Oh111

1 sl week 2nd week Srclweek 4th week

No litraiion -■- Titration

FIGURE 30-3. Serum concentrations of carbamazepine in the presence and absence of appropriate dose titration.

Drug Selection and Seizure Type

The key to selecting effective pharmacotherapy is to base the decision on the seizure type. Several consensus treatment guidelines from the Scottish Intercollegiate Guidelines Network (SIGN), the National Institute for Clinical Excellence in the United Kingdom (NICE), the American Academy of Neurology (AAN), and ILAE all use determination of seizure type as the basis for selection of pharmacotherapy (Table

2Q_30

30-2). While the guidelines make recommendations for specific drugs to be used in certain seizure types, the consensus recommendations utilize only data available from the medical literature. In many cases, a recommendation is not made because there are no published data on which to make an evidence-based decision. Therefore, a drug may not currently be recommended for a seizure type simply because it has not been studied for that seizure type. Absence of a recommendation should not be taken to mean the drug is ineffective for a specific seizure type.

Outside of the evidence-based guidelines, other pharmacologic treatments are commonly used or avoided. For initial treatment of absence seizures, ethosuximide and valproate are commonly used, not only in the United Kingdom, but also in the United States. Zonisamide may be also used for initial treatment of absence and myoclonic seizures. In absence and myoclonic seizures, carbamazepine, oxcar-bazepine, gabapentin, tiagabine, and pregabalin should be avoided, as they have been associated with an exacerbation of these types of seizures.

Table 30-2 Evidence-Based Guidelines for Initial Monotherapy Treatment of Epilepsy

Ton\

Net mcii(iort«i

No! mentioned

AtonK

Wot nvrri(iiiiv.yj

Partial wtth a wilhtHil iMOrtCUiy qerefali/alion

Cartwmaiipf^ne Gabapiwift

LarrotrlcjinH*

OwCiibiUCfiirio

Phe no barbital

Phenytwln lo|jidiiid1e

Valproate

Nor mentioned

PlnenjftQin

CjrlMiYiiiyiiiiW

Valproate

Limeiflglna

Oxjcaib^epint?

LamcHiigirw; VjIproaLc tecondtint?: OobszanV1 Clofwepam Ljevairatotjm iapirjmjte Ljnrotrigini1 Valproate Second-tine; Clolxwiirf1

Clonazepam Lcvelifacetsnn Topirjmate CdrhamarefKne [¿rnodkjirie Oxrarlwepdne VajprtHW Topii ainate SaiiMTri-Wnfr

Ctobuam1 Gabapentin hio! mcntiory*)

Uiii nvntiorv^J

AMIS

iartMiiwcpnif

PhefiytnlnT

VJlproaW

Gatrtpenim

Laninrlqlne'

OsCarbaitpne

Phenobaibitat

When an appropriate AED has been chosen, doses are started very low and titrated over several weeks. Usually a moderate target dose is chosen until the patient's response can be further evaluated in clinic. If seizures continue, the dose should be increased gradually until the patient becomes seizure-free or adverse effects appear.

For some drugs like lamotrigine, specific titration guidelines are established by the manufacturer.

Refractory seizure (i.e., unresponsive to at least two first-line AEDs) treatment is somewhat different. According to the AAN Practice Parameter, topiramate is useful as monotherapy for primary generalized tonicclonic seizures, and there is insufficient evidence to make any recommendation regarding gabapentin, lamotrigine, ox-carbazepine, tiagabine, levetiracetam, or zonisamide.31 Combinations of drugs are not addressed by the AAN, but may be useful in patients with difficult to control primary generalized seizures. This practice parameter also gives the highest recommendation to oxcarbazepine and topiramate as monotherapy in patients with refractory partial epilepsy. Additionally, lamotrigine is noted to be effective as monotherapy for refractory partial seizures, but was associated with a high dropout rate in the clinical trials. All AEDs, except ethosuximide, are effective in combination therapy for partial seizures.

Complications of Pharmacotherapy

Adverse effects of AEDs are frequently dose limiting or can cause a drug to be discontinued. Two types of adverse effects occur with AEDs: concentration related and idiosyncratic (Table 30-3). Concentration-related adverse effects happen with increasing frequency and severity as the dose or concentration of a drug is increased. For many AEDs, common concentration-related adverse effects include sedation, ataxia, and diplopia. These adverse effects should be carefully considered and used as one of the AED selection criteria. For example, if a patient has a job that requires mental alertness, it is best to choose an AED that is less likely to cause sedation (e.g., lamo-trigine).

