Drugs Used in Asthma

Z. PHIRI
Department of Pharmacology
Midlands State University
 overview
• Asthma is a chronic inflammatory disease of
the airways
• Has episodes of acute bronchoconstriction
causing
shortness of breath
cough
chest tightness
Wheezing
rapid respiration
Pathogenisis of Asthma
 Asthma Pharmacotherapy
• Drugs are used for Quick relief and Long-term
control
• Quick relief medications are used to relieve
acute exacerbations and to prevent exercise-
induced bronchoconstriction (EIB) symptoms.
– short-acting beta agonists (SABAs),
– anticholinergics ( severe exacerbations),
– systemic corticosteroids
 Asthma Pharmacotherapy
• Long-term control medications include
-inhaled corticosteroids (ICSs)
-long-acting beta agonists (LABAs)
-long-acting anticholinergics
-combination ICS and LABAs
• Inhaled corticosteroids are the drug of choice
• but is characterized by wide variability in
response among patients glucocorticoid-induced
transcript 1 gene (GLCCI1)
 Inhaled Corticosteroids
• Steroids most potent anti-inflammatory agents.
• ICS are topically active, poorly absorbed, and least
to cause AE.
• e.g. Ciclesonide; Beclomethasone; Fluticasone; Budesonide; Mometasone
• Corticosteroids inhibit the release of arachidonic acid
through phospholipase A2 inhibition,
• Targets underlying airway inflammation by
decreasing the inflammatory cascade,
reversing mucosal edema,
decreasing the permeability of capillaries, and
inhibiting the release of leukotrienes;
decreases airway hyperresponsiveness
 Adverse effects

• ICS deposition on the oral and laryngeal

mucosa cause
oropharyngeal candidiasis
hoarseness
 Leukotriene Receptor Antagonist

• Zileuton is a selective and specific inhibitor of 5-lipoxygenase,

preventing the formation of both LTB4 and the cysteinyl
leukotrienes.
• Zafirlukast is a selective competitive inhibitor of LTD4 and
LTE4 receptors
• All are orally active, metabolized by the liver and highly
protein bound.
• Food impairs the absorption of zafirlukast.
• Zileuton and its metabolites are excreted in urine
• zafirlukast, montelukast, and metabolites undergo biliary
excretion.
• Montelukast has a once-a-day dosing & has no significant
A/Es
 Adverse effects

• Elevations in serum hepatic enzymes

• headache and dyspepsia
 Oral Corticosteroids
• Oral steroids are used for short courses (3-10 d) to gain
prompt control of inadequately controlled acute
asthmatic episodes.
• also used for long-term prevention of symptoms in
severe persistent asthma as well as for suppression,
control, and reversal of inflammation.
• Prednisone, Methylprednisolone,Prednisolone
MOA
• may decrease inflammation by reversing increased
capillary permeability and suppressing
polymorphonuclear leukocyte activity
• corticosteroids reverse beta2 -receptor subsensitivity
and down-regulation
 Oral Corticosteroid
• oral administration is equivalent in efficacy to
intravenous administration.
• Corticosteroids speed the resolution of airway
obstruction and prevent a late-phase
response.
• In children, long-term use of high-dose
steroids may lead to growth failure.
 Adverse Effects
Complications of long-term corticosteroid use may include
C – Cataracts
U – Ulcers
S – Striae, Skin thinning/easy bruising
H – Hypertension, Hirsutism
I – Immunosuppression, Infections
N – Necrosis of femoral heads
G – Glucose elevation
O – Osteoporosis, Obesity/weight gain,
I – Impaired wound healing
D – Depression/mood changes/diabetes/psychiatric disorders
 Anticholinergics
• Short-acting anticholinergics: Ipratropium
• Long-acting anticholinergics: Aclidium bromide, Tiotropium
• block vagally mediated contraction of airway smooth
muscle and mucus secretion.
• It inhibits M3-receptors at smooth muscle, leading to
bronchodilation
• The SAMA ipratropium bromide is available as a pMDI
and nebulized preparation.
• The onset of bronchodilation is relatively slow and is
usually maximal 30–60 min after inhalation but may
persist for 6–8 h.
 Adverse Effects
• LAMAs cause dryness of the mouth in 10%–
15% of patients, but this usually disappears
during continued therapy.
• Urinary retention is occasionally seen in
elderly people
 Methylxanthines
• Theophylline is available in short- and long-acting
formulations. Because of the need to monitor the drug
levels, this agent is used infrequently.
• Enprophylline Aminophylline; theophylline and Doxophylline
• The mechanisms of action of theophylline are still
uncertain.
• The dose of theophylline required to give these therapeutic
concentrations varies among subjects, largely because of
differences in clearance of the drug.
• Theophylline is rapidly and completely absorbed, but there
are large interindividual variations in clearance due to
differences in hepatic metabolism.
• Theophylline is metabolized in the liver, mainly by CYP1A2
 MOA
• Theophylline relaxes smooth muscles of
respiratory tract and suppresses the response
of the airways to stimuli
• May increase tissue concentration of cyclic
adenine monophosphate (cAMP) by inhibiting
2 isoenzymes of phosphodiesterase (PDE III
and, to a lesser extent, PDE IV), which
ultimately induces release of epinephrine
from the adrenal medulla cells
 Side Effects

