'It is more blessed to give than to receive.

7)

Pharm acolos ofR espiration

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 Freely you have received; freely give.

B R O N CH IA L A S TH M A
*B ronchialasthm a:Recurrentparoxysm alattacksofdyspnea
(shortnessofbreath),cough,wheezcs,andchesttightnessdueto
bronchialhyperreactivity.ln betw een the attacks the patientis free of
sym ptom s.

*-l-vpes qfbronchialasthm a;
.

l- :
Extrinsicasthma(early onset-atopic):on thefirstexposureto aspecitiu
antigen in genetically predisposed persons leads to synthesis ofIgE.
O n re-exposure,antigtn-antibody reaction occurs leading to rupture of
themastcellmembrane(degranulation)andallergotoxinsarereleased'
e.g.leukotrienes(LTC4and LTD4).LTsacton specificcysteinylLT
receptorscausing bronchosvasm.innammation ofbronchialmucosa.tpltl/ -

m llcuâ'secretion which are the characteristic m anifestations ofacute

asthm atic attacks.
z-lntrinsicasthma(latuonset-non atopic).
'FactorsPrecitlitatinz Aslhlna (* Trizzerinz J'
J!'7zl!/Jf).'
l-Exposuretotheallergen(aspollen grains-mites-animalswith furl.
z-Exposure to pollutants.dtlst tobacco slnoke cold air.
3-Exposuretofumesin working environmtnt(occupatiolmlasthma).
4-Exercise(exercise-indttcedasthma).
s-Em otionalstress.
6-lkespiratoly tractinfections,com m only viral.
7-Dnms:NSAIDS-nort-sclectivep-blockers-ACE inhibitors-
histaminereleasers(lnop hine-trilnttaphan-curarel-histamine-likedrugs
(phcntolamineand tolazolinel-muscarinicagonists.

*Lines oftreatm entofbronchialasthm a:

l-Avoid theprecipitating factors(seebefore).
z-Desensitization(hyposensitization).
3-D nlg therapy.

*DI'U:Therapy in BronchialAstima:
A -B ronchodilators:
l-sympathomim eticjz-Agonists.
z-M ethylxanthines.
3-Am imuscarinicdrugs(M uscarinicantagonists).
B -A nti-inflam m atorv drtm s:
l-c orticosteroids. '
z-kaeukotriene inhibitors.
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2
'It is more blessed to give than to receive.

3-D tgranulation inhibitors = M astcellstabilizers.

N.B.:
*A nti-inflam m atory drugs are notbronchodilators and are acoordingly
used in prophylaxis butare notused in acute attacksof bronchialasthm a.
*NSAIDSarecontraindicatcd in bronchialasthma(why?).

W - B ronchodilators:
l-#a-adx.tlzzïs/.&.
, '

M echanism ofaction:stimulation ofjz-receptors->activation oI'

adenylate cyclase -..>synthesis ofc-/tM -?.
Pharm acolozicalactions:
1-Bronchodilatation,
2-M astcellstabilization and inhibition ofrelease of allergotoxins.
3-R eduction ofm ucus secretion.
4-Inhibitm icrovascularleakage.
s-lncreaseactivity ofcilia(increasemucociliary transport).
Classification:
A-selective/îp-.
?'
l,
confâ'/5'.'They arethemostimportantdrugsin
treatm entofbr-
onchialasthm a. tlley include:
l-shol-t-actinc I
h-azonists(SABA):Salbutamoland Terbutaline-given
ever.y4 hours- theyaregiven by inhalation forrapid relieveofacute
attacksofbronchialasthm a= asthm a relievers.They arealso given orally
(forprophylaxis),andby injection (insevereacuteasthma= status
asthmaticus).
z-Long-actinM oacaqonists:Salm eteroland Form oterol- given every 12
-

hours - they are-given by inhalation .

Bam buterolisgiven orally.

LA BA are givtn forprophylaxis. k.
j .
, ,t

#Al1selectivejz-agonistsarenon-catech'
olamines!passBBB andnot
m etabolized by CO M T orM A O .

*Adverse effects:
l-lremorsoftheskeietalmuscles.
zq achycardia(mostlyretlex duetoV.D.andhypotension).
3q olerance(duetodown-regulationofjz-rtceptors,cora cted by co-
administrationofinhaledcorticosteroids).
4-N el-vouslension.
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3
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+R ole in bronchialasthm a:
l--fhe drugs ofchoice in acute attacks:short-acting drugs are given by
inhalation and are know'n as ''asthm a relievers''.
z-Loag acting drugs are given as tong-tcrrn prophylaxis and are know n as
''aslhm a controllers'' They are tlsed w ith inhaled corticosteroids.
3-satbutarnolisgiven IV in statusasthmaticus(severeacuteasthma).
B -N on-selective /7-.,z1,
kr()?J/'
&/J.'
n ey arenotcom monly used because ofcardiac adverseeffectsas
tachycardia,palpitation arrhhytluuiaandanginalpainsduetoj11-
stim ulation.
-
Adrenaline (inhalationand S.C.).
-
lsoprenaline(inhalation andS.L.).

