epilepsy

Question 1

classification of seizures

Answer 1

-Seizure type is classified based on the initial manifestation of the seizure as generalized, focal, or unknown (if seizure onset is either missed or obscured)
-generalized is easier to treat (than partial)

Question 2

physiology of seizures

Answer 2

-abnormal neuronal discharges from seizure focus and spread to other parts of brain and produce abnormal movements, sensations or thoughts.
-May be due to excessive excitatory neurotransmitters mediated by glutamate:

Activation of glutamate’s NMDA (N-methyl-D-aspartate) receptor
->
displace Mg2+ ion
->
facilitate calcium entry to neurons
->
potentiates excitatory glutamate neurotransmission via activating nitric oxide synthesis
->
further activation of NMDA receptor activation and calcium influx
->
depolarization shift in seizure foci
->
abnormally long action potentials(depolarizations)
->
initiation of seizure

-Suppression of inhibitory neurotransmitter (GABA) (gamma-aminobutyric acid!!) also involved in cause of seizure.

-Increase in calcium influx via T-type channels in thalamic neurons.

Question 3

mechanisms of anticonvulsants

Answer 3

-1. Inhibition of sodium or calcium influx responsible for neuronal depolarization.
-MOA - Suppress abnormal repetitive depolarizations in seizure focus more than they suppress normal neuronal activity -> Includes carbamazepine, phenytoin, topiramate
-MOA – block T-type calcium channels involved in initiation of generalized absence seizures -> Includes ethosuximide and valproate

-2. Inhibition of excitatory glutamate neurotransmission
-MOA – inhibit glutamate neurotransmission (may affect the formation of seizure focus) -> Includes felbamate, topiramate and valproate

-3. Augmentation of inhibitory GABA neurotransmission
-MOA – enhance GABA activation of the GABA-chloride ionophore -> Includes benzodiazepine and barbiturates
-MOA – Enhance activation of GABAA receptor -> Include topiramate
-MOA – increase GABA release -> Includes gabapentin
-MOA – inhibits GABA degradation -> Includes valproate

Question 4

traditional (standard) drugs for seizure disorders

Answer 4

-carbamazepine
-phenytoin
-valproate
-phenobarbital
-primidone
-ethosuximide

Question 5

carbamazepine

Answer 5

-MOA – blocks voltage-sensitive sodium channels in neurons

-Indications – Primary generalized tonic-clonic, simple or complex partial with or without secondary generalization, trigeminal neuralgia and bipolar disorder (do not use in absence seizures)

-Precautions – Cardiac disease, hepatic disease, blood cell abnormalities can be significant, MAO inhibitors should be d/c 14 days prior to initiation of therapy.

-ADRs –
-CNS effects: !diplopia, drowsiness!, ataxia, syncope (read paper before taking)
-Hematologic effects: blood dyscrasias!
-Other: !hepatitis, rash, (if RASH develops D/C), Steven- Johnson Syndrome (SJS), SIADH!, renal failure, N, V, D (dose-related), hyponatremia
-teratogenic!- cranial, cardiac, spina bifida defects

-DDI – P450 enzyme inducer! – increases metabolism of other drugs. Caution w/ Phenytoin, warfarin, thyroid drugs and OCPs -> increase OCP dose

-Monitor –CBC, platelets, LFT, BUN/Cr, carbamazepine levels (4-12 mcg/ml)
-can cause leukopenia, thrombocytopenia, etc. -> check CBC

-auto induction- taking it induces its own metabolism
-takes 20 days
-need higher dose of meds in the initial 20 days -> then back off
-check levels with bloods

Question 6

phenytoin

Answer 6

-MOA – similar to carbamazepine
-Indications – partial and generalized tonic-clonic seizures, status epilepticus (do not use in absence seizures!!!)
-Precautions: hepatic disease, CI in pregnancy (teratogenic – cardiac effects)

-Kinetics:
-Absorption: slow rate, tube-feed interactions
-Distribution – protein binding, adjust for low albumin
-Metabolism – enzyme inducer!!!!

-narrow TI
-once your on the brand dont switch it, if it works it works

Question 7

phenytoin ADRs and DDI

Answer 7

-ADRs –
-CNS effects: nystagmus!, sedation, ataxia, cognitive imparitment (all dose-related)
-Hematologic: aplastic anemia
-Other: !gingival hyperplasia, hirsutism, acne, liver toxicity, rash, SJS, (if RASH develops D/C)!

