Pharmacologic Therapy

ß2-Adrenergic Agonists

ß2-Agonists relax airway smooth muscle by directly stimulating ß2-adrenergic receptors.2 They also increase mucociliary clearance and stabilize mast cell membranes. Inhalation dosage forms are most commonly used, but oral and injectable dosage forms are also available. P2-Agonists have significantly better bronchodilating activity in acute asthma than theophylline or anticholinergic agents.

Adverse effects include tachycardia, tremor, and hypokalemia, which are usually not troublesome with inhaled dosage forms. Oralp2-agonists have increased adverse effects and should be avoided in patients who are able to use inhaled medications. Oral P2-agonists should not be used in acute asthma because of a delayed onset of action compared to the inhaled route. Inhaled P2-agonists are classified as either short-or long-acting based on duration of action.

Short-Acting Inhaledp2 -Agonists

® Inhaled SABAs are the most effective agents for reversing acute airway obstruction caused by bronchoconstriction and are the drugs of choice for treating acute severe asthma and symptoms ofchronic asthma as well as preventing exercise-induced bronchospasm.1 Inhaled SABA have an onset of action of less than 5 minutes and a duration of action of 4 to 6 hours. Using an MDI with a spacer is quicker and at least as effective as administration by nebulization.

Albuterol (known as salbutamol outside the United States), the most commonly used inhaled SABA, is a racemic mixture (50:50) of albuterol enantiomers. The Renantiomer is the active component, whereas the S-enantiomer is inactive and may be associated with unwanted effects. Levalbuterol, the pure R-enantiomer of albuterol (and referred to as R-salbutamol outside the United States), is available as an MDI

and solution for nebulization. Levalbuterol and albuterol are similar in efficacy, but

the acquisition cost of levalbuterol is substantially higher. Nonselective P2-agonists (e.g., metaproterenol) are not used commonly due to the potential for increased adverse effects.

Doses used for quick relief in chronic asthma are provided in Table 14-1. Usual rescue doses may be doubled for mild exacerbations. The regular use of inhaled SABAs is not recommended.1

Long-Acting Inhaled 02-Agonists

Salmeterol and formoterol are LABA that provide up to 12 hours of bronchodilation after a single dose. Both agents are approved for chronic prevention of asthma symptoms. Salmeterol is a partial agonist with an onset of action of approximately 30 minutes. Because of this delayed onset, patients should be cautioned not to use sal-meterol as a quick-relief medication. Formoterol is a full agonist that has an onset of action similar to that of albuterol, but it is not currently approved for the treatment of acute bronchospasm.

Inhaled LABA are indicated for add-on therapy for asthma not controlled on low to medium doses of ICS. Adding an LABA is at least as effective in improving s^ymp-toms and decreasing asthma exacerbations as doubling the dose of an ICS.22,23 Adding an LABA to ICS therapy also reduces the amount of ICS necessary for asthma control.24

Although both formoterol and salmeterol are effective as add-on therapy for moderate persistent asthma, neither agent should be used as monotherapy for chronic asthma. There may be an increased risk of severe asthma exacerbations and asthma-related deaths when LABA are used alone or added to standard therapy. , The labeling for all drugs containing LABA contains a "black-box" warning against their use without an ICS. The risk of increased severe asthma exacerbations does not ap-

27 28

pear to be increased in adults receiving both an LABA and ICS. '

Salmeterol and formoterol are available in fixed ratio combination products containing fluticas one and budesonide, respectively. Combination products may increase adherence because of the need for fewer inhalers and inhalations. However, they offer less flexibility in dosage adjustment of individual ingredients when that is considered necessary. Doses used for long-term control of chronic asthma are provided in Table 14-2.

