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?