Ashma Bronkial Drugs

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    Asthma is associated with mast cells,eosinophils, and T lymphocytes. Mastcells are the allergy-causing cells thatrelease chemicals like histamine.Histamine is the substance that causesnasal stuffiness and dripping in a cold orhay fever, constriction of airways inasthma, and itchy areas in a skin allergy.Eosinophils are a type of white blood cellassociated with allergic disease. Tlymphocytes are also white blood cells

    associated with allergy and inflammation.

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    Signs and Symptoms of

    Bronchial AsthmaWith bronchial asthma, you may haveone or more of the following signs and


    Shortness of breath

    Tightness of chest


    Excessive coughing or a cough that

    keeps you awake at night

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    Drugs to Treat Bronchial

    Asthma1. Drugs Used to relieve the Symptoms of


    Drugs which open up the airways are calledbronchodilators because they act by dilating(opening up) the bronchial tubes. They are used

    to reverse or decrease obstruction to the flow ofair to the lungs caused by narrowing of thesetubes. This occurs in bronchial asthma which is achronic inflammation, causing spasm of themuscles in the bronchial tubes (bronchospasm),

    swelling of the lining surfaces and an increasedproduction of secretions. Narrowing of theairways may also occur in chronic chestdisorders such as emphysema and bronchitis. Inthese disorders the small bronchial tubes are

    scarred, distorted and narrowed by repeatedinfections (e.g. bronchitis)

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    2. Drugs Used to Prevent Asthma

    Non-steroidal Anti-inflammatory Drugs

    Sodium cromoglycate (in Aerocrom, Cromogen,

    Intal) and nedocromil sodium (Tilade) act on thesurface of special cells (mast cells) to prevent therelease of chemicals (in response, for example, to anallergen) which cause bronchospasm (wheezing) andinflammation of the lining of the bronchial tubes. They

    are used toprevent attacks of asthma but are noteffective if taken after the reaction has started. Theyshould be tried on adults who need to use abronchodilator more than once a day and who get nightsymptoms and/or who should not take corticosteroids.

    Sodium cromoglycate should be tried for at least sixweeks in children before using corticosteroids. They arealso effective for preventing wheezing triggered byexercise, aspirin, industrial dusts, chemicals and coldair. Nedocromil should not be used in children.

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    Steroidal An t i -Inf lammatory Drugs


    Corticosteroids by inhalation are the treatment ofchoice to prevent asthma attacks in children andadults who need to use an adrenoreceptorstimulant bronchodilator more than once a day orwho get night symptoms. They are of doubtfulvalue in chronic bronchitis and emphysema. Theytake 37 days to produce maximum benefit andthey are best used with a spacer device to preventdeposits in the mouth and throat causing thrush.Preparations of corticosteroids for inhalation

    include beclometasone (Aerobec, Asmabec,Beclazone, Becloforte, Becodisks, Becotide,Filair, Qvar,in Ventide), budesonide (Pulmicort)and fluticasone (Flixotide, in Seretide).

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    Types of Bronchodilators for


    Short-acting bronchodilators

    Short-acting bronchodilators are called"quick-acting," "reliever," or "rescue"

    medications. These bronchodilators relieveacute asthma symptoms or attacks veryquickly by opening the airways. The rescuemedications are best for treating sudden

    asthma symptoms. The action of inhaledbronchodilators starts within minutes afterinhalation and lasts for two to four hours.Short-acting bronchodilators are also used

    before exercise to prevent exercise-induced

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    Short-Acting Bronchodilator InhalersAvailable in the United States Include:

    Albuterol(AccuNeb, ProventilHFA,

    VentolinHFA, also available as a genericsolution for nebulizers)

    Alupent(Metaproterenol, available as a

    generic solution for nebulizers, seebelow)

    Levalbuterol (Xopenex)

    Pirbuterol (Maxair)
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    1. Albuterol