Corticosteroids

Corticosteroids are the most potent anti-inflammatory agents available for the treatment of asthma and are available in inhaled, oral, and injectable dosage forms. They decrease airway inflammation, AHR, and mucus0production and secretion. Corticost-eroids also improve the response to P2-agonists.20

Inhaled Corticosteroids

0 ICS are the preferred therapy for allforms ofpersistent asthma in all age groups.1 ICS are more effective than cromolyn, leukotriene modifiers, nedocromil, and theo-phylline in improving lung function and preventing emergency department visits and hospitalizations due to asthma exacerbations.1,22 The primary advantage of using ICS compared to systemic corticosteroids is the targeted drug delivery to the lungs, which decreases the risk of systemic adverse effects. All ICS are equally effective if given in equipotent doses (Table 14-3). Product selection should be based on preference for dosage form, delivery device, and cost.

Although some beneficial effect is seen within 12 hours of administration, 2 weeks of therapy is necessary to see significant clinical effects. Longer treatment may be necessary to realize the full effects on airway inflammation and remodeling.

ICS have a flat dose-response curve; doubling the dose has a limited additional ef-1 29 30 31

fect on asthma control.' Considerable variability in response to ICS exists, ' and increasing the doses may be of greater benefit in severe asthma than in mild-to-mod-

erate asthma. The ICS are effective when given twice daily and may be effective when given once daily for mild asthma.

Local adverse effects of ICS include oral candidiasis, cough, hoarse voice, and dys-phonia. The incidence of local adverse effects can be reduced by using a spacer or valved holding chamber and by having the patient rinse the mouth with water and expectorate after using the ICS. Decreasing the dose reduces the incidence of hoarseness. For most delivery devices, the majority of the drug is deposited in the mouth and throat and swallowed. Systemic absorption occurs via the pulmonary and oral routes. Although only a fraction of the drug is delivered to the lungs, 100% of the drug reaching the lungs is absorbed systemically.1

Systemic adverse effects are dose dependent and rare at low to medium doses. However, high-dose ICS have been associated with adrenal suppression, decreased bone mineral density, skin thinning, cataracts, and easy bruising. Growth suppression in children occurs primarily in the first year of treatment and may be due to delayed

growth with the potential of future catch-up growth. Systemic Corticosteroids

Systemic corticosteroids are effective as both long-term control and rescue medications. Because of serious potential adverse effects, systemic corticosteroids should be used for long-term asthma control only in patients who have failed other therapies. If systemic therapy is necessary, once-daily or every-other-day therapy should be used with repeated attempts to decrease the dose or discontinue the drug.

Systemic corticosteroids are the cornerstone of treatment for worsening asthma not responding to bronchodilators and for acute severe asthma. For patients with nonre-sponsive worsening asthma, a short course or "burst" of systemic corticosteroids is effective for gaining control and preventing progression.1

In acute severe asthma, systemic corticosteroids should be given to all patients who have moderate to severe exacerbations or who do not respond to initial bronchodilat-

or therapy. Corticosteroids reduce inflammation, increase the response to P2-agonists, hasten recovery, decrease hospital admissions, and reduce relapse rates. The onset of

action is delayed, and a clinical response may not be seen for 4 to 12 hours. For this reason, systemic corticosteroids should be started early in the course of acute exacerbations or worsening asthma. The oral route is preferred in acute severe asthma; there is no evidence that IV corticosteroid administration is more effective.1 Recommended doses for acute asthma exacerbations are shown in Table 14-4.

Table 14-2 Usual Dosages for Long-Term Control Medications in Asthma

Medieatiait

DesijtFtiiti

0- * YMH

5-11 Vean

Adult Dos«

Comment!

Inhaled Corticosteroids IseeTable 14

-5, fsti mated Comparative Daily Dosages for Inhaled Corticosteroids)

SgrlEEmk (Qrjl I Ca rlicoitcroidii

Applies U all Ihrefr <ar1i£01f Eroidx.

