ANTI ASTHMATIC

AGENTS
Controllers/anti inflammatory drugs
1. Corticosteroids

Types and administration

1. Inhaled corticosteroids (ICS):
- beclomethasone,
- Budesonide
- fluticasone
- mometasone
triamcinolone
2. Systemic corticosteroids:
• Oral CS: - prednisone, prednisolone
• IV CS: hydrocortisone, methylprednisolone
Mechanism of action
• Blocks the release of arachidonic acid
(via phospholipase A2 inhibition), consequently
halting the release of inflammatory mediators
• Stabilize mast cells
• Block immune response, decrease antibody
formation
• Antagonise histaminergic and cholinergic
responses
• Enhance beta-2 adrenoceptor responsiveness to
agonists (Catecholamines)
Effects:
• ↓ airway hyperresponsiveness
• ↓ airway mucosal edema
• ↓ capillary permeability
• ↓ leukotriene release
Inhaled corticosteroids (ICS)
• Inhaled corticosteroids (ICS) are the drugs of first choice
in patients with any degree of persistent asthma (mild,
moderate, or severe).
• Severe persistent asthma may require the addition of a
short course of oral glucocorticoid treatment.
• No other medications are as effective as ICS in the long-
term control of asthma in children and adults.
• If appropriately prescribed and used, ICS therapy may
reduce or eliminate the need for oral glucocorticoids in
patients with severe asthma.
• To be effective in controlling inflammation,
glucocorticoids must be taken continuously.
• Current guidelines recommend selecting ICS therapy for
a newly diagnosed patient with asthma at dosing
equivalent to the patient's asthma classification.
• Patients achieving 3 to 6 consecutive months of improved
asthma control may be considered for a reduction in ICS
dosing as clinically indicated.
• Short-term oral CS treatment (< 7 days) are of acute
severe exacerbations
• Tapering is required if oral CS is given > 2 weeks
Pharmacokinetics of inhaled glucocorticoids.
Actions on lung:
• ICS do not directly affect the airway smooth muscle.
Instead, ICS therapy directly targets underlying airway
inflammation by:
1. decreasing the inflammatory cascade (eosinophils,
macrophages, and T lymphocytes),
2. reversing mucosal edema,
3. decreasing the permeability of capillaries,
4. inhibiting the release of leukotrienes.
• After several months of regular use, ICS reduce the
hyperresponsiveness of the airway smooth muscle to a
variety of bronchoconstrictor stimuli, such as allergens,
irritants, cold air, and exercise.
Route of administration
Inhalation:
• The development of ICS has markedly reduced the
need for systemic corticosteroid treatment to achieve
asthma control.
• Appropriate inhalation technique is critical to the
success of therapy.
• Metered-dose inhalers have propellants that eject the
active medication from the canister.
• Patients should be instructed to SLOWLY and
DEEPLY inhale upon activation of these inhalers to
avoid impaction of the medication onto the laryngeal
mucosa rather than the bronchial smooth muscle.
• Improper use of a metered-dose inhaler can
result in a large fraction of inhaled
glucocorticoids to be deposited in the mouth,
pharynx, and/or swallowed .
• The 10 to 20 percent of the metered dose of
inhaled glucocorticoids that is not swallowed is
deposited in the airway.
• If ICS are inappropriately inhaled, systemic
absorption and adverse effects are much more
likely.
• ICS delivered by dry powder inhalers require a
different inhaler technique.
• Patients should be instructed to inhale QUICKLY and
DEEPLY to optimize drug delivery to the lungs.
• Even properly administered, corticosteroid
deposition on the oral and laryngeal mucosa can
cause adverse effects such as oropharyngeal
candidiasis and hoarseness.
• Patient counseling incorporating a rinsing of these
tissues via the swish and spit method should avoid
these adverse events.
Oral/systemic CS