• Unwanted effects of theophylline are usually related to

plasma concentration and tend to occur at Cp greater
than 15 mg/L.
• Has a narrow therapeutic range
• The most common side effects are headache, nausea,
and vomiting (due to inhibition of PDE4), abdominal
discomfort, and restlessness.
• increased acid secretion, diuresis
• At high concentrations, cardiac arrhythmias may occur
• Cix in DM, peptic acid, gout, alcoholism
 Mast cell stabilizers
• These agents block early and late asthmatic responses,
interfere with chloride channels, stabilize the mast cell
membrane, and inhibit the activation and release of
mediators from eosinophils and epithelial cells.
• inhibit acute responses to cold air, exercise, and sulfur
dioxide.
• Cromolyn sodium (oral inhalation) has no intrinsic anti-
inflammatory, antihistamine, or vasoconstrictive effects
• Cromolyn is a prophylactic anti-inflammatory agent
• It is an alternative therapy for mild persistent asthma.
• It is not useful in managing an acute asthma attack, because it
is not a bronchodilator.
• Due to its short duration of action
• Adverse effects are minor and include cough, irritation, and unpleasant
taste
 Monoclonal Antibodies, Anti-asthmatics

• Monoclonal antibody effects vary depending on their

receptor target.
• Omalizumab binds to IgE on the surface of mast cells
and basophils.
• It reduces the release of these mediators that promote
an allergic response.
• Mepolizumab, reslizumab, and benralizumab inhibit IL-
5 binding to eosinophils and result in reduced blood,
tissue, and sputum eosinophil levels.
• Dupilumab inhibits IL-4 receptor alpha, and thereby
blocks IL-4 and IL-13 signaling
 Omalizumab
• Recombinant DNA-derived monoclonal antibody that selectively
binds to human immunoglobulin E
• This leads to decreased binding of IgE to its receptor on the surface
of mast cells and basophils.
• Reduction in surface-bound IgE limits the release of mediators of
the allergic response
• It is indicated for moderate-to-severe persistent asthma in patients
aged 6 years or older who are poorly controlled with conventional
therapy.
• Its use is limited by the high cost, route of administration
(subcutaneous), and adverse effect profile.
• Adverse effects include serious anaphylactic reaction (rare),
arthralgias, fever, and rash. Secondary malignancies have been
reported
Drugs Used In COPD
COPD
• disorder in which patients
may have dominant
features of
• chronic bronchitis,
• emphysema, or asthma.
• The result is reversible
airflow obstruction
 COPD
• Patients typically present with a combination of
signs and symptoms of chronic bronchitis,
emphysema, and reactive airway disease
• Chronic bronchitis is the presence of a chronic
productive cough for 3 months during each of 2
consecutive years
• Emphysema is abnormal, permanent
enlargement of the air spaces distal to the
terminal bronchioles, accompanied by
destruction of their walls and without obvious
fibrosis.
 Signs and symptoms

• Symptoms include the following:

• Cough, usually worse in the mornings and productive

of a small amount of colorless sputum

• Breathlessness: The most significant symptom, but

usually does not occur until the sixth decade of life

• Wheezing: May occur in some patients, particularly

during exertion and exacerbations
 COPD TREATMENT GOALS
• to improve a patient’s functional status and
• quality of life by preserving optimal lung
function,
• improving symptoms, and
• preventing the recurrence of exacerbations.
• improve lung function or decrease mortality;
• however, oxygen therapy (when appropriate)
and smoking cessation may reduce mortality.
 Management

• Smoking cessation continues to be the most important

therapeutic intervention for COPD.
• Risk factor reduction (eg, influenza vaccine) is
appropriate for all stages of COPD.
• Short-acting bronchodilator
• long-acting bronchodilator(s);
• cardiopulmonary rehabilitation
• inhaled glucocorticoids if repeated exacerbations
• long-term oxygen therapy;
• consider surgical options such as lung volume
reduction surgery (LVRS) and lung transplantation
 COPD Management
• Most of the medications used are directed at the following
4 potentially reversible causes of airflow limitation in a
disease state that has largely fixed obstruction:

• Bronchial smooth muscle contraction

• Bronchial mucosal congestion and edema

• Airway inflammation

• Increased airway secretions

 Bronchodilators

• are the backbone of any COPD treatment regimen.

• They work by dilating airways, thereby decreasing airflow resistance.
This increases airflow and decreases dynamic hyperinflation.
• provide symptomatic relief but do not alter disease progression or
decrease mortality.
• Beta2 agonists and cholinergic/muscarinic antagonists combination
therapy results in greater bronchodilator response and provides
greater relief.
• long-acting bronchodilators are more beneficial than short-acting
ones.
• The inhaled route is preferred,
• Adverse effects include dry mouth, dry eyes, metallic taste, and
prostatic symptoms.
 Bronchodilators
• blocks the action of acetylcholine at muscarinic receptors in the bronchial airways
(M3) by preventing increase in intracellular calcium concentration, leading to
relaxation of airway smooth muscle
• Aclidinium; Revefenacin; Umeclidinium bromide.
• Revefenacin is a once-daily, long-acting muscarinic antagonist . It is indicated for
maintenance treatment of COPD.
• Phosphodiesterase inhibitors increase intracellular cyclic adenosine
monophosphate (cAMP) and result in bronchodilation.
• may improve diaphragm muscle contractility and stimulate the respiratory center.
• Theophylline is a nonspecific phosphodiesterase inhibitor and is now limited to use
as an adjunctive agent.
• Roflumilast (Daliresp) and cilomilast (Ariflo) are second-generation, selective
phosphodiesterase-4 inhibitors.
• Cilomilast is completely absorbed following oral administration and has a half-life
of approximately 6.5 hours
 Use of oral cannabinoid drugs in COPD

• associated with increased rates of adverse

outcomes in older patients with (COPD).
• COPD patients increasingly use prescription
synthetic oral cannabinoid drugs to treat
chronic musculoskeletal pain, insomnia and
refractory dyspnea,
• nabilone or dronabinol
 Management of Inflammation
• Inflammation plays a significant role in the
pathogenesis of COPD.
• Inhaled corticosteroids are not recommended as
monotherapy and should be added to LABAs
• Intravenous steroids are often used in high doses for
acute exacerbations in the inpatient setting;
• Nonsteroidal anti-inflammatory medications have not
been shown conclusively to have any benefit in COPD.
• However, macrolide antibiotics have been shown to
have anti-inflammatory effects in the airways of COPD
patients e.g azithromycin
• erythromycin reduced the frequency of exacerbations
• A/E : increase in hearing decrements combined with
the concern for breeding antimicrobial resistance Limit
use of macrolides
 Management of Infection

