(Tikrit Journal of Pharmaceutical Sciences 2011 7(1

Role of aminophylline for sever acute asthma in adults

Abdul sattar Hussien abdullh
Department of Medicine, Collage of Medicine, University of Tikrit, Tikrit, ra! Received 26/4/2011 cce!ted "/"/2011

Abstract
Aminophylline is a bronchodilator It is used to treat breathing problems such as asthma, chronic bronchitis and emphysema "a Randomized, double blind, placebo controlled trial study compared the clinical effect of intravenous aminophylline group and placebo group in the management of sever acute asthma. A total of 100 patients(5 females, and ! male"their age range from 1#$55 years. %he study &as conducted in %i'rit teaching hospital during the period from (anuary to the August) *00#. after history ta'en ,all patient under$gone complete general e+amination , and chest e+amination ,measurement of height and pea' e+piratory flo& rate (,-.R" and compared to the predicted average normal ,-.R (liter)minute" to ma'e sure that the patient had acute sever asthma according to classification of asthma severity(*/".measurement of ,a0* and heart rate done for each patient by using of 0edside 1onitor before treatment.50 patients received placebo (*! female and * male" and 50 patients received aminophylline (*2 female and ** male".those patients follo&ed after one hour from treatment by measurement of ,a0* , heart rate and ,-.R. %he result of the group treated &ith aminophylline sho& that significant increase in ,a3* from 22.4 before treatment to #0.5* one hour after treatment &hile in group treated &ith placebo sho& that increase in ,a3* from 22.!4 before treatment to 2#./4 one hour after treatment .Asthmatic patients treated &ith aminophylline sho& significant increase in ,-.R from *40.12 (liter)minute" before treatment to *#2.2!(liter)minute" one hour after treatment &hile in group treated &ith placebo sho& that increase in ,-.R from *!2.5* (liter)minute"before treatment to *!#. 0 (liter)minute" one hour after treatment, the group treated &ith aminophylline sho& that significant decrease in heart rate from 1! .4* beat )minute before treatment to155.52 beat )minute one hour after treatment &hile in group treated &ith placebo sho& that a non significant decrease in heart rate from 1!/.2! beat )minute before treatment to1!0.1* beat )minute one hour after treatment

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ntroduction
Aminophylline is a bronchodilator. Aminophylline &or's in several &ays it rela+es muscles in the lungs and chest to allo& more air in, decreases the sensitivity of the lungs to allergens and other substances that cause inflammation, and increases the contractions of the diaphragm to dra& more air into the lungs. (1" Aminophylline is used to treat the symptoms of asthma, bronchitis, and emphysema. Aminophylline has been used e+tensively in acute asthma, but its role is unclear especially &ith respect to any additional benefit &hen added to beta*$agonists ( *" Intravenous aminophylline is effective in children &ith acute asthma and &as the bronchodilator of choice for many years. o&ever, &ith the advent of inhaled beta*$ agonists and anticholinergic agents an alternative, less invasive, therapeutic strategy is currently available (/" Aminophylline is a compound of the bronchodilator theophylline &ith ethylenediamine in *1 ratio. %he ethylenediamine improves solubility, and the aminophylline is usually found as a dihydrate .It is more soluble in &ater than theophylline ( ".

Mechanism of action
i'e other methylated +anthine derivatives, aminophylline is both a

1. competitive nonselective phosphodiesterase inhibitor(5" &hich raises intracellular cyclic adenine monophosphate (cA1,", activates ,rotein 'inase A ,A (!", inhibits %umor necrosis factor$alpha %.$alpha(4". and leu'otriene synthesis, and reduces inflammation and innate immunity (2". *. nonselective adenosine receptor antagonist (#". Aminophylline is less potent and shorter$acting than theophylline. Its most common use is in the treatment of bronchial asthma. auses bronchodilatation, diuresis, and cardiac stimulation, and gastric acid secretion by bloc'ing phosphodiesterase &hich increases tissue concentrations of cyclic adenine monophosphate (cA1," &hich in turn promotes catecholamine stimulation of lipolysis, glycogenolysis, and gluconeogenesis and induces release of epinephrine from adrenal medulla cells. %heophylline and its &ater$ soluble derivative aminophylline have since been &idely used in the treatment of asthma. 3f the methyl+anthines, theophylline is the most potent bronchodilator, and it may also e+hibit anti$inflammatory and immnuomodulatory actions,(1/" improve respiratory muscle function, hasten mucociliary clearance, and act GH

