEIZURES
Lennox-Gestaut syndrome
childhood epileptic encephalopathy= multiple seizure types= 10% of epilepsies presenting <5 yo
patho unknown= idiopathic or triggered by underlying disorder (meningitis, tuberous sclerosis, malformations)-> prognosis varies but generally poor, mental regression is common
1st line: Valproate = no optimal therapy highlighted though
specialized anticonvulsants tx:
1. Rufinamide (Banzel)- hepatic metabolism (complex interactions with other seizure meds)-> contra in pts w. FAMILIAL SHORT QT SYNDROME
2. Felbamate (Felbatol) 2nd line for partial/complex seizures-> lot of interactions-> contra in liver dz, blood dyscrasias
3. Clobazam (Onfi, Sympazan)= benzo-> adjunctive tx in pts greater than or equal to 2 yrs-> effect potentiated by drugs like omeprazole
Phenytoin
Brand name: Dilantin
chem structure like barbiturates
indicated: generalized and focal seizures
Moa: block frequency, use, and voltage dependent neuronal Na channels-> limit repetitive firing of AP
Distribution: enters brain rapidly and redistributes-> highly protein bound (90%) rapidly and reversibly bound= AFFECTED BY: LOW ALBUMIN, RENAL FAILURE, AGE, OTHER DRUGS
Metabolism: ELMINATION CHANGES FROM 1ST ORDER (LINEAR) TO ZERO ORDER (NONLINEAR) IN THE THERAPEUTIC RANGE
increases in pregnancy-> DO NOT USE IN PREGNANCY (FETAL HYDANTOIN SYNDROME (CLEFT PALATE, CONGENITAL HEART DZ, INTELLECTUAL DISABILITY AND OTHERS))
BBW: administration of IV FORM-> DO NOT EXCEED 50 MG/MIN IN ADULTS OR 1TO 3 MG/KG/MIN-> RISK OF SEVERE HTN AND CARDIAC ARRHYTHMIAS
SE:
NYSTAGMUS
LETHARGY
COGNITIVE IMPAIRMENT
GINGIVAL HYPERPLASIA
AE: Low / med/high/ severe -> no numbers needed
Fosphenytoin (Cerebryx)
water soluble prodrug of phenytoin (replaced phenyt for IV)
used in acute attacks status epilepticus or as seizure prophylaxis-> used as a loading dose when starting phenytoin
AE: Cerebellar symptoms (ataxia, vertigo, nystagmus, diplopia), pruritis, burning sensation
bbw like phenytoin
Carbamazepine (CBZ)
Brand names: Tegretol, Carbatrol
MOA: primarily via inhibition of voltage gated NA channels
also used for bipolar disorder and trigeminal neuralgia
unique metabolism: Autoinduction (drug induces CYP450 and increases its own metabolism)
Drug interactions:
CBZ= enzyme inducer-> other drugs may induce or inhibit metab-> sedative
AE:
common: HYPONATREMIA, nvd, HA, dizzy, blurred vision
rare: STEVENS JOHNSON/TOXIC EPIDERMAL NECROLYSIS-> HLA-B 1502 OR HLA-A 3101 ASIAN POPULATIONS
Pt ed: DO NOT CRUSH OR CHEW-> “GHOST” OF SHELL IN STOOL W/ Tegretol XR
carbatrol can be opened and mixed w/ food
exposure to heat and humidity may harden tablets-> decreasing bioavailability
newer drug: Oxcarbazepine (Trileptal) se same but No autoinduction still high interactions
Oxcarbazepine (Trileptal)
Derived from carbamazepine-> fewest drug ineractions-> less potent than carbamazepine
Indications: focal and generalized tonic-clonic seizures, neuropathic pain, bipolar disorder
MOA: Blocks Na+ channels
SE: sedation, HA, dizziness, rash, vertigo, ataxia, nausea, hyponatremia (more common w/ trileptal vs. carbamazepine)
AE: SJS/TEN
drug interactions: other AEDs and verapamil
improved SE profile over carbamazepine bc NOT AN ENZYME INDUCER BC DIFF SIDE CHAIN WHICH ALLOWS IT TO BE METABOLIZED AND ELIMINATED DIFFERENTLY
Hyponatremia assoc w/ Oxcarbazepine and Carbamazepine
well described AE
PT MAY BE ASYMPTOMATIC-> may develop over the first few months of therapy
monitoring: BASELINE AND @ THERAPEUTIC LEVEL and IF DEVELOP SXS OF HYPONATREMIA WHILE ON CHRONIC THERAPY
RF: older age, higher serum level of oxcarbazepine/carb, on >1 drug for seizure, concurrent use of antihtn meds (diuretics mainly), history of hyponatremia w/ either drug
Valproic acid/ Valproate- know this one
Brand name: Depakote
Indications:
Generalized and Focal seizure= MOST EFFECTIVE ANTISEIZURE MEDICATIONS
absence epilepsy, migraine prophylaxis, anxiety disorders, bipolar disorder
Drug interactions: other seizure meds, aspirin
MOA: blocks voltage dependent sodium channels, increase GABA CONC by blocking GABA transaminase, act against T-type calcium channels
