Week 2 - Drugs used in asthma

Tinatin Jomidava
Asthma
Asthma is an inflammatory disease of the airways
Characterized:
• Clinically by recurrent bouts of shortness of breath, chest
tightness, and wheezing, often associated with
coughing;
• Physiologically by widespread, reversible narrowing of the
bronchial airways and a marked increase in bronchial
responsiveness to inhaled stimuli; and
• Pathologically by lymphocytic, eosinophilic inflammation
of the bronchial mucosa.
• It is also characterized pathologically by “remodeling” of
the bronchial mucosa, with thickening of the lamina
reticularis beneath the airway epithelium and hyperplasia
of the cells of all structural elements of the airway wall:
 vessels,
 smooth muscle,
 secretory glands and
 goblet cells.
Mild asthma - symptoms occur only occasionally, as:
• on exposure to allergens or certain pollutants,
• on exercise, or
• after viral upper respiratory infection.
More severe forms - associated with frequent
attacks of wheezing dyspnea, especially at night, or with
chronic airway narrowing, causing chronic respiratory
impairment.
Consequences are largely preventable, because:
• Effective treatments for relief of acute
bronchoconstriction (“short-term relievers”) and
• For reduction in symptoms and prevention of attacks
(“long-term controllers”) are available.
The causes of airway narrowing in acute asthmatic attacks,
or “asthma exacerbations,” include:
• Contraction of airway smooth muscle;
• Inspissation of viscid mucus plugs in the airway lumen;
• Thickening of the bronchial mucosa from: edema, cellular
infiltration, and hyperplasia of secretory, vascular, and
smooth muscle cells.
 Contraction of smooth muscle is most easily reversed by
current therapy;
 Reversal of the edema and cellular infiltration requires
sustained treatment with anti-inflammatory agents.
Short-term relief
• Most effectively achieved by agents that relax airway
smooth muscle:
• the most effective and most widely used- β-adrenoceptor
stimulants ;
• Another drugs for airway constriction reversal:
Theophylline, a methylxanthine drug, and antimuscarinic
agents.
Long-term control
• Most effectively achieved with an anti-inflammatory agent
such as an inhaled corticosteroid.
• Less effectively with: A leukotriene pathway antagonist or
an inhibitor of mast cell degranulation, such as cromolyn or
nedocromil.
Clinical trials - treatment for severe asthma with a humanized
monoclonal antibody, omalizumab, which is specifically
targeted against IgE, the antibody responsible for allergic
sensitization.
The distinction between “short-term relievers”
and “long-term controllers” is blurred.
 Inhaled corticosteroids(long-term
controllers)- produce modest immediate
bronchodilation.
 Theophylline( bronchodilator)-inhibits some
lymphocyte functions and modestly reduces
airway mucosal inflammation.
 Theophylline may also enhance the anti-
inflammatory action of inhaled
corticosteroids.
 This is also true of long-acting β-adrenoceptor
stimulants, like salmeterol and formoterol,
which are effective in improving asthma
control when added to inhaled
corticosteroid treatment, though neither is
anti-inflammatory when taken as a single
agent.
PATHOGENESIS OF
ASTHMA
• Mediated by immune globulin (IgE).
• Foreign materials (allergens) provoke IgE production;
• The most common are proteins from: House dust
mite, cockroach, animal danders, molds, and pollens.
• IgE antibody production is genetically determined;
• IgE bind to mast cells in the airway mucosa .
On reexposure to a specific allergen, antigen-antibody interaction on the surface of the
mast cells triggers:
• Release of mediators stored in the cells’ granules;
• The synthesis and release of other mediators: the histamine, tryptase, leukotrienes
C4 and D4 , and prostaglandin D2 - released through the airway mucosa,
triggering the muscle contraction and vascular leakage responsible for the acute
bronchoconstriction of the “early asthmatic response.”
This response is often followed in 3–6 hours by a second, more sustained phase of
bronchoconstriction, the “late asthmatic response,” which is associated with an influx of
inflammatory cells into the bronchial mucosa and with an increase in bronchial reactivity that
may last for several weeks after a single inhalation of allergen.
• The mediators responsible for this late
response are thought to be cytokines
produced by TH2 lymphocytes, especially
interleukins-5, 9, and 13.
• These cytokines attract and activate
eosinophils, stimulate IgE production by
B lymphocytes, and stimulate mucus
production by bronchial epithelial cells.
• It is not clear whether lymphocytes or mast
cells in the airway mucosa are the primary
source of the mediators responsible for
the late inflammatory response!
• Benefits of corticosteroid therapy are
attributed to their inhibition of the
production of pro-inflammatory cytokines
in the airways.
 Most asthma attacks are not triggered by inhalation of allergens.
 They are triggered by viral respiratory infection.
 Some adults with asthma have no evidence of allergic sensitivity to allergens, and even in people with
allergic sensitivity, the severity of symptoms correlates poorly with levels of allergen in the atmosphere.

