RESPIRATORY DRUGS /

ASTHMA
DR. FIRMALINO
 Objectives
Explain the pathogenesis of bronchial
asthma
Name the drugs used in the
management of bronchial asthma
List the pharmacokinetics &
pharmacodynamics of drugs used in
bronchial asthma
List other drugs used in the different
respiratory disorders
 Bronchial Asthma
A disease of the airways that is
characterized by hyper-
responsiveness of the
tracheobronchial tree to a multiplicity
of stimuli
 Manifested physiologically by a
widespread narrowing of the air
passages (bronchoconstriction) and
clinically by paroxysm of dysnea,
shortness of breath, chest tightness,
cough, and wheezes associated
increased mucus, lymphocytic &
eosinophilic bronchial inflammation
 Pathogenesis
Exposure to allergen synthesis of
IgE binds to mast cells in the airway
mucosa
Re-exposure to allergen/antigen Ag-
Ab interaction on the surface of the
mast cell triggers:
1. Release of mediators of anaphylaxis:
histamine, tryptase, PGD2, leukotriene
C4, PAF provoke contraction of the
airway smooth muscle
 Synthesis and release of other mediators or
a variety of cytokines: interleukines 4 & 5,
granulocyte-macrophage colony stimulating
factor, tumor necrosis factor, tissue growth
factor from T cells and mast cells attract
and activate eosinophils and neutrophils
eosinophil cationic proteins, , protease
edema, mucus hyper secretion, increase in
bronchial reactivity, smooth muscle contraction
 Inhaled irritants - afferent pathways
in the vagus nerves travel to the CNS
efferent pathways from the CNS
travel to efferent ganglia
postganglionic fibers release
acetylcholine binds to muscarinic
receptors on airway smooth muscle -
bronchoconstriction
TREATMENT OF ASTHMA
 Bronchodilators
Sympathomimetic Agents (adrenoceptor
agonist)
Directly relax airway smooth muscle by activating
Gs adenylyl cylase-cAMP in the airway tissues that
results in bronchodilatation
Increase the conductance of large Ca+2-sensitive
K+ channels in airway
Inhibit release of inflammatory mediators &
cytokines from the mast cells, basophils,
eosinophils, neutrophils, & lymphocytes
Increase mucocilliary transport
Given orally, by inhalation and parenterally
 A. Selective Beta 2 Agonist
Short-acting (Relievers):
terbutalline,albuterol,levalbuterol,
metaproterenol, pirbuterol)
1Inhaled drugs: onset of action: 1-5 min
Maximal: 15-30 min
Lasting to 2-6 hours
Long acting (Controllers): salmeterol,
bambuterol, formeterol 12hours or more
duration of action.
SE: skeletal muscle tremor, cardiac
tachyarrythmia, nervousness and weakness
Short acting Relievers
Short acting Reliever
 Long acting controllers
Salmeterol partial beta 2 agonist
Bronchodilator, no anti inflammatory
action
 Long acting controller
Formoterol
Full agonist
 Ultra long acting beta
agonist
Indaceterol currently approved in
Europe
Once a day
Used only for COPD
 B. Non-selective Beta-
Agonist
Epinephrine,
ephedrine,
isoproterenol
 Epinephrine
Effective, rapidly acting
bronchodilator, full effect in 15 min &
lasts for 60 to 90 min
Injected subcutaneous .4 ml or
inhaled as microaerosol
Beta 1 effect tachycardia,
arrythmia, worsening of angina
Beta 2 effect bronchodilation
Useful for shock, anaphylaxis,
asthma
 Ephedrine oral tablet
Longer duration
Lower potency
Rarely used today for asthma
 Isoproterenol
Inhaled as microaerosol
Rapid acting - Effect in 5 min, last for
60 to 90 min
Has high mortality in United Kingdom
in 1960s due to arrythmias from high
doses, thus it is not used anymore
for asthma
Isoproterenol
 Methylxanthine drugs
A. caffeine (coffee)
B. theophylline (tea)
C. theobromine (cocoa)
 Theophylline tablet
Aminophylline parenteral
 Mechanism of action

Inhibit cyclic nucleotide phosphodiesterase

result in high concentration of intracellular
cAMP & cGMP
