NOTRE DAME OF DADIANGAS UNIVERSTY (NDDU)

College of Pharmacy
COURSE TITLE PHARMACOLOGY II COURSE CODE Pharm36
CREDIT UNITS 3 units COURSE Human Physiology and
REQUISITES Pathophysiology
CONTACT 3 hours/week Contact Hours/Date 2020 Sept. 2
HOURS 54 hours/sem for this topic
COURSE 3rd yr, 1st SEM SME: Melba M. Roma, RPh, MSPh
PLACEMENT

MODULE 2: RESPIRATORY AGENTS

Content Demonstrate knowledge and understanding on the pharmacology of drugs affecting the
Standards respiratory system
Functional o Discuss the etiology and pathophysiology of Asthma and COPD
Knowledge o Describe the mechanism of action, adverse effects and contraindications of drugs
used to treat Asthma and COPD

Introduction to the Respiratory System

(Flip) Vid watch:
https://www.youtube.com/watch?v=T1G9Rl65M-Q
https://www.youtube.com/watch?v=4aK76DoxKGk

COPD (chronic obstructive pulmonary disease) is a lung disease caused by chronic interference with
lung airflow that impairs breathing, and is not fully reversible. Usually symptoms, for example,
shortness of breath, recurrent coughing, clearing throat, and progressive exercise tolerance, worsen
over time. Many doctors and researchers (for example, the World Health Organization) consider terms
such as chronic bronchitis and emphysema as forms of COPD. The major cause of COPD is smoking.

Asthma is a respiratory condition marked by spasms of the bronchi, due to inflamed and narrowed
airways in the lungs. Asthma causes difficulty in breathing that often results from an allergic reaction.
Many substances may trigger asthma attacks. Asthma usually causes recurring periods of shortness of
breath, wheezing and/or chest tightness. Often, asthma can be fully reversible with medical treatment
and breathing can return to normal.

Compare : COPD vs. asthma

COPD ASTHMA

mainly due to damage caused by smoking due to an inflammatory reaction.

a progressive disease allergic reactions of asthma can be reversible.

Initial symptoms can be similar in both diseases, for example, shortness of breath, chest tightness, wheezing, and cough, which can
lead to confusion or misdiagnosis.

Page 1 of 11
Both diseases can have severe, dangerous signs and symptoms, for example, a bluish discoloration of the skin, and respiratory
distress. Death may even occur.

initial treatments of COPD include bronchodilators initial treatments for asthma include inhaled corticosteroids

COPD usually develops after age 40 and often becomes a chronic Asthma may develop in people of almost any age
disease of lung function

https://www.medicinenet.com/copd_vs_asthma_differences_and_similarities/article.htm#symptoms_and_signs_6_similarities_between_copd_vs_asthma

The objective of pharmacological treatment of chronic obstructive pulmonary disease (COPD) is to

prevent and control symptoms, reduce the frequency and severity of exacerbations, and improve
general health status and exercise tolerance. None of the classes of drugs currently used in the
treatment of COPD are able to modify the progressive decline in lung function which is the hallmark of
this disease . Smoking cessation is currently the only intervention which has been shown to reduce the
progression of COPD. It is important to try to control symptoms of COPD with pharmacological
treatment.

General proposals: 
1. There should be a stepwise increase in treatment, according to the severity of the disease. The
step-down approach used in the chronic treatment of asthma is not applicable to COPD.
2. Treatment needs to be chronic and maintained at the same level for long periods of time,
unless significant side effects or exacerbations occur.
3. Since individual patient response to the pharmacological treatment is variable, it is important
to monitor pharmacological treatment closely and, if necessary, adjust it frequently.

Drugs currently recommended for the treatment of COPD are:

1. Bronchodilators (selective β2-agonists, anticholinergic antimuscarinic agents and
methylxanthines);
2. glucocorticoids;
3. other types of medication (vaccines, antibiotics, α1-antitrypsin augmentation therapy, mucolytic
agents, antioxidants, immunoregulators, antitussives and vasodilators).
4. An inhibitors of phosphodiesterase type 4 (PDE4), a new class of drugs for COPD are in the late
phase III of clinical development.

 It must be emphasized that each treatment regimen needs to be patient-specific as the
relationship between the severity of symptoms and the severity of lung function is influenced
by other factors, such as the frequency and severity of exacerbations, the presence of
complications, the presence of respiratory failure, the presence of other diseases, and general
health status.

