Adrenergic (Sympathomimetic) Bronchodilators
History and Development
The drugs known as adrenergic bronchodilators are all analogues of
epinephrine, the naturally occurring neuromediator.
Agent
Epinephrine
Ephedrine
Isoproterenol
Isoetharine
Metaproterenol
Metaproterenol
Terbutaline,
albuterol, bitolterol,
pirbuterol
Salmeterol
Date
1910
1927
1940
1951
1973
1981
1980s
Levalbuterol
1999
1994
Event
Used as an aerosol for asthma
Used as an aerosol for asthma in US
Used as a bronchodilator
Used as an aerosol for asthma
Used in US in a metered dose inhaler
Used in US as a solution for nebulization
ß2 specific agents used in the US that
are available as solution, MDI, oral or
injectable
First long-acting bronchodilator
available in the US
First single-isomer B2 agonist released
Clinical Indications for Adrenergic Bronchodilators
I.
General Indications
a. Relaxation of airway smooth muscle in the presence of reversible
airway obstruction associated with acute and chronic asthma,
bronchitis, emphysema, bronchiectasis, and other obstructive
airway diseases
II.
Indications for Short-Acting Agents
a. Relief of acute reversible airflow obstruction in asthma or other
obstructive airway diseases
i. Ultra-short-acting (<3 hours duration)
1. epinephrine
2. isoproterenol
3. isoetharine
ii. Short-acting (4 to 6 hours duration)
1. metaproterenol
2. terbutaline
3. albuterol
4. bitolterol
5. pirbuterol
6. levalbuterol
III. Indications for Long-Acting Agents (12 hours duration)
a.
b.
c.
d.
IV.
Maintenance bronchodilation
Control of Bronchospasm
Control of Nocturnal symptoms
Specific Agents
i. Salmeterol
ii. Formoterol
Indications for Racemic Epinephrine
a. Used for its potent alpha-adrenergic vasoconstricting effect to
i. Reduce airway swelling after extubation
ii. Reduce airway swelling during epiglottitis, croup or
bronchiolitis
iii. Control airway bleeding during endoscopy
b. Administered by inhaled aerosol or direct tracheal instillation
Specific Adrenergic Agents and Formulations
I.
Catecholamines
a. The sympathomimetic bronchodilators are all either
catecholamines or derivatives
b. The basic structure is composed of a benzene ring with hydroxyl
groups at the third and fourth carbon sites and an amine side
chain attached to the first carbon position
c. Specific Agents
i. Epinephrine
1. both α and ß receptor stimulation
2. occurs naturally in the adrenal medulla
3. used for severe asthma, anaphylaxis and as a
cardiac stimulant
ii. Racemic Epinephrine
1. both α and ß receptor stimulation
2. Used for its potent alpha-adrenergic vasoconstricting
effect (see above)
iii. Isoproterenol
1. ß1 and ß2 receptor stimulation
2. Widely used for bronchodilation until the advent of
more ß2 specific agents
3. Main disadvantages are its short duration and strong
cardiac effect
iv. Isoetharine
1. ß2 > ß1 receptor stimulation
2. Cardiac (ß1) is minimal compared to epinephrine or
isoproterenol
3. First ß2-specific bronchodilator in the US
d. Effects of Catecholamines
i.
ii.
iii.
iv.
v.
II.
III.
