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Clinical pharmacology of drugs
acting on the respiratory organs
function
Bronchial asthma
Bronchial asthma is a disease caused by
increased responsiveness of the
tracheobronchial tree to various stimuli. The
result is paroxysmal constriction of the bronchial
airways. Bronchial asthma is the more correct
name for the common form of asthma. The term
'bronchial' is used to differentiate it from
'cardiac' asthma, which is a separate condition
that is caused by heart failure. Although the two
types of asthma have similar symptoms,
including wheezing (a whistling sound in the
chest) and shortness of breath, they have quite
different causes.
Bronchial asthma (cont’d)
Bronchial asthma is a disease of the lungs
in which an obstructive ventilation disturbance
of the respiratory passages evokes a feeling of
shortness of breath. The cause is a sharply
elevated resistance to airflow in the airways.
Despite its most strenuous efforts, the
respiratory musculature is unable to provide
sufficient gas exchange. The result is a
characteristic asthma attack, with spasms of the
bronchial musculature, edematous swelling of
the bronchial wall and increased mucus
secretion.
Antiasthmatic Drugs
Bronchodilators
I.
1.
2.
3.
β receptor agonists
Theophylline
Muscarinic antagonists
Anti-inflammatory agents
II.
1.
2.
Steroids
Anti-leukotriene agents
Anti-allergic agents
III.
1.
2.
Stabilizer of inflammatory cell membrane
H1 receptor blocker
Beta Adrenoceptor Agonists




Adrenaline: α,β agonist
Ephedrine: α,β agonist
Isoprenaline：β1 ,β2 agonist
β2-selective agonists

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Salbutamol:
Terbutaline :
Clenbuterol:
Formoterol:
Salmeterol:
Bambuterol:
intermediateacting
long-acting
BRONCHODILATORS
Sympathomimetics
 The sympathomimetics, also called beta agonists or adrenergic agents,
can be thought of as rescue medications because they provide rapid
relief of labored breathing during an asthma episode. Derivatives of
adrenaline, or epinephrine, they are chemically altered to maximize this
natural compound’s airway muscle relaxing effect while minimizing the
heart, muscle, and nervous system side effects of the parent compound.
All of the currently available beta agonists are superior to both adrenaline
and ephedrine for duration of action and less-pronounced side effects.
 These potent , when inhaled, provide rapid relief of bronchial obstruction.
Duration of action varies from four to six hours. An exception is
salmeterol (Serevent®) which works for up to twelve hours but has a
slower onset of action of about an hour. These agents are excellent for
the prevention of wheezing triggered by exercise or cold air if taken
before the activity or exposure. A number of products are available.
Individuals may prefer one agent to another for reasons of taste, cost, or
personal preference. Generic agents are now available for albuterol.
Users of generic substitutes should be aware of the potential problem of
dosage variability.
 Side effects are mild affecting less than 10% of users. They include rapid
heart rate, palpitations, restlessness, anxiety, and muscle tremors. Some
children may become "revved up" especially when the oral form is given
or sometimes after receiving an aerosol treatment from a nebulizer.
Maxair® is thought to cause less heart stimulation while metaproterenol
may cause a little more. There is considerable individual variation.
• Salmeterol is a bronchodilator. It works by relaxing muscles in the airways to
improve breathing.
• Salmeterol inhalation is used to prevent asthma attacks. It will not treat an
asthma attack that has already begun. Salmeterol inhalation is also used to
treat chronic obstructive pulmonary disease (COPD) including emphysema
and chronic bronchitis.
• Salmeterol inhalation may also be used for conditions other than those
listed in this medication guide.

Adverse Reactions of β2 agonists:
1)
Skeletal muscle tremor
2)
Cardiac effect: tachycardia, arrhymias
3)
Metabolism disturbance: ketone bodies↑,
acidosis, [K+]o↓
BRONCHODILATORS Theophylline
 This drug is so similar to caffeine that they share the same chemical




formula. Their three-dimensional structures are slightly different. As small
changes in molecular shape often result in major changes in function,
theophylline is 100 times as potent a bronchodilator as caffeine. That
means you would have to drink several pots of coffee or several six-packs
of cola to get the same beneficial effect of a theophylline tablet.
Upset stomach, nausea, rapid or irregular heartbeat, insomnia, hyperactive
behavior, and headaches are all adverse effects that caffeine and
theophylline share. Theophylline has a narrow therapeutic range meaning
that such adverse effects occur commonly The belief that theophylline
hinders learning is unfounded. In fact, most tests demonstrate enhanced
school performance in children taking theophylline. Like caffeine,
theophylline is a diuretic. Many patients taking this agent note increased
urine production and may awaken at night to answer nature’s call.
No longer the mainstay of therapy as it was a decade ago, theophylline still
has a role to play in the treatment of asthma. Once a day dosing makes it
useful in treating nocturnal asthma (asthma occurring during sleep). It
serves an ancillary role in severe cases of asthma. There are also a few
patients who respond better to theophylline than to inhaled
corticosteroids. Some studies suggest that theophylline may have a mild
anti-inflammatory effect but this is far from established.
Both theophylline and caffeine are rapidly absorbed from the
gastrointestinal tract. Modern
theophylline products use specially-formulated tablets or capsules which
delay absorption to produce relatively constant blood levels of
theophylline throughout the day and night with once daily (Theo24® ,
Unidor®, Uniphyll®) or twice daily (Slobid® , Theodur®) use.
Theophylline


Methylxanthine derivatives.
Mechanism of Action:
1.
2.
3.
4.
5.
Inhibit phosphdiesterase (PDE);
Block adenosine receptors;
Increase endogenous catecholamine (CA)
releasing;
Interfere with receptor-operated Ca2+
channels → [Ca2+]i↓;
Anti-inflammatory action

Clinical Use:
1.
2.
3.