Wethylpiednisolofie

1.4.BI It

OJi-2 mg/

7.5-60 mg daily

For lorq term treatmens of severe persistent

31 mgciril

k^d-iily in

L jd.iily in

iri 4 single'

.'hrn i. ^Im : i\Vi .1 .11 >; clyy? in Ijflft

tablets

single dose

single dose

dose of e^ery

either dally or cm alternate days faflernate

CI (.■YLTJi

CH every

UUÏLT day

tVflf rhciopy irmytfCidu» kii LKfrcnal

ollvpt day

rator day

nmpRsdof^

PietlfliHjtoMe-

i mg ûf 4l

Slmtcount

Shoi-coow

yvx-co^je

ihort courses or 'bursts'an? effective for

tablet^ i

■buisli 1-2

nbuistJ:1-I

'burst': 40-60

r.c^irol 'aI^t^ initialing liKtopy

my5 ml

kg/day,

mg/ki/diiy.

riir j.-Uny ji

cn dming a-piiod of gradml detetJcraltan

anrl li riKj/^

DuagÉmum

IDdXlirUD

Single a I

Then' is no tNidenca (hji tapering thodou.'

ml oral

JO mg/day

60 mg/daç.1

divided doses

i(:.l!(ib',iii:i hrpwwmefiit in syrr^jiixrKonnol

IkjukJ

kw 3' so

furî-li

fw 3-NJdtiyi

and pulmonary function pievents netopse

dign

djys

for aMlm 0 1 r yvJVI t/PJIk'nti

PlH^BVOflf

1,25.5i 10.

the low« doie i 1 mg/fej'dayi e<pei iflflce

JO, 4U nig

few« bthavicral side ^iLtis *nd ii ¿pticjri

oial tnbkMs:

to be equally effective

S mg/5 m

Oiil liqiilj

Jilmeiwl1 DPI 50 mcijf M/A

bins

Shauld »m Li' used for symptom rclitf u? exacerbations, Use only with ICS

C çtfflt?n[s of of one Îïefi'faîiiil duration of pflxecrtc^i sgainiT Elti one Winer bliner ™<y mjy occur with "egtibiuse «very 12 uiyiiut MoftdiMdreii ywjfMjefttwn 4 jms of age tour; cannot provide sufficient inspiratory flow ft« adequate.'lu lïnfrlrvriy

Oo not blow into inhaler alio« dose is activated Pcumoieifot* WlZmotji' N/A Content! Content* of one Moit children younger than 4 year» of age capsule of one capsule every cannot provide sufficient inspiratory flow capsule 12 hours for adequate lung delivery every 12 Each capsule is for single use only, additional hours doses should not be administered for ot least 12 hours Capsules should be used only with the Aetotaer inluki and should not be taken orally

Combined medication fluticasone/ Salmeterol*

Budesonide/ formoterol*

DPI 100 mcg/50 meg. 250 mcg/50 meg. 500 mcg/50 meg;

HFAMDI45 mcg/21 meg. IIS mcg/21 meg. 230 mcg/21 meg

UFA MDI 80

Cromolyn/Nedocromil:

puff Nebulizer 20 mg/arrpule

Nedocromil

MDI US mg/ puff

One inhalation twice a day

one ampule 4 dmes a day. Sdietydnd eftcacy not evaWished bdowage 2 years N/A

Two puffs 4

times a day One ampule 4 times a ctay

Two puffs 4 titres a day

One inhalation twiceaday: dose depends on severity of asthma

Two puffs twiceaday

Two puffs twice a day; dose depends on severity of asthma

Two puffs 4

times a day One ampule 4 times a day

Two puffs 4 times a day

FofOtMlf: lOW50 DPI or 45/21 HFA for patients not contio*ed on low- to medium dose ICS 250/50 DPI or 115/21 »»A for patients not controied on medium- to hqh-dose ICS There have been no clinical trials in children less than 4 years of age Most children younger than 4 years of age cannot provide sufficient inspiratory flow for adequate lung delivery Do not blow into inhaler after dose is activated For adults:

80/4.5 for patients not controlled on low- to medium-dose ICS I6IV4.5 for patients not controlled on medium- to high-dose ICS There have been no clinical trials in children younger thin 4 years of age Currently approved for use individuals 12 years of age and older. Dose for children S-12 years of age based on chnical trials using DP I with slightly different delivery characteristics