    The pharmacokinetics of inhaled (R,S)-albuterol followingpulmonary absorption were studied in healthy humansubjects. Ten subjects (5 females and 5 males) inhaled twopuffs (180 microg) of albuterol via a metered-dose inhaler andspacer device. All subjects were nonsmoking and had normalpulmonary function. Charcoal slurries were ingested to block

    gastrointestinal absorption of drug. Venous samples wereobtained from each subject at thirteen time points from 0through 12 h post dose. (R,S)-Albuterol concentration inplasma was measured using a gas chromatography-massspectrometry (GC-MS) assay. The plasma concentration-timeprofiles conformed to a two-compartment extravascular model

    with first-order absorption kinetics. The drug levels reachedmaximum in 12.6 +/- 2.2 (SD) minutes, which is in contrastwith previous reports that maximum plasma concentrationsoccur within 2 to 4 h. The mean peak plasma level was 1469+/- 410 pg/mL. The mean half-life of distribution was 17.9 +/-8.2 min. The mean half-life of elimination was 4.4 +/- 1.5 h.

    Female subjects achieved peak concentration more rapidlythan male subjects (10.4 vs 14.8 min, p = 0.01) and had a

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    2.Ipratropium Bromide

    The bronchodilation following inhalation of ipratropiumis primarily a local, site-specific effect, not a systemic

    one. Much of an inhaled dose is swallowed as shownby fecal excretion studies. Following nebulization of a1-mg dose to healthy volunteers, a mean of 4% of thedose was excreted unchanged in the urine.

    Ipratropium bromide is minimally (0% to 9% in vitro)

    bound to plasma albumin and 1-acid glycoproteins. Itis partially metabolized to inactive ester hydrolysisproducts. Following intravenous administration,approximately one-half is excreted unchanged in theurine. The half-life of elimination is about 1.6 hoursafter intravenous administration. Ipratropium bromidethat reaches the systemic circulation is reportedlyremoved by the kidneys rapidly at a rate that exceedsthe glomerular filtration rate. The pharmacokinetics ofipratropium bromide and albuterol sulfate inhalationsolution or ipratropium bromide have not been studied

    in the elderly and in patients with hepatic or renalinsufficienc

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    3. Albuterol Sulfate

    Albuterol sulfate is longer acting than

    isoproterenol in most patients by anyroute of administration, because it is nota substrate for the cellular uptakeprocesses for catecholamine nor for the

    metabolism of catechol-O-methyltransferase. Instead the drug isconjugatively metabolized to albuterol 4'-O-sulfate.

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    4. Metaproterenol Sulfate


    Less than 10% is absorbed intact.

    MetabolismMetabolized through sulfate conjugation in the GI tract. Themajor metabolite is metaproterenol-o-sulfate.

    Dosage and Administration Tablets

    Adults and Children (9 yr of age and older or at least 60lbs)

    PO 20 mg 3 to 4 times daily.Children (6 to 9 yr of age or weight less than 60 lbs)

    PO 10 mg 3 to 4 times daily. Syrup

    Adults and Children (9 yr of age and older or at least 60lbs)

    PO 10 mL 3 to 4 times daily.

    Children (6 to 9 yr of age or weight less than 60 lbs)

    PO 5 mL 3 to 4 times daily.

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    5. Levalbuterol

    Metabolism and Elimination

    Information available in the published literature suggests thatthe primary enzyme responsible for the metabolism of

    albuterol enantiomers in humans is SULT1A3(sulfotransferase). When racemic albuterol was administeredeither intravenously or via inhalation after oral charcoaladministration, there was a 3- to 4-fold difference in the areaunder the concentration-time curves between the (R)- and(S)-albuterol enantiomers, with (S)-albuterol concentrations

    being consistently higher. However, without charcoalpretreatment, after either oral or inhalation administration thedifferences were 8- to 24-fold, suggesting that (R)-albuterol ispreferentially metabolized in the gastrointestinal tract,presumably by SULT1A3.