I1-M ethvà anthines:

Theonhvlline(* themostcomm only usedpreparation in Egypt)and
Aminophvlline(theophyllintethylene diamine).
+pharm acokinetics:
-
W elIabsorbed orally,theophylline is given as sustained release tablrts
(@ to achieveserum levelsfor12 hours-lessfrequentadministration-less
fiuctuation in serum tevels-to controlnocturnalasthma).
Aminophyllineisgiven asrectalsuppositoryandbyslow IV injection
and IV infusion.
-lkletabolized by H M E .

#M èchanism efactiol::
I-lnhibitphosphdiesteraseùype4 ->1.intracellularC-AM.P (* andc-
GM PI....+bronchodilatation-mastcellstabilization-decreasereleaseof
allergotoxins and decrease cellm igration -decrease bronckiatsecretion.
z-Block ofadenosine receptors -->bronchodiiatation -inhibithistam int
release-increaseadrenalinereleaâetkom adrenklIlèedulla.
3-lm provt diaphragm atic contraction.

+TheRole ofM ethvlxanthines in hronchialasthlna:

l-Am inophyllinemay begiven ver'yslowlyIV (250-500mg.)inacute
attacksifthereisnoresponseto inhaled selective%-agonists(asthma
reliever).
However;ttlis isnotprefen'ed because am inophyllinehaslow
therapet
'lticindexand rapidinjection may leadto.
arrhythmiaandsevere
hypotension.
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'It is more blessed to give than to receive.

z--rheophylline isgiven as sustained release tablets orcapsutes in

prophytaxisofbronchialasthma(asthm acontroller).Aminophyllinemay
bealso given asrectalsuppositories(500mg.)forprophylaxis.
3-Aminophyllineisgiven by IV infusionin statusasthmaticus(severe
acuteasthma).
%zjdverse effectsL
-
'Fheophylline and A m inophylline have low therapeutic index and the
plasm a levelshould be m easured to avoid toxicity.
-
'
l-herapeutjcplasm a concentration oftheopbylline:.
5-20 mg./L (> 5-20
p.
g/mL)and thetoxiclevel> 20mg,/L (> 20 p.
g/mL).
-Adverse effects include: '
I-CN S m anifestations:nervousness,insornnia,headache and
convulsions.
Z-CV S m anifestations:tachycardia,palpitations,arrhythm ias anginal
pains,and hypotension.
* Plasm a levels higherthan 40 m g./L cause arrhythm ias or seizures.
3-G1T m anifestations:aqorexia,nausea,vom iting,ulceration and
proctitis(rectalsuppositov ).
* A nortxia nausea,vom iting,abdom inaldiscom gort,headache and
anxiety som etim es startat l5 m g./L.
4--fhrombophlebitis(ifgivenby (V injection).
#D ruz interactions:
1-'
Fhe clearance clftheophvlline is reduced by:
-
HM E inhibitorsas:Erythromycin (M acrolideantibioticsl-
>-luroquinolones-chloL'am phenicol-cim etidine-contaceptive pills.
Hepatic cirrhosis.
-

-
l-leartfailure(decreasesCOP audso hepaticbLood llow isreduced).
in these conditions the dost oftheophyliine should be rtduced to avoid
toxicity.
2-The ciearanqt theo h lliae is increased bv:
-HM E inducersas:Phenobalbitone-Phénjhoin-lkifampicin- Cigarette
smoking (nicotine). >
The dose oftheophylline jhould be increaseclin these conditionsto
achitvetherapeuticlevel;
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5
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111-A nti-M uscarinic D ruv :

A tropine w aspreviously used in prophylaxis ofbronchialasthm a butis
now replaced by synthetic substitutes.
Exam vles:Ipratropium -o xtropium -Tiotropium .
*lbfechanism ofaction:
They are com petirive antagonists thatblock m uscarinic receptors in
bronchiby com petition w ith acetylcholtne released as a resultofvagal
stim uiation.