(Tikrit Journal of Pharmaceutical Sciences 2011 7(1 centrally to stimulate respiration (1 ". Indeed, the advent of selective * agonists led to a decline in aminophylline use, since studies in acute asthma repeatedly sho&ed that * agonists, given by either inection or inhalation, &ere clearly superior to intravenous aminophylline(15" 1ethyl+anthineshave been associated &ith significant improvements in the .-1 and . during e+acerbations of acute bronchial obstruction %he methyl+anthine theophylline, and its soluble ethylenediamine salt aminophylline, provide not only rela+ation of bronchial smooth muscle in reactive air&ays but may also have salutary effects on diaphragmatic muscle function, ventilatory drive, mucociliary clearance, antidiuretic hormone secretion, and inflammation. Although theophylline has a relatively narro& range of therapeutic concentrations, the drug can be administered safely &ith appropriate consideration to dosing, serum concentrations, concurrent illness and medications, and side effects (14". osage is based on your medical condition, response to therapy, age, drug blood levels, and other drugs you may be ta'ing.(1!" Aminophylline is in the .A pregnancy category . %his means that it is not 'no&n &hether aminophylline &ill harm an unborn baby. Aminophylline passes into breast mil' and could affect a nursing baby. ou may reuire a lo&er dose of this medication in old age.(15" Ither uses of aminophylline Aminophylline has sho&n some promise as a body fat reducer &hen used as a topical cream (sometimes referred to as cutting gel"(10" Aminophylline is also a treatment option for anaphylactic shoc'(11". %he role of aminophylline in pediatric acute asthma has become less clear. %here remains some consensus that it is beneficial in children &ith acute severe asthma, receiving ma+imised therapy (o+ygen, inhaled bronchodilators, and glucocorticoids"(1*" aminophylline over dose %he maor life$threatening events of theophylline into+ication are seizures and heart rhythm disturbances(12"

Jatients and Methods

A Randomized, double blind, placebo controlled trial study compared the clinical effect of intravenous aminophylline group and placebo group in the management of sever acute asthma. A total of 100 patients(5 females, and ! male"their age range from 1#$55 years. %he study &as conducted in %i'rit teaching hospital during the period from (anuary to the August) *00#. After history ta'en ,all patient under$gone complete general e+amination , and chest e+amination ,measurement of height and pea' e+piratory flo& rate (,-.R" and compared to the predicted average normal ,-.R (liter)minute" to ma'e sure that the patient had acute sever asthma according to (*/". classification of asthma severity 1easurement of ,a0* and heart rate done for each patient by using of 0edside 1onitor(a device that loo's li'e a television screen or computer monitor. %he monitor is attached to &ires, called leads. At the other end, the leads are attached to sensing devices attached to the patients body. %he sensing device sends electronic signals to the monitor, &hich displays the readings for the specific body function being monitored before treatment.50 patients received placebo (*! female and * male" and 50 patients received aminophylline (*2 female and ** male". %hose patients follo&ed after one hour from treatment by measurement of ,a0* , heart rate and ,-.R" .ull history &as ta'en

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(Tikrit Journal of Pharmaceutical Sciences 2011 7(1 include name, age, se+, address, occupation, detail history of asthma, including asthma symptoms , number of day symptoms attac's, number of nocturnal symptoms attac's)&, number of times of uses of *$agonist)&, and effect of asthma on physical activity and then clinical assessment according to (A%1A 3%R3 3RI %-1". All patients &ith the follo&ing criteria &ere e+cluded$ pregnancy, ,atient &ith chronic obstructive pulmonary diseases, significant disease of other organs, 'no&n side effect to theophylline or ta'en aminophylline in previous * hours. %he proper measurement of ,-.R &as ta'en by as'ing the patient to ta'e breath normally in rela+ed pattern and as' to ta'e inspiration deeply and then ta'e off e+piration as force as possible to read ,-.R (lit)min" using ,ea' .lo& 1eter. %ype of ,ea' .lo& 1eter is aloscale &right respirometer, registered no(501!0*" -ngland. Aminophylline given 10 mg )'g) hour infusion in 100 cc glucose &ater, placebo given as distal &ater in 100 cc glucose &ater , &e put aminophylline and placebo &hich is the same colorless and odorless in a syringe numbered by pharmacist as one for aminophylline and to& for placebo. %he investigator, patients, medical staff carrying out the treatment, and patients family &ere blind to treatment groups. 0lindly maintained throughout the period of the study. %hose patients &ere follo&ed up after 1 hour by measurement of ,-.R ,,a3* and heart rate. tatistical Analysis &ere done by uncans 1ultiple Range %est by using statistical analysis system program (A". 1eans &ith the same letter are not significantly different. %he statistical result &ere considered highly significant at p value eual or less than 0.01 and significant at p value more than 0.01 and less than or eual to 0.05 and not significant at p value more than 0.05.All data &ere presented as a mean and standard deviation (".