• Patients with severe exacerbation of asthma (status

asthmaticus) may require intravenous administration of
methylprednisolone/ hydrocortisone or oral prednisone.
• Once the patient has improved, the dose of drug is
gradually reduced, leading to discontinuance in 1 to 2
weeks.
• In most cases, suppression of the hypothalamic-pituitary
axis will not occur during the short course of oral
prednisone typically prescribed for an asthma
exacerbation; therefore, dose reduction is not necessary
Spacers:
• A spacer is a large-volume chamber attached to a
metered-dose inhaler.
• Spacers decrease the deposition of drug in the mouth
caused by improper inhaler technique.
• The chamber reduces the velocity of the injected
aerosol before entering the mouth, allowing large drug
particles to be deposited in the device.
• The smaller, higher-velocity drug particles are less
likely to be deposited in the mouth and more likely to
reach the target airway tissue.
• Spacers minimize the problem of adrenal suppression by
reducing the amount of glucocorticoid deposited in the
oropharynx.
• Spacers improve delivery of inhaled glucocorticoids and
are advised for virtually all patients, especially children
less than 5 years old and elderly patients who may have
difficulty coordinating actuation with inhalation.
• Patients should be counseled about regular washing
and/or rinsing of spacers to reduce the risk of bacterial,
mold, or mildew growth inducing an asthma attack.
• Effect of a spacer on the delivery of an inhaled aerosol
Side Effects of corticosteroids
• They are classified as follows
1) Systemic adverse effects from short-term oral
corticosteroids
• Hyperglycemia
• Edema
• Rounding of facial contour
2) Systemic adverse effects from long-term oral
corticosteroids
• Osteoporosis
• Cataracts
• Myopathy
• Hypothalamic-pituitary-adrenal axis suppression
• Psychological depression
 3) Inhaled adrenal corticosteroids side effects
• They do not produce systemic side effects (adrenal
insufficiency)
• Local adverse effects include
- Oropharyngeal candidiasis (can be minimized by rinsing
the mouth and gargling with water immediately after
inhalation)
- Dysphonia (hoarseness)
- Dryness of mouth and throat
- Occasional coughing due to upper airway irritation (can
be minimized by using a spacer attached to the metered-
dose inhaler, which decreases the oropharyngeal
deposition while increasing the lower airway deposition
of the corticosteroid)
Indications
a. Acute severe asthma (status asthmaticus)
• Hydrocortisone - IV
Dose
Slow IV/IM- Adults- 200mg 3-4 times in 24 hrs or as required
Children- 1-5 yrs- 50mg, 6-12yrs- 100mg
Availability- 1 vial = 100mg
b. Acute asthma – oral
• Prednisolone
Dose- give high doses in acute attacks- 30-40mg daily and
reduced gradually until the attack is controlled.
In chronic asthma small doses may be taken in the morning to
reduce interferance of circadian cortisol secretion
Availability- 5mg tablets
c. Chronic asthma –(Prophylaxis) Inhalation
• Beclomethasone – decomit MDI- 100mcg
• Adults- 200mcg bd(2 puffs bd)
• Severe cases 600-800mcg /day

• budesonide- budecort- 200mcg bd

• Fluticasone- flixotide evohaler

Status Asthmaticus

Status Asthmaticus
• Status asthmaticus is an acute exacerbation of asthma
that remains unresponsive to initial treatment with
bronchodilators.
• It is a life threatening form of asthma, because it can
lead to respiratory failure and cardiac arrest.
• Status Asthmaticus requires immediate treatment
(corticosteroids are essential as immediate treatment)
• Air trapping strains on breathing muscle which are
fatigue and exhausted
• Status asthmaticus is frequently associated with
metabolic acidosis, and acidosis reduces the
effectiveness of beta agonist.
2. Anti leukotriene Agents

They include:
1. Leukotriene receptor antagonists (LTRAs)
e.g. zafirlukast, montelukast (oral)