    The primary route of elimination of albuterol enantiomers isthrough renal excretion (80% to 100%) of either the parentcompound or the primary metabolite. Less than 20% of thedrug is detected in the feces. Following intravenousadministration of racemic albuterol, between 25% and 46% of

    the (R)-albuterol fraction of the dose was excreted asunchanged (R)-albuterol in the urine.

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    Special Populations Hepatic Impairment: The effect of hepatic

    impairment on the pharmacokinetics

    of Levalbuterol HCl Inhalation Solution hasnot been evaluated.

    Renal Impairment: The effect of renalimpairment on the pharmacokinetics of

    racemic albuterol was evaluated in 5 subjectswith creatinine clearance of 7 to 53 mL/min,and the results were compared with thosefrom healthy volunteers. Renal disease had

    no effect on the half-life, but there was a 67%decline in racemic albuterol clearance.Caution should be used when administeringhigh doses of Levalbuterol HCl InhalationSolution to patients with renal impairment

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    6. Salmeterol


    Salmeterol acts locally in the lung. Plasma levelsdo not predict therapeutic effect. Depending ondose, T maxis 20 min and mean C maxis 167pg/mL.


    Protein binding is 96%; xinafoate moiety is greaterthan 99%.


    Extensively metabolized by hydroxylation. Elimination

    Eliminated in feces (60%) and urine (25%); halflife is 5.5 days. Xinafoate moiety half-life is 11


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    Special Populations Renal Function Impairment

    Has not been studied in patients with

    renal impairment. Hepatic Function Impairment

    May lead to accumulation of

    salmeterol in plasma. Elderly

    Has not been studied in elderlypatients.

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    7. formoterol


    Inhalation powder

    C maxis 92 pg/mL and T maxis 5 min.

    Inhalation solution

    C maxis 72 pg/mL and T maxis 12 min.


    Protein binding is 61% to 64%.


    Formoterol is primarily metabolized by direct glucuronidation and O-demethylation by CYP-450 2D6, 2C19, 2C9, and 2A6 isozymes.


    Inhalation powder

    Eliminated in the urine (59% to 62%) and feces (32% to 34%).About 10% is excreted unchanged in the urine, and

    about 15% to 18% is excreted in the urine as conjugates. Meanhalf-life is 10 h.

    Inhalation solution

    1.1% to 1.7% excreted unchanged in the urine. The half-life is 7h.

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    Special Populations Children

    The pharmacokinetics of formoterol inhalationsolution have not been studied in children.

    GenderPharmacokinetics did not differ between menand women.

    Elderly/Hepatic and renal functionimpairment

    Pharmacokinetic studies have not been donein elderly patients or in subjects with hepaticor renal function impairment.

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    8. Theofilline


    Theophylline administered in the fed state is completely absorbed after oraladministration.

    Distribution:Once Theophylline enters the systemic circulation, about 40% is bound toplasma protein, primarily albumin. Unbound Theophylline distributesthroughout body water, but distributes poorly into body fat. The apparentvolume of distribution of Theophylline is approximately 0.45 L/kg (range 0.3-0.7 L/kg) based on ideal body weight. Theophylline passes freely across theplacenta, into breast milk and into the cerebrospinal fluid (CSF). Saliva

    Theophylline concentrations approximate unbound serum concentrations, butare not reliable for routine or therapeutic monitoring unless specialtechniques are used. An increase in the volume of distribution ofTheophylline, primarily due to reduction in plasma protein binding, occurs inpremature neonates, patients with hepatic cirrhosis, uncorrected acidemia,the elderly and in women during the third trimester of pregnancy. In suchcases, the patient may show signs of toxicity at total (bound+unbound) serumconcentrations of Theophylline in the therapeutic range (10-20 mcg/mL) dueto elevated concentrations of the pharmacologically active unbound drug.Similarly, a patient with decreased Theophylline binding may have a sub-therapeutic total drug concentration while the pharmacologically activeunbound concentration is in the therapeutic range. If only total serumTheophylline concentration is measured, this may lead to an unnecessaryand potentially dangerous dose increase. In patients with reduced proteinbinding, measurement of unbound serum Theophylline concentration

    provides a more reliable means of dosage adjustment than measurement oftotal serum Theophylline concentration. Generally, concentrations of unbound

