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SYMPATHOMIMETIC AGENTS:
MECHANISM OF ACTION:
o Relax airway smooth muscle
o Inhibit release of bronchoconstricting mediators from mast cells
o May also inhibit microvascular leakage and increase mucociliary transport
by increasing ciliary activity
o The beta agonists stimulate adenylyl cyclase and increase formation of
intracellular CAMP
o Beta-2 effect is most important
Relaxes airway smooth muscle
Inhibits mediator release
Causes tachycardia and skeletal muscle tremor as side effects
Best delivered by INHALATION
o This results in greatest local effect on airway smooth muscle with the least
systemic toxicity
o Aerosol deposition depends on particle size, pattern of breathing and
geometry of the airways
Deposition can be increased by holding breath in inspiration
ADRENALINE:
o Effective, rapidly acting bronchodilator
o Maximal bronchodilation 15minutes after inhaltion
o Stimulates alpha and beta one as well as beta two
Causes tachycardia, arrhythmias and worsening of angina pectoris
These cardiovascular effects are of value for treating the acute
vasodilation and shock as well as the bronchospasm of
ANAPHYLAXIS
EPHEDRINE:
o Longer duration
o Oral activity
o More pronounced central effects
o Lower potency
o Now used infrequently
ISOPRENALINE:
o Potent bronchodilator
o Causes maximal bronchodilation in 5 minutes at doses of 80-120 microg
o Attributed to cardiac arrhythmia and now rarely used
BETA-2 SELECTIVE DRUGS:
o Most widely used sympathomimetics
o They are effective after inhaled or oral administration
o Long duration of action
o Agents include:
SALBUTAMOL
TERBUTALINE
METAPROTERENOL
PIRBUTEROL
o Bronchodilation is maximal within 15-30 minute and persists for 3-4 hours
o Nebulisers much be given in much higher doses and are no more effective
than metered dose inhalers
Should only be given in circumstances when patients are unable to
coordinate inhalation
o LONGER ACTING AGENTS:
SALMETEROL
FORMOTEROL
12 hour duration of action as a result of HIGH LIPID
SOLUBILITY
Appear to interact with corticosteroids to improve asthma
control
Not recommended as sole therapy
o ADVERSE EFFECTS:
FEARS ABOUT POSSIBLE CARDIAC ARRHYTHMIA AND
HYPOXAEMIA
They may increase perfusion of poorly ventilated lung
units, thus transiently decreasing arterial oxygen tension
o This effect is overcome by administration of
supplemental oxygen
Lethal cardiac arrhythmia fears appear to be
unsubstantiated
o Irregularities in cardiac rhythm improve with
improvement in gas exchange effected by
bronchodilator treatment
Heavy use indicates that the patient should be receiving more
effective prophylactic therapy with steroids
Evidence that the risk of adverse effects from chronic treatment
with long-acting beta agonists may be greater for some individuals
due to GENETIC VARIANTS FOR THE BETA RECEPTOR
METHYLXANTHINE DRUGS:
Three important agents:
o THEOPHYLLINE
o THEOBROMINE
o CAFFEINE
Importance as a therapeutic agent in asthma has waned with development of more
selective agents
CHEMISTRY:
o A theophylline preparation commonly used for therapeutic purposes is
AMINOPHYLLINE
MECHANISM OF ACTION:
o Several proposed actions, none has been firmly established
o At high concentrations, they can be shown to inhibit several members of
the PHOSPHODIESTERASE ENZYME FAMILY
Results in higher concentrations of intracellular CAMP and in
some tissues, CGMP
PDE4 appears to be the most involved in actions of
methylxanthines on airways smooth muscle and on inflammatory
cells
o In an effort to reduce toxicity while maintaining efficacy, more selective
inhibitors of PDE4 have been developed
ROFLUMILAST
CILOMILAST
TOFIMILAST
NONE APPROVED FOR USE
o Another proposed mechanism is inhibition of cell surface ADENOSINE
RECEPTORS
Adenosine has been shown to provoke contraction of isolated
airway smooth muscle and histamine release
o PHARMACODYNAMICS:
CNS EFFECTS:
Low and moderate doses, especially caffeine causes MILD
CORTICAL AROUSAL with increased alertness and
deferral of fatigue
Larger doses necessary for more effective bronchodilation
commonly cause nervousness and tremor in some patients
In very high doses, can medullary stimulation, convulsions
and death
CARDIOVASCULAR EFFECTS:
Positive chronotropic and inotropic effects
At low concentrations, they appear to result from inhibition
of presynaptic adenosine receptors in sympathetic nerves
Higher concentrations associated with inhibition of
phosphodiesterase and increased influx of calcium
Usually results in:
o Slight tachycardia
o Increased cardiac output
o Raised peripheral resistance
o Hypertension
Methylxanthines decrease blood viscosity and may improve
blood flow
o Exploited in the treatment of intermittent
