Principles of Drug Therapy for Asthma Treatment

Principles of Drug Therapy
Pharmacology of Drugs Used to Treat Asthma
Marc Imhotep Cray, M.D.
BMS / CK-CS Teacher
http://www.imhotepvirtualmedsch.com/
Integrated Scientific and
Clinical Pharmacology

OBJECTIVES
2
Companion learning strings:
o MedPharm Guidebook UNIT 7: Drugs used in disorders of the respiratory system.
eNotes:
o Respiratory Pharmacology
o Autocoids, Ergots, Anti-inflammatory Agents, and Immunosuppressive Agents
1. Understand the medications used in the treatment of asthma, their
mechanisms of action, and adverse effects.
2. Know the difference between short-acting symptomatic treatments and
long acting preventive therapies.
3. List the mediators of airway inflammation involved in asthma.

Clinical Case
3
An 8-year-old boy is brought to your office because of a chronic cough. His mother
says that he coughs frequently throughout the day and will have symptoms 2 or 3
nights a month as well. This has been a problem on and off for approximately a year,
but seems to be worse in the spring and fall. He also coughs more when he is riding
his bike or playing soccer. He has been treated twice in the past year for “bronchitis”
with antibiotics and cough suppressants but he never seems to clear up completely.
His examination is normal except for his lungs, which reveal expiratory wheezing.
You diagnose him with asthma and prescribe an albuterol inhaler.
What is the mechanism of action of albuterol?
What are the most common side effects of albuterol?
What medications can be used to provide long-term control of the asthma
symptoms?

What is Asthma and How is it Treated?
4
 Asthma, involves constriction of
pulmonary passages and secretion of
excess mucus, and is characterized by
 dyspnea
 Coughing
 wheezing
 chest tightness
 Can be precipitated by triggers such as
 allergens
 cold air
 viral infections
 bacterial infections
 exercise
 Major drug classes used for asthma:
 anti-IgE antibodies
 mast cell degranulation blockers
 smooth muscle relaxants
 anti-inflammatory agents

What is Asthma (2)
5
 Asthma is a disease process characterized by episodic
reversible bronchoconstriction of hyperreactive airways in
response to various exogenous and endogenous stimuli
 Asthma is also associated with chronic inflammation

Types of Asthma
6
 Older classification: Extrinsic and intrinsic
 Newer preferred classification
 Atopic: A type I hypersensitivity reaction with strong
familial tendencies
 Nonatopic: Asthma associated with viral infection (e.g.
rhinovirus, parainfluenza virus) in patients with no family
history of allergies and who have normal levels of IgE
 Drug-induced asthma
 Occupational asthma
 Cardiac asthma

Types of Asthma (2)
7
Alternative classification: Allergic asthma versus nonallergic asthma
 Allergic asthma
 Epidemiology: Occurs more frequently in children
 Associated conditions: Patients may have hay fever or eczema
 Mechanism of allergic asthma: Type I hypersensitivity reaction
 Causes: Pollens, dust, drugs
 Nonallergic asthma
 Epidemiology: Occurs more frequently in adults
 Mechanism of nonallergic asthma: Not type I hypersensitivity reaction;
IgE levels are normal
 Causes: Exercise, cold air, drugs, gastroesophageal reflux, viral infections

Clinical presentation of asthma
8
Symptoms:
 Classic triad is persistent wheezing, chronic episodic dyspnea, and
chronic nonproductive cough
 Symptoms may be worse, or only present at night, due to the physiologic
drop in cortisol secretion
 Night-time cough, which may be the only symptom, is a classic symptom
of asthma.
 Dark rings under the eyes (“allergic shiners”) and a dark transverse
crease on the nose (“allergic salute”) are often seen, especially in
children
 Status asthmaticus is a prolonged asthmatic attack, which can be
fatal

Clinical presentation of asthma (2)
9
Laboratory studies:
 Low peak expiratory flow (PEF)
 FEV1/FVC is often decreased as in other obstructive lung
diseases, and residual volume is increased
 Carbon dioxide is usually low in an acute asthma exacerbation
secondary to hyperventilation
 a rising carbon dioxide concentration in this setting often precedes
respiratory failure
 Eosinophilia may be present