Page 2 of 11
Treatment of stable chronic obstructive pulmonary disease
Bronchodilators are currently the mainstay of the treatment of COPD as they prevent and
improve symptoms.
Bronchodilators are selective short-acting β2-agonists (SABA) such as:
1. salbutamol
2. metaproterenol
3. terbutaline
4. bambuterol
5. pirbuterol
6. Isoetharine
7. bitolterol and
8. fenoterol

or selective long-acting β2-agonists (LABA) such as:

1. salmeterol
2. formoterol

Anticholinergic (cholinolytic) antimuscarinic agents such as:

1. ipratropium bromide
2. oxitropium bromide
3. tiotropium bromide

Methylxanthines such as : Theophyline

● Short- and long-acting β2-agonists and antimuscarinic agents are generally

administered by inhalation (aerosol, dry-powder or nebuliser solution).
● Bronchodilator therapy is most frequently delivered by pressurized metered-dose
inhalers (MDIs) or dry-powder inhalers (DPIs).
● Because of the lower bioavailability in asthma patients, the dose delivered by DPIs
should be doubled compared with that of MDIs ; while a study comparing ipratropium
bromide delivered by MDIs and by DPIs in COPD patients found that there was no
difference between these two types of inhalers .
● The use of a spacer device to improve drug delivery proves particularly useful for
patients who have poor inhalation technique.
● LABAs should not be initiated in patients who are acutely deteriorating with COPD or for
acute symptoms; a short-acting beta-agonist bronchodilator (SABA) should be used for
acute symptoms.
REF: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2707800/

Page 3 of 11
MOA.
Beta-agonists stimulate adenyl cyclase, the enzyme that catalyzes the formation of cyclic-3'5'
adenosine monophosphate (cyclic AMP) from adenosine triphosphate (ATP). Increased cyclic
AMP levels are associated with relaxation of bronchial smooth muscle and inhibition of release
of mediators of immediate hypersensitivity, especially from mast cells. Beta2-agonists relieve
reversible bronchospasm by relaxing the smooth muscles of the bronchioles in conditions
associated with asthma, COPD, or bronchiectasis. Bronchodilation may additionally facilitate
expectoration. Although there are both beta1 and beta2 receptors in the heart, the latter are
more predominant in the lungs, where they serve as the primary adrenergic receptors in
bronchial smooth muscle. In order to reduce cardiac toxicities (e.g., tachyarrhythmias), the use
of beta2 specific agonists is preferred in the treatment of bronchospasm. To further reduce
cardiac toxicities, non-systemic dosage forms given by inhalation are preferred to oral dosage
forms.

Pharmacological actions.
SABA, LABA
Short-acting β2-agonists have a bronchodilatory effect within 1 to 5 minutes and which lasts for
up to 4 hours. Long-acting inhaled β2-adrenergic agonists such as salmeterol and formoterol
have a prolonged bronchodilatory effect for approximately 12 hours. Unlike salmeterol which
has a slow onset of action, formoterol has a rapidly occurring bronchodilatory effect similar to
that of short-acting β2-agonists. Selective β2-agonists mainly work by stimulating the
β2-adrenoceptors on the airway smooth muscle cells. The formation of the drug-receptor
complex activates a stimulatory protein (Gs) which binds to guanosine triphosphate (GTP) with
activation of the adenylate cyclase which leads to an increase in intracellular cyclic adenosine
monophosphate (cAMP) levels which, in turn, activates a cAMP-dependant protein kinase.

Page 4 of 11
Side Effects.
Inhalation limits the absorption and therefore the systematic side effects of β2-agonists. The
main side effect of selective β2-agonists administered by inhalation at clinical doses is muscular
tremor. However, this tends to diminish in intensity during prolonged treatment. This
phenomenon is known as drug tolerance.
Bronchodilation may cause ventilation/perfusion mismatch with a consequent drop in the
arterial partial pressure of oxygen. This is generally transitory and of little importance. Other
side effects of systemically delivered β2-agonists, such as hypokalemia, increase in the plasma
concentrations of glucose, lactose, and free fatty acids are much less common when β2-agonists
are delivered by inhalation.