Results
3ne hundred patients included in the study, 50 patients received aminophylline (*2 female and ** male". ,and 50 patients received placebo (*! female and * male" Regarding gender distribution of study population, the results sho& that ! of them &ere male and 5 &ere females. %he result of group treated &ith aminophylline regarding gender distribution sho& that about &ere males and 5! &ere females. hile group treated &ith placebo sho& that 2 &ere male and 5* &ere female. Asthmatic patients &ere treated &ith aminophylline significantly increase of ,ao* from 22.4 0.24 before treatment to #0.5* 1.1! one hour after treatment at pr 0.000* (table 1 ".Regarding group treated &ith placebo there is lo& significant increase of ,ao* from 22.!4 0.2# before treatment to 2#./4 one hour after treatment at pr 0.001 (table 1 "

TableKHLMNThe mean O PD of JaIQ of studied groupsKsignificant at R"RRHL Sroup aminophylline placebo Tefore treatment c 0.24 22.4 c 0.2# 22.!4 Ine hour after treatment a 1.1! #0.5* b 1.1* 2#./4 pr 0.05

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(Tikrit Journal of Pharmaceutical Sciences 2011 7(1 Also Asthmatic patients &ere treated &ith aminophylline significantly decrease of heart rate from 1! .4* #.00 before treatment to 155.52 1*.!* one hour after treatment at pr 0.0 ! (table * ". Regarding group treated &ith placebo there a non significant decrease of heart rate from 1!/.2! 4.1* before treatment to 1!0.1* 2. one hour after treatment at pr 0.0 ! (table * ".

TableKQLMThe mean O PD of heart rate of studied groupsKsignificant at R"RUL roup aminophylline placebo 0efore treatment a #.00 1! .4* ab 4.1* 1!/.2! 3ne hour after treatment c 1*.!* 155.52 b 2. 1!0.1* pr 0.05

Regarding patients treated &ith aminophylline %here is a significant increase in ,-.R from *40.12 /2.!5 before treatment to *#2.2! *.*0 one hour after treatment at pr 0.01 (table

/ ".hile patients treated &ith aminophylline %here is non significant increase in ,-.R from *!2.5*/#.5# before treatment *!#. 0 /#.4# one hour after treatment at pr 0.01 (table / ".

TableKVLMN The mean O PD of JWXR of studied groupsKsignificant at R"RHL roup aminophylline placebo 0efore treatment b /2.!5 *40.12 b /#.5# *!2.5* 3ne hour after treatment a *.*0 *#2.2! b /#.4# *!#. 0 pr 0.01

%he overall freuency of clinical adverse events &as more common among the aminophylline group. eadache , gastrointestinal tract problem including (nausea, vomiting", irritability and %remor &ere the most freuently reported adverse events, other side effects include diuresis , and diarrhea ( "

Discussion
Asthma is characterized by air&ay inflammation that manifests by reversible airflo& limitation and air&ay hyperresponsivness. Aminophylline is used to prevent and treat &heezing, shortness of breath, and difficulty breathing caused by asthma(1#". ,ao* e+hibited significant GH

increase compared &ith placebo , this is due to that Aminophylline, as a bronchodilator, decrease air&ay constriction ,and this is in agreement &ith the study done by 1ichael ung &ho found that aminophylline continues to have a place in the management of acute sever asthma by improvement of pao*(*0" Also Asthmatic patients &ere treated &ith aminophylline significantly decrease of heart rate compared &ith placebo ,this is may be due to that Aminophylline, as a bronchodilator, decrease air&ay constriction and decrease heart rate result from sever dyspnea. ,-.R e+hibited significant increase compared &ith placebo , this is due to that Aminophylline, as a bronchodilator, decrease air&ay