+Advantazes ofSvnthetic.
slléu/l'flf/câ'overzl/r/ppWc.
'

D isadvanta es o A tro ine A dvanta e.îo L ratro ium

l--l-trtiaryamine-given orally-passes
. l-ouaternaryammonium-givenby
BB B. inhalation.
z-system ic anticholinergic actions: z-M inim aisystem ic anticholinergic
dry m outh -constipation-urine actions.
retention-tachycardia-blured vision .
and elevation oîIOP.
3-CNSactions. 3-NoCNS (cannotpenetrateBBB).
4-c auses dryness ofbronchial 4-N o dryness ofbronchialsecretion.
secretion leading to tbick viscid
sputum. t
s-D tcreases m uco-ciliary clearance 5-N o effecton m uco-ciliary clearanqe. !
ofsecretion.
+RoIe ofAntim uscarinic Drtfz:in Bronchialasthma:
l--fhey are given by inhalatioll in prophylaxisofbronchialasthm a.
A lthough they areeffectivebronchodilators'theresponseto these drugs
variesaccording to the degrct ofinvolvem entofparasym pathetic tone in
bronchospasm .
z-' l71ey areusedin patientswhoareintolerantto j2agonists.
3-Drugsofchoicein bronchospasm caused by non-stlectivep-blockers.
zl--l-hey areadded-teselectivejslqèoniststoachievesynergism.
Theyarealsoused,inchronicobstructivepulmonarydisease(COPD).
WhiteKnightLove

6
'It is more blessed to give than to receive.

B -A nti-intlam m atorv D rues:

1- Corticosteroids (Glucocorticoidsl:
#tkfac/lcrlfâ'rr/ofaction.
.
l-/knti-intlam m ato:y by inhibition ofphospholipase A 2leading to
inhibition ofsynthesis ofleukotrienes and prostaglandins.
z-potentiatethebronchodilatoreffectofjg-agonistsand preventtolerance
(by upregulationofreceptors).
3-lnhibitIgE antibody synthesisandantigen-antibodyreaction (immuno-
suppressiveaction).
zl-lnhibitsynthesis c'fbinflam rnatory cytokines asInterleukins and Tum or
NecrosisFactor(TNF). '
s-lnhibition ofesinophilic and Iym phocytic m ucosalinllam m ation.
Corticosteroids are notbronchodiiatorsand are notused in acute attacks.
*Adverseeffects oflnhaled steroids:
1-oro-pharyngealcandidiasis(moniliasis):prevented bymouth wash
(gargle)aftercorticosteroid inhalation,andtreated by oralNvstatin.
z-Dysphonia(voiceabnonnality,e.g.weaknessandhoarseness).
kl'
heRoleofCorticoateroids in Bronchialasthmo:
ï-lnhaled steroids as Beclom ethasone,A'/lflfccutpnc,Triam cinolone ,
Blldesonide,and F lunisolide used in Drophvlaxis ofbronchialasthm a.
This is the recom m ended and preferred route ofadm inistration to avoid
the system ic adverse effects.
z-l-lydrocortisone sodium succinate or m ethvëprednisolone sodium
succinateIV isthedrug ofchoice in statusasthmatic. .Thisisfollowed
by oralprednisolonefor7-10days(notlongertoavoitisystemicadverse
effects),then gradually witlAdrawntoavoid acuteadremocortical
insufticiency.
3-O ralprednisolone is ustd only in severe persistentasthm a.

11-M ast Cellstabilizers = D ezranulation Inhibitors:

-
D/.
vodïllllncr()rat?/c te(Cromolynsodium = lntalcjandNedocrottjil,
.
.

kM echanism ofaction ,,? .

.

Stabilize the m astcellm em brane inhibitrelease of allergotoxins by

* altering the perm eability ofchloride channels.
Theyarlnotbronchodilatorsandarenotuscdinacuteattacks.
kAdverse e//èctâ'.
'
Throatirritation,cough,chesttightness(ifgivcnasapowderby
spinhaier)dry mouth,andrarelyanaphylxis.
*Role ofM astCellyftzbïfïzcra in Bronchialasthm a:
Used only forproohvlakisbeforeexpostlreto theantigen in olxupational
asthm a,and bcfore éxercise in exercise-indllced asthm a.
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7
 Freely you have received; freely give.

They reduce:severity of sym ptom s-need forbronchodilators-bronchial

hyperreactivity.They are given by inhalation,eitherin the form of
solution(by nebulizerorinhaler)orintheform ofpowder(by spinhaler).
+otheruu çcâ'.'Allergicrhinitis(asnasalspray )-Allergicconjunctivitis(as
eyedrops).