Increased heart rate
Increased blood pressure
Bronchodilation
Vasodilation of skeletal muscle blood vessels
Glycogenolysis – conversion of glycogen to glucose in the
liver and muscles
vi. Skeletal muscle tremor
vii. CNS stimulation
e. Keyhole Theory of ß2 Specificity
i. The larger the amine side chain attachment (“key”) to the
catechol base, the greater the specificity to the ß2
receptors (“keyhole”)
f. Metabolism of Catecholamines
i. Rapidly inactivated by the enzyme COMT
1. found in the liver, kidneys and throughout the body
2. results in short duration
ii. No effect if taken orally
1. inactivated in the gut and liver
2. can be administered by injection or inhalation only
iii. Readily inactivated by heat, light, or air
1. must store in amber bottle
2. must refrigerate
3. may leave a pink residue in the nebulizer or the
patient’s sputum
Resorcinol Agents
a. A modification of the catecholamine structure
i. A hydroxyl group is moved from the carbon-4 site to the
carbon-5 site
ii. Bulky side chain for increased ß2 specificity and minimal ß1
effects
iii. Not inactivated by COMT
1. have increased duration
2. can be taken orally
b. Specific Agents
i. Metaproterenol
ii. Terbutaline
Saligenin Agents
a. A different modification of the catechol nucleus at the carbon-3
site
b. Bulky side chain for increased ß2 specificity and minimal ß1
effects
c. Not inactivated by COMT
i. Have increased duration
ii. Can be taken orally
IV.
V.
VI.
d. Specific Agents
i. Albuterol
ii. Pirbuterol
Bitolterol
a. Special case – converted slowly in the body to the catecholamine
colterol
b. Bulky side chain for increased ß2 specificity and minimal ß1
effects
c. Sustained release with duration up to 8 hours
Levalbuterol: The R-isomer of Albuterol
a. Other adrenergic bronchodilators are racemic mixtures
containing both the R-isomer and the S-isomer in equal amounts
b. Levalbuterol is the pure R-isomer of racemic albuterol
c. There is some evidence that the S-isomer may have undesirable
effects
d. Side effects of tremor and increased heart rate were less with
Levalbuterol
e. The 1.25 mg dose showed a higher peak effect on FEV1 with an
8 hour duration compared with racemic albuterol
Long-Acting ß-Adrenergic Agents
a. Offer the advantages of less frequent dosing and protection
through the night for asthmatic patients
b. Specific Agents
i. Sustained-Release Albuterol Tablets
ii. Salmeterol
iii. Formoterol
c. Clinical Uses
i. Long-acting ß-adrenergic agents are indicated for
1. maintenance therapy of asthma, which is not
controlled by regular low-dose inhaled steroids
2. chronic obstructive lung disease needing daily
inhaled bronchodilator therapy for reversible airway
obstruction
ii. Long-acting ß-adrenergic agents are NOT used for rescue
treatment of bronchoconstriction in asthma
1. shorter acting agents such as albuterol should be
used
Mode of Action
1.
α-Receptor stimulation
a.
vasoconstriction of mucosal vessels to reduce nasal and
upper airway swelling and congestion
2.
ß1-Receptor stimulation
a.
3.
increased heart rate, force and contractility
ß2 -Receptor stimulation
a.
bronchodilation (↑ cAMP)
b.
inhibition of inflammatory mediator release from mast cells
c.increased mucociliary clearance
Routes of Administration
I.
II.
III.
Inhalation route
a. Advantages
i. Rapid onset
ii. Smaller dose (than oral)
iii. Less systemic side effects
iv. Painless and safe
v. Delivered directly where needed
b. Disadvantages
i. Therapist time
ii. Coordination problems with MDI
iii. Inexact dosage
c. Continuous Nebulization: Terbutaline and albuterol
i. refilling of a small-volume nebulizer
ii. volumetric infusion pump with an SVN
iii. large-reservoir nebulizer (HEART, HOPE)
Oral Route - only for non-catecholamines
a. Advantages
i. Easy
ii. Short administration time
iii. Reproducible dosage
iv. Familiar (compliance)
b. Disadvantages
i. Larger doses needed
ii. More side effects
iii. Catecholamines not effective
Parenteral (SQ or IV)
a. Advantages
i. Very rapid onset
ii. Controlled dose
b. Disadvantages
i. Not as safe
ii. Systemic, more side effects
iii. Pain from needle stick
c. Agents
i. SC: epinephrine, terbutaline
ii. IV: isuprel, albuterol - last resort, requires continuous
cardiac monitoring
Side Effects
1.