Result to smooth muscle relaxation, stimulation of
cardiac function, decrease inflammation
Inhibition of cell surface receptors for
adenosine
resulting to relaxation of airway smooth muscle
Anti-inflammatory effect: inhibit synthesis &
secretion of inflammatory mediators from mast
cells & basophils
 Pharmacodynamics of
methylxanthines
CNS:
mild cortical arousal with increased
alertness & deferral of fatigue
bronchodilatation
Nervousness, tremor, insomia
In high doses: medullary stimulation and
convulsions / death
Primary SE: nervousness and tremor
 CVS:
have positive inotropic and chronotropic
effects
Arrythmia
Sinus tachycardia and increased cardiac
output
Increases the PVR and BP slightly
Decrease blood viscosity and may
improve blood flow - pentoxifylline
 GIT: stimulate secretion of gastric acid
and digestive enzymes
Kidneys: weak diuretics
Skeletal muscles: have potent effects in
improving contractility and in reversing
fatigue of diaphragm in patient with COPD
Smooth muscle: bronchodilatation, inhibit
antigen-induced release of histamine
from lung tissue,
 Enprofylline
more potent bronchodilator but less potent in
inhibiting adenosine receptors
Pharmacokinetics
Absorbed readily after oral or parenteral
administration
Distributed into all body compartments
Cross the placenta & pass into breast milk
Eliminated primarilly by metabolism in the
liver
 Toxicities
Sudden death
Headache, palpitation, dizziness,
nausea, hypotension, precordial pain
Tachycardia, severe restlessness,
agitation,
Emesis/vomiting
Focal & generalized seizures
 Drug Interactions
Erythromycin, cimetidine, cirrhosis, CHF,
acute pulmonary edema increase half-
life
Phenotoin, barbiturates, cigarette
smoking, rifampicin, oral contraceptives
increase clearance
 Anti-Muscarinic Agents
Atropine , ipratropium, tiotropium
Competetively inhibits the effect of
acetycholine at muscarinic receptors
effectively block the contraction of
the airway smooth muscle and
increase in secretion of mucus
Effective bronchodilators
Atropine
Ipratropium
 Tiotropium
Long acting, for COPD
 Clinical Uses
Delivered by inhalation, or parenteral
Slightly less effective than beta agonist
Ipratropium is useful in patients intolerant
to beta 2 agonist as an additional drug
Tiotropium is long acting & approved for
COPD, but not for asthma alone,
but may be used for asthma if combined w/ a
beta agonist in patients not controlled by
inhaled corticosteroid
 II. Corticosteroids -
Preventers
Mechanism
anti inflammatory, inhibits cytokines
Do not relax the airway smooth muscle
but reduce bronchial reactivity
Contraction of engorged vessels
Inhibition of infiltration of asthmatic
airways by lymphocytes, eosinophils &
mast cells
Potentiation of beta agonists
 Clinical uses
Improving all indices of asthma
control
severity of symptoms, test of airway
caliber, bronchial reactivity, frequency
of exacerbation and quality of life
Reserved for urgent cases in px who
do not improve w/ other treatment
Used as aerosol controller therapy
 SE: oral candidiasis, hoarseness, osteoporosis,
cataract (ciclesonide is claimed to have less
chance for toxicity since it is tightly bound to
serum proteins & has less access to skin,
bone & eyes
Preparations:
Oral: prednisone or IV: methylprednisolone initially
for 1 wk,
Then Aerosol inhalant as maintenance to avoid
systemic side effect: beclomethasone, flunisolide,
budesonide, ciclesonide, triamcinolone,
fluticasone, mometasone
Inhaled Corticosteroid side effect
Oral Candidiasis
 Corticosteroids
Prednisone oral tab
 Corticosteroid
Methylprednisolone IV
 Cromolyn sodium & Nedocromil
(Preventers)
Prevent mast cell degranulation
Taken prophylactically only & not for treatment since it
cannot reverse bronchospasm
Used as aerosol microfine powder or suspension for