4-6 week trial may be needed to determine maximum benefit Dose by mdi may be inadequate to affect hyper-responsiveness One dose before exercise or allergen exposure provides effective prophylaxis for 1 -2 hours. Not as effective as «haled -agonists for EiB Once control is achieved, the frequency of do«r>g may be reduced

Leukotriene Modifiers:

Montelukast 4 mg or S mg chewable tablet;

4 itig granule packets 10 rr>g tablets Zafirkikast 10 or 20 mg tablets

4 mjat bedtime (l-S years of age)

Zlleuton

600 mg tablets N/A

S mgat bedtime (6-14 years of age)

10 mg twice ft day {Ml y^arsof age)

10 mgat bedtime

40mgdarfy (20 mg tablet twiceaday)

600 mg 4 times a day

Montelukast exhibits a flat dose-response curve. Doses above 10 mg win not produce a greater response in adults No more efficacious than placebo in infants 6-24 months

For zafirlukast. administration with meats decreases bioavailability: take at least 1 hour before or 2 hot*s after meals Monitor for signs and symptoms of hepatic dysfunction for zlleuton. monitor hepatic enzymes (AIT)

Mrrhylir.ini hi ncv

Theophylline Liquidi.

Starling tftu: 10 mq/Kgrttay; usual rri^niigirX

Starting rtxc to mg/kgAia^ usuoC

mg/Vg/tiay

Starling coie lUing/fcg/tliy up to SflOmc]

Adjust dosage to acfwve s«u m concentration of 5 U rncg/VnL at iUiJiJy-ilJlt'ial least i6 hoiiswssnc dosage) (Xie Id wide inter patient vj' ability in tl^TOCtiy&K' tliWWWfc (Wlflnt serum theophylline level monitoring «Sim ¡¿I

Hjstdincd-

rotsaie tabids jnd CiUHlti rrujcrnum uSvil

Lesslhan I yea oltiflQbgoio wtcfc>H 5 = mydigAliiy I yWniair .indoklei: lb rrvi/kgAJdj-

rruMnuiri

800 myttjy

I m munomwlijlatof r.

Gmaltiumab ^uboitaneous N/A

150-175 mi) Do not administer more than ISO mg p« it f ¡njitiKyi sh

1-4 Monitor for anafJiytaxiS fix iw? houri afte* at departing lean the lirst three irycc (ions embody weight and pfitreautient seiuiKi igE

(fvlfl inh?ak>i\ iWmiiyi.? mL after i«0ililiHUlj0fi with \A niL

tliirile wiilw h* injection

DPH powder inhaler EIE enercise-induced bronchoipdsm HI A, hyiailuoroellane (inhnlei propellantl; KIS, inhaled oortkosteroick IgE, -jriiirii^jtjh iiiri £ M£>t iwMftd-do** ■ M&, and ^fxac y not fiHWiShfliSAfiA.itB't-itllnQS '4{X>rtiic 5C SubflUHlWOUily.

"tn Decemibei 300t;in 'DA Ad'/r^oty Panel retoiTii-nencied banning use of <5ei>evem) srlmelerol and Fom.IiI flo«mt>leicJ) 'or (realm/nt c* d-jLhM. Use of rite combi^rion produce Advai If luticascrtwAa Imeur-rol) and iy ivLuclu [ (budeionldeylfcH nwrcei ol) iveie not included m [he recommended ban.

Dosages are provided (or pioducls that have been app»oved by lhe U.S. Food and Drug Administtation or have sufficient clinical trial safely iftacy fitJH Ifithif Jf5(irOl>ii»i(Hfriri3«TB-iufittiMhiii Ui*

Table 14-3 Estimated Comparative Daily Dosages for Inhaled Corticosteroids for Asthma iiiMn ME 1.

