Adrenergic (Sympathomimetic) Bronchodilators
History
and Development
The drugs known as adrenergic
bronchodilators are all analogues of epinephrine, the naturally occurring
neuromediator.
|
Agent |
Date |
Event |
|
Epinephrine |
1910 |
Used as an aerosol for asthma |
|
Ephedrine |
1927 |
Used as an aerosol for asthma in
US |
|
Isoproterenol |
1940 |
Used as a bronchodilator |
|
Isoetharine |
1951 |
Used as an aerosol for asthma |
|
Metaproterenol |
1973 |
Used in US in a metered dose
inhaler |
|
Metaproterenol |
1981 |
Used in US as a solution for nebulization |
|
Terbutaline, albuterol,
bitolterol, pirbuterol |
1980s |
ß2 specific agents used in the |
|
Salmeterol |
1994 |
First long-acting bronchodilator
available in the |
|
Levalbuterol |
1999 |
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.
Maintenance bronchodilation
b.
Control of Bronchospasm
c.
Control of Nocturnal symptoms
d.
Specific Agents
i.
Salmeterol
ii.
Formoterol
IV.
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
d.
Effects of
Catecholamines
i.
Increased heart rate
ii.
Increased blood pressure
iii.
Bronchodilation
iv.
Vasodilation of skeletal muscle blood vessels
v.
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
II.
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
III.
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
d.
Specific Agents
i.
Albuterol
ii.
Pirbuterol
IV.
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
V.
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
VI.
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.
increased heart
rate, force and contractility
3.
ß2 -Receptor stimulation
a.
bronchodilation
(↑ cAMP)
b.
inhibition of
inflammatory mediator release from mast cells
c.
increased
mucociliary clearance
Routes
of Administration
I.
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)
II.
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
III.
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