-DDI – !p450 enzyme inducer!, highly protein bound (90%)!!! -> may displace other drugs and increase their effects, decreases Vit k levels, tube feedings decrease phenytoin absorption
-test the levels by blood since so many things affecting it
-adjust for low levels

-Monitor – CBC, LFT, phenytoin level (total = 10-20 mcg/ml; free = 1-2.5 mcg/ml)
-comments – dose dependent kinetics, different formulations w/ different bioavailabilities
-MC pts with low albumin -> liver, kidney, pregnancy, poor nutrition, burn pts
-at lower doses -> presents with first order kinetics -> linear
-at higher doses -> kicks in zero order kinetics -> exponential increase in dose

Question 8

valproate

Answer 8

-several formulations available
-valproic acid (Depakene) (PO)
-valproate Na (Depacon INJ and Depakene syrup -PO)
-divalproex Na (Depakote, Depakote ER) - best ADRs

-MOA – several different MOA to control seizures (broad spectrum!)
-Inhibits voltage-sensitive Na channels and T-type Ca channels
-increase GABA synthesis and  GABA degradation
-decrease glutamate synthesis
-Indications – partial seizures, all types of generalized seizures, bipolar disorder, migraine
-Precautions – Hepatic disease. Contraindicated in pregnancy (teratogenic – spina bifida)

Question 9

valproate ADR and DDI

Answer 9

-ADRs –
-CNS effects: sedation, ataxia, tremor, encephalopathy
-Hematologic: thrombocytopenia
-Other: hair loss (13-24%)!, hepatic damage!, pancreatitis, N, V, WEIGHT GAIN!, increased appetite, rash
-teratogenic
-encephalopathy

-DDI – P450 enzyme inhibitor, but may induce CYP2A6. Also highly protein bound (99%) -> dose adjust as needed
-Monitor – CBC w/ platelet, LFT, valproate levels (50-100 mcg/ml) -> dont need to know levels for any of the drugs

Question 10

phenobarbital

Answer 10

-PO, IV
-MOA – short acting barbiturate, enhances GABA-mediated chloride influx that causes membrane hyperpolarization
-Indications – Partial and generalized tonic-clonic, status epilepticus; barbiturate – sedative, hypnotic.
-Precautions - renal/hepatic impairment, tolerance and dependence can develop

-ADRs –
-CNS effects: CNS depression, sedation, paradoxical excitement and hyperactivity, inhibits cognitive functions esp. in children
-Other: abuse potential, resp depression, N,V,D
-teratogenic- finger abnormality, cleft lip, etc.

-DDI - enzyme inducer !!!!!
-Monitor – CBC, LFTs, mental status, phenobarbital levels (10-40 mcg/ml)

Question 11

primidone

Answer 11

-PO
-metabolized to phenobarbital, but also has actions like phenytoin
-ADRs same as Phenobarbital

Question 12

ethosuximide

Answer 12

-PO
-MOA – inhibits T-type Ca channels in thalamic neurons
-Indications – absence seizures in children, not very effective in adult population
-ADRs – CNS effects, gi distress
-DDI – valproate inhibits, no other significant interactions

Question 13

newer/adjunct drugs

Answer 13

-clorazepate
-felbamate
-gabapentin
-lamotrigine
-topiramate
-levetiracetam
-zonisamide
-oxcarbazepine
-tiagabine
-pregabalin
-lacosamide
-vigabatrin
-rufinamide
-clobazam
-ezogabine
-eslicarbazepine
-perampanel

Question 14

clorazepate

Answer 14

-PO
-very popular
-MOA – benzodiazepine anxiolytic with depressant effects on the central nervous system
-Indications – Partial sz, anxiety, alcohol withdrawal syndrome
-ADRs – somnolence
-DDI – many

Question 15

felbamate

Answer 15

-PO
-MOA – unclear, may inhibit glutamate neurotransmission
-Indications – monotherapy or adjunctive for treatment of partial seizures after other drugs failed. Also used for TX of seizures associated w/ Lennox-Gastaut syndrome in children! – non-FDA.
-Precautions – Aplastic anemia and hepatic failure have occurred
-ADRs – HEPATOTOXICITY!!!!, CNS effects, GI effects
-DDI – P450 inhibitor/inducer!!!
-Monitor – CBC, LFT

Question 16

gabapentin

Answer 16

-PO
-the kitchen sink of drugs
-MOA – unclear, may increase GABA release
-Indications – adjunct for partial seizures with or without secondary generalized seizure in pts > 12 y.o., adjunct for treatment of partial seizures in pediatric pts 3-12 y.o., post-herpetic neuralgia. Non-FDA: bipolar disorder and chronic pain.
-ADRs - !!!CNS depression, weight gain!!!, pedal edema
-DDI – not significant

Question 17

lamotrigine

Answer 17

-PO
-MOA – inhibits glutamate release and inhibits voltage sensitive sodium channels
-Indications - monotherapy or adjunctive for treatment of partial seizures in adults. Can also be used as adjunct for tonic-clonic seizures. Non-FDA - TX of seizures associated w/ Lennox-Gastaut syndrome in children and adults.