 Bronchospasm can be provoked by nonallergenic stimuli such as: distilled water, exercise, cold
The tendency to develop bronchospasm on stimuli that do not affect healthy nonasthmatic
airways is characteristic of asthma and is called “nonspecific bronchial hyperreactivity” to
distinguish it from bronchial responsiveness to specific antigens.
Asthmatic Bronchospasm might be reversed or
prevented by drugs that:
• Reduce the amount of IgE bound to mast cells (anti-IgE
antibody),
• Prevent mast cell degranulation (cromolyn or nedocromil,
sympathomimetic agents, calcium channel blockers);
• Reduce the number and activity of eosinophils in the airway
mucosa (anti-IL-5 antibody),
• block the receptor for IL-4 and IL-13 (anti-IL-4α receptor
antibody),
• Block the action of the products released (antihistamines and
leukotriene receptor antagonists);
• Interfere with the action of inflammatory cytokines (anti-IL-5
and anti-IL-13 monoclonal antibodies)
Aso:
• Inhibit the effect of acetylcholine released from vagal motor
nerves (muscarinic antagonists);
• Directly relax airway smooth muscle (sympathomimetic
agents, theophylline).
The second approach
• Reducing the level of bronchial responsiveness:
Increased responsiveness->>> airway inflammation- a feature of late
asthmatic responses.
This strategy is implemented by:
 Reducing exposure to the allergens that provoke inflammation;
 Prolonged therapy with anti-inflammatory agents, esp. inhaled
corticosteroids.

The current view of asthma treatment may be summarized as follows:

The treatments commonly used at present are indeed effective for the most
common form of the disease, as it presents in children and young adults with
allergic asthma, but there are other phenotypes of asthma for which these
therapies are less effective, and that represent an unmet medical need.
BASIC PHARMACOLOGY OF AGENTS USED IN
THE TREATMENT OF ASTHMA
The drugs most used for management of
asthma are:
 Adrenoceptor agonists, or
sympathomimetic agents ( “relievers”
or bronchodilators) and
 Inhaled corticosteroids ( “controllers”
or anti-inflammatory agents).
Goals of therapy
1. Reducing impairment;
2. Reducing risk;
SYMPATHOMIMETIC
AGENTS
Adrenoceptor agonists are mainstays in the treatment of asthma.
Their binding to β-adrenergic receptors—abundant on airway smooth
muscle cells—stimulates adenylyl cyclase, increases intracellular cAMP;
Thereby:
 Relaxing airway smooth muscle and inhibiting release of
bronchoconstricting mediators from mast cells.
 May inhibit microvascular leakage and increase mucociliary transport.
Adverse effects(especially of β1, β2):
• Tachycardia;
• Skeletal muscle tremor;
• Decreases in serum potassium levels.
Sympathomimetic agents widely used in the treatment of asthma:
• Albuterol and other β2 -selective agents.
The place of epinephrine and isoproterenol has diminished because of
their effects on the rate and force of cardiac contraction (mediated mainly
by β 1 receptors).
β-adrenoceptor agonists
• Best delivered by inhalation;
• Greatest local effect on airway smooth muscle
with the least systemic toxicity.
Aerosol deposition depends on:
 The particle size;
 The pattern of breathing;
 The geometry of the airways.
Optimal size (2–5 μm) administration ->> 80–90%
is deposited in the mouth or pharynx.
• Particles < 1–2 μm remain suspended and may
be exhaled.
Bronchial deposition of an aerosol is increased by:
• Slow inhalation of a nearly full breath and by 5
or more seconds of breath-holding at the end
of inspiration.
 Epinephrine