Pathogenesis of Asthma
10
Extrinsic and Intrinsic Asthma (See NIP 7-7)
Pharmacotherapy of asthma depends on understanding the
disease pathogenesis
 In the immunologic, or antigen challenge model, IgE
antibodies produced by airway mucosa mast cells mediate
asthma

Pathogenesis of Asthma (2)
11
 B lymphocytes synthesize IgE antibodies after exposure
to an antigen>>> IgE antibodies attach to mast cells and,
with re-exposure to antigen, form antigen-antibody
complexes
 complexes trigger synthesis and release of mediators, such
as histamine, leukotrienes (LTC4 and LTD4), and
prostaglandins, from mast cells>>> bronchoconstriction and
vascular leakage result

Asthma Pharmacotherapy
12
 When exposure to allergens cannot be avoided, drug
therapy is needed
 Major goals is to reverse asthmatic symptoms and prevent
recurrent episodes by disrupting actions of endogenous agents
that worsen bronchospasm and inflammation
 Major classes of drugs* for asthma are (1) anti-IgE
antibodies (2) blockers of mast cell degranulation (3)
smooth muscle relaxants (4) antiinflammatory agents
* Six classes of drugs used to treat asthma: 1) β-adrenoreceptor agonists
2) acetylcholine antagonists 3) glucocorticoids 4) leukotriene modifiers 5)
chromones and 6) anti-IgE monoclonal antibodies

Asthma Pharmacotherapy (2)
13
 Bronchodilators were first and most effective treatment,
but
 a better approach is prophylactic use of antiinflammatory
agents to control bronchial inflammation
 With these agents, patients with asthma are rarely hospitalized,
seriously ill, or in need of emergency treatment

Asthma Pharmacotherapy (3)
14
 With prophylactic use of antiinflammatory agents pts can
control their disease, and therapy is much less expensive than
previous emergency management
 Now, antiinflammatory agents are the first-line therapy for
patients who have more than occasional symptoms
 Bronchodilators are still used but only when antiinflammatory
therapy is inadequate, and then in smaller amounts

(1) Anti-lgE Antibodies
15
 One of the more novel therapies is use of anti-IgE antibodies
 In theory, drugs acting as anti-IgE antibodies would prevent IgE binding
to mast cell surfaces
 This action reduces formation of activated antigen-IgE complexes
and suppress release of mediators that induce immediate
bronchoconstriction in the early phase
 Mediators such as histamine, prostaglandins, and leukotrienes are
unable to cause sneezing, wheezing, itching, and coughing

Anti-lgE Antibodies (2)
16
 The most notable anti-IgE antibody, Rhumab-E25 (Omalizumab), is a
recombinant humanized monoclonal antibody to IgE
 By binding to circulating IgE in the blood, Rhumab-E25 blocks release of
inflammatory mediators by keeping IgE from binding to mast cells
 This antibody, administered by parenteral injection, is currently in phase III clinical
trials for seasonal allergic rhinitis and allergic asthma

Marc Imhotep Cray, M.D. 17
Immunologic basis of
anti-IgE antibodies
MOA
Raffa RB etal. Netter's Illustrated Pharmacology, Updated Ed. Figure 7-9

Rhumab-E25
18
 Omalizumab blocks release of inflammatory mediators by
keeping IgE from binding to mast cells
Omalizumab

(2) Mast Cell Degranulation Blockers
(Chromones)
19
 Cromolyn block mast cell degranulation by suppressing release of
mediators of immediate bronchoconstriction (early response) and reduce
eosinophil recruitment that causes airway inflammation
 Does not directly alters smooth muscle tone or reverses bronchospasm
 Both banded in U.S.
 inhaled as aerosols, can be used for intrinsic (antigen-induced) or extrinsic
(non–antigen-induced) asthma