Idiosyncratic adverse effects are not dose or concentration related and will almost always result in the AED being discontinued. Rash, hepatotoxicity, and hematological toxicities are the most common idiosyncratic reactions seen with AED. Because many of these adverse effects are life threatening or potentially life threatening, the AED should be discontinued immediately when the reaction is observed. Carbamazepine, phenytoin, phenobarbital, valproate, lamotrigine, oxcarbazepine, and felbamate are most likely to cause these types of reactions. Many of these reactions are thought to occur primarily on an immunological basis, which raises the possibility of cross-reactivity. This is especially true for carbamazepine, phenytoin, phenobarbital, and ox-carbazepine, where 15% to 25% of patients who have an idiosyncratic reaction to one drug will have a similar reaction to the other drugs.

Table 30-3 Characteristics of Common AEDs

Dron

Mti Nanism of Action

Plinrmacokin^tií

Dos»

F"ar»meteít

¡aodingdaif:

KWÍ-Mfer

Mot recommended

10-Jí hcwswltli

ÍUMO tMíflSimO

chiúnlc doscm

doie-reljted

íífljiíríflr wgfcmtf tu

tortcKy

dtanbuiiro».

OJS- I 9 Lrtiq

Iii lite J^JiKií tü

Rorsíri ttfxXftif.

target over J-4

bf-i

w<><+4

ÍWtMfrtGiBtMltot

Adcflii: 1D-20 mg/

rottft

kg/day asa divided

Hepai&c

dtw

thidíÉfl: M-30iTij/

tg/day asa dMded

UimE ^rum Cifncrnl'otiun H*n<te_

Qnia-RslllsiJ U^tfH

IdioiynLrílii

Adverse Cfecli i'jitMiíijjiífJrH1

Fiji íodiari channel IhKllrriOn

DifJopii, drowsineii, nausea («laitirl

Aflknlif JiiMnfe n^pautrernji k'urcpi'iilji QffeOpCHHi^ iah

EdwturinnkJi

HaffWiv l>r>iiri ^■pa'sitf kaA^ne of dbHftrifett

EdwturinnkJi

Modulate coktvn dianneli tuaifrifl <¡mt, Hin iiwirnrttffiífed due 1o increased

AlaínríVTdfitedüíí: IniMeat 2ÍOrrg lwfco ü.nly .11 iü iltraie to 5W-UQ00 mg tvnkedWy

HaffWiv l>r>iiri ^■pa'sitf kaA^ne of dbHftrifett

ftiiíiwycApiiiKiKfi ™fr mi (K3-7LB |jmoHi

Alaila.

VHjitkjfl

rcflxmiatc

■rihihil üljumjie activity

[purfáTjí^r N01 fecodnnraflöMl Aie to increased *4*nt rifan VlaSnrírMíncfdlüífi I.KW-ijeOOnVAv In Soi 'Idivided (toses

HOt-Vk;

Monaherapy Ja houís Ccmturent enjyrne

MHluiCf:,: >1 16 liijuil

Apfxiiiw infame of cfur^fwrw frotan frvinVi^ Í5-33*

fVunapyítaitfHf.wi rairr hk'futl;

NoctrntHirt

Arui^íy, insomne nausea

Ancftón aplmiií anemia, headache.

hfpOíai<niCiCy, weight KJÜ

Gibtpfflttl

MDÚOlKt

ímd«T(? (fcií

Ha UN ir

Notes1alíiJ*d

DitJw:lnes:.

PttilVicfal rfenw

calcUn

N:JI rivofiinvi^hsJ

5"? hotlli (¡prúflOUiíUlJl

wdation

wí'Kjhl c^brl

(taiméis

(Aje to sha!

K> ere atlnlne

indtnhioce

h¡#H[ft

chwisriccl

fiftBA

AVí-nfínmtfdtiM:

AnatiffH vatuirifat

activity

900-3,60: mg/day

tfutriMforv

in 3o«4dlvtded

0.6-0.8 LAg

doses (coses

Protein bMnp

up to ICjOOO

less titan 10%

mg'day have been

Pnmory ehminaton

toUf.ttini)

route:

Renal

Lacosamide

Stow sodium

loading dne

HaH-Ue

Mot estaWsised

Ataxia.

