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Case Presentation:Seizures and Antiepileptic DrugManagement
Christine Rizkalla, RPh, BScPhmPharmacy ResidentSeptember 13, 2006
Objectives� Present case and care plan for CC
� Outline the etiology, pathophysiology, and clinicalpresentation of epilepsy� Focus on refractory epilepsy
� Evaluate antiepileptic drug (AED) treatment forepilepsy� focus on newer AEDs agents in refractory complex partial
seizures
� Highlight practical considerations of therapeutic drugmonitoring of AEDs
Case - HPI� ID
� CC, 32 yo F
� DOA:
� September 5� from another
hospital: DOA=Aug 26)
� Vitals� HR=85, BP=100/60
� Labs
� Hb=104, ferritin<1,ALP=141
� CBZ level Sept 5 at18:52=28umol/L
RFA: seizures + abdo pain
Case – PMH� Epilepsy
� complex partial seizures (CPS) since age ~13, tonic-clonic� Abdo discomfort spreading to whole body, subsequent
stiffening, lip-smacking, spasms of hand or face� Not a surgical candidate� Tried “a variety” of meds
� GI� abdominal cysts, ascites, GIB, Crohn’s - diarrhea
� Deafness� Impaired vision� Developmentally delayed� Depression� Anemia
Meds prior to admission
1. CBZ 400mg qam +300mg qhs
2. Lamotrigine 100mgqam + 125mg qpm
3. Clobazam 10mg tid4. Mg oxide 250mg tid5. L-thyroxine 0.137mg
od6. Prednisone 5mg od7. Ranitidine 150mg bid
8. Folic acid 5mg od9. Fe gluconate 300mg
od10. MOM 30ml od11. Docusate Na 100mg
tid12. Hyoscine bromide
10mg tid
Meds
“Pharmacy to clarify”Pentasa 1500mg po tidPentasa 1500mg tid
pantoprazole 40mg od
“Pharmacy to clarify”prednisone 5mg od
ranitidine 150mg bidranitidine 150mg bid
Mg oxide 250mg tidMg oxide 250mg tidMg oxide 250mg tid
lamotrigine 100mg bidlamotrigine 100mg qam +125mg qhs
lamotrigine 100mg bid
clobazam 10mg qam + 30mgqhs
clobazam 10mg po tidclobazam 10mg qam + 30mgqhs
CBZ CR 800mg bidCBZ CR 400mg qam +300mg qhs
CBZ CR 600mg qam +800mg qhs
TGHFAR AWAYHOME
l-thyroxine 0.137mg odl-thyroxine 0.137mg od
Folic acid 5mg odfolic acid 5mg od
docusate Na 100mg tid
MOM 30ml od
Fe gluconate 300mg odFe gluconate 300mg od
vit C 500mg od
vit B + C 300mg od
TGHFAR AWAYHOME
Issues
1. �Refractory seizures
2. Abdominal cysts
3. Pain� inadequate treatment
� Contribution of ferrousgluconate
4. Crohn’s disease� diarrhea
� Contribution of Mg oxide
� ?prednisone duration
5. Depression� apparently untreated
6. Medication Reconciliation7. Communication
� Deaf� Developmentally delayed
Refractory Epilepsy – unansweredquestions
� primary refractory
� secondary to decreaseddrug absorption (Crohn’s)
� secondary to pain �lowered seizurethreshold
� secondary toinappropriate AEDselection
� drug monitoring
EPILEPSY
Definitions, etiology,pathophysiology
Definitions� Small numbers of neurons discharge
abnormally � normal homeostasis disrupted� seizure
� Seizure = clinical event that results from anabnormal electrical disturbance in the brain
� Epilepsy = chronic neurological disorder inwhich patients experience recurrentseizures.
