Chapter II: Drugs

affecting on respiratory
system
Dr. Mahmoud H. Taleb
Assistant Professor of Pharmacology and Toxicology
Department of Pharmacology and Medical sciences
Faculty of Pharmacy- Al azhar University

Dr. Mahmoud H. Taleb

Dr. Mahmoud H. Taleb

Dr. Mahmoud H. Taleb

 Asthma:

Bronchial asthma is a condition characterized by repeated

attacks of paroxysmal dyspnea. It is now recognizes that
chronic asthma involves a characteristic inflammatory
response in the airways that is present in patients with very
mild asthma. Bronchial hyperresponsiveness or an
exaggerated bronchoconstrictor response to many different
stimuli is characteristic of asthma. There is remains
considerable debate about the types of inflammatory cells
and mediators involved in asthma.

 Lymphokines may be important mediators in

increasing the inflammatory response, and
interleukin-5 release by lymphocytes also may be
important in acting to prime the eosinophils in the
mucusa.

Dr. Mahmoud H. Taleb

hanisms of response to inhaled irritants

Dr. Mahmoud H. Taleb

Drugs Used in Asthma:

Introduction
The clinical hallmarks of asthma are recurrent,
episodic bouts of coughing, shortness of breath,
chest tightness, and wheezing. In mild asthma,
symptoms occur only occasionally, eg, on
exposure to allergens or certain pollutants, on
exercise, or after a viral upper respiratory
infection. More severe forms of asthma are
associated with frequent attacks of wheezing
dyspnea, especially atnight, and even chronic
limitation of activity. Asthma is the most common
chronic disabling disease of childhood, but it
affects all age groups
Dr. Mahmoud H. Taleb

Asthma therapies are thus

sometimes divided into two
categories: "short-term
relievers" and "long-term
Short-term relief is most effectively achieved with bronchodilators, agents
controllers."
that increase airway caliber by relaxing airway smooth muscle, and of
these the -adrenoceptor stimulants , a methylxanthine drug, and
antimuscarinic agents are also used for reversal of airway constriction.

Long-term control is most often achieved with an anti-inflammatory agen

such as an inhaled corticosteroid, with a leukotriene antagonist, or with
an inhibitor of mast cell degranulation, eg, cromolyn or Ketotifen.
Dr. Mahmoud H. Taleb

A. Goals of therapy
A. Reducing impairment:
B. Prevent chronic and a. troublesome
symptoms.
C. Require infrequent use of inhaled shortacting B2 agonist for quick relief of symptoms.
D. Maintain normal pulmonary function.
E. Maintain normal activity levels (including
exercise and other physical activity and
attendance at work or
school).
Dr. Mahmoud H. Taleb

Drugs Used to Treat Asthma

1-Bronchodilator drugs:

Activation of 2-adrenoceptors on the smooth muscle of the airways causes

activation of adenylyl cyclase with a subsequent increase in the intracellular
concentration of cyclic AMP.

(A) Adrenergic agonists

Inhaled adrenergic agonists with B-2 activity are
the drugs of choice for mild asthma that is, in
patients showing
only occasional, intermittent symptoms .Directacting B- agonists are potent bronchodilators that
relax airway smooth muscle.
Quick relief: Most clinically useful B2 agonists
have a rapid onset of action (5-30 minutes) and
provide relief for 4Dr.toMahmoud
6 hours.
H. Taleb
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 They are used for symptomatic treatment

of bronchospasm, providing quick relief of
acute bronchoconstriction. [Note:
Epinephrine is the drug of choice for
treatment of acute anaphylaxis.] 2
Agonists
have no anti-inflammatory effects, and
they should never be used as the sole
therapeutic agents for patients with
persistent asthma.

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 Monotherapy with short-acting 2 agonists may be

appropriate only for patients
identified as having mild intermittent asthma, such as
exercise-induced asthma. The direct-acting 2-selective
agonists, such as terbutaline ,and albuterol offer the
advantage of providing maximally attainable
bronchodilation with little of the undesired
effect of or 1 stimulation.
Adverseeffects
, such as tachycardia, hyperglycemia, hypokalemia, and
hypomagnesemia are minimized with dosing via
inhalation versus systemic routes.

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 B-Anticholinergic drugs:
Atropine is a competitive blocker of acetylcholine at
muscarinic cholinergic receptors and thus can cause a
variety of effects due to loss of parasympathetic
activity, including blurring of vision, increase in heart
rate, and drying of secretions in the salivary glands
and respiratory tract. This limits its usefulness as a
bronchodilator. Atropine is best used by inhalation,
which reduces, but does not eliminate entirely, these
unwanted side effects.

