CLIN. PHARM (Dr.
Salvador)
SYMPATHOMIMETIC AGENTS
Relax airway smooth muscles and inhibit bronchoconstricting
mediators from the mast cells
Inhibit microvascular leakage and increase mucociliary transport
by increasing ciliary activity
Can stimulate adenylyl cyclase and increase the formation of
intracellular Camp
Best characterized action of adrenoreceptor agonist is the
relaxation of the airway smooth muscle.
Causes tachycardia and skeletal muscle tremor as side effects
These include:
o Epinephrine- reserved for special situations since they increase the
rate and force of cardiac contraction
o Ephedrine
o Isoproterenol- reserved for special situations since they increase the
rate and force of cardiac contraction
o Albuterol
In general, adrenoreceptor agonists are best delivered in
inhalation, this results to a greater local effect on airway
smooth muscle with the least systemic toxicity
Aerosol deposition depends on; particle size, pattern of
breathing and geometry of airways
o Particles with optimal size range of 2- 5 mm, 80-
90% of the total dose of aerosol is deposited in the
mouth and oropharynx
o Particles under 1-2um remain suspended and
exhaled
o Bronchial deposition of aerosol is increased with
slow inhalation of nearly full breath and by more
than 5 seconds of breath- holding at the end of
inspiration.
EPINEPHRINE
Effective, rapidly acting bronchodilator when delivered
subcutaneously or inhaled as microaerosol
Maximal bronchodilation is achieved in 15 mins after inhalation
and lasts 60- 90 mins
Side effects: arrhythmias, tachycardia and worsening of angina
(since it stimulates a, b1 and b2 receptors)
EPHEDRINE
Longer duration, oral activity, more pronounced central effects
and much lower potency
Infrequently used for asthma
ISOPROTERENOL
Potent bronchodilator
Inhaled as microaerosol
Causes maximal bronchodilation within 5 minutes, and lasts for
60- 90 mins
Side effects: arrhythmia (rarely used today)
BETA2- SELECTIVE DRUGS
Beta2- selective adrenoreceptor agonist, particularly albuterol
are the most widely used sympatomimetics for the tx of
bronchoconstriction of asthma at present
ASTHMA
05 SEPT 2017
They differ structurally with epinephrine in having a larger
substitution on the amino group and in the position of the
hydroxyl group on the aromatic ring
They are generally effective after inhalation or injection and have
longer duration of action
Albuterol, terbutaline, metaproterenol and pirbuterol- are
available as metered- dose inhalers
o Given in inhalation, these drugs produce
bronchodilation equivalent to isoproterenol maximal
in 15- 30 mins and persists for 3- 4 hours
o All can be diluted in saline for administration from a
handheld nebulizer
Most preparations of b2- selective agonists are a mixture of R
and S isomers (only R activates b- agonist receptor, S isomer
may promote inflammation)
Albuterol and terbutaline are also available in tablet form, but
principal effects include tremor, nervousness and weakness
Only terbutaline is available for subcutaneous injection (indicated
for severe asthma when aerosol therapy is not available or
ineffective)
New generation of long- acting b2- selective agonist includes
salmeterol (partial agonist) and formoterol (full agonist)
o Long duration of action (12 hours or more)
o Interact with corticosteroids for more effective
asthma control
o Not recommended for monotherapy lack
anti- inflammatory effect
Indacaterol- ultra long- acting b agonist used only for thr tx
of COPD
METHYLXANTHINE DRUGS
a. Theophylline- from tea
b. Theobromine- cocoa
c. Caffeine- coffee
Chemistry
a. Theophylline- 1, 3 dimethylxanthine
b. Theobromine- 3, 7 dimethyxanthine
c. Caffeine- 1, 3, 7 trimethylxanthine
Amoniophylline- theophylline- ethylendiamine complex; common
preparation of theophylline
MECHANISM OF ACTION
a. Inhibits phosphodiesterase families (PDE) in high concentration,
specifically PDE4 high conc. of intracellular Camp (cardiac
stimulation, smooth muscle relaxation)
Inhibition of PDE4 reduces the release of cytokines and
chemokines reduce migration of immune cells
b. Inhibition of cell surface receptors from adenosine
Adenosine receptors modulate adenylyl cyclase activity and
this adenosine provoke contraction of smooth muscle
airway and histamine release from airway mast cell
c. Research revealed that the efficacy of theophylline is due to the
third action: enhancement of histone deacetylation
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PHAMACODYNAMICS
Theophylline- most selective in its smooth muscle effects
Caffeine- most marked CNS effects
A. CNS Effects
o Low- moderate doses- mild cortical arousal with increased
alertness and deferral of fatigue
Caffeine contained in beverages is sufficient to
cause nervousness and insomnia for sensitive
individuals and slight bronchodilation in asthma
o Larger doses- more effective in producing bronchodilation
in asthma and causes nervousness and tremors
o Very high doses- medullar stimulation and convulsions and
may lead to death
B. CARDIOVASCULAR EFFECTS
o Direct positive chronotropic and inotropic effects
In low concentrations, these positive
chronotropic and inotropic effects is caused by
inhibition of presynaptic adenosine receptors in
sympathetic nerves increasing catecholamine
release at nerve endings