Pathophysiology1. Abnormality in K+ conductance, defect in voltage-sensitive ion
channels, deficiency in membrane ATPases linked to iontransport, deficiency of inhibitory NTs or increased excitatoryNTs, inadequate supply of glucose, O2, Na+, K+, Cl-, Ca2+, aminoacids, abnormal pH
2. Unstable cell membrane (or surrounding supportive cells)
3. Paroxysmal discharges� Synchronously
4. Break down of normal membrane conductances and inhibitorysynaptic currents
5. Spread locally (focal seizure) or more widely (generalized)NEJM 2003;349(13):1257-1266 DiPiro’s
Principles of Medical Pharmacology 1998
Epilepsy
Partial Generalized
Simple Complex Absence Tonic-Clonic Tonic Clonic Atonic
Epilepsia 1981;22:489-501
(may secondarily generalize)
Partial (focal)� 20% of epilepsy cases� Arise from 1
hemisphere, but canspread to becomesecondarily generalized� most believed to be a
result of insult to brain
NEJM 2003;349(13):1257-1266
� Involuntary twitching, jerking, autonomic sx’s (i.e.vomiting, sweating, epigastric sensation), alteredsensory perceptions, psychic sx’s (deja-vu, fear)
� automatisms� Simple
� consciousness not impaired� EEG: localized spiking in neocortical or limbic area
� Complex� consciousness is impaired� EEG: spiking in both temporal lobes
Generalized Seizures
� Originate in bothhemispheres
� Consciousness alwaysimpaired
� many have strong geneticcomponent
� believed to result fromalteration in circuitrybetween the thalamus andcerebral cortex
NEJM 2003;349(13):1257-1266
Absence� Sudden onset, interruption of
activities, blank stare +/- upwardrotation of the eyes
� Generally in young children throughadolescence
� Can have mild clonic, atonic, ortonic components and autromatisms
� Often no memory of event
� EEG: characteristic 3-per-secondspike wave
NEJM 2003;349(13):1257-1266
2. Tonic-clonic – 60%� Tonic-clonic (grand mal):
� May be preceded by aura� Sharp tonic contraction -> rigidity + clonic
movements.� May fall, cry, moan, lose sphincter control, bit
tongue, develop cyanosis� EEG: constant spiking, whole brain� <5minutes� Post seizure: may be unconscious, go into deep
sleep
� May have tonic and clonic seizuresseparately.
NEJM 2003;349(13):1257-1266
Status Epilepticus
� Defined as continuous,generalized, convulsiveseizure lasting >30 minutes or>/=2 discrete seizures wherebaseline consciousness is notregained between episodes
� Major medical emergency,associated with significantmorbidity and mortality
CHEST 2004; 126:582-591
Etiology
� 68.7% Idiopathic� 13.2% Stroke
� 5.5% Developmental defects� 4.1% Central nervous system tumours
� 3.6% CNS infections� 1.8% Degenerative diseases
� Electrolyte abnormalities, drug causes
Diagnosis
� History� MRI – neurological radiological evaluation of
choice� Computerized tomograph – much less sensitive
� Labs: glucose, urea, lytes, LFTs, Ca2+, serumalcohol, serum/urine screen for illicit drugs
� EEG� Seizure activity characterized by sharp wave/spike� Our patient: 1 EEG: normal – what does this tell us?
� Risk factors� ?Genetic
predisposition
� Head trauma� CNS infections
� Mental retardation� Stroke (CVD)
� Neurodegenerativedisorders
� Tumor
� Precipitating factors� Sleep, sleep
deprivation
� Sensory stimuli� Illness
� Emotional stress� Hyperventilation
� Hormonal changes(i.e. menstruation)
Drug causes� Amphetamines� Anticholinergics� Anticholinesterases� Antidepressants� Antiemetics� Antihistamines� Antipsychotics� BBs� Cephalosporins� Cocaine� Cyclosporine� Estrogen� anesthetics
� Imipenem� Isoniazid� Lithium� Methotrexate� Methylphenidate� Metronidazole� narcotic analgesics� Penicillins� Quinolones� sympathomimetics,
theophylline, tramadol� Abrupt AED withdrawal
Ann Fr Anesth Reanim. 2001 Feb;20(2):171-9 CHEST 2004;126(2):582-591Managing epilepsy and co-existing disorders.
Boston: Butterworth-Heinemann; 2002;155-173
Prognosis� Most important predictive factor for
remission: Number of seizures in the first 6months after first presentation.
� Shortened life expectancy� depending on etiology
� 20% risk of death with each episode of statusepilepticus
Clin Neuropharmacol. 2003;26(1):38-52
NEJM 1996;334(3):169-175
Refractory Epilepsy
� Often considered refractory when failed 3 or more AEDs� Despite medical therapy, seizures persist in
� 20% primary generalized� 35% partial
� VA Cooperative study:� 60% had satisfactory control after 1st monotherapy� 55% (of 40%) responded to alternative monotherapy� ½ of remaining had improvement with 2 AEDs
� Kwan & Brodie (2000):� 47% seizure-free without adverse events� 1/3 became seizure-free after intro of alternative monotherapy
Clin Neuropharmacol. 26;1:38-52 Neurology 62;2004:1262-1273
NEJM 340;20:15651570
Pharmacotherapy
When is treatment required?
� Usually not after 1st seizure� May consider txt if: neurological deficit, EEG
shows unequivocal epileptic activity, pt request,structural abnormality in brain.