Law Dally Doie

MrrJiuin

LKuly Dmc

High Dally Doit

Child

Child

Chrld

Child

Child

Child

ft-4

6-11

0-4

5-11

0-4

S-11

Mtdiiltisn

Yuri

Y«r=

Ad ul Ci

Vrarl

rein

AduEn

Ywt

run

Adults

6ei-tamer IMW HfA

N/A

ea-rw)

80-240

H/^

Above

Abmt

WA

Above

Abo1«

won

meg

mçTy

■M-3I0

î20meg

430 meg

■ithw an mi^fnjif

meg

rïKg

CkAJMOfivdiCW

N/A

160-400

130-W0

N/A

Abc^

N/A

Above

Abowe

<Kt 160, Of .WOmog/

meg

nvg

■fOO-SClO

«B-IJ00

Siflmog

1JOO mog

mhiltdon

mCQ

iflCfl

fkjd&ortàt

Q.H-D.5

ai nug

N/A

Above

1 mg

N/A

Abcw

Î mg

N/A

inhalalKjn luipenscn

my

0.5-1

1 mg

for rtebuhraiksn

nig

ftunisoH&HfA

M/rt

160 meg

120 meg

N/A

J¿0 meg

Abow

N/A

040 mog

Above

SO iTKCrtXiff

3Ï9-G40

fripnx^

mog

sboTO

fhjniûscn\i UFA uur*i

I76ir¥"fj

SB-17E

M-J64

Ahove

Ahove

Abo««

Ahoiic :ii?

Ahew^

44, HQ,«¿20meg/

meg

m."jg

I7S-3S2

17S-3S2

A4-4+0

342 meg

meg

449 meg

met]

mcj

meg

Hutkmûœ CW

N/A

100-200

100-300

N/A,

Above

Abow

N/A

Abo lie

Abe«

50, lWXof 250 mqç/

■»eg

rrcg

350-400

300-500

400 meg

SOOmeg

inltiliiicai

meg

meg

Mumflfliiirhi pAr

N/A

N/A

200 meg

N/A

N/A

400 meg

N/A

h|/A

AlXWi

2DU rncg/inhiilition

400 meg

DPI. dry fxw:d<?j inhjltir; HF^t^dronuorMlkinii MDl, metered dûa? inhaler, N.'A, safeiy md eiikaey not established. From Réf. I.

DPI. dry fxw:d<?j inhjltir; HF^t^dronuorMlkinii MDl, metered dûa? inhaler, N.'A, safeiy md eiikaey not established. From Réf. I.

Therapy with systemic corticosteroids should generally be continued until the PEF is 70% or more of the predicted value or personal best. The duration of therapy usually ranges from 3 to 10 days, but longer therapy may be necessary for severe exacerbations. Tapering the corticosteroid dose in patients receiving short bursts (up to 10 days) is not necessary because any adrenal suppression is transient and rapidly revers-ible.120

Anticholinergics

Anticholinergic agents (see Tables 14-1 and 14-4) act by inhibiting the effects of acetylcholine on muscarinic receptors in the airways. They only protect against cholinergic-mediated bronchoconstriction and are not as effective as P2-agonists in

asthma. Anticholinergic drugs may cause bothersome adverse effects such as blurred vision, dry mouth, urinary retention, and constipation. However, the inhaled anticholinergic agents are quaternary amines that are not absorbed systemically and have limited adverse effects.

Ipratropium bromide (Atrovent) is available as an MDI and solution for nebuliza-tion. It has an onset of action of approximately 30 minutes and a duration of action of 4 to 8 hours. Care should be taken to avoid contact of the spray or nebulized solution with the eyes, as it can cause mydriasis and blurred vision.

The addition of ipratropium bromide to inhaled P2-agonist therapy in acute severe asthma improves pulmonary function and decreases hospitalization rates in both adult and pediatric patients.34 The benefit of combining ipratropium and albuterol appears to be greatest in moderate to severe exacerbations, and the combination should be considered first-line therapy in severe exacerbations.

Tiotropium bromide (Spiriva) is a long-acting inhaled anticholinergic available in a DPI; it has an onset of action of approximately 30 minutes and a duration of action longer than 24 hours. There is little evidence supporting the use of tiotropium bromide in asthma.

