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Airway Pharmacology
Bronchodilators
β-Adrenergic Agonists – relax the smooth muscle by elevating cytosolic cAMP, which leads to a decreased cytosolic Ca2+
Drug
Used for:
Epinephrine*
Isoproterenol
Problems
Additional Notes
Cannot be taken orally because
Acts on all adrenergic receptors and
of COMT
has significant side-effects
Excessive cardiac stimulation
Beta-selective and resistant to
COMT inactivation
Albuterol*
Used inhalation or orally
- Treatment for acute attack
Terbutaline*
Beta-selective and resistant to
recommended
COMT inactivation + decreased
and exercise-induced
cardiac stimulation + onset of
bronchoconstriction
action 5-15 minutes (2-3 dur.)
Orally or parenterally
- Treatment for acute attack
Salmeterol*
Regularly scheduled use not
Regularly scheduled use not
Beta-selective and resistant to
recommended
COMT inactivation + decreased
and exercise-induced
cardiac stimulation + onset of
bronchoconstriction
action 5-15 minutes (2-3 dur.)
Long-term treatment of
moderate-severe persistent
asthma almost always in combo
with corticosteroids
Sinus tachycardia, tremor and
anxiety, nausea, hyperglycemia,
hypokalemia
-
Problems with short-acting Beta agonists:
o
After repeated use, TACHYPHYLAXIS occurs (effectiveness decreases)

-
Phosphorylation of occupied receptor, PKA, B-ARK leads to downregulation of Beta receptors
Problems with long-acting Beta agonists
o
When used as monotherapy, salmeterol and formoterol may increase risk of respiratory-related death or
respiratory-related life-threatening experience (especially for blacks)
Anticholinergics – Parasympathetic (vagal) pathways participate in bronchospasm in some asmatics and
acetocholine stimulates mucous secretion
Drug
Used for:
Problems
Notes
Ipratropium Bromide*
Administered by Inhalation
Minimal (dry mouth)
Quaternary analog of
Little is absorbed in GI tract and
atropine to minimize
does not enter CNS
absorption and distribution –
Produces bronchodilation (slowly)
less side-effects
and inhibits mucous secretion
Tiotropium
Duration of action is 24 hours vs. 4-
Quaternary analog of
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6 or ipratropium – once a day dose
scopolamine
Glucocorticoids – MOST IMPORTANT anti-inflammatory drugs
-
Do NOT directly induce bronchodilation
o Inhibition of inflammatory cell proliferation
o Inhibition of leukocyte entry into tissue
o Inhibits down-regulation and promotes up-regulation of β2-adrenergic receptors
 Creates stronger effects when used with Beta blockers
Drug
Used for:
Prednisone
Treatment of moderate to severe
Prednisolone
acute attacks
Problems
Notes
Response seen in 6 hours
Prednisone converted to drug in
liver
Methylprednisolone
Treatment of moderate to severe
Response seen in 6 hours
acute attacks
Acetate form is given IM
Oral administration
Triamcinolone
Inhalation
acetonide*
Triamcinolone* itself is used
Acetonide derivative
orally
Beclomethasone
Fluticasone
Inhalation
Onset of action can take
Used only for prophylaxis because
days-weeks
lag time
Low bioavailability
Inhalation
Onset of action can take
days-weeks
Low bioavailability
Treat both acute exacerbations
1) Iatrogenic Cushing’s
Steroid insensitive = FEV1
and chronic inflammation
Osteoporosis**
does not improve 15% after
Diabetes
7 days of high dosage
2)HPA suppression
Can lead to adrenal
insufficiency in withdrawal
-
Short term therapy: oral and/or IV for 3-10 days
-
Long term therapy: inhaled glucocorticoids for less side-effects
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Anti-Leukotrienes
Leukotriene Receptor Antagonists
5’Lipoxygenase inhibitor
Drug
Used for:
Problems
Notes
Zafirlukast*
Competitive antagonist at
Slow onset (2-14 days)
Taken orally
LTD4 receptors
Inhibits P450 2C9 & 3A4 =
Approved for children over 5
potential for drug
Monetlukast*
interactions
Churg-Strauss syndrome has
LIVER TOXICITY
been reported
Competitive antagonist at
DOES NOT BLOCK P450
Taken orally – 1 per day
LTD4 receptors
No evidence for liver
Approved for children over 2*
toxicity
Zileuton*
Inhibits 5’-lipoxygenase and
Drug interactions – inhibits
Taken orally – only
hence inhibits synthesis of
metabolism of
prophylactically
leukotrienes
theophylline, warfarin, and
propranolol
Mast cell stabilizers
Drugs
Used for:
Problems
Notes
Cromolyn sodium*,
Inhalation of dry powder
Have very few side-
Only 1% absorbed from GI
Nedocromil,
Prophylactic treatment for
effects, but low efficacy
– minimal side-effects
Pemirolast
asthma and exercise-induced
makes them seldom used
bronchoconstriction
Methylaxanthines
Drugs
Used for:
Problems
Notes
Theophylline*
Induces bronchdilation and has anti-
CNS effects –
Administered as oral
inflammatory effects – mechanism
nervousness, insomnia,
tablets or IV – NOT
unknown
headache
inhaled
1) Inhibits phosphodiesterase
GI effects – related to
NOT used for acute
2) Antagonizes adenosine receptors
increased acid secretion –
rescue therapy
3) Inhibits activation of inflammatory
may worsen asthma
**Very narrow
Cardiac arrhythmias and
therapeutic range
cells
4) Increased cAMP
seizures are at increased
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Alternative to long-acting Beta agonists in
risk with high
combo with glucocorticoids for moderate
concentrations
persistent asthma
Antibodies to IgE
Drugs
Used for:
Omalizumab Mouse-human chimeric Ab to the Fc
Problems
Notes
Appears to increase the
SC injection
component of IgE – prevents IgE binding
risk of cancer***
to mast cell
Cost $10,000 per year