-Precautions –
-Caution in renal, hepatic and cardiac disease
-life threatening skin rashes have occurred (titrate slowly to reduce risk) - based on dose not rate
-are they on other drugs that are inducers or inhibitors? -> important for titration
-New data regarding increased risk of oral clefts if used during pregnancy.

-ADRs - CNS effects, sedation, dizziness, ataxia, diplopia, blurred vision, folate deficiency, weight gain, if RASH develops D/C
-DDI- not significant
-Monitor – drug level (2-20 mcg/ml)

Question 18

topiramate

Answer 18

-PO
-MOA – several; block Na channels in neurons, enhance GABA activity and blocking glutamate activity. Weak carbonic anhydrase inhibitor
-Indications – adjunctive tx of partial seizures and generalized tonic-clonic seizures in pts 2-16 y.o
-TX of seizures associated w/ Lennox-Gastaut syndrome in children > 2yo
-Also FDA approved for migraine and cluster headaches!!!
-Non-FDA indications -> bipolar disorder, infantile spasms, neuropathic pain

-Precautions- hepatic and renal disease, angle closure glaucoma has occurred
-ADRs - CNS effects-word searching!!, psychomotor slowing (titrate slowly), dizziness, weight loss!, kidney stones (2-4x general popn), oligohydrosis/hyperthermia, metabolic acidosis

-DDI – CYP2C19 inhibitor; CYPA4 inducer

Question 19

levetiracetam

Answer 19

-keppra PO
-MOA – may prevent hypersynchronization of epileptiform burst firing and propagation of seizure activity
-Indications – adjunctive treatment of partial seizures in adults.
-Precaution – adjust dose in renal impairment
-ADRs – CNS effects including behavioral and psychotic symptoms!!!!!, (hostility, irritability, agitation, depression)
-DDI – not significant

Question 20

zonisamide

Answer 20

-PO
-MOA – unclear, may inhibits sodium and calcium influx, does not affect GABA activity. Weak carbonic anhydrase inhibitor
-Indications – adjunctive treatment of partial seizures in pts over 16 y.o.
-Precautions – Severe sulfonamide like adverse reactions like Steven Johnson syndrome!!!! have occurred (D/C if rash develops), do not use in sulfa allergic pts!!!!!, caution in renal disease
-ADRs – similar to topiramate!
-DDI – CYP3A4 substrate
-Monitor – renal function

Question 21

oxcarbazepine

Answer 21

-PO
-MOA – inhibits sodium influx in neurons
-Indications – monotherapy or adjunct in partial seizures in adults and as an adjunct to partial seizures in children 4-16 years old
-Precautions – can cause clinically significant hyponatremia, significant decrease in effectiveness of oral contraceptives

-ADRs – CNS effects, diplopia, nystagmus GI effects, hyponatremia!!!, rash, less hematologic ADRs than carbamazepine
-DDI – CYP2C19 inhibitor, CYP3A4 inducer
-Monitor – electrolytes

Question 22

tiagabine

Answer 22

-PO
-MOA – enhances GABA activity
-Indications: Adjunct for partial seizures in adults and children > 12 y.o
-Precautions – can cause nonconvulsive status epilepticus
-ADRs – CNS effects, stupor, muscle weakness
-DDIs – CYP3A4 substrate

Question 23

pregabalin

Answer 23

-schedule V
-MOA – reduces excitatory transmitters. Has analgesic, anticonvulsant and anxiolytic effects
-Indications – Adjunct for partial seizures. Also FDA approved for treatment of Neuropathic pain associated w/ diabetic neuropathy and postherpetic neuralgia.
-Precautions – Caution in CHF
-ADRs – CNS effects, headache, weight gain, edema, CK elevations

Question 24

lacosamide

Answer 24

-schedule V, PO, INJ
-MOA – enhances slow inactivation of voltage sensitive Ns channels
-Indications – Adjunct for partial seizures
-Precautions – Can cause PR interval prolongation (baseline EEG)!!!!!!!!
-ADRs – CNS effects, double vision
-DDIs – not clinically significant

