I.

Pharmacotherapy of bronchial asthma (BA)

By Dr. Ahmed S. Ali & Prof Magada. Hagras
Dept of pharmacology faculty of medicine KAAU. Revised version 1429 H -2008 G
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What is BA ?
• BA is A syndrome of bronchial
inflammation, airway hyper-
responsiveness and reversible airways
obstruction
• BA is characterized by episodes of
bronchoconstriction causing shortness of
breath , cough, chest tightness, wheezing
and rapid respiration.
• The clinical course is characterized by
exacerbations and remissions

Overview of Current Asthma Drugs

ROLE OF PHARMACOTHERPY : Pharmacological therapy alone will not give a good control of
asthma. Mattress and pillow covers should be free of mites. Removal of carpeting and vacuuming of
furniture helps. Animal pets at times are the offending allergens and may have to be removed from home
* Many international and national guidelines for diagnosis and management of BA are available and
their implementation allow rational use of drugs . these include:
1-Saudi national protocol for diagnosis and management of bronchial asthma 2nd ed. 2005
2-Best Treatment Guidelines For Bronchial Asthma: http://medind.nic.in/maa/t07/i3/maat07i3p264.pdf

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I- BRONCHODILATORS
1.1.Selective β2- adrenoceptor agonist.

The β2-selective adrenoceptor agonist drugs are the most widely used sympathomimetics for
the treatment of asthma at present. They are effective after inhaled or oral administration and have a
relatively long duration of action. They are available in all dosage forms ( inhalation, oral, potential )
Short acting β2-selective agonists : Ex : ALBUTEROL & TERBUTALINE: are available
as metered-dose inhalers.. Bronchodilation is maximal within 15-30 minutes and persists for 3-4
hours. All can be diluted in saline for administration from a hand-held nebulizer also available in
tablet form. terbutaline is available for subcutaneous injection (0.25 mg).
Long-acting β2-selective agonists includes : SALMETEROL & FORMOTEROL.
Salmitrol has slow onset of action, both drugs achieve their long duration of action (12 hours or
more) as a result of high lipid solubility. They usually used in prophylaxis.
Pharmacological action & Mechanism :
In general, stimulation of B2 receptors relaxes airway smooth muscle, inhibits mediator release, and
causes tachycardia and skeletal muscle tremor as side effects.
Mechanism :
These drugs Stimulate adenylyl cyclase ( at adrenergic B2- receptors ) and increase the
formation of intracellular cAMP.
Adverse drug effects : :
Minor adverse effects such as : Skeletal muscle tremor, nervousness, occasional weakness;
lowering of K & Mg blood level ( occasionally observed after oral administration )
Administration:
In general, adrenoceptor agonists are best delivered by inhalation because this results in the greatest
local effect on airway smooth muscle with the least systemic toxicity. Aerosol deposition depends on
the particle size, the pattern of breathing (tidal volume and rate of airflow), and the geometry of the
airways.. Deposition can be increased by holding the breath in inspiration.
Other non specific β2- adrenergic agonist
EPINEPHRINE : Used in anaphylactic shock
Is an effective, rapidly acting bronchodilator when injected subcutaneously (0.4 mL of 1:1000 solutions)
or inhaled as a microaerosol from a pressurized canister (320 mcg per puff). Maximal bronchodilation is
achieved 15 minutes after inhalation and lasts 60-90 minutes. Because epinephrine stimulates α and β1
as well as β2 receptors, tachycardia, arrhythmias, and worsening of angina pectoris are troublesome
adverse effects.
EPHEDRINE. & ISOPROTERENOL : are rarely used for asthma.

CLINICAL INDICATION : short acting β2-adrenoceptor agonists are the drugs of

choice for the immediate phase of the asthmatic attack

1.2. THEOPHYLLINE
Chemistry: IT is 1,3-dimethylxanthine; commonly used as a Theo-
ethylenediamine 1:1 complex. { aminophylline }. Its available tablets, capsules & SR
formulations & injections .

