Clinical Clerk Rhinitis and Asthma

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Allergic Rhinitis and Asthma

Clinical Clerk Teaching Sessions

London, OntarioDr. DW Moote & Dr. JA Mazza



Objectives to describe the diagnosis and treatment

of allergic rhinitis and asthma

to identify asthma medications and thecircumstances in which to use them



Bring your own case

Anything on the ward to discuss with respectto Clinical Immunology & Allergy? There will

be time for at least one other topic for discussion

Adverse Drug Reactions

Anaphylaxis

Insect Venom Allergy

Urticaria

Food Allergy

Etc.



Prevalence of Allergic Rhinitis

10±20% population

all ages, onset usually before 30 yrs

most common chronic illness in personsunder 30 yrs

not life threatening, but threatens quality of

life costs about $200 million/yr in Canada

50% individuals don¶t seek medical attention



Diagnosis rhinorrhea,

obstruction

itching, sneezing,ocular symptoms

other allergysymptoms, familyhistory

?pain, headache,toothache



Allergic salute nasal crease



Skin testing



Rhinitis

treatment Environmental

control measures

Medications Immunotherapy



Dust mite avoidance



Pollen avoidance



Animal dander avoidance



Pine B

irchGrass

Pollen



Medication options Antihistamines

Decongestants

oral

topical

Intranasal glucocorticoid sprays

Immunotherapy



Antihistamine problems

Sedation/Driving behaviour

Cost-benefit of newer products

Use in pregnancy and breast feeding Drug interactions±contraceptives

Dosing interval / half-life

Tachyphylaxis / subsensitivity Use in asthma

Cardiac risk?

Cancer?



Antihistamines are common allergic rhinitis present in 15% of

population

antihistamines are profitable

none are perfect



Gallup poll

801 adults²Sept 89 Productivity

74% say symptoms make them less productive

impairment due to side effects 14/240 work-days

Driving 67% aware medications may impair driving

61% drive anyway

53% are very or fairly concerned about others driving while

using antihistamines

Machine operation 30% operate machinery (includes household power tools)

when taking allergy medications



Drowsiness attributed to blockade of central histaminergic

receptors

antagonism of serotonin and acetylcholine, andalpha-adrenergic stimulation may be involved

second generation antihistamines lipophobic: poor penetration into CNS

bind preferentially to peripheral receptors

relatively free of anti-serotonin, anticholinergic, and alpha-blocking effects

incidence of sedation is not zero, and may increasewith larger doses



Cost/B

enefit chlorpheniramine

12¢/day

non-sedating agents$1.00/day

generic loratadine,cetirizine 11±80¢/day

most drug plans won¶tcover OTC meds. TryRx only hydroxyzine(sedating) or half acetirizine 20 mg.



Antihistamine kinetics Older antihistamines

recommended dosing intervals date to

1940

no systematic studies until 1980¶s,because of difficulty measuring low blood

levels chlorpheniramine, brompheniramine,

hydroxyzine all have half-lives longer than20 hrs

Why QID dosing?



Half-life Wheal suppression

Cetirizine 10 hours 24 hoursLoratadine 11 hours 12-24 hours

Terfenadine 17 hours 12-24 hours

Astemizole 9.5 days weeks

Antihistamine kinetics Duration of action longer than

expected from half-life

most can be dosed once daily



Simons K, J Clin Pharm 1990

Half LivesElderly: 13.5 4.2 h Adults: 9.2 2.5 hChildren: 5.4 1.8 h

Diphenhydramine kinetics



Children Adults Elderly Reference

Diphenhydramine 5.4 s1.8 9.2 s2.5 13.5 s 4.2Simons, J ClinPharm 2000

Chlorpheniramine 13.1 s 6.3 21±27 22.6 s 11.0Simons 82, 90

Rumore

Loratadine 15 (28 for

metabolites)

Desloratadine 27

Cetirizine 10.6 11.8 Simons 1988

Fexofenadine 11±16

Antihistamine Kinetics



Subsensitivity / tachyphylaxis

Long-term administration of firstgeneration antihistamines associatedwith apparent loss of efficacy

Compliance a problem

No change in half-life with long termdosing

No loss in efficacy at suppressingsymptoms or skin tests for 12 weeks withrigorous monitoring of compliance, up toone year in dog studies



Rhinitis andP

regnancy Ideally, no medication in first trimester, but consider

impact of disease itself

Antihistamines: chlorpheniramine (alsodiphenhydramine, hydroxyzine), OK data, loratadineand cetirizine now Category B

pseudoephedrine, topical decongestants²?no

intranasal steroids²see asthma data

immunotherapy²continue, but don¶t start. Usuallyreduce dose to minimize risk of anaphylaxis.