Mast Cell Degranulation Blockers (2)
20
 Poorly absorbed, so adverse effects are restricted to deposition site
 Cromolyn (nasal spray) is preferred for young patients
 Cromolyn alter Cl− channel function, which
1) on airway neurons underlies cough inhibition,
2) on mast cells delays antigen-evoked bronchoconstriction, and
3) on eosinophils prevents inflammatory responses to antigens

Mast Cell Degranulation
Blockers MOA Illustrated

(3) Bronchodilators
(smooth muscle relaxants)
22
 Drugs that expand pulmonary airways (bronchi)-bronchodilators-block the
early response by inhibiting immediate bronchoconstriction
 smooth muscle relaxation
 Some agents, especially theophylline and β2-adrenergic agonists, inhibit late
response inflammation
 Used when a persistent cough and bronchial constriction are present
 In addition to relaxing smooth muscles and reducing airway reactivity,
bronchodilators reduce coughing, wheezing, and shortness of breath
 Agents are usually given via inhalation, but some can be given orally or
parenterally (intravenous, intramuscular, or subcutaneous route)

Bronchodilators (2)
23
 Most drugs have a rapid onset of action (within minutes), but
the effect usually wanes in 5 to 7 hours
 Some agents, especially theophylline, inhibit the delayed
response to antigen
 Most common bronchodilators are
1) methylxanthines (eg, theophylline, caffeine)
2) β-adrenergic agonists (eg, isoproterenol, albuterol,
epinephrine)
3) cholinergic antagonists (eg, atropine, tiotropium)

Methylxanthines
25
 methylxanthines theophylline, caffeine, and
theobromine, found in cola, tea, and coffee
 are bronchodilators that reduce bronchial smooth
muscle activity by causing increase intracellular cAMP
levels

Methylxanthines (2) Mechanism of Action
26
MOA:
 Signal molecules (eg, transmitters, drugs) activate GPCRs on
airway smooth muscle cells and increase the conversion rate of
ATP to cAMP >>> increased cAMP levels>>> relax bronchial muscle
and reduce airway reactivity
 Phosphodiesterase stops cAMP effects and reduces cAMP levels
by catalyzing hydrolysis of cAMP to AMP
 Methylxanthines prevent cAMP hydrolysis
 Or, theophylline may block cell surface receptor effects of
adenosine, which may induce bronchoconstriction and
inflammation

Methylxanthines (3)
27
 These drugs may also be antiinflammatory
 Theophylline, most widely prescribed and of low cost, comes as:
 short-acting tablets and syrups,
 sustained-release capsules and tablets, and
 intravenous doses
 The synthetic dyphylline may help patients who are unable to
use theophylline

Methylxanthines
RaffaRBetal.Netter'sIllustratedPharmacology,UpdatedEd.Figure12

Methylxanthine: Adverse Effects
29
Methylxanthine doses must be closely watched
 Low doses have little effect, if any, whereas high doses can affect
central nervous, cardiovascular, skeletal muscle, GI, and renal
systems
 Theophylline is most selective at sm. mm.; caffeine induces most
marked CNS effects
 Even at low to moderate doses, they enhance cortical arousal &
alertness & defer fatigue
 In hypersensitive patients, insomnia and nervousness may occur

Methylxanthine: Adverse Effects (2)
30
 Methylxanthines reduce blood viscosity, increase blood flow,
increase cardiac output, & induce tachycardia in healthy subjects
 In sensitive persons, cardiac arrhythmias are common
 These drugs strengthen contractions of isolated skeletal muscles in
vitro and improve contractility & reverse fatigue of diaphragm in
pts with COPD>>accounts for their usefulness in COPD
 Although methylxanthines enhance gastric acid and digestive
enzyme secretion in GI tract and induce a slight diuresis, these
effects are minor

RaffaRBetal.Netter'sIllustratedPharmacology,UpdatedEd.Figure13

β-Adrenergic Agonists
32
 β-adrenergic agonists enhance sympathetic discharge
 Used to relieve a sudden asthma attack or block
exercise-induced asthma
EFFECTS:
 Relax bronchial smooth muscle, inhibit mediator
release, increase transport of mucus, and alter
composition of mucus by stimulating β adrenoceptors