� After a 2nd seizure� Risk of further seizure increases to 80-90%
Goals of Therapy
� Ultimate goal: no seizures and no side effects
� Optimal quality of life� Assess concerns of patient
� social isolation, relationships, stigma
� Recognize comorbidities
General Principles
� Monotherapy vs. polytherapy
� Agent depends on type of seizure, toxicityprofile, pt preference
� Start low, go slow
Therapeutic Options
Status Epilepticus
� *lorazepam 0.1mg/kg IV at 2mg/min
� phenytoin 20mg/kg IV at 50mg/min
NEJM 1998;338(14):972-976
ethosuximide
valproate
lamotrigine
*CBZ, phenytoinarecontraindicated
CBZ,
gabapentin,
valproate,Lamotrigine (mixed),
oxcarbazepine,
phenobarbital,phenytoin,topiramate (mixed)
CBZ,
gabapentin,
valproate,Lamotrigine (mixed),oxcarbazepine,phenobarbital,
phenytoin,topiramate (mixed),
clonazepam
Drug ofchoice
AbsenceTonic- ClonicPartial
Treatment NEW ONSET Summary
NEJM 340;20:1565-1570 Neurology 2004;62:1252-1260
Clin. Neuropharmacol. 2003;26:38-52 NEJM 1996;334(3)168-175
Carbamazepine� Related to TCA’s� MOA: blocks voltage-dependant Na channels� S/E’s:
� Dose dependent: N/V, diplopia, H/A, dizziness, leukopenia,hyponatremia
� Idiosyncratic: rash, agranulocytosis, aplastic anemia,hepatotoxity� Drug I/A’s
� Auto – inducer (lamotrigine, corticosteroids)� Cimetidine, valproate, isoniazid increase levels� TCA’s, MAOIs� OCP
� Dose: 600-1600mg/day� Availability of CR
� Cost: $
NEJM 1196;334(3):168-175
Clin. Neuropharmacol. 2003;26:38-52
Phenytoin� MOA: blocks voltage-dependant Na channel� S/E’s
� Dose dependent: sedation, ataxia, nystagmus,diplopia, folate/vit D deficiency, osteomalacia,hirsutism, gingival hypertrophy
� Idiosyncratic: rashes, bone marrow suppression,hepatotoxity
� Drug I/A’s� acute inhibitor, chronic inducer� Cimetidine, disulfiram, INH increase phenytoin
� Cost: $
NEJM 1196;334(3):168-175
Clin. Neuropharmacol. 2003;26:38-52
Valproic Acid� Effective for all types of epilepsy� MOA: ? ↑ GABA, ?Na channel blockade
� S/E’s� Dose dependent: N/V/D, ↑ appetite, ↑ weight, tremor, hair
thinning, hyperammonemia� Idiosyncratic: thrombocytopenia, hepatoxicity, bone marrow
depression
� IXN’s:� Inhibitor
� Dose: 1000-2500mg/day
� Cost: $
Pharmacokinetic monitoring – tips andreminders
� Treat the patient, not the level!� Phenytoin
� most important example of zero-order kinetics. >90%protein bound. Adjust for low albumin.
� 4-7 days after initiation, 3-5 weeks later, then q6-12months(IV: +4hrs after load)
� Valproic acid� Likely not helpful to monitor levels
� Gabapentin� Dose dependent absorption
� Measure troughs
Epilepsia 2005;46(Suppl.4):31-37 Clin Neuropharmacol. 2003;26(1):38-52
Drug Information Handbook 2005
Efficacy of New AEDs in RefractoryEpilepsy
� NB: No class I evidence comparing newAEDs to the old or new AEDs to each other inREFRACTORY epilepsy
Neurology 2004;62;1261-1273
NoNoYesZonisamide*
NoNoYesLevetiracetam
NoYesYesOxcarbazepine
NoNoYesTiagabine*
YesYesYesTopiramate
NoYesYesLamotrigine
NoNoYesGabapentin
Tonic-ClonicPartialmonotherapy
Partialadjunctive
Drug
Newer antiepileptic agents inREFRACTORY Epilepsy
Neurology 2004;62;1261-1273
Lamotrigine
� MOA: Prolongs inactivation of voltage-dependentNa+ channels
� S/E’s� Dizziness, ataxia, diplopia, nausea, rash (dose-related)
� Drug I/A’s� OCP ↓ lamotrigine, lamotrigine ↓[OCP] at doses
>200mg/day� *Inducers (i.e.CBZ) decrease concentrations
� Dose� With valproate: 50-100mg/day� With inducers: 200-500mg/day
� Cost: $$
Epilepsia 2005;46(Suppl.4):31-37 Neurology 1993;43:2284-2291
Clobazam
� MOA: potentiates inhibitory effect of GABA� Efficacy: effective in refractory epilepsy- most
consistent results with partial.
