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RESPIRATORY PHARMACOLOGY

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

CROMOLYN AND NEDOCROMIL:


 CROMOLIN SODIUM (DISODIUM CHROMOGLYCATE) AND
NEDOCROMIL SODIUM:
o Stable but extremely insoluble salts
o When used as aerosols they effectively inhibit both antigen and exercise-
induced asthma and chronic use slightly reduces the overall level of
bronchial reactivity
o These drugs HAVE NO EFFECT ON AIRWAY SMOOTH MUSCLE
TONE
 Ineffective in reversing asthmatic bronchospasm and must be taken
PROPHYLACTICALLY
 MECHANISM OF ACTION:
o Thought to share a common mechanism of action
 Alteration in the function of delayed chloride channels in the cell
membrane, thus inhibiting cell activation
 This action on AIRWAY NERVES is though to be responsible for
nedocromils inhibition of cough
 On mast cells, thought to mediate INHIBITION OF EARLY
RESPONSE TO ANTIGEN CHALLENGE
 On eosinophils, INHIBITION OF THE INFLAMMATORY
RESPONSE to inhalation of allergens
o Thought also to be specific for respiratory tissue
 CLINICAL USE:
o Blocks the bronchoconstriction caused by:
 Allergen inhalation
 Exercise
 Sulfur dioxide
 Variety of causes of occupational asthma
o When taken regularly both agents modestly but significantly reduce
symptomatic severity and the need for bronchodilator medications
o Cromolyn is also useful in reducing symptoms of ALLERGIC
RHINOCONJUNCTIVITIS
o Because the drugs are so POORLY ABSORBED, adverse effects are
minor and are localised to the sites of deposition
 Throat irritation
 Cough
 Mouth dryness
o Serious adverse effects are rare
 Reversible dermatitis
 Myositis
 Gastroenteritis
 Pulmonary infiltration and anaphylaxis have been reported
o Minimal toxicity has meant high degree of use in children, particularly
those rapidly growing

LEUKOTRIENE PATHWAY INHIBITORS:


 Leukotrienes result from the action of 5-lipoxygenase on arachidonic acid and are
synthesised by a variety of inflammatory cells in the airway
o LTB4 is a potent neutrophil chemoattractant
o LTC4 and LTD4 exert many effects kown to occur in asthma
 TWO APPROACHES TO INTERRUPTING THE LEUKOTRIENE PATHWAY
EXIST:
o INHIBITION OF 5-LIPOXYGENASE
 Thereby preventing leukotriene synthesis
 ZILEUTON 400-800mg 2-4 times daily
o INHIBITION OF BINDING OF LTD4 to its receptor on target tissues
 Thereby preventing its action
 ZAFIRLUKAST (20mg twice daily), MONTELUKAST (10mg
adults, 4mg kids once daily)
 Both have been shown to improve asthma control and to reduce the frequency of
exacerbations
 They are taken ORALLY
o Hence useful in those who poorly comply with inhaled regimens
 Very useful in those who have asthma particularly sensitive to ASPIRIN
o Thought to result from inhibition of cycloxygenase shifting arachidonic
acid metabolism from the prostaglandin to the leukotriene pathway

OTHER DRUGS IN THE TREATMENT OF ASTHMA:


 ANTI-IGE MONOCLONAL ANTIBODIES:
o A monoclonal antibody was selected that appeared to be targeted against
the portion of IgE that binds to its receptors on mast cells
OMALIZUMAB inhibits the binding of IgE to mast cells but does
not activate IgE already bound to these cells and thus does NOT
provoke mast cell degranulation
 Therapy over ten weeks reduced the magnitude of both the early
and the late bronchospastic response to antigen challenge
 Lessens asthma severity and steroid requirements, especially in
those with a clear environmental precipitant
o Those most likely to respond are THOSE IN MOST NEED:
 Frequent exacerbations (especially those requiring hospitalisation,
decreased by 88%)
 High requirement for steroids
 Poor pulmonary function

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