Leukotriene Modifiers

Leukotriene modifiers (see Table 14-2) either inhibit 5-lipoxygenase (zileuton) or competitively antagonize the effects of leukotriene D4 (montelukast and zafirlukast). These agents improve FEV1 and decrease asthma symptoms, rescue drug use, and exacerbations due to asthma. Although these agents offer the convenience of oral therapy for asthma, they are significantly less effective than low doses of ICS.1,35 Combining a leukotriene receptor antagonist with an ICS or LABA is not as effective as an ICS plus an LABA.1

Table 14-4 Dosages of Selected Drugs for Asthma Exacerbations

Medlcntlon

Ad nil Dose

Comments lihtiid isti

Aliurrraf neb JiMr wlunoii M3 mg/ Jrtl., l.Jimg/ 3 ffL, li ft^/i fflL, S mg/hil

MCH M nvt J/tJuff tiYdHwiWpl

3 mil

0.15 rr<lAii itlirinkJTi Jin-ijJnwy ¡Onr-r.ites far i doii j ihtn OLlS-i.3 m^Vltg ..p la Id Ti-h Kansas rwided; a 0.5 Ajj/hcur by cwitiixinjs nrbiiliLiSEn

4 -1 pulfe <w/ Jtuft-iMie j far SdOKithen cn«ry l^l ■iciursii-ifliElion njiwuvcr as needed Lte VK: jJd mjEk in ch.Id li n le^i 'hai> 4 y«r»

ijUL*i?S rnyflig ^Tii^i-x.nnly^r lJSmgl eve<y »nHur« fa 5

dowi (her, MB-OB mg/tg ifUqimgnei) i-ih&juat iHTfdfd

MOH5 mcgJfrjIT ibuie«H MDI doit

MUI BO miy/piV f 10 be ftjif at (Miani«jibLiiiiai

5jri«Hnk IVubtuHnWutlfl^ftgGniiH

{pififphrtstt lUQCfl mgAnLJ flfll mg/Vg u(? »{l3-(LS ing eneiy itj mniiB for 3 iJmes ii Te/txitaiinc CuQl —sy/^ja c«iy SOmi'ul« Tdt

[1 rogttH) 3 dcMt fTipy hiourf

2.S-5 mj «wi* 10 mir*jiei tx JdowMhen 2i-10mg trti y 1 hours si ritital- oi l\j lli> mg^iaur by tnntr-uous rtebdSHtiDn fuiii evMy 30 ffli-ijlit up IK 4 hours, (l-ifn entry 1-4

l.J^ n-^ H'i-n y It* Sdosfli, rhw ii5-Jmg l-4hrAir-!i! rifscd iee ditjKio1 ,VL3I ier alb.ili'ic. MQIdow

OJI-tS ng cwiy JO ini-ijlei b"

3 dose; JC 0.25 mg JOmnuteifcf likmiC

Only selec;ii*i aoflnisn are recjmmpided. Fcf i^iin: drlivTiy, c li.'r wfi^l^ K min Tgm tf

UWiilYUBi r^h.iliTmlbf CKV-nums acni'iiitrjtiori.May iniKviih ipmHfrtMnidHitar solution in mikl-K>-modefSi#«xKi>Jbai4x>£1 MZI phi ifrC ii i!ilfKtniesi<i(J>uHied iherapy wiih ap:Tjcfia1r .ld-r* n'lVjtici l«-irrqur a;id C-Mthng tjf [rj ned pfiscnne-

. ™jll:-JCrri:l .ldin-n -.' i-'i-^l iiiiOor ",ili1hH- ingdoit t/iUxjifoi pioH(ieico<r<iJ'ii!liil'tcKy ¿"d HlvMy-H« not beflnp^mtEd by™m"uoii5 wbiiteilbn

Man rot hrrn sliidirfl "i tcjc^t1 .nil- t.7

trzrkVi aD-«nlagtof ayiliT c ilwiapyo^r MKMol

Ma pfown jL-^nlsgt of ^yilit.c Shtiapya^f MUMOl

ArlKhalinDrgKi

JjJittM^iir/rt hOfliílf

UH!iiqMr3>nniMi4( 03rtlS JOrnliHHeifcf ícJcie^ L!IW dL'muded JdtjiÉitfiín dtnLtfJed