2. 5-lipoxygenase inhibitor:
e.g. zileuton (oral)
Mechanism of action
• Zileuton:- selective inhibition of 5-lipoxygenase (thus
preventing conversion of arachidonic acid to
leukotrienes)
• Zafirlukast and montelukast:- inhibit leukotriene (LT)-D4
receptors and LTE4 receptors
Pharmacological effects
• Effects (by targeting leukotriene):
• ↓ smooth airway contraction
• ↓ vascular permeability and mucus secretion
• Reduced activation of inflammatory cells
Properties of leukotreines:
a. Previously known as slow reacting substances
of anaphylaxis
– may be overproduced when Cox1/2 are
inhibited.
b. Contribute to bronchoconstriction,
inflammation, edema and mucus secretion,
thereby obstructing airways in asthma.
c. Cysteinyl leukotreines such as LTD4 are the
most potent bronchoconstrictors
zafirlukast
Pharmacokinetics
• Take 20 mg tablet either 1 hour before or 2 hours after
breakfast and dinner since food reduces the bioavailability
of zafirlukast
Therapeutics uses of zafirlukast
1. Prevention of asthmatic attacks in patients 12 years and
older, with a therapeutic trial being the only way to
determine which asthma patients will show a clinical
improvement
• Not a rescue medication itself during an acute asthmatic
attack because it does not act quickly enough.
• However, does reduce the need for a rescue beta2 -
agonist in chronic asthma patients.
2. Improves pulmonary function in mild-to-moderate
asthma
3. Effective in aspirin-induced asthma that is caused by
an overproduction of leukotreines resulting from the
inhibition of prostaglandin synthesis by aspirin.
4. Effective in prevention of cold-air-induced
bronchoconstriction in patients with mild-to-moderate
asthma.

Contraindications of zafirlukast
• Breast-feeding
Drug interactions of zafirlukast
• zafirlukast plus warfarin produces an increased
prothrombin time with possible bleeding because
zafirlukast inhibits the cytochrome P450 enzymatic
degradation of warfarin
Montelukast sodium
Mechanism of action:
• Another cysteinyl-leukotreine1 receptor blocker that
prevents the bronchoconstriction, mucus secretion and
vascular leaks caused by LTD4
Therapeutic uses of montelukast
1. Effective in adults 15 years and older (10 mg tablet daily)
and in pediatric patients 6-14 years (5 mg chewable tablet
daily)
2. Effective in preventing exercise-induced bronchospasm
3. Should not be used as a rescue medication for acute
asthma episodes
Zileuton
Mechanism of action
• A 5-lipoxygenase inhibitor - therefore, also inhibits
actions of LTB4
Therapeutic uses of zileuton
• Administered orally four times a day and is effective in
preventing exercise-induced asthma, cold-air induced
asthma and aspirin-induced asthma
• Reduces nocturnal symptoms and bronchial obstruction
in nocturnal asthma
Clinical uses
• Exercise-induced bronchospasm
• Mild persistent asthma + allergic rhinitis
• Asthma and aspirin-exacerbated respiratory disease
• Additive benefit for moderate-to-severe persistent asthma
• Considered in patients with difficulty with compliance or
inhaler technique (e.g., children)
Side effects

• Common: headaches, fatigue, dyspepsia

• Neuropsychiatric adverse effects: behavior and mood-
related changes (especially montelukast)
• Zafirlukast and zileuton:
• Potentially hepatotoxic, requiring liver function test
monitoring
• Drug interactions (including increased warfarin effect)
• Eosinophilic granulomatous polyangiitis can develop
when antileukotrienes are given to patients with steroid-
dependent asthma.
• Zileuton increases alanine transaminase to more than 3-
fold in 3% of treated patients.
• However, will revert back to normal when drug is
discontinued.
• Measurement of alanine transaminase before therapy
with periodic monitoring is recommended
• It is contraindicated in patients with hepatic diseases
and those with occasional dyspepsia
• Precautions
• Zafirlukast and zileuton:
• Contraindicated in liver disease/hepatic impairment
• Monitor for mood and behavioral changes
• Montelukast:
• Monitor for mood and behavioral changes
• Contains phenylalanine (not recommended for patients
with phenylketonuria)
3. Mast Cell Stabilizers (Chromones)