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 Ipratropium bromide (Atrovent) is a quaternary isopropylsubstituted derivative of atropine that can not cross the
blood-brain barrier and therefore has practically no central
effect; it also shows some degree of bronchoselectivity.
The actions of ipratropium bromide are otherwise similar
to those of atropine, and its therapeutic use is confined to
aerosol administration. The drug is administered by
inhaler and each puff contains 20g, the exact place of
ipratropium bromide in the treatment of asthma remains
somewhat uncertain, and the drug appears to have little
advantage over the selective 2-agonists.

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 C-Methylxanthines
The 3 important are theopylline, theobromine,
and caffeine.
Their major source of intake by humans is beverages such as tea,
cocoa, and coffee, respectively. Their effects are as follows:
CNS effects: in low to moderate doses, the methylxanthines,
especially caffeine, cause mild cortical arousal with increased
alertness and deferral of fatigue, in unusually sensitive
individuals, the caffeine contained in beverages (e.g., 100mg in a
cup of coffee) is sufficient to cause nervousness and insomnia.
Nervousness and tremor are primary side effects in patients
taking large doses of aminophylline for asthma.

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 Cardiovascular effects: the methylxanthines have direct

positive chronotropic and inotropic effects on the heart. At
low con., these effects appear to result from increased
calcium influx, probably mediated by increased cyclic AMP.
At higher con., sequestration of calcium by the sarcoplasmic
reticulum is impaired, so intracellular calcium con. Is
increased and myocardial contraction is strengthened.
Methylxanthines have occasionally been used in the
treatment of pulmonary edema associated with heart failure.
These agents also relax vascular smooth muscle except in
cerebral blood vessels, where they cause contraction.

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 GIT effects: they stimulate secretion of both gastric

acid and digestive enzymes.
Kidneys: they, especially theophylline, are weak
diuretics. This effect may involve both increased
glomerular filtration and reduced tubular sodium
reabsorption. This effect is not sufficient
therapeutically.

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 Smooth muscle: the bronchodilatation produced by

the methylxanthines is the major therapeutic action.
Tolerance does not develop, but side effects,
especially in the CNS, may limit the dose. In addition
to this direct effect on the airway smooth muscle,
these agents inhibit antigen-induced release of
histamine from lung tissue; their effect on
mucociliary transport is unknown.
agent.

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 Skeletal muscle: the therapeutic actions of the

methylxanthines may not be confined to the airways,
for they also strengthen the contractions of isolated
skeletal muscle in vitro and have potent effects in
improving contractility and in reversing fatigue of the
diaphragm in patients with chronic obstructive lung
disease.

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Dr. Mahmoud H. Taleb

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 2- Anti-inflammatory steroids:
Glucocorticoid drugs such as prednisone, prednisolone,
dexamethasone and Budesonide are known empirically to
relieve airway obstruction in bronchial asthma, but the
mechanism of their action is complex.
The possible actions include:
Anti-inflammatory activity.
Reduction of tissue sensitivity to antigens.
Inhibition of contraction of bronchial smooth muscle.
Mucolytic action.
Increased responsiveness of 2-adrenoceptors.

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Recently, glucocorticoid drugs such as beclomethasone

dipropionate and beclomethasone valerate, budnoiside,
predisone have been developed for administration by
inhalation. Inhalation of these compounds is as effective as oral
prednisone in patients starting on steroids. Only a small amount
of the steroid administered in this manner is systemically
absorbed. Therefore there is little or no systemic effect or adre
nal suppression and the problem of growth suppression in
children may be avoided. The major problem with this form of
therapy to date has been the development of fungal infections
(candidiasis) in the oropharynx in about 10% of patients
because of suppression of phagocytic activity by the high local
concentrations of corticosteroid.

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 3- Mast cell stabilizers

Cromolyn sodium (sodium cromoglycate), and Ketotifen

It inhibits the release of mediators such as histamine and

leukotrienes from the secretory granules of mast cells following the
challenge of antigen interacting with specific IgE antibodies. The
exact mechanism underlying the action of cromolyn sodium is not
clear, but the drug is active only against type I (immediate) allergic
reactions and not against delayed or immune reactions. However,
cromolyn sodium is also effective in asthma induced by exercise
and by exposure to cold dry air. Therefore it is suggested that
cromolyn sodium acts as a nonspecific stabilizer of the mast cell
membrane and/or granules.

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 Cromolyn sodium is absorbed poorly from the

gastrointestinal tract and therefore is effective only when
deposited directly into the airways. Two methods of
administration are currently used for asthma. In adults,
the drug can be given by a "Spinhaler" apparatus that
causes a capsule to be punctured so that its powdered
contents are entrained into inspired air and deposited in
the airways. The usual dose is 20 mg inhaled four times
daily. In children, who may have difficulty in using this
device, the drug may be given by aerosol.