β-Adrenergic Agonists (2)
33
 Bronchodilation is mediated by β2 adrenoceptors located on
smooth muscle cells in airways
 Nonselective β-adrenoceptor agonists (eg, epinephrine, ephedrine,
isoproterenol) stimulate all β adrenoceptors (β1 and β2 classes)
 These nonselective actions often produce adverse effects,
particularly in CNS and cardiovascular system
 Selective drugs that activate only β2 receptors (eg, albuterol,
terbutaline, salmeterol) are most commonly prescribed
sympathomimetic agents

β-Adrenergic Agonists MOA Illustrated
34

Nonselective β-Adrenergic Agonists
35
 Agents that activate both β1 and β2 adrenoceptors
have long been used to treat asthma
 These drugs are potent, rapidly acting bronchodilators,
but their stimulation of the cardiac system is a serious
drawback

Nonselective β-Adrenergic Agonists (2)
36
Major agents are epinephrine, ephedrine, and isoproterenol:
 Epinephrine is either inhaled or given SQ and is the active agent in many OTC
preparations
 Maximal bronchodilation is achieved 15 minutes after injection and lasts approximately 90
minutes
 B/c this drug stimulates cardiac output, increases heart rate, and exacerbates angina,
physicians rarely prescribe it
 Ephedrine, used in China more than 2000 years ago, has longest history of use
of any antiasthmatic
 longer duration of action, lower potency, and greater oral activity than epinephrine
 marked adverse effects, particularly in the CNS, and is rarely administered
 Isoproterenol has rapid onset of action, with peak bronchodilation occurring
within 15 minutes of injection

Selective β-Adrenergic Agonists
37
 Selective β2-adrenoceptor activators are most widely
prescribed sympathomimetic drugs
 because of their β2 selectivity, oral activity, and rapid onset and long
duration of action (4 hours)
 Major drugs- metaproterenol, terbutaline, albuterol,
salmeterol, and formoterol -have minimal β1-mediated effects
on nervous and cardiac systems
 Inhalation route allows greatest local effects with fewest
adverse effects
 Inhaled agents cause bronchodilation equal to isoproterenol
and persists for 4 hours

Selective β-Adrenergic Agonists (2)
38
 Terbutaline, metaproterenol, and albuterol can be given orally as
tablets
 Terbutaline, the only drug that can be used subcutaneously, is
given for severe asthma attacks or if insensitivity to inhaled agents
exists
 Two new drugs, salmeterol and formoterol, have a long duration
of action and high lipid solubility
 Both drugs at high concentrations move slowly into airway smooth
muscle, so effects can last up to 12 hours
 Both also enhance antiasthmatic actions of corticosteroids

Catecholamine Action on α and β Receptors of Heart and Bronchial Tree
RaffaRBetal.Netter'sIllustratedPharmacology,UpdatedEd.Figure7-14

Antimuscarinic Agents (Muscarinic Antagonists)
40
 Acetylcholine mediates its physiologic effects via 2 types of
receptors:
 muscarinic and nicotinic
 Muscarinic receptors are GPCRs that are densely expressed in
the airways
 When stimulated, muscarinic receptors cause muscle
contraction>>> leads to narrowing of airways and
bronchoconstriction

Antimuscarinic Agents (2)
41
 Muscarinic antagonists, or anticholinergics, prevent
acetylcholine from producing smooth muscle contractions &
excess mucus in bronchi
 Ipratropium bromide and atropine are most commonly used
 Anticholinergics are less effective than β2-adrenergic activators
 However, these drugs enhance bronchodilation induced by
β2-adrenoceptor agonists, so patients often take both
anticholinergics and β2 agonists
 Major adverse effects = dry mouth, bitter taste, scratchy throat,
and headache