Interaction with contraceptives CPS states increased incidence of

contraceptive failure when combined with

antihistamines Based on 16 case reports, self reported²De

Sano 1982

ampicillin plus ³cold tablet´ (four patients)

penicillin plus ³cold tablet´

penicillin, caffeine, chlorpheniramine, ASA,phenylephrine for ³cold´

antihistamines for ³hay fever, but some of these

³antihistamines´ were really decongestants



Interactions with contraceptives Other databases do

not support any

associationwhatsoever!²Szoka 1988



Antihistamines & thyroid CPS cautions against use of some

antihistamines in patients with ³thyroid

disease´ this is extrapolated from problems inhyperthyroid patients given stimulants, e.g.pseudoephedrine, and the fact that someantihistamines are found in combinations

not relevant to antihistamines alone, or topatients with treated thyroid disease



Antihistamines & Cardiac Risk

Mainly in predisposed individuals (torsades de

pointes), with daily dosing and either metabolicidiosyncrasy or drug interaction

Newer preparations are safer, not without risk of QT prolongation

Risk in older (sedating) antihistamines isidentical, but associated mainly with overdose

Is it just that non-sedating preparations get totoxic levels without awareness of side effects?



Antihistamines & Cancer

Rat study included rats givenintraperitoneal injections of

anthihistamine after being injectedwith tumor cells

» Brandes, L. J Natl Cancer Inst

Despite controversy, human datadoesn¶t support concerns raised byrat study



Antihistamines & Asthma

CPS sometimes lists asthma ascontraindication, presumably because of

anticholinergic ³drying´ effect In fact, modest bronchodilator effect

chlorpheniramine, hydroxyzine, clemastine,terfenadine, cetirizine

Prevent challenge with histamine,antigen, hyperventilation, exercise, butnot methacholine



Oral decongestants

pseudoephedrine

available alone, and incombination

phenylpropanolamine

available until October 2000,only in combination

also found in dietary³supplements´

phenylephrine

replaces pseudoephedrine inmost combinations



Phenyl-propanolamine

Conclusions. The results suggest thatphenylpropanolamine in appetite

suppressants (odds ratio 15.92), andpossibly in cough and cold remedies(odds ratio 1.49), is an independent riskfactor for hemorrhagic stroke in women.

(N Engl J Med 2000;343:1826-32.) P aracelsus 16th century: ³the right dose

differentiates a poison from a remedy´



Intranasal steroids

much moreeffective than oral

medications,especially for congestion

add if p.r.n.antihistamine useexceeds threetimes a week for any significant time



Ben Johnson²Seoul 1988



Steroids & growth suppression



Allen DB, J Allergy Clin Immunol 2000

Metabolism



Oral Intranasal Inhaled

Mometasone <0.1% <0.1% <1%

Fluticasone <1% 1.8% 12±26%

Triamcinolone 23% NA 22%

Budesonide 10% 33% Aq 30% turb

Beclomethasone 15±25% NA 15±25%

Bioavailability nasal steroids



Bioavailability

Risk comparisons

between products

are few assays used in

different studies arenot directly

comparable longer half-life

drugs would requirelonger monitoring



Kevin T Kavanagh,

Nasal septal perforation



Septal perforation

Anecdotes of association with topicalnasal steroid use

Not seen in prospective studies of nasalsteroids

Retrospective anecdotes unreliable,since most physicians don¶t look at

septum before prescribing dose US recommends regular follow-up

observation in patients on chronic nasalsteroids



Wilson et al, J Allergy Clin Immunol 1998

Plasma half-life

B

eclomethasone 0.5 hours

Budesonide 2.3 hours

Triamcinolone 3.6 hours

Mometasone 5.8 hours

Fluticasone 14.4 hours

Steroid half-life



Systemic activity

Wilson AM et.al., J Allergy Clin Immunol 1998;102:598-604.

placebo

budesonide

mometasone furoate

triamcinoloneacetate



Normal nasal mucosa

(even after years of daily use)



Short stature 14 year old boy, 4

foot 8 inches, with

a history of asthmarequiring oralcorticosteroids



Pederson, S. et.al., J Allergy Clin Immunol 1999

Growth rate



Growth suppression mainly data from asthma studies

less common with once daily preparations

probably not sustained

short term studies can be flawed bydifferences in maturity of cohorts

worst case scenario²probably about 1cm if lifetime use, but consider prednisone!



Immunotherapy

for rhinitis or asthma



Treatment for rhinitis

make sure you know what it is

try avoidance first

try p.r.n. oral medications add an intranasal steroid if

antihistamines needed > 3x/wk

fine tuning consider immunotherapy if

avoidance and medications fail



Asthma

C di A th C



Canadian Asthma Consensus:2003, updated to December

2004CMAJ 2005; 173 (6suppl): S1±S56

LP Boulet et al.CMAJ 1999;161(11Suppl)

LP Boulet et al.C an Respir J 2001;8(Suppl A):5A-27A



Canadian Asthma Consensus Report, 1999

Approach to Asthma

Confirm diagnosis objective measure of lung function

Assess severity

Achieve control rapidly

Assess environment and other contributing factors

Educate patients

Determine minimum medication needed to maintainoptimal control

Action plan for exacerbations



Canadian Asthma Consensus Report,1999

Asthma management:

6 Components Educate patients

Assess asthma severity and control

Avoid or control asthma triggers

Medication plan: chronic management

Management plan: acute exacerbations

Regular follow-up care




Parameter Frequency or Value

Daytime symptoms < 4 days/wk

Night-time symptoms < 1 night/wk

Need for short-acting B2-agonist < 4 doses/wk

Physical activity Normal

Exacerbations Mild, infrequent

Absence form work or school None

FEV1 or PEFR 85-90% of personal best

PEF diurnal variation < 15% diurnal variation

Asthma Control



Medication for Chronic Asthma Management



Canadian Asthma Consensus




Medication for Chronic

Management Inhaled Corticosteroids

initial anti-inflammatory therapy [level I]

400-1000 µg/d (or higher) starting dose[level III]

early use better functional outcome

[level III] Insufficient data for short courses of

steroids in children with mild, intermittentasthma [Level II]




ProductDose, ug/d

Low Medium High

BDP pMDI and spacer 500 501 ± 1000 >1000

BUD Turbuhaler 400 401 ± 800 >800

FP pMDI and spacer 250 251 ± 500 >500

FP Diskus 250 251 ± 500 >500

BDP pMDI (HFA) 250 251 ± 500 >500

BUD wet nebulization 1000 1001 ± 2000 >2000

Dose Equivalencies for

Inhaled Corticosteroids




Long-Acting Beta-Agonists:

Salmeterol and Formoterol not recommended as maintenance

monotherapy [level I]

consider as an alternative to increased dosesof inhaled steroids; should be an adjuncttherapy to moderate or higher doses of inhaled steroids [level I]

formoterol is rapid acting and may be usedfor rescue therapy, but at greater cost [2001revision]



F-agonists and corticosteroids

combination

Barnes PJ. Br J C lin P harmacol 199




Leukotriene-Receptor Antagonists

Monteleukast and Zafirlukast consider as an alternative to increased doses

of inhaled steroids; may be an adjunct

therapy to moderate or higher doses of inhaled steroids [level II]

insufficient evidence as first-line anti-inflammatory therapy; but primary treatment

of choice for patients who cannot or will notuse inhaled steroids [level IV]




Asthma Therapy

5 Most Important Aspects Achieve acceptable disease control

Control the environment

Asthma education: guided self-managementand use of an action plan

Inhaled steroids are the first line anti-inflammatory therapy

Additional therapy can be added to moderatedoses of steroid if acceptable control is notobtained



Approach to a Patient with

Poor Asthma Control Confirm diagnosis of asthma

Objective assessment of airflow rates s MeCh

Assess device technique Assess adherence and barriers

Assess environment/triggers

Co-morbidities (eg.P

ost-nasal drip, GER,OSA)

Action Plan for exacerbations

Escalate therapy



New therapies & concepts

New therapy

Xolair (omalizumab)

Alvesco (ciclesonide)

New concepts

Symbicort maintenance and reliever

therapy $100 each



Sampson, J Allergy Clin Immunol

New therapies: Omalizumab



Ciclesonide

Not very active asparent molecule,

less oropharyngealside effects

Activated in lungby esterases,

becomesbudesonide, thenexcreted



Ciclesonide

Approved for asthma, dosing issuggested at 100µg = 200µg

budesonide, (but may be lower) Now approved for nasal spray also,

but not launched as of March 2008

Main difference is reducedoropharyngeal candidiasis (nothoarseness)



Symbicort SMART

Oxeze (formoterol) fast enough onsetto use as reliever (c.f. salmeterol)

Budesonide/formoterol combinationnow approved for relief as well asmaintenance

Some advantages with respect toconvenience, symptom control

Total Asthma Exacerbations Requiring



Total Asthma Exacerbations RequiringMedical Intervention

0

Bud/Form + SABA 330

events

280

200

120

40

3 6 9 12 15 19 23 27 31 35 39 43 47 51 55

4 x BUD + SABA294

events

Weeks since randomisation

0

280

200

120

40

3 6 9 12 15 19 23 27 31 35 39 43 47 51 55

Bud/Form SMART

16 0 events

0 3 6 9 12 15 19 23 27 31 35 39 43 47 51 55

280

200

120

40

# rate reduction 46 to 53% vs bothgroups; p<0.001

O¶Byrne PM et al. Am J RespirCrit Care Med 2005; 171:129-136



Resources for rhinitis & asthma

J Allergy Clin Immunol. The Diagnosis andManagement of Rhinitis: An Updated PracticeP

arameter. 2008 Supp, Vol. 122, No 2S CMAJ. Canadian Asthma Consensus

Guidelines September 2005 Volume 173,Supp

Asthma, Cecil Medicine, Chapter 87



Other resources for reference

Drug allergy, Greenberger P, J Allergy ClinImmunol. 2006, Vol. 117, Issue 2, Pages

S464-S470 Anaphylaxis, Simons FER, J Allergy Clin

Immunol, Feb 2008 Vol. 121, Issue 2, PagesS402-S407

Mini-Primer on Allergic and ImmunologicDiseases, J Allergy Clin Immunol, February2006 & February 2008

Clinical Clerk Rhinitis and Asthma

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