Asthma: maintenance treatment
Chronic obstructive pulmonary disease
(COPD)
Central sleep apnea (CSA)
Adverse Reactions:



Narrow margin of safety. Toxic effects are
related to its plasma concentrations.
Gastrointestinal distress, tremor, and insomnia.
Cardiac arrhythmias, convulsions → lethal.
Muscarinic Antagonists



There are M1, M2, M3 receptor subtype in
the airway.
Selectively blocking M1, M3 receptor is
resulted in bronchodilating effect.
Ipratropium bromide binds to all M-R
subtypes (M1, M2 and M3 ), and inhibits
acetylcholine-mediated bronchospasm.
BRONCHODILATORS
Anticholinergic Drugs



In the treatment of asthma, anticholinergic drugs are both old and
new. One hundred years ago, atropine, the parent drug of this
class, was smoked as a cigarette for asthma. Its usefulness was
limited by unacceptable side effects of rapid heart rate, hot skin,
and dry mucous membranes. Excessive doses could even
provoke delusions and irrational behavior.
Ipratropium (Atrovent®) preserves the bronchodilator effects
while eliminating these adverse effects. Atrovent® is not as
potent as the sympathomimetics and is not considered a first
choice medication. It has an additive effect when beta agonists
are insufficient for symptom relief. It can serve as an acceptable
alternate when sympathomimetics aren’t tolerated.
Atrovent® should be inhaled four times daily for maximum
effectiveness. It's available in multidose inhaler form and in unit
dose ampoules for nebulizer use. The only common side effect is
dry mouth. Combivent® is a convenient, combination product
composed of albuterol and ipratropium.
Anticholinergic Drugs
Anti-inflammatory Agents
Asthma medications may be divided into two broad
categories, bronchodilators and anti-inflammatory agents. Within
each category are several subclasses and variety of products.
While bronchodilators relieve the symptoms of coughing and
wheezing, the anti-inflammatory agents treat the underlying
cause of asthma. The asthmatic state involves fundamental
changes in the way the bronchi regulate their internal diameter.
When the cells lining the inner surface of the bronchial tubes are
injured, forces designed to control airway size become
unbalanced. Bronchoconstriction (airway narrowing) becomes
predominant.
Anti-allergic Agents
 Madiators release inhibitors.
 No bronchodialator action but can prevent
bronchoconstriction caused by a challenge
with antigen to which the patient is allergic.
The Cromones: Cromolyn &
Nedocromil
 These agents act primarily to stabilize mast cells. They
have an extraordinary safety record but high cost and
the need for frequent dosing (four times daily for
cromolyn, three times for nedocromil) limit their use.
Cromolyn may require administration for up to a month
before its protective effect is fully noted. Nedocromil is
usually helpful within a few days. Neither drug is as
potent as the inhaled corticosteroids. Another limiting
factor of nedocromil (Tilade®) is its unpleasant
aftertaste. Rinsing the mouth with water helps.
 Both drugs are good preventers of exercise-induced
asthma when taken before activity. Because of their
safety record, they are the drugs of first choice for
children. Both are available as multidose inhalers.
Cromolyn (Intal®) is approved for children as young as
two years and is available in unit dose ampoules for
nebulizer use.
Ketotifen
 H1 receptor blocker.
 Prevent and inverse down-regulation of β2-
receptor.
Anti-leukotriene agents

Cysteinyl leukotrienes is a important
inflammatory mediator:


Bronchoconstriction, increased bronchial
reactivity, mucosal edema, mucus
hypersecretion, etc.
Leukotrienes resulte from the action of 5lipoxygenase on arachidonic acid.
Common agents:

I.
zafirlukast and montelukast: LTD4-
receptor antagonists
II.
zileuton: 5-lipoxygenase inhibitor
Glucocorticoids (GCs)

Mechanism of Action:
1.
Broad anti-inflammatory efficacy
①
②
2.
Block the synthesis of arachidonic acid by
phospholipase A2.
Reduce bronchial reactivity.
Increase the responsiveness of βadrenoceptors in the airway.
Corticosteroids

Routes of administration:



Systemic administration: including oral and
injection. More severe toxicity.
Inhalation:
Common inhalant GCs:

FP, BDP, BUD, TAA, FNS
Corticosteroids
 Continued use of inhaled corticosteroids reduces bronchial
hyperreactivity. This means that for many patients asthma
symptoms will disappear as will the need to use additional
asthma medications. Use of these medications in children with
asthma has been found to restore or preserve normal lung
growth. Children with moderate asthma who don’t receive
inhaled corticosteroids may reach adulthood with significantly
smaller lungs. In adults with asthma, use of inhaled
corticosteroids reduces the rate of lung tissue loss over time.
 A variety of agents are available for use. All are effective on a
twice-daily routine. Azmacort® comes with its own built-in
spacer but its small volume is not optimal. Aerobid® has a taste
that some users find unpleasant. A menthol form, Aerobid-M®
tastes better. Budesonide (Pulmicort®) is marketed as a
multidose, dry powder inhaler that provides precision dosing
without a Freon® propellant.
Step-wise approach to the treatment of asthma according to recent guidelines.
LTRA, leukotriene receptor antagonist; SR, slow release. The dose of inhaled
corticosteroids refers to beclomethasone dipropionate