Antimuscarinic drugs
Antimuscarinics are delivered in the same way as bronchodilators. Antimuscarinics are
quaternary ammonium derivatives which, after inhalation, undergo <1% absorption from the
pulmonary or gastrointestinal tract. The parasympathetic nervous system has a role in the
regulation of the bronchial tone. Vagal fibres activate nicotinic and M1 muscarinic receptors on
the parasympathetic ganglia of the respiratory tract; short postganglionic fibers release
acetylcholine which stimulates the M3 muscarinic receptors on the airway smooth muscle cells
with consequent increase in motility. In addition, M3 muscarinic receptor stimulation
increases bronchial secretion. Inflammatory mediators such as eicosanoids, histamine, and
bradykinin may further produce parasympathetic reflexes which partly explains their
bronchoconstriction effect.
Antimuscarinic bronchodilators are non-selective antagonists of cholinergic muscarinic
receptors. Their effect on airway obstruction is mainly due both to M3 muscarinic receptor
antagonism in the airway smooth muscle cells, with consequent bronchodilation, and to M3
muscarinic receptor antagonism, with a reduction in the basal and stimulated cholinergic
parasympathetic activity with consequent reduction in airway obstruction.

Theophylline
Theophylline, a methylxanthine, is one of the least expensive bronchodilators. Given its very
low solubility in water, theophylline is administered intravenously as aminophylline.
Aminophylline is a theophylline and ethylenediamine mixture, which is 20 times more soluble
than theophylline alone. The bronchodilatory effect of theophylline is due both to relatively
non-selective inhibition of cyclic neucleotide phosphodiesterases and to competitive
antagonism of adenosine receptors.

Page 5 of 11
Theophylline is generally administered orally in conventional form or, more frequently, through
sustained-release preparations or intravenously (like aminophylline).

Glucocorticoids
Inhaled glucocorticoids currently available include beclomethasone dipropionate, budesonide,
flunisolide, fluticasone propionate and triamcinolone acetonide. There are no significant
differences between these drugs in terms of their efficacy and tolerability. Mometasone and
ciclesonide, two new glucocorticoids in advanced clinical trials, seem to have a longer duration
of action with the possibility of once a day administration. Ciclesonide is a prodrug which is
activated by a pulmonary esterase, with the possibility of increased selectivity of action and
reduced systemic side effects resulting from glucocorticoid absorption. Glucocorticoids do not
cause relaxation of the airway smooth muscle and therefore have no effect on acute
bronchoconstriction. The anti-inflammatory mechanisms of action of glucocorticoids are largely
due to the inhibition of gene expression which encodes for proinflammatory cytokines in the
airway inflammatory cells . Part of the anti-inflammatory effect of glucocorticoids may be due
to the induction of lipocortin. Lipocortin is a protein which inhibits phospholipase A2.

Asthma
The mainstay of asthma therapy is the use of inhaled corticosteroids (ICS) alone or in
combination with long-acting beta2-agonists (LABAs) as controller medications. These agents
lead to improvements in lung function and symptoms and reduce the need for short-acting
beta2-agonists (SABAs) for quick relief. LABAs are not to be used as monotherapy for controlling
asthma. While the corticosteroid reduces inflammation, the long-acting beta2-agonist acts
principally to dilate the airways by relaxing airway smooth muscle.

β2-Selective agonists

• β-Adrenergic drugs are used as drugs of first choice in paroxysmal bronchospasm.

• β-Adrenergic drugs are used most often as inhalants. In acute cases of asthma β-mimetics are
also administered parenterally. Although when these drugs are used parenterally the relaxing
effect is produced the most rapidly, this manner of administration can cause dangerous
complications in the cardiovascular system.
• β-Adrenergic drugs differ in terms of selectivity of action on β-receptors, the time and power
of action and the intensity of adverse effects.

Non-selective β-adrenergic drugs are used in bouts of acute bronchospastic dyspnoea because
of their immediate and highly effective action and the possibility of parenteral administration.

Page 6 of 11
Selective and non-selective β-adrenergic drugs differ mainly in their side effects. When selective
β-adrenergic drugs are administered, much less dangerous cardiologic complications are
observed.
The inflammatory effects seen in asthma result from the release of physiologically active
chemicals from a variety of inflammatory cells.
Pharmacological treatment, therefore, uses:
1. anti-inflammatory drugs (corticosteroids),
2. mast cell stabilizers,
3. leukotriene modifiers, and
4. IgE monoclonal antibodies.