4-8 puffí pvfiy Jfl mullan rlMdíd up 10 3 iMiri

¡l?J[iup ..ti t ur :k-í í.S-mgitxjIfd p<r Jniviali Míí 113 iríg ¡pat'Oiíum bomcle/SÚnicgalbuiciat per p-jffj

Sytttmlc IUul}farticosreroidí

MfJty^príJiiJsoídiií jfiwjdmijni &J mijitijy) iltl^ Pf F

P^edtai sobrar i TCrtt d1 predi: led ex pefMr\i

! £mL (^L^iy-^ÜrT ry.-ftí^r 3dOS«.Miífl .Ivnn'di'ü

4-8 pLiff? tTffi\ 2C riíiuiíj JS neeced up in 2 bcu--.

i pofíí twfy 3D mrtuMtü Mcddlifinihaiii

8 puffe tvay W minut» as needed qjp to IhtAjrs

JfO-eO rr-gjUjy po ¡n 1 or I cu did Se»! unbl P£f reachei ~i¡}'*z of pred.Lled ch píríQTial bíi!

.W^y n-íin npbvíÍEP" ^^ na be uaduHni-toHK'apv; sh&JdLc K) Cid ro Íhí rípy hr «veis (ttxerbíllenL

itt].[.jfi uí (3|B»tiWtl dOti ftt* piLf.1 de- lurChHn twnflie 00« íhi pai¡wi tvMo;ji¡M(l Jh w !h WC índíh ':lrn>pr tfmi ir jd -ÍI t cdiriiwd ¡(»aiKfüuin h'ümd^Mplíbr iiptQ^haurs

KUnqtfflWClttiflIiKttMiCd Mtliriín o(tntñipkjti toíbutsrtí does not p<a*icis fjrlhrr brr^r: cn:e:hr pariml 'thDLpitaljcd USÍ WühVHt jrrifjofmiSfof íhitírflriVJiJTSer than ¿ge 4

FÍ:- OutjMfiirrí 'bjiM'.uic JÜ-6Í nancrinn:: e v i dirtkd dcwei tar íc^al -nT S—10 -days m iduhs ftSl J-e-:: 1-J rig.k^/dji.'. iTuiam..in íO rr^/c¿y tor J-iQdíyfl

EC. eímef^snev dípanrraíit Hl>. meisi«H}cif nhale;: PEF, pean sísíaioiT 'tow: S£ ¡utKUdntaisJj: VHC. «Sved holding diarmt>ír. ÍMdnei 12 jwí cí agí antf ¡fair>g(<.

Mwest Thei» a no knowi advantage <v hignei dosel of co'duoiMnoiflt m ¡«pí as<h*nj w e Htie *iy m-am¿tic oí IV admHiiHwion a»

IMJ ;ypv,ded()l fjnsil :¡nF m jtijo'pfcn i Tal ¡mpn red.

ttie taaí coua oí¡rptar*: c«ih;oiieniíds íw an «íiimí í*a<wtidi)Of 'eqi,í 19 anED visr of hospir; !aii(v nuj i35[fm>m 1 os iCdayi.Fofcciic-aiier-od faiifnp! aF lhar. 1 wrk, 1hrnt na nc^cl ia 1^pof Hit diy^i. For glrly lorií¡rr epursr^ ér-.rj. up ha lú 1hrrr pfrihibiy ^ na rcrrl 1a lap1:. if

ICJ C!r. tí fhjítpd H any poi-h In thí 1r? il ir*nt of in «íhmj mK(fb)tlon, f nam Rrr. I.

The leukotriene receptor antagonists zafirlukast (Accolate) and montelukast (Sin-gulair) are generally well tolerated and dosed twice daily and once daily, respectively. Significant increases in hepatic enzymes have been reported in postmarketing studies for zafirlukast but not montelukast. Zafirlukast also inhibits the CYP2C9 and CYP3A4 isoenzymes and may increase prothrombin time in patients receiving warfarin; the International Normalized Ratio should be monitored if warfarin and zafirlukast are used concomitantly. Montelukast does not appear to inhibit the cytochrome P-450 enzymes.