42
Antimuscarinic Agents
MOA Illustrated

(4) Anti-inflammatory Agents: Corticosteroids
43
 Corticosteroids are antiinflammatory drugs similar to natural
corticosteroid hormones produced by the adrenal cortex
 Tx with these agents improves symptoms of asthma, allergic rhinitis,
eczema, and rheumatoid arthritis
 Corticosteroids inhibit late phase allergic reactions (including late
asthmatic response to antigen challenge) by various mechanisms,
eg., reduced
1)number of mast cells lining surfaces of airway mucosal cells;
2)chemotaxis and activation of eosinophils; and
3)cytokine production by eosinophils, monocytes, mast cells, and
lymphocytes

Corticosteroids (2)
44
 Corticosteroids taken regularly reduce bronchial
reactivity, enhance airway quality, & decrease
severity & frequency of asthma attacks
 However, corticosteroids do not directly relax smooth
muscle
 Would be only ones needed to treat asthma if their
adverse effects were not so pronounced

Corticosteroids (3)
45
Commonly used agents
prednisone,
methylprednisone,
beclomethasone,
flunisolide,
 budesonide, and
mometasone

Corticosteroids: Clinical Uses
46
 Corticosteroids have marked adverse effects on
nonrespiratory systems, so inhalation (maintenance therapy
in asthma, via inhaler) or intranasal (in allergy, as nasal spray)
route is preferred
 Intranasal corticosteroids relieve stuffy nose, nasal irritation,
and other discomforts

Corticosteroids: Clinical Uses (2)
47
 Corticosteroids inhaled by mouth effectively prevent asthma
attacks
 Regular doses of aerosol agents are smaller than doses used in
pill form
 Smaller, regular doses reduce side effect risk and may
eliminate a need for oral steroids
 Oral prednisone or IV methylprednisone is used only when pts
are insensitive to inhaled drugs or need urgent treatment for
severe asthma attacks

Corticosteroids:
Clinical Uses (3)
 Spacers (chambers) can be
attached to metered-dose
inhalers to reduce velocity
& particle size of drug;
amount of drug reaching
lungs is maximized, and
quantity of drug deposited
in mouth is minimized
 Spacers are crucial for Tx
with corticosteroids, which
have many adverse effects

Corticosteroid
Actions in
Bronchial Asthma
Illustrated
49

Corticosteroids: Adverse Effects
50
 Taking corticosteroids orally (prednisone) and intravenously
(methylprednisone) can cause unwanted side effects
 Short-term use (days) of prednisone can lead to
 increased appetite,
 wt. gain,
 diarrhea,
 headache,
 mood changes & insomnia, and
 possibly hyperglycemia & hypertension
 Cessation of short term corticosteroid use or taking smaller doses of
these agents usually minimizes or eliminates effects

Corticosteroids: Adverse Effects (2)
51
 Adverse effects that accompany long-term (months to
years) oral and IV therapy are
 suppressed immune system,
 increased cholesterol levels, and
 rapid wt. gain
 Long-term use may also promote osteoporosis, cataracts, and
thinning of the skin

Corticosteroids: Adverse Effects (3)
52
 Efforts to develop safer corticosteroids with antiinflammatory
properties but lacking adverse effects are ongoing
 Lipophilic steroids, such as beclomethasone, flunisolide, budesonide, and
mometasone, have a strong safety profile and are almost devoid of orally
precipitated systemic effects

Corticosteroids:
Adverse Effects
Illustrated
53

(4) Anti-inflammatory Agents:
Leukotriene Antagonists
54
 Leukotrienes are arachidonic acid derivatives involved in inflammatory
processes including asthma and anaphylaxis
 The enzyme 5-lipoxygenase catalyzes synthesis of arachidonic acid into
unstable intermediates>>> which are converted into leukotrienes
 A number of airway cells (including mast cells, macrophages, eosinophils,
and basophils) synthesize, store, & secrete several subtypes of
proinflammatory leukotrienes
 Leukotriene B4 (LTB4) attracts additional leukocytes, and LTC4 and LTD4 increase
bronchial reactivity, bronchoconstriction, and secretion of mucus