claudication with PENTOXIFYLLINE
GASTROINTESTINAL EFFECTS:
Stimulate secretion of both gastric acid and digestive
enzymes
EFFECTS ON KIDNEY:
Weak diuretics
May involve increasing GFR and reduced tubular sodium
reabsorption
EFFECTS ON SMOOTH MUSCLE:
Bronchodilation is the major therapeutic action in asthma
Tolerance does NOT develop
EFFECTS ON SKELETAL MUSCLE:
Strengthen contractions of isolated skeletal muscle and
improve contractility and reverse fatigue of the diaphragm
in patients with COPD (even with no reversible
component)
o Accounts for theophyllines ability to improve
ventilatory response to hypoxia and to diminish
dyspnoea
CLINICAL USE OF METHYLXANTHINES:
o Theophylline is the most important bronchodilator
Relieves airflow obstruction in acute asthma and reduces severity
of symptoms in chronic asthma
o Theophylline should be used ONLY where methods to measure blood
levels are available
NARROW THERAPEUTIC WINDOW
o TOXICITY INCLUDES:
Anorexia
Nausea
Vomiting
Abdominal discomfort
Higher levels cause seizure or arrhythmia
o Plasma clearance of theophylline varies widely
Theophylline is metabolised by the liver and should be used with
caution in patients with liver disease
Induction of liver enzymes may occur in smokers, hence increasing
clearance in these patients
o Improves long-term control of asthma when taken as the sole maintenance
treatment or when added to inhaled steroids
o Low cost
ANTIMUSCARINIC AGENTS:
Interest in the potential value of antimuscarinic agents increased with
demonstration of the importance of the VAGUS nerve in bronchospastic response
of lab animals
MECHANISM OF ACTION:
o Competitively inhibit the effect of acetylcholine at muscarinic receptors
o In the airways, acetylcholine is released from efferent endings of the vagus
nerves and muscarinic antagonists block the contraction of airway smooth
muscle and increase in secretion of mucous
o In the doses given, antimuscarinic agents inhibit only that portion of the
response mediated by muscarinic receptors which VARIES BY
STIMULUS
CLINICAL USES:
o Selective quaternary ammonium derivative of atropine IPRATROPIUM
BROMIDE
Can be delivered at high doses by inhaled route because it is poorly
absorbed into the circulation and does not readily enter the CNS
o These agents are valuable in those intolerant of beta-2 agonists
o Addition of ipratropium ENHANCES THE BORNCHODILATION
produced by nebulised salbutamol in acute severe asthma
o Longer acting, selective agent TIOTROPIUM
Also taken by inhalation
Single dose of 18 micrograms has 24 hour duration of effect
Improves functional capacity of patients with COPD and reduces
the frequency of exacerbations
CORTICOSTEROIDS:
MECHANISM OF ACTION:
o Presumed to act by their broad antiinflammatory efficacy
o They do not relax airway smooth muscle directly but reduce bronchial
reactivity and reduce the frequency of asthma exacerbations if taken
regularly
o Also induce contraction of engorged vessels in the bronchial mucosa and
potentiate effects of beta receptors agonists
o Most important action is inhibition of the lymphocytic, eosinophilic
mucosal inflammation of asthmatic airways
CLINICAL USES:
o Effective in improving all indices of asthma control
Severity of symptoms
Tests of airway calibre
Bronchial reactivity
Frequency of exacerbations
Quality of life
o Oral and parenteral treatments reserved for those who require urgent
treatment
Given in doses of 30-60mg daily, decreased after improvement in
airway obstruction
o AEROSOL TREATMENT is the most effective way to avoid systemic
adverse effects:
BECLOMETHASONE
BUDESONIDE
FLUNISOLIDE
FLUTICASONE
MOMETASONE
TRIAMCINOLONE
o High doses of aerosol may cause adrenal suppression, but the risks of
systemic toxicity from chronic use appear negligible compared with those
of the oral steroid they replace
o Special problem of aerosol steroid:
OROPHARYNGEAL CANDIDIASIS
Reduced by water gargling after each inhaled treatment
o Chronic use of inhaled steroids effectively reduces symptoms and
improves pulmonary function in patients with mild asthma
Eliminates the need for oral steroids in patients with more severe
disease
Reduces bronchial reactivity
Now routinely prescribed for patients who require more than
occasional inhalations of a beta agonist for relief of symptoms
ANTITUSSIVE AGENTS:
Opioid analgesics are among the most effective drugs available for the
suppression of cough
o Often produced at doses well below analgesic effects
o Different receptor involved
Opioid derivatives most often used as antitussives:
o DEXTROMETHORPHAN (15-30mg tds)
o CODEINE (15mg)
o LEVOPROPOXYPHENE (50-100mg and may cause sedation)
o NOSCAPINE
Antitussives are often given in combination with expectorants to thin and liquefy
the sputum