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Pharm 3 > Seizures > Flashcards

Seizures Flashcards

1
Q

Definitions

A

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

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2
Q

Mechanisms of seizures

A
  1. Abnormal firing of neurons-> increased excitability, ion channels (Na, Ca)
  2. Increased excitatory amino acids-> Glutamate, aspartate
  3. Decreased inhibitory process-> GABA
  4. Interference w/ metabolic processes
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3
Q

Classification of seizures

A
  1. Focal seizures: Old classification= partial
  2. Generalized seizures: involve both hemispheres of the brain from the beginning of seizure
  3. Unknown onset: newer term from International League Against Epilepsy (ILAE)-> includes: tonic-clonic, atonic, and epileptic spasms
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4
Q

Exitatory vs Inhibitory factors

A

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

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5
Q

Focal vs Generalized seizures - summary

A

good summary

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6
Q

MOA targets of antiseizure drugs

A
  1. Voltage-gated ion channels
  2. Inhibition of GABA
  3. Synaptic release components
  4. Ionotropic glutamate receptors
  5. Disease specific targets
  6. mixed/unknown
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7
Q

Anticonvulsant MOA

A
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8
Q

“spectrum” of antiseizure drug activity

A

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

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9
Q

Tx of epilepsy- principles

A

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

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10
Q

tx of epilepsy choosing AED

A

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

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11
Q

tx of epilepsy monitoring

A

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

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12
Q

Problems w/ some traditional 1st gen AEDs

A

poor water solubility
extensive protein-binding
autoinduction of cytochrome p450 system (carbamazepine)
many drug-drug interactions (all)
Phenobarbital- schedule lV drug

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13
Q

AE of antiseizure meds

A

GI (N/V)
Sedation
Ataxia
Rash
Hyponatremia
weight gain or loss
teratogenicity
osteoporosis

summary= DIZZINESS, DROWSINESS, GI

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14
Q

Pharmacokinetics of AEDs

A

gray= 1st gen higher protein binding
blue= 2nd gen mod
green= 3rd gen Low protein binding

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15
Q

Phenobarbital (PB)

A

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

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16
Q

Primidone (Mysoline)

A

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

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17
Q

Benzodiazepines

A

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

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18
Q

Clonazepam (Klonopin)

A

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

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19
Q

Lennox-Gestaut syndrome

A

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

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20
Q

Phenytoin

A

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

21
Q

Fosphenytoin (Cerebryx)

A

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

22
Q

Carbamazepine (CBZ)

A

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

23
Q

Oxcarbazepine (Trileptal)

A

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

24
Q

Hyponatremia assoc w/ Oxcarbazepine and Carbamazepine

A

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

25
Q

Valproic acid/ Valproate- know this one

A

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

26
Q

Problems w/ older

A

1st gen and 2nd gen AEDS

27
Q

Gabapentin (Neurontin, Gralise)

A

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

28
Q

Gabapentinoid- Pregabalin (Lyrica)

A

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

29
Q

Lamotrigine (Lamictal)

A

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

30
Q

Topiramate (Topamax)

A

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

31
Q

Levetiracetam (Keppra)

A

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

32
Q

Ethosuximide (Zarontin)

A

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

33
Q

Fenfluramine (Fintepla)

A

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

34
Q

Vigabatrin (Sabril)

A

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

35
Q

Lacosamide (Vimpat)

A

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

36
Q

Tigabine (Gabitril)

A

indications: Focal seizures

MOA: GABA re-uptake inhibitor

SE: dizzy, lack of energy, somnolence, nausea, nervousness

drug interactions: pharmacokinetics affected by other AEDs

37
Q

Status epilepticus

A

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

38
Q

Tx of status epilepticus

A
  1. Fast acting benzodiazepine
    a. Lorazepam (Ativan) IV
    b. Midazolam (Versed) IM, intranasal, buccal
    c. Diazepam (Valium) IV or rectal
  2. Slower acting antiseizure
    a. Phenytoin/fosphenytoin
    b. Divalproex
    c. Levetiracetam
39
Q

Diazepam (Valium)

A

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

40
Q

Tx algorithm for Generalized convulsive status epilepticus- b familiar w/

A
  1. Prehospital care: vitals + Diazepam or Midazolam-> go to hospital
  2. initial hospital care: asses airway + catheter + IV fluids (thiamine, pyridoxine, glucose, naloxone, AB
  3. Impending GSCE (0-30 min) = IV Lorazepam and repeat in 5 min
  4. Established GSCE (30-60 min)
    1st line: Phenytoin, Valproate, Levetiracetam
    2nd line: Phenobarbital
    3rd line: Lacosamide
41
Q

DRESS

A

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

42
Q

AED assoc w/ DRESS, SJS, TEN

A

carbamazepine, oxcarbazepine, lamotrigine, phenytoin, phenobarbital, primidone, zonisamide

43
Q

Drug review- good summary slide

A
44
Q

Concerns about AEDs in pediatric pts

A
  1. Gabapentin-> weight gain and behavioral AE
  2. Lamotrigine -> Skin rash, cns, slow titration
  3. Topiramate-> CNS AE, weight loss, slow titration
45
Q

concerns about AEDs in Elderly pts

A

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)

46
Q

Discontinuation or Withdrawal of AED therapy

A

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

47
Q

Epilepsy in pregnancy

A

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

48
Q

Teratogenic risk profiles of antiseizure meds

A

least bad: lamotrigine and levetriacetam
carbamazepine, oxcarbazepine, zonisamide
phenytoin, phenobarbital, topiramate
worst: Valproic acid

49
Q

pt counseling information

A

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

Pharm 3 (10 decks)

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