PR interval

channel

Data una\aitable

Appropriately 13 hours

dizziness.

prorogation

inactivation;

fAameno/Kedoie:

Volume oí d/st'/bubon:

diplopia.

mod übte

200-400 nyj/day.

061 Axj

heaJaclvc,

coOapsin

Start at 100 mg/

Protein bmd<ng

nausea.

response.

day m 2 divided

less than 15%

vomiting

mediato«

doses and titiate

Primary elimination

ptote«v2

upward according

route

torespexwe

40% renal

60% hepatic

Lamotrigine

Fan sodium

loading d>te-

MaV-Mr

Mot estaMshed

Ataxia.

Rash

Channel

Not recommended

Monotterapy. 24 hours

drowsiness.

iivxliv,>1too

due to increased

Concurrent enzyme

headache.

risk of rash

inducers: 12-15 hours

insomnia,

Motfiferhwedose

Concurrent enzyme

sedattcn

150-800 mg/day

inhibitors:

in 2 or 3 divided

55-60 hours

doses Coses

Appof<vf,xAjmeo(

s»x*ild be initiated

dntnbution:

and titrated

I.I LAg

according to the

Proton binding

rrum/a(turefs

55%

recommendations

Primary eimwofion

toredme the risk

route

of rash

Hepatic

levetiracetam

ModiJate

¿OOtflOgdlWir

HaMsfe.

Not established

Somnolence.

Depression

synaptic

Not reconmended

6-8 hous

dizziness

vesicle

due to excessive

Apparent volume of

protein

adverse effects

dnicibuiion.

MamtenaKedose.

0.5-0.7 LAg

IXJOO-JjOOO

Protein binding:

mg/day. Start at

less th*i 10%

1.000 m^day and

Primary etvmnatky»

tilrated iipward

route

as mdicaed by

70% renal

response

30% hepatic

CKcaibazepine

Fast sodium

loading dc^e

HaVMfe

Not established

Diplopia.

Hyponatremia.

channel

Not recorrmended

Parent drug

dizziness.

2S-30% cross

inactivation

due to ercessive

AfprcsamaieV 2 Iwu*

somnolence

sensitivity In

adverse effects

I0monoh>«kwy

patients vsuh

ftonurxiKe dote.

Meuboke

hypersensitivity

600-1.20C mg/day

^prortmateV9hours

to

Start at )00 mg

Apparent volumeo!

carbamazepine

twice daily and

dHiribuHott:

titrated upward

05-0.7 LAg

asmd«;tedby

Protein binding:

response

40%

Primary etrnmation

route

Hepatic

Phenobarbital

last sodium

loading don*

Hati-Me

15-40 meg/

Atari*,

Attention deficit.

channel

io-ai mgkg as

AOuRS.-ry-iAi hours

mi ios-1 u

drowsiness.

cognitive

inactivation

single a divided IV

Children: 37-73 hous

MmdA)

sedation

impairment.

infusion or orally in

Neonates:

hyperactivity.

divided loses over

approximately 115

osteoporosis.

24-48 hjurs

hous

passive-

fAwierxifice dcne.

Vobmeoldrsmbutloa

aggressive

Adults 1 -1 mg/kg/

0./-1 L/kg

Dehavtor

d.iy .is a Single or

Proum binding:

divided Jose

Approximate*/ 5C%

CMdren J-6 rrvykg/

Primary etvwwrw

dayasdvided dose

route

Neonates; 1-3 mg/kg/

Hepatic

dsyasdudeddose

Phenytoin

Fast sodK*n

Loading dose

Ho,U1e.

10-20 meg'

Atania,

Anemia, gingiva)

channel

Adults 15-20 mg/

Fcflows capacity

rri (40-79

diplopia.

h>perpiasia.

inactlvation

kg singW IV dose c*

limited o»

Mmol/l)tcu(

drowsiness.

hirsutism

divided jfal dose

Michaelis Merten

ccncen&atton

sedation

lymphade-

Infants le» than 3

pharmacokinetics

l-2mcgtrl

ncpathy.

months 10-15 mg/

Ha* We increases

(4-8MmoW)

osteopexosjs.

kg single W dose

as the dose and

urtoound

rash

Neonates: 15-20

iCtum concentration

concenftalton

mg/Vg single HZ

Increases.

dose

Vcbmeaf distnbut¡on

fAxnifnoKedcxe.