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4- Leukotriene Pathway Inhibitors

Efficacy in blocking airway responses to exercise and to
antigen challenge has been shown for drugs in both
categories: zileuton, a 5-lipoxygenase inhibitor, and
zafirlukast and montelukast, LTD4-receptor
antagonists. All have been shown to be effective
when taken regularly in outpatient clinical trials.
Their effects

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 5- Monoclonal antibodies eg. Omalizumab

Omalizumab is a recombinant DNA derived
monoclonal antibody that selectively binds to
human immunoglobulin E (IgE). This leads to
decreased binding of IgE to the high-affinity IgE
receptor on the surface of mast cells and
basophils. Reduction in surface-bound IgE limits
the degree of release of mediators of the allergic
response. Omalizumab may be particularly useful
for treatment of moderate to severe allergic
asthma in patients who are poorly controlled with
conventional therapy. Due to the high cost of the
drug (approximately $600 for a 150-mg vial),
limitations on dosage, and available clinical trial
data, it is not presently used as first-line
Dr. Mahmoud H. Taleb
therapy.

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Drugs Used to Treat Chronic

Obstructive Pulmonary
Disease

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 DRUGS AFFECTING THE COUGH REFLEX

The cough reflex is mediated by receptors located in the
mucosa or deeper structures of the larynx, trachea, and
major bronchi, and by mechanoreceptors that detect
changes in bronchial intramural tension. Stimuli are
transmitted via the vagus to the cough center in the
medulla. Efferent impulses originating from the cough
center are transmitted through cholinergic pathways to the
abdominal and intercostal muscles and to the diaphragm,
producing sudden explosive expiratory movements.

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Antitussive Drugs:
Opioid antitussive agents:
Opioid analgesics are most effective in depressing the
cough center. Codeine thus appears to be a more
effective cough suppressant relative to its analgesic
activity. The usual antitussive dose is 15-20 mg as
required.

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 Codeine also has significantly less respiratory

depressant effect than morphine. The development of
tolerance and physical dependence is a major
drawback to morphine-like drugs, and for this reason,
their long-term use as antitussive agents is dis
couraged.They can, however, be used for short-term
cough suppression. Because of the low dose of
codeine required, and its relatively low addiction
liability, it may be more suitable than other opioid
drugs for long-term antitussive use

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Nonopioid antitussive agents:

Dextromethorphan is a synthetic opioid derivative that is

an effective antitussive agent, suppressing the response of
the cough center but lacking analgesic or habituating
properties. It is the d-isomer of levomethorphan, which is a
potent opioid analgesic. This demonstrates that the
analgesic activity, as well as the addictive properties, are
exerted through receptors with stereospecificity, while the
antitussive receptor sites lack the opioid stereospecificity.
Levopropoxyphene is similarly an antitussive that lacks the
analgesic activity of its isomer dextropropoxyphene.
Other nonopioid drugs that have some antitussive activity
in addition to their other pharmacological actions include
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phenothiazines, antihistamines,
and benzononatate

 Mucolytic Agents:
Mucolytic inhalants are mucokinetic substances that liquefy
mucus and aid the elimination of excess solidified mucus in
patients with respiratory disease. Excess mucus may be
liquefied by proteolytic agents and disulfide bond cleaving
agents. Acetylcysteine. It possesses a reactive sulfhydryl
group that splits the disulfide bonds of the mucin molecule and
thereby reduces the viscosity of mucus. This drug is an
extremely effective mucokinetic agent, but it is little used
because it causes many side effects such as stomatitis, nausea,
vomiting, rhinorrhea, and especially bronchospasm.
Bromohexine (Rx Bisolvon,Solvex,,Mucocare) It stimulates
lysosomal activity , leads to hydrolysis of mucopolysaccharides
and decrease the viscosity of the mucus
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Drugs Used to Treat Allergic

Rhinitis
Rhinitis is an inflammation of the mucous
membranes of the nose and is characterized by
sneezing, itchy nose/eyes, watery rhinorrhea, and
nasal congestion. An attack may be precipitated
by inhalation of an allergen (such as dust, pollen,
or animal dander). The foreign material interacts
with mast cells coated with IgE generated in
response to a previous allergen exposure ,The
mast cells release mediators, such as histamine,
leukotrienes, and chemotactic factors, that
promote bronchiolar spasm and mucosal
thickening from edema and cellular infiltration.
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 Combinations of oral antihistamines with

decongestants are the first-line therapies
for allergic rhinitis. Systemic effects
associated with these oral preparations
(sedation, insomnia, and, rarely, cardiac
arrhythmias) have prompted interest in
topical intranasal delivery of drugs.

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Drugs used to treat allergic rhinitis

A. Antihistamines (H1-receptor
blockers) eg. Chlorophenermine
malate,cyproheptadine, loratidine,
cetrizine, and fexofenadine
B. -Adrenergic agonists eg,
phenylephrine. Ephedrine ,
oxymetazoline and naphazoline.
C. Corticosteroids eg. fluticazone,
Budesonide
D. Cromolyn and ketotifen
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Thank
you!
Dr. Mahmoud H. Taleb

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