α,β-Adrenergic agonists : Epinephrine (Adrenalin); Epi Pen

The combination of the catechol nucleus, the β-hydroxyl group, and the N-methyl give EPI a
direct action and a strong affinity for all adrenergic receptors. Epinephrine usually is
administered slowly by IV injection to relieve acute asthmatic attacks not controlled by other
treatments. Intravenous injection produces an immediate response.

Adverse effects include palpitations, tachycardia, sweating, nausea and vomiting, respiratory
difficulty, dizzines, tremor, apprehension and anxiety.

Lipooxygenase inhibitors and antagonists at LT-receptors

a. Leukotrienes are an important group of mediators released from the inflammatory cells.
Peptideleukotrienes LTC4, LTD4 and LTE4 act extremely bronchospastically,
b. A mixture of leukotrienes LTC4-LTE4 is referred to as a slow-acting anaphylactic factor.
c. LTB4 influences the overreactivity of the bronchi together with other mediators which
are derived from inflammatory cells.
d. There are several ways of suppressing reactions caused by LTs, eg. inhibiting the activity
of 5-LOX, inhibiting LT synthase, blocking LT-receptors.
e. 5-LOX inhibitors may be very important in the treatment of asthma, hay fever, psoriasis,
intestinal ulceration and arthritis.
f. Many compounds which inhibit 5-LOX have been obtained. Zileuton is one of those
drugs which have been introduced into therapy.

Zileuton, ZYFLO
Zileuton is metabolized in the liver to inactive O-glucuronide (major metabolite).
The most serious side effects of zileuton is elevation of liver enzymes.

Page 7 of 11
If symptoms of liver dysfunction (e.g., nausea, fatigue, pruritis, jaundice, or flulike symptoms)
occur, the drug should be discontinued.

Antagonists at LT-receptors
a. Three types of LT receptors have been discovered in the lungs. Their stimulation leads to
the spasm of the smooth muscles of the bronchi. It is believed that in the treatment of
asthma LTD4 -antagonists may be crucial.
b. Antagonists at LT-receptors inhibit the spasm of the bronchi and inflammatory
reactions. They also suppress the migration of lymphocytes in the respiratory tract and
inhibit the activity of macrophages.
c. Zafirlukast (Accolate ®), Pranlukast, Montelukast (Singulair®), Ablukast and
Tomelukast are classified as T-receptor antagonists. Zafirlucast and Ablucast are
indicated in the treatment of acute seasonal rhinitis and bronchial asthma.

Montelukast is a high-affinity, selective antagonist of the cysLT1 receptor. It is available in tablet,

chewable tablet, and granules for administration mixed with food.
Zafirlukast, like montelukast, is a selective antagonist for the cysLT1 receptor and antagonize
the bronchoconstructive effects of all leukotrienes .

Drugs stabilizing mast cells

1. •The development of the late phase of allergic reaction is caused by the release of
inflammatory mediators. The inhibition of this process is called prevention. In the
prevention of asthma drugs stabilizing mast cells, such as cromoglycate disodium,
nedocromil disodium and ketotifen are used.
2. They are administered to prevent attacks of bronchospasm. When they are used during
bronchospasm they do not act.
3. These drugs prevent releasing inflammatory mediators from mast cells, but they do not
inhibit the binding of IgE with these cells, or the interaction of IgE with an antigen.
4. When preventive drugs are used for a long time, they decrease the reactivity of the
smooth muscles of the bronchi, the number and severity of bronchospasm attacks. Their
use is necessary when bouts of bronchospasm occur more often than 1 or 2 times a
week.
Drugs stabilizing mast cells
• Cromoglicate disodium and nedocromil disodium are administered as micronised powder for
inhalation.
• Nedocromil acts many times more strongly than cromoglicate.
• Ketotifen is well absorbed from the gastrointestinal tract and it is used orally as tablets,
capsules or syrup. Ketotifen has depressive action on the CNS.

Page 8 of 11
Omalizumab (XOLAIRE®)
The clinical role for omalizumab is in the treatment of allergic asthma. It is approved for the
treatment of adults and adolescents 12 years of age and older whose symptoms are not
controlled with inhaled glucocorticoids and who have a positive skin test for airborne allergens.
The bioavailability after subcutaneous administration is 62%, with slow absorption resulting in
peak serum levels in 7 to 8 days from a single dose. Steady-state plasma concentration is
reached in 14 to 29 days with multiple dosing regiments. Omalizumab is available as a
lyophilized powder for injection in single-use, 5 ml vials.
file:///C:/Users/acer/Downloads/anthiasthmatic-drugs-2014.pdf

Other drugs
Vaccines
Vaccination can reduce severe complications and mortality from influenza in elderly patients,
including those with COPD. Vaccination is recommended once in the autumn or, once in the
autumn and once in the winter each year. Pneumococcal vaccines have been used in COPD
patients and can reduce complications of pneumonia in elderly patients, but there is no
evidence to support its general use in COPD patients.