• They include Cromolyn (nebulization) and nedocromil

Mechanism of action
• Prevents the degranulation of mast cells, thereby
preventing local inflammation
• Prevents early and late inflammatory effects
Mechanism of anti-asthmatic action of cromolyn sodium
• 1) Cromolyn sodium inhibits the degranulation of mast
cells, preventing the release of histamine and other
mediators of bronchospasm:
- Cromolyn sodium reduces the transmembrane influx of
Ca2+ ions induced by IgE antibody-antigen interactions on
the sensitized mast cell surface
• 2) Cromolyn sodium inhibits the recruitment of
neutrophils and eosinophils to the pulmonary epithelium:
- Cromolyn sodium inhibits neutrophil chemotactic factor
(NCF)
• 3) Cromolyn attenuates the ability of platelet activating
factor (PAF) to cause airway hyperreactivity
• Cromolyn and nedocromil are effective prophylactic anti-
inflammatory agents but they are not useful in managing
an acute asthma attack, because they are not direct
bronchodilators.
• These agents can block the initiation of immediate and
delayed asthmatic reactions.
• use in asthma, cromolyn is administered either by
inhalation of a microfine powder or as an aerosolized
solution.
• Because it is poorly absorbed, only minor adverse effects
are associated with it.
• Pre treatment with cromolyn blocks allergen- and
exercise-induced bronchoconstriction.
• Cromolyn is also useful in reducing the symptoms of
allergic rhinitis.
• A 4 to 6-week trial is required to determine efficacy.
• Given its safety, an initial trial of cromolyn is often
recommended, particularly in children and pregnant
women.
• Toxic reactions are mild and include a bitter taste and
irritation of the pharynx and larynx
• Due to short duration of action, these agents require
frequent daily dosing, which has been shown to affect
adherence and, therefore, therapeutic efficacy
• N/B Neither cromolyn nor nedocromil should replace ICS
or quick-relief B2 agonists as the mainstay of asthma
therapy.
Therapeutic uses of cromolyn sodium for asthma
1) Cromolyn sodium, when used prophylactically
before exposure will inhibit:
a) Immediate allergen-induced airway narrowing
b) Late phase allergen-induced airway narrowing

2) Pretreatment with cromolyn sodium will block:

a) Exercise-induced bronchoconstriction
b) Cold, dry air-induced bronchoconstriction
3) Cromolyn sodium is not capable of reversing
asthmatic bronchospasm
a) Cromolyn sodium cannot be used to treat an
acute episode of asthma.
b) The only use of cromolyn sodium is in the
prevention of bronchospasm

4) There is no way to reliably predict whether a

patient will respond to cromolyn sodium
a) A 4-6 week trial may be required to determine
the efficacy of cromolyn in asthmatic patients
5) In patients with severe asthma who respond poorly to
individual drugs, therapeutic benefits may be enhanced
by combining cromolyn sodium with an adrenal
corticosteroid and/or a bronchodilator such as a beta2-
adrenergic agonist or theophylline
a) If combined therapy is prescribed, then one must
individualize the dose of each drug in order to obtain
maximal benefit with minimal adverse reactions

Side effects of cromolyn sodium

• Throat irritation
• No significant toxicity due to minimal systemic
absorption
4. Monoclonal Antibodies- Anti IgE

• Can be given to patients having severe forms of

disease.
• They bind to IgE antibodies present on mast
cells.
• If administered I/V or subcutaneously,
humanized monoclonal antibodies decrease
levels of IgE antibodies, decreasing tendency of
severe asthma, in both phases
(immediate/delayed).
• IgE plays a central role in immediate
bronchoconstriction and the influx of
inflammatory cells
• Also improve nasal/ conjunctival symptoms and
allergic manifestations.
• These are reserved for severe cases, if you
want to reduce dose of corticosteroids and there
are undetectable levels of IgE antibodies in
plasma and no antigen antibody reaction occurs
Clinical use
 For persistently uncontrolled allergic asthma despite
high-dose ICS and ≥ 1 other controller(s)
 For patients with:
• Age ≥ 6 years
• An elevated IgE level (30–700 IU/mL)
• Positive allergen skin test or specific IgE tests to a
perennial allergen
 Reduces CS requirements
Type(s) and administration