Question 25

vigabatrin

Answer 25

-PO
-MOA – irreversibly inhibits GABA metabolism
-Indications – Refractory Epilepsy and Infantile Spasms!!!!
-Precautions – Permanent Vision Loss in 30% of pts due to narrowing of visual field!!!!!!!! (Restricted/Limited use – can only be obtained directly from manufacturer by qualified prescribers)
-ADRs – CNS effects, Vision loss

Question 26

rufinamide

Answer 26

-PO
-MOA – prolongs inactivity of NA channel
-Indications – Lennox-Gastuat Syndrome!!!
-Precautions – Significant shortening of QT interval
-ADRs – CNS effects, rash
-DDIs – several CYP450 interactions

Question 27

clobazam

Answer 27

-PO
-MOA - benzodiazepine
-Indications - Lennox-Gastuat syndrome – sz adjunct
-Precautions – dependence, SJS, toxic epidermal necrosis, somnolence, do not stop abruptly as sz may occur, suicidality and ideation
-ADR – constipation, drooling, ataxia, dysarthriam insomnia, lethargy, sedation, somnolence, aggressive behavior, uti, cough, fever
-DDI – Contraindicated with thioridizaine
-Reversal for benzodiazepine is flumazanil

Question 28

ezogabine

Answer 28

-PO
-MOA – enhancing transmembrane potassium currents and reduces excitability by augmenting GABA activity
-Indications – Partial onset seizures
-Precautions – Prolonged QT interval, skin pigmentation, confusion, dizziness, somnolence, ophthalmic disorders, hallucinations, psychotic disorder, suicidality, Severe urinary retention, mental and psychiatric side effects. Requires Medguide (posted on blackboard)
-ADR – abnormal gait, Aphasia, Asthenia, Disturbance of attention, Dysarthria, Impairment of balance, Incoordination, Memory impairment, Tremor, Vertigo, Blurred vision, Diplopia, Fatigue
-DDI – carbamazepine, orlistat, lamotrigine, phenytoin, calcifedol

Question 29

eslicarbazepine

Answer 29

-MOA – a dibenzazepine carboxamide that inhibits voltage-gated sodium channels (VGSC), especially in rapidly firing neurons.
-Indications – partial seizures
-Precautions – SJS, dec in T3 & T4, hyponatremia, SIADH, pancytopenia, agranulocytosis, elevated transaminases and bilirubin, anaphylaxis, andgioedema, neurologic issues, suicidality and ideation

-ADR – N/V, Ataxia, Dizziness (19%-28% ), Headache, Somnolence, Tremor, Vertigo , Blurred vision, Diplopia, Fatigue
-DDI – several

Question 30

perampanel

Answer 30

-MOA – educing neuronal excitation via the noncompetitive antagonism of the ionotropic-AMPA-glutamate receptor on postsynaptic neurons
-Indications – Partial seizure, Tonic-clonic seizure; Adjunct
-Precautions – avoid use with EtOH, may worsen mood and increase anger, falls, hepatic impairment, Drug reaction with eosinophilia and systemic symptoms (DRESS), dizziness, vertigo, gait disturbance, somnolence, and fatigue-related events, suicidality, ideation, renal impairment
-ADR – Abnormal gait, Ataxia , Dizziness , Headache, loss of equilibrium, somnolence, Irritability, Mood disorder,, Fatigue
-DDI – many

Question 31

therapeutic spectrum of antiseizure drugs

Answer 31

-start with an old one that you know works and add on a newer maybe
-dont memorize

Question 32

antiseizure drugs with potential to worsen generalized seizure types

Answer 32

carb and pheny- inducer -> affect other drugs

Question 33

drugs for status epilepticus

Answer 33

-BENZOS
-1. Lorazepam (Ativan) (IV/IM) (PO) ** preferred drug **
-Rapid onset with longer duration than diazepam
-Can repeat doses every 10-15 min
-2. Diazepam (Valium) (IV) (PO) (PR)
-Rapid onset but shorter duration than lorazepam
-Can repeat doses every 15-20 min

-PHENYTOIN (IV)
-2nd line if unresponsive to BDZ therapy
-insoluble in most diluents, stability issues, specific administration guidelines
-Slow onset, long duration
-Dosing: Loading dose, maintenance dose
-if you give fast rate -> HTN

-FOSPHENYTOIN (IV/IM)
-prodrug of phenytoin
-better solubility/stability
-Expensive

-VALPROATE
-LEVETIRACETAM

Question 34

drugs for refractory status epilepticus

Answer 34

-pentobarbital coma
-midazolam
-propofol
-Ketamine
-Isoflurane & Desflurane – highly refractory -> general anesthesia