• In patients with COPD, chronic infection or colonization

of the lower airways is common from S pneumoniae, P
aeruginosa H influenzae, and M catarrhalis.
• use of antibiotics used for the treatment of acute
exacerbations where there is increased dyspnea,
sputum production and sputum purulence
• No evidence supports the continuous or prophylactic
use of antibiotics to prevent exacerbations
• the addition to doxycycline to corticosteroids was
found to improve treatment for acute exacerbation of
COPD (AECOPD).
 Management of Sputum Secretion
• Management of Sputum Viscosity and Secretion Clearance
• Mucolytic agents reduce sputum viscosity and improve
secretion clearance.
• The oral agent N -acetylcysteine has antioxidant and
mucokinetic properties and is used to treat patients with
COPD.
• However, the efficacy of mucolytic agents in the treatment of
COPD remains controversial.
• decrease cough and chest discomfort,
• they do not improve dyspnea or lung function and elicit
bronchospasm
• When used as an inhalational therapy, N -acetylcysteine should
be administered along with a bronchodilator such as albuterol
in order to counteract potential induction of bronchospasm.
 PPIs and Oxygen
• PPIs for Exacerbations and the Common Cold
• the addition of a proton pump inhibitor (PPI) to
conventional therapy may significantly decrease COPD
exacerbations but not the incidence of the common cold,
• Oxygen Therapy and Hypoxemia
• COPD is commonly associated with progressive hypoxemia.
• Oxygen administration reduces mortality rates in patients
with advanced COPD because of the favorable effects on
pulmonary hemodynamics.
• Oxygen therapy generally is safe.
• The major physical hazards of oxygen therapy are fires or
explosions.
 Vaccination
• Vaccination to Reduce Infections
• Infections can lead to COPD exacerbations.
• The pneumococcal vaccine should be offered
to all patients older than 65 years or to
patients of any age who have an FEV1 of less
than 40% of predicted.
• The influenza vaccine should be given
annually to all COPD patients.
 Alpha1-Antitrypsin Deficiency Treatment
• reducing the neutrophil elastase burden by smoking
cessation, and augmenting the levels of AAT.
• Available augmentation strategies include
pharmacologic attempts to increase endogenous
production of AAT by the liver (ie, danazol,
tamoxifen) and
• Intravenous AAT augmentation therapy is the only
available approach that can increase serum levels to
greater than 11 mmol/L, the protective threshold
• Use of mepolizumab has been associated with a
lower rate of exacerbation in a subgroup of COPD
patients with eosinophilia predominance
Allergic Rhinitis
 Allergic Rhinitis
• an inflammation of the nasal membranes that
is characterized by
sneezing,
nasal congestion,
nasal itching
rhinorrhea,
Types: seasonal & perennial
 Management

• Environmental control measures and allergen

avoidance
• Pharmacologic management: oral
antihistamines, decongestants, or both;
regular use of an intranasal steroid spray
• Immunotherapy: severe disease, poor
response to other management options, and
comorbid conditions or complications; as add
on
 Medication Summary
• Patients with intermittent symptoms are often treated
adequately with oral antihistamines, decongestants, or
both as needed.
• Regular use of an intranasal steroid spray may be more
appropriate for patients with chronic symptoms.
• Daily use of an antihistamine, decongestant, or both
can be considered either instead of or in addition to
nasal steroids.
• The newer, second-generation (i.e., nonsedating)
antihistamines are usually preferable to avoid sedation
• Ocular antihistamine drops (for eye symptoms),
intranasal antihistamine sprays, intranasal cromolyn,
intranasal anticholinergic sprays, and short courses of
oral corticosteroids may also provide relief.
 Drugs for Allergic Rhinitis
• Antihistamines (H1-receptor blockers)
• Corticosteroids
• α-Adrenergic agonists
• Other agents: cromolyn
 First-generation antihistamines

• The older are effective in reducing most

symptoms of allergic rhinitis,
• Administration at bedtime may help with
drowsiness, but sedation and impairment of
cognition may continue until the next day.
Chlorpheniramine
Diphenhydramine
Hydroxyzine
 Second-generation antihistamines

• nonsedating antihistamines.
• They compete with histamine for histamine receptor type 1 (H1)
receptor sites in the blood vessels, GI tract, and respiratory tract,
which, in turn, inhibits physiologic effects that histamine normally
induces at the H1 receptor sites.
• Other adverse effects (eg, anticholinergic symptoms) are generally
not observed.
• Topical azelastine and olopatadine are nasal sprays antihistamines.
• azelastine is effective at managing both allergic and nonallergic
rhinitis.
• Cetirizine , Levocetirizine, Fexofenadine , Loratadine
• Desloratadine – Long-acting tricyclic histamine antagonist selective
for H1-receptor. Major metabolite of Loratadine,
 Leukotriene receptor antagonists