Adults 0 7 L/kg

Adults 5-7 mg/kg/

Children: 0.8 l/kg

day.assngleo«

Neonates: UL/Vg

divided Jose

Protein binding:

CUMren: ¿-15 mg/

Adults, children:

kg'day. as divided

88-92%

dose

Neonates: 65%

Neonates: 3-6 mg/

Primary ehmnation

kg'day. as divided

route

dose

Hepatic

Pre<fabalm

Modulate

Loading dyse

ftaW4e.

Not estabflsfwd

Ataxia, blurred

Edema. weight

calcium

Not recommended

63 hours. proportional

vision.

gain

channels

due to increased

to creatinine

dizziness.

acherse effects

clearance

dry mouth.

tAchntefkMcedoie:

Apfxxtrui'otumrof

somnolence

Initiate at 150 mg/

distribution

day in 20» 3

051 Ag

divided Joses

ProieM tundfig.

and titfite to a

NegKgMe

mawmim dose of

Primary tdmination

eoomgday

route.

Renal

Ri/lnamide

Unknown,

Loading dyse.

Ha<f-LJfe

Not established

Dizziness.

may

Data unbailable

6-10 hours

fatigue.

enhance

Maintenance dose

Appa.-eni\otomeot

headache.

tnactivatlon

Children 45 mg/kg/

distribution

nausea.

oi sodium

day of 3200 mg/

AppfociTiately 07 lAq.

somnolence.

channels

day; stau at

varies with dose

vomiting

10 mg/tg/day In

Pr<xe>n bMng:

2 drvideJ doses

34% (27% to albvnVn)

and titfite upward

Primary etrminatxx)

acccxding to

route.

Adults: 3;00 mg' day. start at 400-800mg/d,»y in 2 dlvtJed doses ond Www upward according to res pony_

Tiagabine

Enhance GA8A

Load<ng dxe

Hatf-Afe

Not established

Dizziness,

«.1»v«y

i<».0«i«r*iOc\l

f«V« Ml ni.vy 7-91 w >

wiiuA'i«.':.

cfcie to excessive

Cc«curr«ic enzyme

irrii ability.

adverse effects

induce« 25-45 hours

stowed

fAHntenMiedote:

Apparent vohjrrv of

thinbrig

32-56 m^'day in

¿jrnbutibn-

4 divide! doses.

0.6-08 LAg

Doses should be

Protein binding.

titrated jp.vjrd

96%

ov-er 6 *e<*k\

Primary eivrunotion rout*r

starting at

Hepatic

A nxVdiy

ropiiamate

fast sodium

Loading One.

Ha<f-t4e:

Not established

Ataxia.

Acute glaucoma.

channel

Mot recommenced

Mcnotherapy 21 hours

dizzmess.

metabolic

inactivation.

due to excessive

Goncurent wv>me

drowarvess.

acidosis.

inftbit

adverse effects

indurers; 11-16 hours

stowed

oli^ohldiosis.

glut ¿mate

Main f<Ywce (tee

Apparent ivtomeot

thlnbng

paresthesia.

activity.

100-400 nvj/day in

dMritxjtion.-

renal calculi.

enhance

2 or 3 dMded

0.55-08 L/Vg

weight loss

GABA

doses. Coses

Protein binding:

activity

should be started

13-17%

ait 2S-50 mg/

ftwruyyeAmirwiion

day and gradually

route:

titrated jp.vjrd

£0% rend

over 3-« weeks

40% hepatic

to avoid excessive

adverse effects

Vjlprc* ackJU

Fait sorfexn

loadvtgdow:

HaVUe-

50-100 meg/

Drowsiness,

He patot owelty.

divalproex

channel

Xi-40 mgltg

Adults: 8-15 hours

rrt <346-693

iiausea.

osteoporosis.

sodium

inactlvation

Maintenance dtxe.

Children: 4-15 hours

pmcCUChtten

sedation.

pancreatitis,

Adults 15-45 mg/

Infants less tlun 2

mjyregdre

tremor

wwghi gain

kg'day h 2-4

months: 65 hour

ccnontraticns

divided loses

up to ISO meg'

CWdren: $-60 mg/

01-0.5 lAg

rrldAW

kg'day h 2-4

Protemtund'ng.

prndT)

divided loses

•X%(decie**twrth

Increasing serum

concent/at tons)

Wimay WtrnirMrior) footer

Hepatic

W^lMtnn

Inhibits GABA

(hUd/eir. month-2

HoN-Me. 7.5 hows.