Question 35

management of epilepsy in pregnancy

Answer 35

-1. Seizure control
-choose drug according to seizure type
-Use monotherapy if possible
-monitor serum levels

-2. Reduce/monitor for teratogenicity
-folic acid supplementation
-appropriate testing
-Vitamin K during last month

-you can consider taking pregnant pt off antiseizure if they have had NO 6 months prior to trying to conceive -> then you ween them off before trying to conceive
-almost a year long process
-stick to one drug tx
-if you keep them on -> monitor before, beginning of each trimester (minimum), and first 8 weeks postpartum

Question 36

switching or discontinuing anticonvulsants

Answer 36

-1. Switching:
-get new drug to effective dose
-taper old drug slowly over several weeks
-is the drug causing SJS, CBC issues

-2. Discontinuing
-seizure free for 2-5 years (on drug therapy)
-single type of seizure
-normal neuro exam/IQ
-EEG normalized
-> TAPER minimum 3 months

-taper off (or stop completely if SJS) -> BRIDGE with a benzo -> load on another drug

** AVOID abrupt withdrawal of any anticonvulsant medication b/c seizures may precipitate – except in cases of a significant ADR – then drug must be stopped**!!!!!!!!!!!!!!!!!!!!

Question 37

summary

Answer 37

-Seizure type is classified based on the initial manifestation of the seizure as generalized, focal, or unknown (if seizure onset is either missed or obscured. Of note, the terms simple partial, complex partial, and secondarily generalized have been eliminated, since they were difficult to define pragmatically and were often used incorrectly.
-(Seizures can be classified as either partial or generalized. Partial seizures are simple or complex. Generalized seizures are further subdivided as tonic-clonic, absence, myoclonic or atonic)
-The Pathophysiology of seizures involves abnormal neuronoal discharges, excessive glutamate activity, suppression of GABA activity and/or increases in Ca influx in thalamic neurons
-Mechanisms of action of the antiepileptic drugs are targeted towards the underlying pathophysiology of seizure activity and may include inhibiting calcium and sodium influx which is responsible for neuronal transmission, inhibiting glutamate and augmenting GABA
-Traditional antiepileptic drugs include carbamazepine, phenytoin, valproate and phenobarbital. They can be used to treat all seizure types. They are all narrow therapeutic index drugs with significant ADRs and potential teratogenic effects
-Ethosuximide is preferred for the treatment of absence seizures in children
-There are several newer drugs for the adjunct treatment of epilepsy. Overall, they are better tolerated than the traditional drugs but not as effective as monotherapy. There are selected ADRs that are specific to the individuals agents. For example, topiramate causes kidney stones.
-The drug of choice for status epilepticus is lorazepam IV or IM. Other treatment options for status epilepticus include phenytoin, Fosphenytoin, phenobarbital, pentobarbital, midazolam or propofol
-In general, pregnant patients should be maintained on the seizure medications they were taking prior to pregnancy with increased prenatal screening
-In general abrupt withdrawal of any seizure medication should be avoided, unless the patient is experiencing a significant or life-threatening ADRs.
10. Most antiepileptic drugs may increase suicidal ideation and require product labeling and Medication guides indicating this

Question 38

1. Jane Doe is a 28-year-old woman recently diagnosed with partial simple seizures. She was started 2 weeks ago on Tegretol 400 mg/day in 2 divided doses. She has come back to your office for follow up. She had one seizure episode since her medication was started. Her current Tegretol level is 2.5 mcg/ml (therapeutic is 4-12 mcg/ml)

Answer 38

a. What change would you make at this point?
-give 300 twice a day

b. What adverse reactions may the patient experience?
-CNS depression
-weight gain
-diplopia

c. What else should you educate this patient about?
-monitoring- check CBC
-inducer- DDI- OCP
-SJS

d. Write a prescription for the new dose of Tegretol?

Question 39

2. JJ, a 4-year-old female with absence seizures needs a prescription. The child has difficulty swallowing capsules. She weighs 44 pounds.

Answer 39

a. What is the treatment of choice in this case?
ethosuximide

b. What should be included in your patient education discussion?
-CNS depression
-gi distress
-DDI – valproate inhibits, no other significant interactions

c. The pediatric dose for the drug you should choose is 15 mg/kg/day in 2 divided doses. The drug is available as 250 mg/5 ml syrup (473 ml bottle). Write the prescription.
-44 / 2.2 = 20
-20x15 = 300
-300/2 = 150mg 2x day

Question 40

know which drugs are inducers and inhibitors

Answer 40

-older agents are more effective
-newer agents have less side effects
-try combinations
-low dose old and higher dose new