Leukotriene Antagonists (2)
55
 Evidence that inhaled leukotrienes increase bronchial
reactivity and that antigen challenge in sensitized airways
augments leukotriene synthesis…
 …supports a role for these mediators in asthma and a
rationale for development of drugs that block leukotriene
or 5-lipoxygenase action

Leukotrienes
Synthesis
Illustrated
56

57
Efforts to develop drugs that disrupt proinflammatory actions of
leukotrienes produced 2 types of drugs:
1) 5-lipoxygenase inhibitors and
2) leukotriene antagonists
 Zileuton reduces leukotriene synthesis rate by blocking 5-lipoxygenase
 Zafirlukast and montelukast, LTD4 antagonists, block leukotriene
receptors and prevent these mediators from causing an asthmatic
response
 When taken regularly, these drugs work as well as inhaled corticosteroids
in reducing frequency of asthma attacks
 However, leukotriene antagonists are less successful for relieving symptoms,
reducing bronchial reactivity, and improving airway quality

58
 These drugs are effective and safe when taken orally, an
advantage compared with inhaled corticosteroids
 Strong safety profile and excellent oral activity account for
popularity of leukotriene antagonists for children
 Leukotriene antagonists also reduce responses in aspirin-
induced asthma, a disorder affecting nearly 10% of patients
with asthma

Leukotriene
Antagonists
MOA
Illustrated
59

Management of Acute Asthmatic Attack
60

The National Asthma Education and
Prevention Program 1997 Guidelines (Updated)
61
Ressel GW, Centers for Disease Control and Prevention, National Asthma Education and Prevention Program. NAEPP updates
guidelines for the diagnosis and management of asthma. Am Fam Physician . 2003;68:169–70.
RECOMMENDATIONS FOR PHARMACOLOGIC MANAGEMENT OF ASTHMA IN ADULTS AND CHILDREN OLDER THAN 5
Asthma Severity Symptom Frequency Medications
Mild intermittent <2 days/week,
<2 nights/month
No regular therapy; short-acting β2 –agonists as needed for symptom
relief
Mild persistent >2 per week but
<once per day
>2 nights/month
Low-dose inhaled glucocorticoids. Alternate: cromolyn, nedocromil,
leukotriene modifier, or sustained release theophylline
Moderate persistent Daily,
>1 night/week
Low- to medium-dose glucocorticoids and long-acting inhaled β2 -
agonists. Alternate: leukotriene modifier or theophylline
Severe persistent Continual during day,
frequent at night
High-dose glucocorticoids and long-acting inhaled β2 -agonist and (if
needed) systemic glucocorticoids. Consider omalizumab for allergy
sufferers

Case Summary
62
Summary: An 8-year-old boy with asthma is prescribed an
albuterol inhaler.
 Mechanism of action of albuterol: β2 -Adrenoceptor agonist in bronchial
smooth muscle causes smooth muscle relaxation, inhibits the release of
mediators from mast cells, and stimulates mucociliary clearance
 Most common side effects of albuterol: Skeletal muscle tremor,
tachycardia, and cough
 Medications for long-term control of asthma: Inhaled corticosteroids,
long acting β2 -adrenoceptor agonist, cromolyn, or nedocromil; second-
line agents include oral theophylline, leukotriene inhibitors, or systemic
corticosteroids

Further study:
64
Pharmacology Course Website
References:
Drazen JM, O’Byrne PM. Risks of long-acting beta-agonists in achieving asthma control. N
Engl J Med .2009;360:1671.
Lim KG. Management of persistent symptoms in patients with asthma. Mayo Clin Proc .
2002;77:1333–8.
Panettieri RA, In the Clinic. Asthma. Ann Internal Med . 2007;146:ITC6–16.
Ressel GW, Centers for Disease Control and Prevention, National Asthma Education and
Prevention
Program. NAEPP updates guidelines for the diagnosis and management of asthma. Am Fam
Physician . 2003;68:169–70.
Salpeter SR, Wall AJ, Buckley NS. Long-acting beta-agonists with and without inhaled
corticosteroids and catastrophic asthma events. Am J Med . 2010; 123:322.

Principles of Drug Therapy for Asthma Treatment

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