Not established

Convulsion.

Vision loss and

transaminase

years; 50 mg/kg'day

proportional to

(tor»less.

blindness

In 2 divided doses

creatinine clearance

headacl*?.

Muhu Iniriate at

Vobmeof dnti\bot>on

nasopharyngitis.

>.000 m^day in

l.llAg

somnolence.

2 divided doses.

Protein txnding. negligible

weight gain

titrate ip to 3,000 Primary route of mg/doy eitrunation. Renal

Renal kOueCiO S0-80ml/mn decrcov dove by 25%; CiCI 30-50 mty mill iJivriviy ■ (hay ■

bySMfeCrO 10-30

bySMfeCrO 10-30

Zcrt ¡amide

¿(XKlLTg tfox.

Mil establish«! 0izs«ie5s. Meiabolk acidosis.

'vtxlium.iixj

WuL M^nnniL'ndft]

* :J«ITLII<t> g; Itur,

^HiTKilifKi1 dii|iihklr[iM\

□ktm

dL£ to titcessive

AppawtvoHimetif

paresthesia.

100-600 mg/ St

100 fiyyity avl WraLid upward aiiidlcaOrd l^r response

diiributwi. lJit/fe) fturitfi fimftigt 40%

WirtVfy dvr'MLjrftin noun?: HCpMfc

renjlcskii

tiAEft, (jdmrTia-aminobutyrk: acd. F<om Rek 21.3i-30.

tiAEft, (jdmrTia-aminobutyrk: acd. F<om Rek 21.3i-30.

Chronic Adverse Effects

Because AEDs are administered for long periods of time, adverse effects due to prolonged drug exposure are of concern. Chronic adverse effects tend to be primarily idiosyncratic in nature. Some chronic adverse effects associated with AEDs include peripheral neuropathy and cerebellar atrophy. Other chronic adverse effects are extensions of acute adverse effects, for example, weight gain.

32,33

One chronic adverse effect that is of concern is osteoporosis. Carbamazepine, phenytoin, phenobarbital, oxcarbazepine, and valproate have all been shown to decrease bone mineral density, even after only 6 months of treatment. Data on the relationship between other AEDs and osteoporosis are not currently available. Multiple studies have shown the risk of osteoporosis due to chronic AED use to be similar to the risk with chronic use of glucocorticosteroids. Patients taking carbamazepine, ox-carbazepine, phenytoin, phenobarbital, or valproate for longer than 6 months should take supplemental calcium and vitamin D. Additionally, routine monitoring for osteoporosis should be performed every 2 years and patients should be instructed on ways to protect themselves from fractures.

Practical Issues

Comorbid Disease States

Patients with epilepsy often have comorbid disease states. Disorders such as chronic headaches and asthma are frequent problems. For patients who also have asthma, care must be taken to identify drug interactions between AEDs and medications used for asthma. These interactions may necessitate close monitoring for changes in efficacy or increased toxicity, and dosage changes of other drugs may be necessary when an AED

is added or removed. Patients with chronic headaches need special attention in the selection of an AED. Agents known to prevent headache (e.g., valproate and topiramate) may be preferred among several choices, and agents associated with increased headaches (e.g., lamotrigine and felbamate) may be a secondary or tertiary alternative.

Depression is a common problem in patients with epilepsy, with approximately 30% having symptoms of major depression at some point. 4 Patients with epilepsy should be routinely assessed for signs of depression, and treatment should be initiated if necessary. Certain AEDs may exacerbate depression, for example, levetiracetam and phenytoin. Other AEDs (e.g., lamotrigine, carbamazepine, oxcarbazepine) may be useful in treating depression. Changes in mood can be precipitated by the addition or discontinuation of an AED. If treatment for depression is necessary, caution should be exercised in choosing an agent that does not increase seizure frequency and does not interact with AEDs.

Switching Drugs

Changing from one AED to another can be a complex process. If the first drug is stopped too abruptly, breakthrough seizures may occur. Stopping or adding a drug can introduce various problems such as drug interactions which should be considered in any regimen change. Typically the new drug is started at a low initial dose and gradually increased over several weeks. Once the new drug is at a minimally effective dose, the drug to be discontinued is gradually tapered while the dose of the new drug continues to be increased to the target dose. During a transition between drugs, patients should be cautioned about the possibility of increased seizures or adverse reactions.

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