111-LeukotrieneA ntazonists (Inhibitorsl:

*M echanism oft7c/Jt)?7.'
l-inhibition ofs-Lipooxygenase aad inhibition ofleukotrienes synthesis
by Zilettton.
z-com petitive antagonists ofcysteinylieukotriene receptors by
M ontelukastand Zafirlukast.
#Role in Bronchialasthm a: ,
They aregivenorally(@ easytouse)forproohvlaxisagainstbronchial
asthm a. @ M ontelukastis approved for children asyoung as6 m onths.

OtherD rlfkr: in Treatm entof BronchialAsthma:

Om alizum ab:
* A nti-lgE m onoclonalantibody synthesized by recom binantD N A
technology.
*M echanism ofaction:bindsto IgE and prevents binding oflgE to its
receptors on m astcells,thus inhibits antigen-lgE reaction m astcell
dep anulation and release ofallergotoxins.
* ë Low ers IgE in plasm a to undetectable levels in about 10 w eeks.
*1tisgivtn by S.C.injectionin severechronicbronchialasthmanot
controlled by inhaled steroids and LA B A

D rues Contraindicated in B ronchialzjsthm a.

.
I-NSAIDS(exceptparacetamol).
z-Non-selectivej-Blockers(Propranolol-Nadolol-Timolol-sotalol).
3-M orphine(depressesR.C.,cough centre,andreleaseshistamine).
zl-lluscarinicragéinists= Parasympathomimetics(Carbachol-Bethanechol-
Piloco ine-physostigmine-Neostigmine).
5-A CE inhibitorsascaptopril.
j-otherdrugs:Histamineliberators(mophine-curare-trimetaphanl-
Barbiturates(dueto depressionofR.C.).
WhiteKnightLove
'It is more blessed to give than to receive.

Couzh Therapv (Treatm entofcouzh)

*cough isasymptom --riotadisease-caused by infection (pneumoniaand
T.B.),allergy(bronchlalastluna,iaryngitis),diseases(HF andref'
lux
esophagitis)ordrugs(asACE inhibitors).
wl-reatm enlofcough is m ainly by treatm entofthe underlying cause
*-l-here are 2 typts ofcough know n as l'dry oruseless cough''w hich is
treated by ''
A tlti-tltst
b'ive #rl/eâ''' and ''productive or usefulcotlgh''which
is treated by ''
Expectorants''and M ucolvtics.

1-A nti-tussive X FN/S';

A nti-tussive drugs are divided according to theirm echanism ofaction
into centralanti-tussives-w hich supress cough centre-and peripheral
anti-tussives w hich actby suppression ofthe cough retlex by suppression
ofsensorynerveendings(stretchreceptors)intherespiratorymucosa.
A -c entralA nti-tussives:
l-N on-narcotic non addictive drugs:D extrom ethorvhan Narcotine
Oxeladineand Benzonatate(actsalsoperipherally aslocalanaesthetic
chemicallyrelated to tetracaine).
z-N arcotic less addictive drugs as codeine, pholcodine.
3-N arcotic highly addictive drugs as m orptnille.tnethadone,heroin:
are notused as anti-tussives anym ore.

B -peripheralA nti-tussives:
1-D em ulcents as liquorice given as lozenges,pastilles and syrup:used in
pharyngitisand laryngitis.
l-steam ilthalation with tincture benzoin c0.and m entholw hich
stim ulates the secretion ofm ucus,used in tracheo-bronchitis.
Lt-Localanaesthetics as benzonatate:see before.
4-* Guafenesin:used in com m on cold and acutebronchitisto relievt the
symploms
j,) .
. .

11- Expectorants:
Expectorants are divided into:
A -sedative expectorants which sootht therespiratory m ucosa by
stim ulating m ucussecretion and increasewatercoutentofsput-um
(liquefy and dissolvesputum)thusdecreasing thefrequencyofcough but
becom esm ore ''productive'' They include:
l-saline Expectorants:as sodium or potassium iodidt.lodide irritates and
stim ulates secretion pf exocrine glands including bronchialglands.
They are used in chronic bronchitis
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A dverse effects:
l-A llergy.
z-lodism :m etallic taste,sialadenitis,lacrim ation,rhinitis.
3-lnterfernce w ith thyroid function.
4-* Bitterflavorlim its its use.
ContraindicationsL
l-A llergy to iodine.
2-Acutebronchitis(irritation causesmore inflammation).
3-T.B .:iodidem ay dissolvefibroustissue and causespread ofinfection.
4-Pregnancy:iodine m ay affectthe fetalthyroid.

z-Alkaline Exoectoî'anta:assodium orpotassium acetate benzoate or

citrate w hich are converted into bicarbonate w hich increases bronchial
waterysecretionanddissolvesmucus(seeusesofNaHCO;inpeptic
ulcer).
D-N auseantExnectorants' .Tincture ipecacuanha,Tincture senega,
A m m onium chioride and arnm onium carbonate given in sub-em etic
doses to induce nausea --+vagalstim ulation -+increase w atery secretion
in bronchi(seeperipheralemeticsin GIT pharmacology).