An effective, rapidly acting bronchodilator:

 Injected subcutaneously (0.4 mL of 1:1000 solution) or
 Inhaled as a microaerosol from a pressurized canister
(320 mcg per puff).
Maximal bronchodilation achieved - within 15ms after
inhalation and lasts 60–90ms. Because epinephrine
stimulates α and β 1 as well as β 2 receptors, its
potentially serious adverse effects are:
 Tachycardia,
 Arrhythmias,
 Worsening of angina pectoris.
Current use - treatment of the acute vasodilation and
bronchospasm of anaphylaxis.
Aerosol delivery of other, more β-selective agents has
largely displaced its use in asthma.
 Ephedrine; Isoproterenol
Ephedrine was used in China >2000 years before its introduction into Western medicine in
1924.
• Ephedrine has a longer duration than epinephrine,
• Oral activity,
• More pronounced central effects,
• Much lower potency.
Ephedrine is now used infrequently in treating asthma.
Isoproterenol
• Potent nonselective β1 and β2 bronchodilator.
• When inhaled as a microaerosol from a pressurized canister, 80–120mcg, causes
maximal bronchodilation within 5ms and has a 60-90-m duration of action.
• An increase in asthma mortality in the UK in the mid-1960s was attributed to cardiac
arrhythmias resulting from the use of high doses of inhaled isoproterenol.
• Not used anymore
 Beta 2 -Selective Drugs
β2 -selective adrenoceptor agonists, particularly albuterol:
• Most widely used sympathomimetics for acute
bronchoconstriction ;
• Differ structurally from epinephrine in having a larger
substitution on the amino group and in the position of the
hydroxyl groups on the aromatic ring.
• Effective after inhaled or oral adm;
• Longer duration of action than epinephrine or isoproterenol.
Albuterol, terbutaline, metaproterenol, pirbuterol as
metered-dose inhalers.
 Cause bronchodilation equivalent to isoproterenol.
 Bronchodilation is maximal within 15ms, persists 3–4hs.
 All can be diluted in saline for administration from a hand-
held nebulizer.
Albuterol and terbutaline are also available in oral form;
only terbutaline - for subcutaneous inj. (0.25 mg)
Long-acting β2 -selective agonists, with 12-h
durations of action, such as salmeterol and formoterol:
• Achieve long duration of bronchodilation as a result
of high lipid solubility.
• This permits them to dissolve in the smooth
muscle cell membrane in high concentrations.
• They interact with inhaled corticosteroids to
improve asthma control.
• Because they have no anti-inflammatory action, they
should not be used as monotherapy for asthma.
Ultra-long-acting β agonists, such as
indacaterol, olodaterol, vilanterol, and bambuterol,
need to be taken only once a day, but because their
prolonged bronchodilation masks symptoms of bronchial
inflammation, they should be used only in combination
with an ICS for asthma.
 METHYLXANTHINE DRUGS

The three important methylxanthines are theophylline,

theobromine, and caffeine.
• Their major source is beverages (tea, cocoa, and coffee,
respectively).
• The use of theophylline has almost ceased with greater
efficacy of inhaled adrenoceptor agonists for acute asthma
and of inhaled anti-inflammatory agents for chronic asthma.
• Accelerating this decline in theophylline’s use are its toxicities
(nausea, vomiting, tremulousness, arrhythmias) and
• the requirement for monitoring serum levels because of its
narrow therapeutic index.
• This monitoring is made all the more necessary by individual
differences in theophylline metabolism and frequent drug-drug
interactions.
• It is still used in some countries because of its low cost.
 METHYLXANTHINE DRUGS
 Effects on the CNS, kidney, and cardiac and skeletal arrhythmias. High doses relax vascular smooth muscle
muscle, smooth muscle, GIT. except in cerebral blood vessels, where they cause
 Theophylline- most effective bronchodilator; contraction. May improve blood flow.