1. Omalizumab
mechanism of action
• An allergic component mediated by antigen-specific IgE
attached to receptors on mast cells causes the release of
histamine and leukotrienes that increase mucosal inflammation
producing spasm of airway smooth muscle.
• Omalizumab forms a complex with circulating free IgE which
lowers free IgE serum concentrations to undetectable levels.
• This prevents IgE from binding to mast cells preventing the
release of histamine and leukotrienes from mast cells.
Route of administration of omalizumab
• Subcutaneous injection every 2-4 weeks
• It is very expensive
• Patient cost is $12,000 per year
Side effects
• Urticaria, injection site reaction
• Headache
• Precautions
• Anaphylaxis/severe hypersensitivity reaction is a
contraindication.
• Monitor for parasitic infections (helminth).
• Cerebrovascular events have been reported
• N/B- It is currently not known whether long-term lowering
of free IgE serum concentrations could increase the risk
of malignancy…since in a completed study for less than 1
year, malignant neoplasms occurred in 0.4% of 4,127
patients exposed to omalizumab as compared to 0.1% of
2,236 controls.
• The high cost, the need for subcutaneous injections, and
the concern about its long-term safety restricts the use of
omalizumab to patients with severe asthma that cannot be
controlled by other drug.
Other monoclonal antibodies - Anti-IL-5 Receptor
Types and administration
• Mepolizumab (subcutaneous)
• Reslizumab (intravenous)
• Benralizumab (subcutaneous)
Mechanism of action and effects
• IL-5 is a pro-eosinophilic cytokine contributing to
eosinophilic inflammation.
• Mepolizumab, reslizumab:- monoclonal antibody to IL-5
• Benralizumab:- cytotoxic monoclonal antibody against
IL-5 receptor alpha
Clinical uses
 For severe eosinophilic asthma
• Mepolizumab:
• For blood eosinophil count ≥ 300 cells/μL
• Patient age: > 12 years
• Reslizumab:
• For blood eosinophil count ≥ 400 cells/μL
• Patient age: > 18 years
• Benralizumab:
• For blood eosinophil count ≥ 300 cells/μL
• Patient age: > 12 years
Asthma medications are also used for the
following conditions:

A. Chronic obstructive pulmonary disease (COPD):

• A common chronic disease of the airways characterized
by airflow limitation.
• Obstructive inflammation is noted in the small airways,
lung parenchyma, and pulmonary vasculature.
• Patients usually present with dyspnea and chronic cough.
• Bronchodilators and corticosteroids are part of the
regimen for treating COPD.
B. Eosinophilic granulomatous polyangiitis (EGPA):
• Vasculitis characterized by necrotizing granulomas,
eosinophilia, and eosinophilic tissue infiltration.
• The vasculitis affects small- and medium-sized arteries.
• Multiple organs can be affected, including the
pulmonary, renal, gastrointestinal, cardiovascular,
and nervous system.
• Among the treatments is mepolizumab.
C. Allergic rhinitis:
• A condition characterized by rhinorrhea, sneezing,
and itching of nose, eyes, and palate.
• Allergens trigger an allergic nasal response where
nasal mast cells release histamine and other
mediators.
• Corticosteroid nasal sprays are commonly
prescribed. E.g. AVAMYS nasal spray- contains
fluticasone furoate.,beclomet nasal spray- contains
beclomethasone
• Other less-used therapies available include
cromolyn nasal spray, ipratropium nasal spray, and
montelukast.
• THE END