B stim ulantExpectorants:
- --
-
..

*'Fhey ''stimulate''healing ofmucosa(vulnerary action).

wThey have ''deodorant''action.
w-l-hey decrease the am ountofsputum .
lrrhey havc m ild antiseptic action.
*'Ihey are used in suppurative lung diseases as bronchiectasis and lung
abscess.
*Examples:Cl'eosote.Guaiacol.Ternenehvdrate(terpenehydrate
contains 42% alcoholw hich crosses the placem a and m ay lead to
j'kc
11ongeni
talanomalics).
M ucolvtics:
They liquefy viscid sputum and facilitate theaction ofexpectorants.
l-BromhexineIBisolvonh andAmbroxol:
D epolym erize m ucopolysaccharide ofthe ground substance ofm ucus.
(Ambroxoiistheactivemetaboliteofbromhexine).
z-A cetvlcvsteine:
Contain freeSH group which break disulfidebondsin mucus.They are
given orally,by inha'lation, orby i
njtction.
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10
'It is more blessed to give than to receive.

A ctions:
l-M uçolytic by breaking disultidebondsofmucus.
z-llepatoprotection in acuteparacetamoltoxicity todetoxify NABQI
(toxicmetabolite)by donation offreeSH groups.
3-A ntioxidantaction.
Indications:
l--rreatmentofproductivecoughasadjuvanttherapywithexpectorants.
z--l-reatmentofacuteparacetamol(acetaminophen)
toxicity= e acetam inophen antidote.
3-* Diagnosticbronchialstudies(to cleartheairway).
J-@ D ornasealfa:
-
By inhalation.
-
M ucolytic in patients w ith cystic fibrosis.
x-prepared by recom binantD N A technology from Chinese ham steroval'y
cells.

4-* Erdosteine:used asm ucolytic in actlte bronchitis.

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M anazem entofa Case ofBronchialAsthma.

.
A cute A ttaclo':
DrucUsed:Shortactingseltctivejz-agonistassalbtttamol.
R oute ofadm inistration:Inhalation.
Dose:1-2puft-
s(100-200 p.g.).
M echanism ofaction:see before.
A dverse effects:see before.

lfnoresponsetoselectivepz-agonists:
D rua U sed:A m inophylline.
Routeofadm inistration:Slowly IV injection.
D ose:250-500 m g.
M echanism ofaction:see before.
A dverse effects:see befort.
Therapeutic and toxic olasm a concentrations:see before.
D ruz interactions:see before.

StatusAsthmaticus (Severe Jcîfre asthm al:

l-H ospitalization.
z-oxygen therapy (40-601$).
3-l-lydocrtisone 200 m g.IV /4-6 hours for24 hours follow ed by oral
predisolone for2 w eeks.
4-IV fluidsas glucose 5% to correctdehydration.
6-salbutam olby nebulizerorIV injection.
7-ytm inophylline IV infusion.
S-Antibiotics(totreatassociated chestinfection).
g-Anxiolytics(benzodiazepines-asdiazepam -aresafeasthey donot
depressR.C.).

P rlm hjllactic Treatm ent:

l-Avoid:exposureto theantigen (dust,fumes,and tobaccosmokel-.
stress and exercise ifthey induce asthm atic atlacks.
3-Avoiddrugsthatinduceasthma(seebefore).
4-Desensitization(Hyposensitization).
s-D rugs used forprophylactic treatm ent:
WhiteKnightLove
'It is more blessed to give than to receive.

Drttg Group Example Atpîf/cofadministration

l-l-zongacting R -agonists: -salmeteroland -lnhalation.
Form oterol.
-
Bam buterol. -o ral.
z-M ettlylxanthines: -'l-heophylline. -SR oraltablets or capsules.
-
A m ino h lline. -lkectalsu osito .
3-corticosteroids: -Beclom ethasone. Inbalation.
-Fluticasone.
l-A ntim uscarinics:
z I ratro itlm . (nhalation.
s-M astCellStabilizers: -Disodium cromogtycate. lnhalation (powderby
'
-
Nedocrom il. spinhaier-solution by
nebulizeror inhaler .
6-Leukotriene A ntagonists:
*5-LO X inhibitors: Zileuton.
*cysteinylleukotriene receptor ()ral.
anta onists: M ontelukast-zaflrlukast.

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