 Caffeine-most marked CNS effects.  Stimulate gastric acid and digestive enzymes secration
(dicaf. Coffee too).
 All methylxanthines cause mild cortical arousal with
 Weak diuretics
increased alertness and deferral of fatigue.
 A cup of coffee can cause nervousness, insomnia; Slight
bronchodilation in patients with asthma.
 Larger doses- more effective bronchodilation cause
nervousness and tremor.
 Very high doses can cause medullary stimulation,
convulsions, and even death.
 Cardiovascular - Slight tachycardia, an increase in
cardiac output, and an increase in peripheral
resistance, potentially raising blood pressure slightly.
 In sensitive individuals, few cups of coffee may result in
ANTIMUSCARINIC
AGENTS
 Competitively inhibit the action of acetylcholine at
muscarinic receptors and are therefore referred to as
“anticholinergic agents”.
 Effective bronchodilators.
 Even when administered by aerosol, the
bronchodilation achievable with atropine, the
prototypic muscarinic antagonist, is limited by
absorption into the circulation.
 Greater bronchodilation, with less toxicity, is achieved
with ipratropium bromide, which can be inhaled in high
doses because of its poor absorption into the circulation.
 Although Bronchodilation and inhibition of
bronchoconstriction by antimuscarinic agents are
incomplete, their use is of clinical value, especially for
patients intolerant of inhaled β agonists.
CORTICOSTEROIDS
Glucocorticoids have long been used in the treatment of
asthma.
• Act by their broad anti-inflammatory efficacy, mediated
by inhibition of production of inflammatory cytokines.
• Do not relax airway smooth muscle directly
• They reduce bronchial hyperreactivity;
• Reduce the frequency of exacerbations if taken
regularly.
Their effect on airway obstruction is due to their:
• Contraction of engorged vessels in the bronchial
mucosa;
• Potentiation of the effects of β-receptor agonists,
• Most important action-inhibition of the infiltration of
asthmatic airways by lymphocytes, eosinophils, mast
cells.
Numerous and severe toxicities, especially when given
repeatedly.
Clinical Uses
Clinical studies consistently show them to be effective in improving all
indices of asthma control:
• Severity of symptoms,
• Tests of airway caliber
• Bronchial reactivity,
• Frequency of exacerbations
• Quality of life.
Because of severe adverse effects when given chronically,
 Oral and parenteral corticosteroids are reserved for urgent treatment
(other treatment options not working).
 For severe asthma exacerbations, urgent treatment with an oral dose of
30–60mg prednisone/d or an IV dose of 0.5–1 mg/kg
methylprednisolone every 6–12hs;
 Decreased after airway obstruction has improved.
 Systemic therapy can be discontinued in 5–10 days, but symptoms may
worsen in some patients as the dose is decreased to lower levels.
Glucocorticoids
 Inhalational treatment is the most effective to  High doses of inhaled steroids->> mild adrenal
avoid the systemic adverse effects; suppression,
 Beclomethasone, budesonide, ciclesonide,  Risks of systemic toxicity from their chronic use
flunisolide, fluticasone, mometasone, and are negligible compared with those of the oral.
triamcinolone- deliver them to the airways with
minimal systemic absorption.
 800 mcg of inhaled beclomethasone is equivalent
to about 10–15mg/d of oral prednisone for the
control of asthma, with far fewer systemic effects.
 Cautions in switching patients from chronic oral to
ICS therapy- to taper oral therapy slowly to avoid
precipitation of adrenal insufficiency.
 In patients requiring continued prednisone
treatment despite standard doses of an ICS, higher
inhaled doses are often effective and enable
tapering and discontinuing prednisone
treatment.
 CROMOLYN & NEDOCROMIL