Zileuton (Zyflo) is not commonly used because of the need for dosing four times daily, potential drug interactions, and potential hepatotoxicity with the resulting need for frequent monitoring of hepatic enzymes.

Cromolyn and Nedocromil

Cromolyn sodium (Intal) and nedocromil sodium (Tilade) are inhaled anti-inflammatory agents that block both the early-and late-phase response possibly by inhibiting release of mediators from mast cells. Both agents are alternatives to ICS for treatment of mild persistent asthma, but they are significantly less effective than low doses of ICS (see Table 14-2).1 Cromolyn and nedocromil are similar in efficacy to the leukotriene antagonists and theophylline for persistent asthma. Both drugs require dosing four times daily until symptoms stabilize, after which the dosage frequency can be reduced

to three times a day for cromolyn and twice daily for nedocromil. Patients may notice improvement in 1 to 2 weeks, but maximal benefit may not be seen for 4 to 6 weeks.

One dose of cromolyn or nedocromil prior to exercise or allergen exposure will provide prophylaxis for 1 to 2 hours. These agents are not as effective as albuterol for prophylaxis of exercise-induced asthma.

Both agents are well tolerated with adverse effects limited to cough and wheezing. Bad taste and headache have also been reported with nedocromil.

Methylxanthines

Theophylline (see Table 14-2) causes bronchodilation by inhibiting phosphodies-terase and antagonizing adeno-sine. It may also have mild anti-inflammatory and immu-nomodulatory properties.36 Its use is limited because of inferior efficacy as a controller medication compared to ICS, a narrow therapeutic index with potentially life-threatening toxicity, and multiple clinically important drug interactions.

Target serum theophylline concentrations are 5 to 15 mg/L (28-83 pmol/L); an increased risk of adverse effects outweighs the increased bronchodilation in most pa-

tients above 15 mg/L (83 pmol/L). Headache, nausea, vomiting, and irritability may occur at serum concentrations less than 20 mg/L (110 pmol/L) but are rare when the dose is started low and increased slowly. More serious adverse effects, including cardiac arrhythmias, seizures, toxic encephalopathy, and death can occur at higher con-centrations.20

Theophylline is primarily metabolized by CYP1A2 and CYP3A4 and is involved in a large number of disease and drug interactions. Theophylline exhibits nonlinear pharmacokinetics in the therapeutic range; therefore, serum concentration changes

due to dosage adjustments and drug interactions may not always be predictable. Theophylline also exhibits interpatient variability in hepatic clearance; consequently, serum theophylline concentrations should be monitored.

Omalizumab

Omalizumab (Xolair) is a recombinant humanized monoclonal anti-IgE antibody that inhibits binding of IgE to receptors on mast cells and basophils, resulting in inhibition of mediator release and attenuation of the early-and late-phase allergic response. It is indicated for treatment of moderate to severe persistent asthma in patients 12 years of age or older whose asthma is not controlled by ICS and who have a positive skin

test or in vitro reactivity to perennial allergens. Omalizumab significantly decreases ICS use, reduces the number and length of exacerbations, and increases asthma-related quality of life. It is also effective in improving asthma control in severe asthmatics receiving combination therapy with high-dose ICS and LABAs.1 However, its place in

therapy is limited by its high cost.

Omalizumab is given as a subcutaneous injection every 2 to 4 weeks, and the initial dose is based on the patient's weight and initial total IgE serum concentration. The dosage should not be adjusted based on subsequent total serum IgE measurements (see Table 14-2). Drug clearance depends on patient weight, and dosage should be adjusted if there is a significant change in body weight. Doses greater than 150 mg should be administered as separate injections at multiple sites.

The most common adverse effects are injection site reactions and include bruising, redness, pain, stinging, itching, and burning. Anaphylactic reactions are rare but may be delayed 2 hours or more after drug administration.40 Reports of delayed anaphylactic reactions have led to a "black box" warning in the labeling and a medication guide warning of this risk.

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