Divalproex= long acting formulation compromised of sodium valproate and valproic acid
high protein binding-> high drug interactions
AVOID IN PREGNANCY-> TERATOGENIC NEURAL TUBE DEFECTS
MOST TERATOGENIC OF ALL ANTISEIZURE DRUGS
AE: GI, TREMOR, WEIGHT GAIN, RASH SJS, ELEVATED LFT, HEPATOTOXICITY RARE, LIVER FAILURE CAN BE FATAL, hyperammonemia (VHE)-> valproate- related hyperammonemic encephalopathy
If you VALue your liver, be careful when taking VALproic acid= acute hepatocellular injury
Problems w/ older
1st gen and 2nd gen AEDS
Gabapentin (Neurontin, Gralise)
structurally related to GABA
does not bind to GABA A OR GABAB receptors and does not appear to affect degradation or uptake of GABA
Moa: uncertain
Indications: focal onset seizures, neuropathic pain, postherpetic neuralgia, off label: use includes restless legs syndrome and hiccups
interactions: no major, sedatives
AE:
MC: dizzy, somnolence, fatigue, ataxia, weight gain, edema
rare: rash, tremor, DIPLOPIA, DRESS (drug rxn w/ eosinophilia and systemic symptoms
Caution: kidneys excrete drug unchanged= MUST REDUCE IN PTS W/ RENAL IMPAIRMENT
Gabapentinoid- Pregabalin (Lyrica)
chemically related to gabapentin
indications: adjunctive therapy for focal seizures:
-neuropathic pain including diabetic neuropathy and postherpetic neuralgia, fibromyalgia
MOA: binds to a specific subunit of voltage gated Ca channels which modulates Ca influx-> inhibits neuronal excitability by inhibiting release of excitatory nt, serotonin, dopamine, substance P, and calcitonin
SE/AE: Arrhythmias, Thrombocytopenia
Metabolism-> Renally excreted-> relatively unchanged so dose adj required
Drug interactions- none other than other seizure meds
CONTROLLED SUBSTANCE DUE TO RISK OF ABUSE
Lamotrigine (Lamictal)
MOA: inhibition of Voltage sensitive Na channels-> decreases release of glutamate and aspartate
Indications: adjunctive therapy for focal onset seizures-> primary generalized tonic clonic seizures-> Lennox Gastaut syndrome
IMPROVES DEPRESSION IN PTS W/ EPILEPSY
Interactions: PHenytoin, CBZ, VPA inhibits, hormone replacement therapy increases clearance and decreases blood levels
WARNINGS: RASH INCLUDING DRESS
AE:
MC: N, dizzy, somnolence, blurred vision, insomnia
RARE: STEVENS JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS TEN
Caution: PTS W/ STRUCTURAL OR FUNCTIONAL HEART DISEASE, conduction system disease, congenital heart disease, ventricular arrhythmia, or multiple risk factors for coronary artery disease
Topiramate (Topamax)
Indications: focal (partial) onset seizures, primary generalized tonic clonic seizures, adj therapy for lennox gastaut syndrome, Migraine prophylaxis
MOA: many
AVOID IN PREGNANCY
AE:
Mc: WEIGHT LOSS, WORD FINDING DIFFICULTIES, KIDNEY STONES, METABOLIC ACIDOSIS, OLIGOHYDROSIS
rare: glaucoma
Interactions: lithium, antiseizure drugs, contraceptives, cns depressants
Levetiracetam (Keppra)
chemically unrelated to other AEDs
Indications: focal and primary generalized tonic clonic seizures, status epilepticus, juvenile myoclonic epilepsy, seizure prophylaxis
MOA: many
drug interactions: CNS depressants
SE: better SE than other anticonvulsnats
-weakness, dizziness, ataxia, somolence
Ethosuximide (Zarontin)
for Absence seizures
MOA: increases seizure threshold and suppresses paroxysmal “spike and wave” pattern in abscence seizures-> thought to inhibit T-type Ca2+ channels-> depresses nerve transmission in motor cortex
SE: N, HA, dizziness, lethargy
Drug interactions: other seizure meds and SSRIs
cautions: COAGULATION DISORDERS, LUPUS, RENAL DZ, HISTORY OF SUICIDAL IDEATION
PE: Administer w/ food or milk to minimize GI upset
Fenfluramine (Fintepla)
indicated for seizures assoc w/ Dravet syndrome (DS)-> infancy epilepsy
MOA: uncertain
AE: drowsiness, lethargy, reduced appetite, weight loss
MUST DO BIANNUAL ECHO TO MONITOR FOR DEVELOPMENT OF VALVULOPATHY AND/OR PULMONARY HTN
Vigabatrin (Sabril)
indications: refractory focal seizures (adj) and infantile spasms (monotherapy)
MOA: inhibits enzyme responsible for GABA catabolism (GABA transaminase)