inhalation only since it is not absorbed in GIT
Effectively inhibit both antigen and exercise-induced
asthma,
Also useful in reducing symptoms of allergic
rhinoconjunctivitis
SE: throat irritation, cough, mouth dryness, chest
tightness and wheezing, reversible dermatitis, myositis,
gastroenteritis, pulmonary infiltration with eosinophils and
anaphylaxis
 Leukotriene-Receptor
Antagonist
Alternate non steroidal controllers of
asthma
Leukotriene is a potent neutrophil
chemo attractant resulting to
Bronchoconstriction,
increased bronchial reactivity,
mucosal edema,
mucus hyper secretion
 Mechanism of action of leukotriene
inhibitors
Block the action of leukotrienes by:
Inhibition of the binding of leukotriene C4, D5, E4
to its cys-LT1 receptor on target tissues, thereby
preventing its action
Inhibition of 5-lipoxygenase, thereby preventing
leukotriene synthesis
Result
bronchodilatation,
Decreased bronchial reactivity
Decreased mucosal edema
Decreased mucus secretion
 Drug categories
A. 5-lipoxygenase inhibitor ZILEUTON
600mg QID
May cause hepatotoxicity
Inhibits the formation of LTB4
Leukotriene-receptor (LTD4) antagonist
ZAFIRLUKAST 20mg BID
MONTELUKAST 10mg OD
 Taken orally
Zafirlukast: absorbed rapidly
90% bioavailability
99% protein-bound
Metabilized extensively by hepatic
CYP2C9
Half-life: 10hrs
 Montelukast: absorbed rapidly
60-70% bioavailability
99% protein-bound
Metabolized extensively by CYP3A4 &
CYP2C9
Half-life: 3-6 hrs
 Zileuton: absorbed rapidly
Metabolized extensively by CYPs & UDP-
glucuronosyltransferases
hepatotoxic
Short-acting drug
Half-life: 2.5 hrs
93% protein-bound
 Others effects
Have demontrated an important role for
leukotrienes in aspirin-induced asthma
Their effect on symptoms, airway
caliber, bronchial reactivity and airway
inflammation are less marked than the
effects of inhaled corticosteroids, but
they are almost equally effective in
reducing the frequency of exacerbations
 Other Drug in the Treatment of
Asthma
1. Anti-IgE monoclonal Antibodies
Drugs that reduce the amount of IgE-bound
to mast cells
Inhibits synthesis of IgE by B-lympocytes
Omalizunab(anti-IgE Mab)
Most important effect: reduction of the frequency
& severity of asthma exacerbations, Reduce
corticoid requirements, improves allergic rhinitis
Delivered as a single SC injection every 2-4
weeks
Elimination: liver reticuloendothelial system, bile
 2. Calcium channel Blockers
Inhibit airway narrowing induced by
variety of stimuli
3. Nitric Oxide Donors
Relaxation of smooth muscle and
vasculature
Very lipophilic drug, can be inhaled as a
gas
More useful in pulmonary hypertension
 Possible Future Therapies
Monoclonal antibodies directed against
cytokines
Antagonist of cell adhesion molecules
Protease inhibitors
Immunomodulators
Macrolide antibiotic Clarithromycin
against Chlamydia pneumonia or
Mycoplasma pneumonia (infection
allegedly aggravates or cause asthma)
 Other Respiratory Agents
A. Mucolytic Agents
1. Acetylcysteine (mucomyst)
Reduce the thickness ang stickiness of
purulent and non-purulent pulmonary
secretions
Antidote for paracetamol poisoning
2. Carbocysteine (SCMC)
Act by regulating and normalizing the
viscosity of secretion from the mucus cell of
respiratory tract
 3. Bromhexine
Depolymerization of
mucopolysaccharides, direct effect on
bronchial glands
Liberation of lysosomal enzymes
producing cells which digest
mucopolysaccharide fibers
 B. Mucokinetic & Secretolytic
1. Ambroxol
Increase respiratory tract secretions
Enhance pulmonary surfactant production
Stimulates cilia activity
C. Expectorant
1. Vagal stimulants: glyceryl guiacolate,
salt solution
2. Direct stimulants: KISS, bromhexine,
SCMC, ambroxol
 D. Antitussives
1. Narcotic antitussives: heroin, codeine,
morphine
2. Non-narcotic antitussive:
Dextromethorphan
END