- Approved for treatment of moderatesevere allergic asthma
Pulmonary Artery Hypertension
Prostaglandins
Drugs
Used for:
Problems
Notes
Very short half-life, needs
Exercise capacity and
(primary or scleroderma)
continuous IV infusion
symptoms improved
Mortality decreased*
Flushing, hypotension, rebound
Epoprostenol* Pulmonary Hypertension
hypertension
Treprostinil
Analog of epoprostenol with
Infusion site pain, rebound
Administered by
longer half-life (2-4hours)
hypertension with abrupt
continuous SC infusion
discontinuation
Endothelin Antagonists
Drugs
Used for:
Problems
Notes
MAJOR Birth defects*
Orally administered for PAH
and ETb receptors in
Hepatotoxicity*
patients with severe symptoms
endothelium and vascular and
Drugs that inhibit CYP 3A4
Takes 3-5 days to reach steady-
bronchiolar smooth muscle
may increase plasma
state because it induces its
Produces vasodilation and
concentrations of bosentan
own metabolism by
bronchodilation
and potentiate hepatotoxicity
stimulating CYP 3A4 and 2C9
Bosentan* Endothelin-1 antagonist at Eta
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Antitussives (cough suppressants)
Drug
Used for:
Problems
Notes
Codeine
Opoid receptor agonist – elevates
Antitussive effect
Converted to morphine by
cough threshold in CNS
antagonized by naloxone
CYP 2D6
Addictive*
Dextromethorphan Antitussive effect NOT
Little effect on GI motility,
Converted to dextrorphan
antagonized by naloxone and it
unlike opoids
by CYP 2D6
has NO opoid-like analgesic
No effect on ciliary
Administered orally
addictive properties
motility
Overdose produces other
Blocks re-uptake of
CNS effects, excitation,
serontonin*
hallucinations has lead to
Drug Interactions – do
abuse*
NOT use with MAOIs or
fluoxetine
Expectorants
Drug
Used for:
Guaifenesin Oral treatment for dry,
Problems
Notes
*makes cough more
unproductive coughs, due to
productive*
colds and minor URT infections
Promotes action of cilia
– stimulates flow of respiratory
secretions
Drugs for Allergic Rhinitis
Supplemental Questions:
1) Which class of drugs is useful for treating bronchoconstriction associated with an acute asthma attack?
a. β-adrenergic agonists are very important for the treatment of acute attacks and may be the sole
treatment for mild intermittent asthma
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2) What mediators effect the late phase response in asthma?
a. LTD4 along with Eosinophil cationic protein and MBP cause the cilia to stop beating, which retards
clearance of the mucous
3) Name two β-agonists used to treat mild-moderate acute asthma attacks
a. Albuterol and Turbutaline are used for acute asthma attacks
4) How does salmeterol differ in its actions/use from albuterol?
a. Salmeterol is a long-acting β2-agonist that has a longer duration of action, but slower onset of
action than albuterol
i. As a consequence, salmeterol is not used for treatment of acute exacerbations, but
prophylaxis of attacks
ii. Salmeterol is taken on a regular schedule (2x a day) – useful duration of action = 12hours,
but doesn’t peak until 3 hours – therefore NOT used for acute attacks
5) What is the major drawback of use of albuterol and terbutaline?
a. Sinus tachycardia, palpitations, increased BP occurs in 10% of patients on albuterol
b. Tachyphylaxis occurs with both these drugs with repeated use
6) Compared with oral corticosteroids inhaled corticosteroids have few adverse effects. What is one of the
most frequent side effects of the inhaled corticosteroids?
a. Oral candida infections (thrush) common with inhaled drugs due to local immune suppression
b. Dysphonia (horseness), cough
c. At very high doses systemic effects may occur
7) How does the administration of Zafirlukast and Zileuton differ from most other drugs used to treat
asthma?
a. Both are taken orally
i. Zafirlukast has a relatively slow onset of action and is only used for prophylaxis
ii. Zileuton has very high 1st pass metabolism and short half-life (1-2.3 hours)
1. Dosage 600mg x 4/day (because of such high metabolism)
8) What is the mechanism of action of cromolyn sodium and the related drug nedocromil?
a. Cromolyn sodium inhibits the release of histamine and other autocoids from mast cells in lung
during allergic responses by blocking elevation of cytoplasmic calcium, which:
i. Blocks degranulation
ii. Blocks sysnthesis of autocoids
iii. Inhibits synthesis of TNFα and interleukins
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b. Cromolyn sodium and nedocromil also do not induce bronchodilation
c. Can take several weeks for maximum benefit
9) What is the major problem with the use of theophylline in the treatment of asthma?
a. Theophylline has a NARROW THERAPEUTIC WINDOW
i. Bronchodilation needs the window to be 5-15 micrograms
1. Dosage given in time-release tablets which should not be chewed
ii. At greater than 30 micrograms, arrhythmias and seizures occur
1. 20-30 tablets can be fatal b. Do not treat overdose with Ipecac!!
i. Needs multidose charcoal and whole bowel irrigation
10) What is the most important difference between atropine and ipratropium?
a. Atropine is a tertiary amine that is normally not used because of severe side-effects
b. Ipratropium is the quaternary analog of atropine (minimizes absorption and distribution)
11) Compare the times for onset of action of the following drugs. Which is suitable for treatment of a mildmoderate acute asthma attack?
a. Beclomethasone
b. Prednisone
c. Cromolyn sodium
d. Salmeterol
e. Albuterol
f. Zafirlukast
g. Zileuton