SE: drowsiness, fatigue, HA, dizziness-> HIGH RISK OF VISUAL FIELD LOSS
high risk drug: part of REMS program = Risk Evaluation and Mitigation Strategies
Lacosamide (Vimpat)
MOA: sodium channel blocker
CARDIAC WARNINGS-> not recommended w/:
known conduction/rhythm abnormalities, AV blocks, afib, atrial flutter, concomitant drugs that increase PR interval prolongation, severe cardiac dz, myocardial ischemia, MI, heart failure
indications: focal seizures, primary generalized tonic clonic seizures
AE:
common: blurred vision, dizziness, vertigo
Rare: cardiac warnings and DRESS
Tigabine (Gabitril)
indications: Focal seizures
MOA: GABA re-uptake inhibitor
SE: dizzy, lack of energy, somnolence, nausea, nervousness
drug interactions: pharmacokinetics affected by other AEDs
Status epilepticus
more than or equal to 2 seizures occur w/out full recovery of consciousness btwn episodes
can be focal/generalized and convulsive or nonconvulsive
life-threatening -> requires emergency intervention
Tx of status epilepticus
- Fast acting benzodiazepine
a. Lorazepam (Ativan) IV
b. Midazolam (Versed) IM, intranasal, buccal
c. Diazepam (Valium) IV or rectal - Slower acting antiseizure
a. Phenytoin/fosphenytoin
b. Divalproex
c. Levetiracetam
Diazepam (Valium)
indications: acute active seizures
muscle spasm/rigidity, alcohol withdrawal syndrome, alt status epilepticus, anxiety
MOA: increases GABA activity
SE: Sedation and habit forming
Contrain: GLAUCOMA
BBW: Benzo w/ opioids + abuse, misuse, addiction + dependence and w/drawal
interactions: many
AVOID ABRUPT CESSATION
Tx algorithm for Generalized convulsive status epilepticus- b familiar w/
- Prehospital care: vitals + Diazepam or Midazolam-> go to hospital
- initial hospital care: asses airway + catheter + IV fluids (thiamine, pyridoxine, glucose, naloxone, AB
- Impending GSCE (0-30 min) = IV Lorazepam and repeat in 5 min
- Established GSCE (30-60 min)
1st line: Phenytoin, Valproate, Levetiracetam
2nd line: Phenobarbital
3rd line: Lacosamide
DRESS
Drug Rxn w/ Eosinophilia and systemic symptoms
rare-> life threatening
cutaneous eruption, hematologic abnormalities, lymphadenopathy, and or internal organ involvement
triggered by antiseizure medications + allopurinol, sulfonamides, minocycline, vancomycin
HIGHLY SUSCEPTIBLE POPULATIONS:
CARBAMAZEPINE-> EUROPEAN, JAPANESE, HAN CHINESE
PHENYTOIN-> HAN CHINESE, THAI
*drugs that cause DRESS: carbamazepine, phenytoin, lamotrigine, oxcarbazepine, phenobarbital
AED assoc w/ DRESS, SJS, TEN
carbamazepine, oxcarbazepine, lamotrigine, phenytoin, phenobarbital, primidone, zonisamide
Drug review- good summary slide
Concerns about AEDs in pediatric pts
- Gabapentin-> weight gain and behavioral AE
- Lamotrigine -> Skin rash, cns, slow titration
- Topiramate-> CNS AE, weight loss, slow titration
concerns about AEDs in Elderly pts
Gabapentin (elimination low in renal fxn, edema, cns effects)
Lamotrigine (cns effects, rash, slow dosage titration)
Topiramate (elimination low in renal fxn, cns effects, weight loss, nephrolithiasis, slow dosage titration)
Discontinuation or Withdrawal of AED therapy
assess risk of recurrent seizure
SHOULD B SEIZURE FREE FOR 2-5 YRS ON AEDS
withdraw pt over an extended period of time
complicated: single type of seizure, normal neurologic exam/normal IQ, EEG normalized w/ tx
Epilepsy in pregnancy
Pre pregnancy: AEDs may result in OCP failures
During: potential teratogenicity, effect of seizures on fetus, higher risk pregnancy, change in AED pharmacokinetics
Postpartum: change in pharmacokinetics-> passage through breast milk
Teratogenic risk profiles of antiseizure meds
least bad: lamotrigine and levetriacetam
carbamazepine, oxcarbazepine, zonisamide
phenytoin, phenobarbital, topiramate
worst: Valproic acid
pt counseling information
compliance: noncompliance is a major cause of status epilepticus and failure to respond to AEDs
improving compliance:
cargiver
reinforce compliance every time
simplify dosage regimen to daily
tailor dosage to pts schedule
provide compliance enhancers
help pt develop system to take meds and record AED dosing