In higher concentrations, positive chronotropic
and inotropic effects are associated with the
inhibition of phosphodiesterase and increased in
cAMP may increase influx of calcium
At much higher doses, sequestration of calcium
by sarcoplasmic reticulum is impaired
o Ordinary consumption of coffee, and other methylxanthine-
containing beverages usually produce slight tachycardia,
increase CO and increase in PVR, increasing blood
pressure slightly
o For sensitive individuals, few cups of coffee may result to
arrhythmias
o In large doses, these agents may relax vascular smooth
muscle except for the cerebral blood vessel (it causes
constriction)
o In certain condition, methylxanthines decreases blood
viscosity and improves blood flow (pentoxifylline)
C. EFFECTS ON GI TRACT
o Methylxanthines stimulate both gastric acid and digestive
enzymes
o Even decaffeinated coffee has a potent stimulant for
secretion, therefore its not the coffee that is responsible
to secretion
D. EFFECTS ON KIDNEY
o Methylxanthine esp. theophylline are weak diuretics, this is
due to increased GFR and reduced tubular sodium
reabsorption
E. EFFECTS ON SMOOTH MUSCLE
o Its effect is the major therapeutic action in asthma
o Tolerance does not develop, but adverse effects may limit
the dose
o In sufficient concentration, these agents inhibit antigen-
induced release of histamine from lung tissue.
F. EFFECTS ON SKELETAL MUSCLE
o Strengthens contractions
o Potent effects in improving contractility and reverse fatigue
of diaphragms of patients w/ COPD
o This effect on diaphragmatic performance accounts for
theophyllines ability to improve the ventilatory response to
hypoxia and to diminish dyspnea even in px with
irreversible airflow obstruction.
CLINICAL USES
Theophylline is the most effective bronchodilator of the
xanthines
Theophyline should be used only where methods to measure
theophylline blood levels are available because it has a narrow
therapeutic window and its therapeutic and toxic effects are
related to its blood levels.
Plasma conc. of 5- 20 mg/L improvement in pulmonary fxn
With 15 mg/L anorexia, nausea, vomiting, abdominal
discomfort, headache and anxiety
At higher levels (>40mg/L) can cause seizures or arrhythmias
Theophylline is metabolized in liver (so it may lead to toxic conc
when given to pxs w/ liver dse)
Clearance is increase by inducing hepatic enzymes such as
smoking or by changes in the diet
Mean normal plasma clearance for adult is 0.69 ml/kg/min
Children have faster clearance than adults, but neonates have
the slowest clearance
Theophylline is effective as monotherapy for long- term control
or when added to inhaled corticosteroids
For oral therapy w/ the prompt release formulation, usual dose
3- 4 mg/kg for every 6 hours
ANTI- MUSCARINIC AGENTS
Mechanism of Actions
- Competitively inhibit the effect of Ach at muscarinic receptors
- When Ach is release from the efferent endings of vagus nerve,
muscarinic antagonists block the contraction of airway smooth
muscle and as well as the secretion of mucus.
- Very high concentration is required
- Atropine- prototypical muscarinic antagonist
- The selectivity of atropines effect on bronchodilation can be
increased by administering the drug by inhalation or by the use
of ipratropium bromide
- Ipratropium are not effective in COPD, the use of tiotropium can
use for COPD
CORTICOSTEROIDS
Mechanism of Actions
- Presumed to act by their broad anti-inflammatory effect,
mediated by inhibition of production of inflammatory cytokines
- They do not relax the airway muscle directly, but reduce the
bronchial reactivity and reduce the frequency of asthma
exacerbations when taken regulary
- Their effect on airway obstruction may be due to their
contraction of the engorged vessel in the bronchial mucosa and
their potentiation of the effects of b- receptor agonists
- Their most important action is the inhibition of the infiltration of
asthmatic airways by the lymphocytes, eosinophils and mast
cells
CLINICAL USES
Urgent tx begins with oral dose of 30- 60 mg prednisone/day or
an IV dose of 1 mg/kg methylprednisone every 6- 12 hours
In most px, systemic corticosteroids therapy is discontinued
after 7-10 days
Administration of corticosteroids is given early in the morning
after the endogenous corticosteroid production has peaked and
for nocturnal control of asthma, it is given in the late afternoon
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 Aerosol tx- the most effective way to avoid systemic adverse
effects of corticosteroids therapy such as beclomethasone, ANTI- IgE MONOCLONAL ANTIBODIES
budesonide, circlesonide, flunisolide, fluticasone, mometasone, Monoclonal antibody is selected to target the portion of IgE that
triamcinolone binds to its receptor on mast cells and other inflammatory cells
4 puffs twice daily of 400 mcg/d is equivalent to about 10- 15 Omalizumab- inhibits the binding of IgE to mast cells but does
mg/d of oral prednisone not activate IgE already bound to these cells thus does not
Adverse Effects: provike mast cell degranulation
Oropharyngeal candidiasis - Most important effect is reduction of the frequency and severity
- To reduce the risk, have the pxs gargle water and spit after each of asthma exacerbations, even while enabling a reduction in
inhaled tx corticosteroid requirements
- Hoarseness of voice