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Pharmacological action
Theo has several pharmacological effects; including CNS ( stimulation ) ; CV ( Tachycardia ); GIT
; in addition to the effects mentioned below.
Effects on smooth & skeletal muscles
The bronchodilation produced by the methylxanthines is the major therapeutic action in
asthma. Tolerance does not develop, in sufficient concentration it also inhibits antigen-induced
release of histamine from lung tissue. The effect of theo on diaphragmatic performance rather than
an effect on the respiratory center may account for Theo's ability to improve the ventilatory response
to hypoxia and to diminish dyspnea even in patients with irreversible airflow obstruction.
Pharmacokinetics
• Absorption : Most preparations are well absorbed from the gastrointestinal tract,.
Numerous sustained-release preparations ( less frequent drug administration, less fluctuation
of Theo blood levels, possibly more effective treatment of nocturnal bronchospasm.)
• Distribution : well distributed & not strongly bound to plasma protein
• Metabolism : Metabolized in liver
• Elimination ; metabolites by the kidney
Toxicity & ADE : .
The clinically important side effects are related to the level and can be avoided by adjusting the dose
: they include :
• Anorexia, nausea, vomiting, abdominal discomfort, headache,
• Mild anxiety , insomnia may occur at concentrations > 15 -20 ug/ml
• Arrhythmias occurs at levels > 20ug -30 ug/L
• Levels > 40 mg/L may cause serious arrhythmias & seizures
• Severe toxicity may lead to death if untreated
Precaution : TDM: therapeutic drug monitoring is essential
Theo has narrow therapeutic range ( 9-15 ug/ml ) ; determination of drug level ( TDM ) is
important to optimize its use and avoid toxicity The plasma clearance of Theo varies widely. so usual
doses may lead to toxic concentrations of the drug in patients with liver disease. Conversely, clearance may
be increased through the induction of hepatic enzymes by cigarette smoking or by changes in diet. In normal
adults, the mean plasma clearance is 0.69 mL/kg/min. Children clear Theo faster than adults (1-1.5
mL/kg/min). Neonates and young infants have the slowest clearance ( average half –life in neonates about 30 h )
Rabid injection should be avoided

CLINICAL INDICATION : considered as 3rd line drug to be added in severe asthma

and may be considered in small dose in chronic asthma
( avoid rabid injection )

Two proposed Mechanism of action??

1- in vitro using at high concentration theo inhibits several phosphodiesterase (PDE) enzyme family
( especially PDE4). This results in higher concentrations of intracellular cAMP and, in some tissues, cGMP.
Cyclic AMP is responsible for several cellular functions including, stimulation of cardiac function, relaxation
of smooth muscle, and reduction in the immune and inflammatory activity of specific cells.
2-Another proposed mechanism is inhibition of cell surface receptors for adenosine. These receptors
modulate adenylyl cyclase activity, and adenosine has been shown to provoke contraction of isolated airway
smooth muscle and histamine release from airway mast cells.

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1.3 IPRATROPIUM BROMIDE (antimuscarinic

{ cholinergic antagonists)
• A quaternary ammonium derivative of atropine,.
• can be delivered in high doses by inhalation;
• it is poorly absorbed into the circulation and does not readily enter
the central nervous system.
• May be valuable for patients intolerant to inhaled B2-agonist
agents.,
• It is also effective in patients with COPD that includes a partially reversible component.
• Clinical indication : as an adjunct to other bronchodilator therapy, particularly
in severe acute asthma ( enhances the bronchodilation produced by nebulized albuterol
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2- ANTI-INFLAMMATORY ( IMMUNOMODULATOR & RELATED ) DRUGS

2.1. CORTICOSTEROIDS
Mechanism of Action
Broad anti-inflammatory efficacy, mediated by inhibition of production of inflammatory cytokines.
and lymphocytic, eosinophilic mucosal inflammation of asthmatic airways.
Inhaled corticosteroids (ICS)
Aerosol treatment is the most effective way to avoid the systemic adverse effects of corticosteroid
therapy. ICS INCLUDE : BECLOMETHASONE, BUDESONIDE,
Inhaled corticosteroids are effective in improving all indices of asthma control severity of
symptoms, tests of airway caliber and bronchial reactivity, frequency of exacerbations, and quality of
life
Adverse effects of inhaled corticosteroids are few :
Oropharyngeal candidiasis can occur, as can dysphonia (voice problems), but these are less likely to
occur if 'spacing' devices are used which decrease oropharyngeal deposition of the drug and increase airway deposition.
Regular large doses can produce adrenal suppression, particularly in children.; RISK OF
OSTEOPROSIS AND CATARACT IN ELDERLY IS ALSO CONSIDERED .
Systemic corticosteroids
PREDNISONE {Oral}: and; METHYL PREDNISOLONE (IV) ; BETAMETHAZONE (im)?
are reserved for patients who require urgent treatment, i.e., those who have not improved adequately
with bronchodilators or who experience worsening symptoms despite maintenance therapy.