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    Following oral dosing, Theophylline does not undergoany measurable first-pass elimination. In adults andchildren beyond one year of age, approximately 90%of the dose is metabolized in the liver.Biotransformation takes place through demethylationto 1 methylxanthine and 3-methylxanthine andhydroxylation to 1,3- dimethyluric acid. 1-methylxanthine is further hydroxylated, by xanthine

    oxidase, to 1-methyluric acid. About 6% of aTheophylline dose is N-methylated to caffeine.Theophylline demethylation to 3-methylxanthine iscatalyzed by cytochrome P-450 1A2, whilecytochromes P-450 2E1 and P-450 3A3 catalyze the

    hydroxylation to 1,3-dimethyluric acid. Demethylationto 1-methylxanthine appears to be catalyzed either bycytochrome P-450 1A2 or a closely relatedcytochrome. In neonates, the Ndemethylation pathwayis absent while the function of the hydroxylation

    pathway is markedly deficient. The activity of thesepathways slowly increases to maximal levels by one

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    In neonates, approximately 50% of the Theophyllinedose is excreted unchanged in the urine. Beyond the

    first three months of life, approximately 10% of theTheophylline dose is excreted unchanged in the urine.The remainder is excreted in the urine mainly as 1,3-dimethyluric acid (35-40%), 1-methyluric acid (20-25%) and 3-methylxanthine (15-20%). Since little

    Theophylline is excreted unchanged in the urine andsince active metabolites of Theophylline (i.e., caffeine,3-methylxanthine) do not accumulate to clinicallysignificant levels even in the face of end-stage renaldisease, no dosage adjustment for renal insufficiencyis necessary in adults and children >3 months of age.In contrast, the large fraction of the Theophylline doseexcreted in the urine as unchanged Theophylline andcaffeine in neonates requires careful attention to dosereduction and frequent monitoring of serumTheophylline concentrations in neonates with reduced

    renal function

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    9. Aminofilin


    (Note: Information for the pharmacokinetics/dynamics section wastaken from theophylline because aminophylline is a mixture of

    theophylline and base.) Rapidly and completely absorbed in solutionor immediate-release. C maxis 10 mcg/mL (5 to 15 mcg/mL). T maxis1 to 2 h. Food and antacid does not cause any clinically importantchanges; therapeutic range is 10 to 20 mcg/mL.


    40% protein bound (primarily albumin). Unbound theophylline

    distributes throughout the body water, but distributes poorly intobody fat. Vd is 0.45 L/kg (0.3 to 0.7 L/kg) based on ideal bodyweight. Freely passes across the placenta into breast milk and intoCSF.


    Does not undergo any measurable first-pass elimination. About 90%

    of dose is metabolized in the liver in adults and children older than 1yr of age. Caffeine and 3-methylxanthine are the only theophyllinemetabolites with pharmacological activity.


    In neonates, about 50% of theophylline dose is excreted unchangedin the urine (ie, excretion is by the kidneys). 10% of theophylline

    dose is excreted unchanged in the urine in infants 0 to 3 mo of age.

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    10. Beclometason kortikosteroid Absorption

    Rapidly absorbed. Nasal inhalation

    Primarily deposited in the nasal passage; majority of the drug iseventually swallowed. Bioavailability following administration is 44%

    ( Beconase AQ ). Oral inhalation

    Systemic bioavailability from lungs is about 20%.


    87% protein bound (94% to 96% for beclomethasone 17-monoprionate).

    MetabolismMetabolized to beclomethasone 17-monopropionate (active) andfree beclomethasone (very weak activity).


    Primarily excreted in feces. Less than 10% excreted in urine. Thehalf-life is 2.8 h for beclomethasone 17-monopropionate.

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  • 8/12/2019 Ashma Bronkial Drugs