CROMOLYN AND NEDOCROMIL

Were once used for asthma management
Low solubility, poorly absorbed from the GI tract, and must be inhaled
as a microfine powder or microfine suspension
When taken in inhalation, they are effective in inhibiting both antigen
and exercised induced- asthma
These drugs have no effect on overall level of bronchial reactivity and
are ineffective in reversing asthmatic bronchospasm; they are of only
value when taken prophylactically

Mechanism of Actions
Alter the fxn of delayed chloride channels in cell membranes,
inhibiting cell activation
o This action on airway nerves is though to mediate
nedocromils inhibition of cough; on mast cell
inhibition of early response to antigen challenge, and
on eosinophils inhibit inflammatory response to
inhaled allergens
The inhibitory effect on mast cell appears to be specific for cell
type since cromolyn has a little inhibitory effect on mediator
release from human basophils
Also specific for different organs since cromolyn inhibits mast
cell degranulation in human and in primate lung but not in skin
CLINICAL USES
- Pretreatment of cromolyn or nedocromil blocks the
bronchoconstriction caused by allergen inhalation, exercise, by
sulfur dioxide
- 2-4 puffs, 2-4 times daily perennial asthma
- both are also used for allergic rhinoconjunctivitis

LEUKOTRIENES PATHWAY INHIBITOR

leukotrienes result from the action of 5- lipoxygenase on
arachidonic acid and are synthesized by inflammatory cells in
the airways including the eosinophils, mast cells, macrophages
and basophils
o LTB4potent neutrophil chemoattractant
o LTC4 and LTD4 exert many effects known to occur in
asthma including bronchoconstriction, bronchial
reactivity, mucosal edema and mucus hypersecretion
2 approaches to interrupt the leukotrienes pathway
1. Inhibition of 5- lipooxygenase preventing leukotriene
synthesis
e.g. zileuton- least prescribed Churg- Strauss syndrome
2. Inhibition of of the binding of LTD4 to its receptor on target
issues, therby preventing its action
e.g. zafirlukast and montelukast (approved in children as young
as 6 yrs old)