Adverse effects of systemic steroids ;:

Short term steroid use
o Reversible increases in glucose o decreases potassium
o fluid retention with weight gain o mood alterations including rare psychosis
o hypertension o peptic ulcers
o aseptic necrosis of the femur,, o very rare allergic reactions
Long term steroid use
o As those in short term use + o Height and growth, suppression

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 o Suppression of immune system o cataracts,
o hypertension, o hirsutism
CLINICAL INDICATION OF STERIODS : they are indicated inprotocols for
mangement of all forms of asthma , the route, dose , duration depends on severity of astham see
saudi national protocol for diagnosis and mangement of bronchial asthma 2nd edition .
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2.2.CROMOLYN  & NEDOCROMIL
•
Administered only by inhalation
•
Cromolyn sodium (disodium cromoglycate) • C romolyn
and nedocromil sodium solution is
• pretreatment with these drugs blocks the also useful in
bronchoconstriction caused by allergen reducing
inhalation, by exercise, a variety of causes symptoms of allergic rhino conjunctivitis
of occupational asthma • This lack of toxicity accounts for
• They are only of value when taken cromolyn's widespread use in children
prophylactically.
• Mechanism of Action ?? : an alteration in the function of delayed chloride channels in the cell
membrane, inhibiting cell activation. This, leads to inhibition of the early response of mast cells;
and inflammatory response of eosinophils, to inhaled allergens.
• Adverse effects are minor and are localized to the sites of deposition. throat irritation, cough, and
mouth dryness, and, rarely, chest tightness, and wheezing. Reversible dermatitis, mystic, or
gastroenteritis occurs in less than 2% of patients, and a very few cases of pulmonary infiltration with
eosinophilia and anaphylaxis have been reported.
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*
LEUKOTRIENE (LT) INHIBITORS

Background :
• Leucotrienes are products
of 5-lipooxygenase
pathway of arachedonic
acid and involved in the
cascade of bronchial
asthma.
• Cysteinyl leukotriene
1(Cyst L-1) is a potent
airway smooth muscle
bronchoconstrictors
through interaction with
specific receptors (Cyst-LT-
1R)

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• LTB4 is a potent chemo attractant for
Neutrophils, basophiles, eosinophils

ZILEUTON, a 5-lipoxygenase inhibitor thereby preventing leukotriene (LTA4, LTB4) synthesis

ZAFIRLUKAST AND MONTELUKAST, are reversible Cyst L-1 R antagonists.
1. these drugs improve asthma control and to reduce the frequency of asthma exacerbations .
Their principal advantage is that they are taken orally;
2. .Montelukast is approved for children as young as 6 years of age.
3. Montelukast also has the advantage of once daily dosing
ADVERSE drug effects
o zileuton occasional cause liver toxicity.
o Bronchospasm
o Cough; Wheezing; Bad taste; Rash; Laryngeal edema
o Joint pain & swelling; Angioedema
o Headache; Nausea
o Increase in liver Enzymes,
o Rare eosinophilic vacuities
o Interaction with other drugs ( both drugs are Enz. Inhibitors )
PHARMACOKINETICS :
Absorption : adequate oral absorption ( may be delayed by food )
Distribution : strongly bounds to plasma protein ( > 90 % )
Metabolism : extensively metabolized in the liver
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Anti-IgE Monoclonal Antibodies
OMALIZUMAB (XOLAIR).

• Xolair (Omalizumab) is a recombinant DNA-derived

humanized IgG1(kappa) monoclonal antibody that
selectively binds to human immunoglobulin E (IgE).
• Xolair (Omalizumab) is indicated for adults and
adolescents (12 years of age and above) with moderate to
severe persistent asthma who have a positive skin test or in
vitro reactivity to a perennial aeroallergen and whose
symptoms are inadequately controlled with inhaled
corticosteroids. Xolair has been shown to decrease the
incidence of asthma exacerbations in these patients. Safety and efficacy have not been established
in other allergic conditions.
• There are many concern about the possibility of inducing cancer & severe allergic reaction ;

increase incidence of infection ??

REFERENCES :
1. Goodman & Gilman “ the pharmacological basis of therapeutics “ 11th edition chapter
2. Lippincott’s illustrated review “ pharmacology “ 2nd e p 315

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3. Basic & clinical pharmacology B.G. Katzung 8th ed , chapter 20 pp 333
4. http://en.wikipedia.org /Theophylline
5 -Walker S et al: Anti-IgE for chronic asthma in adults and children. Cochrane Database Syst Rev
2006;2:CD003559.
6-Clinical Management Of Airway Disease :Barnes PJ: Drugs for asthma. Br J Pharmacol
2006;147(Suppl 1):S297.
7-Tattersfield AE et al: Asthma. Lancet 2002;360:1313.