Antibiotics
Numerous large-scale controlled studies have shown
antibiotic administration have no effect on the
Prophylactic antibiotics are also ineffective in winter.
the effectiveness of prophylactic antibiotics against
COPD.
that prophylactic antibiotics and chronic
frequency of exacerbations in COPD.
Current available data does not support
bacterial infections or exacerbations of

Mucolytic agents
Mucolytic agents such as ambroxol, erdosteine, carbocysteine, and iodinated glycerol produce
a reduction in the frequency of exacerbations in chronic bronchitis compared with a placebo,
the systematic administration of mucolytic drugs in COPD is not currently recommended.

Antioxidants
Oxidant stress plays an important role in the pathophysiology of COPD. Therefore,
administration of antioxidant agents is an interesting treatment strategy. Although antioxidant
and mucolytic drug N-acetylcysteine has been shown to reduce the frequency of exacerbations
of COPD in most clinical trials (Grandjean et al 2000), a recent 3 year randomized
placebo-controlled multicenter trial has shown that N-acetylcysteine is ineffective at prevention
of deterioration in lung function and prevention of exacerbations in patients with COPD

Page 9 of 11
(Decramer et al 2005). On the basis of current data, N-acetylcysteine is not recommended for
COPD (MacNee and Calverley).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2707800/

DRUG INTERACTIONS

Monoamine Oxidase (MAO) Inhibitors and Tricyclic Antidepressants (TCAs)

All LABAs should be administered with extreme caution to patients being treated with MAO
inhibitors, tricyclic antidepressants (TCAs), or drugs known to prolong the QTc interval because
these agents may potentiate the action of adrenergic agonists on the cardiovascular system.
Allow 2 weeks after discontinuation of MAO inhibitors before initiating therapy with agents in
this category.

Beta-Adrenergic Receptor Blocking Agents

Beta-blockers not only block the pulmonary effect of LABAs but also may produce severe
bronchospasm in patients with asthma or COPD. In general, patients with asthma or COPD
should not be treated with beta-blockers. However, under certain circumstances, such as
prevention of myocardial re-infarction, there may be no acceptable alternatives to the use of
beta-adrenergic blocking agents in patients with asthma or COPD. In this setting, cautious use of
cardioselective betablockers could be considered.

Diuretics
The electrocardiogram (ECG) changes and/or hypokalemia that may result from the
administration of non-potassium-sparing diuretics (such as loop or thiazide diuretics) can be
acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist
is exceeded. Although the clinical significance of these effects is not known, caution is advised in
the co-administration of beta-agonists with non-potassium-sparing diuretics. Concomitant
treatment with xanthine derivatives, steroids, or diuretics may potentiate any hypokalemic
effect of adrenergic agonists.

CYP3A4 Inhibitors
Co-administration of salmeterol and strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir,
atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, and
telithromycin) may result in a significant increase in plasma salmeterol exposure. Due to the
potential increased risk of cardiovascular adverse event, the concomitant use of salmeterol with
these agents is not recommended.

Page 10 of 11
SPECIAL POPULATIONS
Pediatrics
Formoterol inhalation powder (Foradil Aerolizer) has been studied in children ages 5 years and
older for the prevention and treatment of asthma and prevention of EIB; recommended dosage
is the same as for older children. Salmeterol (Serevent) is indicated for the prevention and
treatment of asthma and prevention of EIB in children as young as 4 years. Safety and
effectiveness of indacaterol (Arcapta), arformoterol (Brovana), formoterol (Perforomist),
and olodaterol (Striverdi) have not been established in children. Salmeterol (Serevent) is
contraindicated in patients with severe hypersensitivity to milk proteins.
Pregnancy
All agents in this category are Pregnancy Category C.

https://hhs.texas.gov/sites/default/files//documents/about-hhs/communications-events/meetings-events/dur/042817-4m.pdf

---END OF MODULE 2---

Page 11 of 11