� S/E’s: psychomotor impairment, sedation, tolerancewithin 3 months
� Drug I/A’s: alcohol and CNS depressants� Dose:
� 20-30mg, up to 60mg� can be given intermittently (i.e. catamenial)
� Cost: $
NEJM 1996;334(24):1583-1590 Curr. Ther. Res. 1985; 37:1098-1103
Drug Related Problems1. CC is experiencing recurring seizures secondary to
� inappropriate drug therapy
� Pain
� inadequate absorption
� Inadequate dose of antiepileptic – i.e. CBZ, lamotrigine
And requires optimization of her antiepileptic drugtherapy.
DRPs - continued
2. CC may have developed tolerance to clobazamand may benefit from gradual discontinuation ofclobazam therapy.
3. Patient is experiencing abdominal pain secondaryto unknown pathology and requires analgesia.
Pharmacy Care Plan for EpilepsyManagement
� Clinical Outcome� Reduce frequency of seizures� Reduce pain
� Pharmacotherapeutic Outcome� Provide the optimal combination of antiepileptic
drugs at the right dose, frequency, and duration,with minimal side effects.
Pharmacotherapeutic Endpoints
1-2 daysDecrease to 2-3/10
Pain
48-72hrs≥50% decreaseNumber ofseizures
Time FrameDegree ofChange
Parameter
Alternatives and Assessment
� CBZ� Phenytoin
� Valproic acid� Lamotrigine
� Topiramate� Gabapentin
� Tiagabine� Zonisamide
� Levetiracetam
� Clobazam� Magnesium Oxide
Therapeutic Plan
� Increase CBZ dose� Increase by 200mg/day at intervals of 2-4 weeks
� Increase lamotrigine dose� By 50mg/day every 1-2 weeks
� Keep magnesium oxide� (keep clobazam issue in mind for clinic
follow-up)
Therapeutic Plan Endpoints (Negative)
Durationpreventrash
DurationNo changeLFTs
DurationSlight decrease inWBC’s ok
CBC (WBC’s, Hb)
DurationNo changeVision (diplopia)
DurationNo changeelectrolytes
DurationMinimal change.(Treat with analgesia)
H/A, dizziness
DurationNo change frombaseline
N/V
**CBZ
Time FrameDegree of ChangeParameter
Carbamazepine monitoring
� Take troughs!
� Steady state:2-6 days after initiation (priortherapy)
� Auto-inducer: 2-4 weeks after initiation� Therapeutic concentration: 17-50umol/L
What do you think?
� What is relevant data to know in interpretingthese levels?
� Sept 5 18:52: 28umol/L (?CBZ dose: 10:00)
� Sept 6 08:21: 47umol/L (CBZ dose: 10:40)� Sept 7 22:21: 44umol/L (CBZ dose: 21:25)
Other issues� diarrhea secondary to
?Crohn’s, ?Mg Oxide
� likely not receiving full doseof prednisone secondary tointeraction betweenprednisone and CBZ.
� CC is experiencing signsand symptoms of anemiaand requires therapy
� CC is experiencingsymptoms of depressionand requires therapy
� Pt is at risk ofhypothyroidism, worseninganemia secondary to� Lowered dose of
lamotrigine� Omission of l-thyroxine on
admission
What happened…
� In ER:� Pt continued to have multiple seizures/day on first
day in ER
� Collaboration with Amita:� Called transferring hospital to determine medication
history there� Spoke to patient, patient’s mother, consulted med list for
patient’s medication history� Collaborated with neuro
� Documented
� Increased dose of lamotrigine, Mg oxide
� Neuro opted to keep pt on CBZ 800mg bid� Next day:
� Vomited, severe abdominal pain, dizziness, H/A� ?cause (cyst, drug)
� Determined dose of 5-ASA, prednisone �informed MDs.
� Informed MDs of l-thyroxine, omeprazole �ordered
� Morphine prn for pain helpful� Surgery:
� Abdominal US: large pelvic cyst. Surgery to drain.� ?no Crohn’s: Pentasa + prednisone discontinued
� Spoke to internal medicine to d/c levels, re-draw at day 6, then in 5 weeks� Sept 12 (DAY 8) 09:07: 41umol/L� (CBZ dose: 10:00)
� Depression drug disappearance
Questions?