Tremor
a.
stimulation of the ß2 receptors in skeletal muscle
b.
increased with oral administration
c.
tolerance occurs in days to weeks
2.
Cardiac effects
a.
Increased heart rate
b.
Palpitations
c.
More common with the earlier bronchodilators
3.
CNS effects
a.
Anxiety
b.
Nervousness
c.
Insomnia
d.
Headache
e.
Dizziness
f.
Nausea
g.
Irritability
h.
Need to adjust dose to reduce effects
4.
Metabolic disturbances
a.
↑ blood glucose (hyperglycemia)
b.
↑ insulin
c.
↓ potassium (hypokalemia)
5.
Tolerance to bronchodilator effect
a.
Decrease In peak effect
b.
The response is still significant and stabilizes in weeks
c.
Mechanism
i. Desensitization of ß2 receptors
ii. Down regulation of ß2 receptors (decreased number)
6.
Worsening ventilation-perfusion ratio (decrease in PaO2)
a.
ß2 pulmonary vasodilation causes perfusion of poorly
ventilated lung units
b.
Usually < 10 mmHg drop in PaO2 with return to baseline
within 30 minutes
Hazards
1.
Propellant toxicity
a.
May cause Bronchospasm
b.
Use DPI, SVN or oral route
2.
Sensitivity to Additives
a.
Sulfite preservatives may cause bronchospasm
i. Use unit dose solutions, MDI or DPI
The ß-Agonist Controversy
1.
Asthma Paradox
a.
Increasing incidence of morbidity and mortality from
asthma despite advances in the understanding of asthma
and availability of improved drugs to treat asthma
b.
Causes
i. Use of ß agonists may allow allergic individuals to expose
themselves to allergens and stimuli, with no immediate
symptoms to warn them, but with development of
progressive airway inflammation and increasing bronchial
hyperresponsiveness
ii. Repeated self-administration of ß agonists gives temporary
relief of asthma symptoms through bronchodilation, which
may cause underestimation of severity and delay in
seeking medical help
iii. Insufficient use, through poor patient education, poor
patient compliance or both, of anti-inflammatory therapy
with the use of ß agonists
iv. Accumulation of S-isomer with racemic ß agonists could
have a harmful effect on asthma control
v. There is increased airway irritation with environmental
pollution and lifestyle changes
Conclusions and Recommendations
1.
ß-adrenergic agents should be given by inhalation when possible
2.
Cardiac effects should be monitored closely
3.
Good instruction should be provided in the use of MDI, DPI and
SVN
4.
Over-the-counter medications should not be used instead of
medical help
Drug Calculations
1.
How many milligrams of active ingredient are there in 0.3 ml of a
5% solution of metaproterenol (Alupent)?
50 mg /1 ml = x/0.3 ml
x = 50(0.3)
x = 15 mg
2.
How many milliliters are needed to deliver 5.6 mg of a 2.25%
solution of racemic epinephrine (Micro-Nefrin)?
22.5 mg /1 ml = 5.6 mg / x
22.5x = 5.6
x = 5.6 / 22.5
x = 0.25 ml
3.
How many milligrams of active ingredient are there in 0.5 mL of a
1:200 (0.5%) solution of isoproterenol (Isuprel)?
5 mg / 1 ml = x / 0.5 ml
x = 5(0.5)
x = 2.5 mg
4.
How many milliliters are needed to deliver 5 mg of a 1% solution
of isoetharine (Bronkosol)?
10 mg / 1 ml = 5 mg / x
10x = 5
x = 5 / 10
x = 0.5 ml
5.
How many milliliters are needed to deliver 2.5 mg of a 0.5%
solution of albuterol (Proventil)?
5 mg / 1 ml = 2.5 mg / x
5x = 2.5
x = 0.5 ml