• Alternative to oral antihistamine to treat

allergic rhinitis.
• montelukast seasonal and perennial allergic
rhinitis
• results in a reduction of seasonal allergic
rhinitis symptoms, similar in degree to that of
Loratadine.
 Decongestants

• Stimulate vasoconstriction by directly activating alpha-

adrenergic receptors of the respiratory mucosa.
• Pseudoephedrine produces weak bronchial relaxation
(unlike epinephrine or ephedrine) and is not effective for
treating asthma.
• Increases heart rate and contractility by stimulating beta-
adrenergic receptors,
• and increases blood pressure by stimulating alpha
adrenergic receptors.
• Used alone or in combination with antihistamines to treat
nasal congestion. Anxiety and insomnia may occur.
• Helpful for nasal and sinus congestion.
 Expectorants
• Expectorants may thin and loosen secretions,
although experimental evidence for their efficacy is
limited.
• First generation intranasal steroids corticosteroids,
e.g. beclomethasone, are more bioavailable and
produce more systemic adverse effects
• Nasal steroid sprays are highly efficacious
• control the 4 major symptoms of rhinitis (i.e.,
sneezing, itching, rhinorrhea, congestion).
• They are effective as monotherapy, although they do
not significantly affect ocular symptoms.
 Mast Cell Stabilizers

• Produce mast cell stabilization and antiallergic effects

that inhibit degranulation of mast cells.
• Have no direct anti-inflammatory or antihistaminic
effects.
• Effective for prophylaxis.
• Effect is modest compared with that of intranasal
corticosteroids.
• Excellent safety profile and safe for use in children and
pregnancy e.g. Cromoglicate sodium
• Used daily for seasonal or perennial allergic rhinitis.
• Significant effect may not be observed for 4-7 days.
 Intranasal Anticholinergic Agents
• Ipratropium
• Used for reducing rhinorrhea in patients with
allergic or vasomotor rhinitis.
• No significant effect on other symptoms.
• used alone or in combo with other classes.
 Allergy Extracts

• Grass pollens allergen extracts

• The precise mechanisms of action of allergen
immunotherapy is not known.
• Timothy grass pollen and Ragweed allergen
extract
• House dust mite immunotherapy
 Antihistamines Therapeutic Uses

• Allergic and inflammatory conditions

• Motion sickness and nausea
• Somnifacients
 Adverse effects
• Sedation
• Anticholinergic effects
• Headaches
• Topical preparations: Hypersensitivity
 α-Adrenergic agonists
• Short-acting α-adrenergic agonists such as
phenylephrine, constrict dilated arterioles in the
nasal mucosa and reduce airway resistance.
• Longer-acting oxymetazoline is also available.
• intranasal formulations should be used no longer
than 3 days due to the risk of rebound nasal
congestion
• Administration of oral results in a longer duration
of action but also increased systemic effects.
 Agents for cough
• Opioids
• Codeine, Dextromethorphan
• Benzonatate
 Agents for cough
• Opioids
• Codeine decreases the sensitivity of cough centers in the central
nervous system to peripheral stimuli and decreases mucosal
secretion.
• Common side effects, such as constipation, dysphoria, and fatigue,
still occur. In addition, it has addictive potential.
• Dextromethorphan is a synthetic derivative of morphine that has no
analgesic effects in antitussive doses.
• In low doses, it has a low addictive profile. However, it is a
potential drug of abuse, since it may cause dysphoria at high doses
• Guaifenesin, an expectorant, is available as a single-ingredient
formulation and is also a common ingredient in combination
products with codeine or dextromethorphan
 Agents for cough
• Benzonatate
• Unlike the opioids, benzonatate suppresses
the cough reflex through peripheral action.
• It anesthetizes the stretch receptors located in
the respiratory passages, lungs, and pleura.
• Side effects include dizziness, numbness of the
tongue, mouth, and throat.
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