 Cromolyn sodium and nedocromil sodium were once

widely used for asthma management, especially in
children;
 Now they are mostly of historic interest as asthma
treatments.
 When taken regularly, these agents modestly but
significantly reduce symptomatic severity and the need
for bronchodilator medications, particularly in young
patients with allergic asthma.
 The main indication for current use of cromolyn- reducing
symptoms of allergic rhinoconjunctivitis.
LEUKOTRIENE PATHWAY
INHIBITORS
Leukotrienes are involved in many inflammatory diseases
and in anaphylaxis.
• Leukotrienes result from the action of 5-lipoxygenase on
arachidonic acid;
• Synthesized by inflammatory cells in the airways, incl.
eosinophils, mast cells, macrophages, and basophils.
• Leukotriene B4 is a potent neutrophil chemoattractant,
exert bronchoconstriction, increased bronchial
reactivity, mucosal edema, and mucus hypersecretion.
• Drugs that block their synthesis or interaction with their
receptors. 2 approaches:
1) Inhibition of 5-lipoxygenase, preventing leukotriene
synthesis;
2) Inhibition of the binding of LTD 4 to its receptor on
target tissues, preventing its action.
• Efficacy in blocking airway responses to exercise • Additional advantage of being effective when
and to antigen has been shown for drugs in both taken orally, which is an easier route of
categories: zileuton(5-lipoxygenase inhibitor), administration in children;
and zafirlukast and montelukast(LTD 4 -receptor • Montelukast is approved for children as young as
antagonists) . 12 months of age.
• ll 3 have improve asthma control and reduce the
frequency of exacerbations in clinical trials.
• Not as effective as even low-dose ICS therapy in
inducing and maintaining asthma control, but are
preferred by many patients, esp. by the parents of
asthmatic children;
Montelukast is the most prescribed, because:
• It may be taken without regard to meals;
• Is taken once daily;
• Does not require periodic monitoring of liver function, as
zileuton does;
• Not considered as a first-line therapy;
• The receptor antagonists have little toxicity.
 Early reports of Churg-Strauss syndrome (a systemic vasculitis
accompanied by worsening asthma, pulmonary infiltrates, and
eosinophilia) ;
 They appear to have been coincidental, with the syndrome
unmasked by the reduction in prednisone dosage made
possible by the addition of zafirlukast or montelukast.
TARGETED (MONOCLONAL ANTIBODY)
THERAPY
TARGETED (MONOCLONAL ANTIBODY)
THERAPY
Anti-inflammatory therapy targeting specific inflammatory pathways.
Monoclonal antibodies targeting IgE and IL-5 and an antibody targeting the receptor for IL-4 and IL-13.

Anti-IgE Monoclonal Antibodies:

 Omalizumab -reduces lymphocytic, eosinophilic bronchial inflammation, oral and inhaled
corticosteroid dose requirements, and the frequency and severity of exacerbations.
 Reserved for patients with demonstrated IgE-mediated sensitivity and an IgE level within a range that
can be reduced sufficiently by twice-weekly subcutaneous injection.

Anti-IL-5 Therapy:
 2 humanized monoclonal antibodies targeting IL-5, mepolizumab and reslizumab, and another
targeting the IL-5 receptor, benralizumab,-for the treatment of eosinophilic asthma.
 Another options for severe asthma uncontrolled by ICS/LABA, esp. if associated with peripheral
eosinophilia.
Monoclonal
antibodies for
chronic
refractory
asthma
OTHER ANTI-
INFLAMMATORY
THERAPIES
• The benefit from treatment with cyclosporine seems
real, but toxicity makes this finding only a source of
hope that other immunomodulatory therapies will
ultimately emerge.
• Advances in understanding the immunopathogenesis
of asthma may permit the identification of
specific phenotypes of asthma and identification
of biomarkers of their importance in particular
patients.
• Asthma may benefit from the rapid advances in
treatments developed for other chronic
inflammatory conditions such as rheumatoid
arthritis, ankylosing spondylitis,inflammatory bowel
disease.