(Tikrit Journal of Pharmaceutical Sciences 2011 7(1 constriction ,and this is in agreement &ith the study done by 1itra A. &ho found that aminophylline improved percentage predicted .-1 and ,-. by ! hours(**". and disagree &ith the study done by aniel ,et al, &ho sho& that %here &as no difference in improvement of ,-.R bet&een the treatment and placebo groups(*1" %he overall freuency of clinical adverse events &as more common among the aminophylline group than in placebo group and this is in agreement &ith the study done by 1ichael ung &ho found that the overall freuency of clinical adverse events &as more common among the aminophylline group than in placebo group(*0" T !-alpha production in human mononuclear cells the effects of non-specific phosphodiesterase inhibition.. Clinics "#ao $aulo%. *002 !/ (/" /*12. 1arues (, heng , ,oula'is , uzman (, ostabel . $ento&ifylline inhibits T !alpha production from human alveolar macrophages. Am. (. Respir. rit. are 1ed. 1###MHU[ (*" 50211. ,eters$olden 1, anetti , 1ancuso ,, offey 1(. eu'otrienes underappreciated mediators of innate immune responses.'. J Immunol. *005 14 (*" 52# # . aly (, (acobson A, 'ena . 'Adenosine receptors( development of selective agonists and antagonists.. $rog Clin )iol *es. 1#24 QVR (1" 1!/. aruso 1, ,e'arovic , Raum (, reen&ay .. %opical fat reduction from the &aist. +iabetes, obesity metabolism. *004 [ (/" /00 /.. 0lac'bourne . urgical Recall. ippincott illiams and il'ins, *00#. pp1!# 1itra A ,0assler ,oodman . Intravenous aminophylline for acute severe asthma in children over two years receiving inhaled bronchodilators .chochrane atabase syst. Rev. *005 Apr 12(*"001*4! 0arnes ,(, ,au&els RA. Theophylline in the management of asthma( time for reappraisal -ur Resp (.1## Z54##1.

References
H Q http))&&&.drugs.com)mtm)am inophylline. opyright *000$ *010 rugs.com ,arames&aran ,0elda ( ,Ro&e 0. Addition of intravenous aminophylline to beta2-agonists in adults with acute asthma" ochrane atabase ys. Rev. *000. 1itra A . %he current role of intravenous aminophylline in acute paediatric asthma. 1inerva pediatrics . *00/ Aug55( "/!#$45 Aminophylline ,rofessional 1onograph .http))&&&.drugs.com)pro)ami nophylline$inection.html. -ssayan 1.. yclic nucleotide phosphodiesterases.. J Allergy Clin Immunol. *001102 (5" !4120. eree (, 1artins (3, 1elbostad , oomis , oimbra R.. Insights into the regulation of

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(Tikrit Journal of Pharmaceutical Sciences 2011 7(1 HY einberger 1, endeles . rug %herapy Theophylline in Asthma. -ngl ( 1ed1##! // 1/202 HU 1c.adden -R(. .ethyl&anthines in the treatment of asthma( the rise, the fall and the possible rise again. Ann Intern 1ed1##1 115/*/ . HG http))&&&. eb1. rugs 1edications $ Aminophylline I/. *005$*010 eb1, . All rights reserved. HZ Robert . Ream, aura . oftis, ary 1. 0fficacy of I/ Theophylline in Children 1ith #evere #tatus Asthmaticus Chest *00111#1 20$1 22 H\ hannon 1, 0orron , 0urns 1(, eds. 2addad and 1inchester3s Clinical .anagement of $oisoning and +rug 4verdose. th ed. ,hiladelphia, ,a aunders -lsevier *004chap !5 H[ American ociety of ealth$ ystem ,harmacists, Inc. isclaimer. 1edline plus, Aminophylline, ast Revie&ed $ 0*)01)*00#. QR 1ichael ung , 1i'e outh. *andomised controlled trial of aminophylline for sever acute asthma, 1##2 4# 05$ 10. QH aniel . 1urphy, 1 1ichael .. et al. Aminophylline in the Treatment of cute sthma #hen $2% drener&ics and Steroids Are Jrovided Arch Intern .ed. 1##/15/(15"142 $1422. QQ 1itra A "The current role of intravenous aminophylline in acute paediatric asthma" *00/ Aug55( "/!#$45. QV elson %e+tboo' of pediatrics. 1!th edition. 0 anders company. *00 *1!! .

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