Drugs Acting on the Pulmonary System

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Drugs Acting on the Pulmonary System
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Introduction to Pulmonary Disorders

• In asthma, chronic bronchitis, and rhinitis, the
  effective diameter of the airways is decreased.
• The goal of therapy is to decrease airway
  resistance by
• increasing the diameter of the bronchi
• decreasing mucus secretion or stagnation in the
  airways.

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Asthma

• Asthma is characterized by acute episodes of
  bronchoconstriction caused by underlying airway
  inflammation.
• A hallmark of asthma is bronchial hyperreactivity
  to endogenous or exogenous stimuli.
• In asthmatic patients, the response to various
  stimuli is amplified by persistent inflammation.

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Early-phase response

• Antigenic stimuli trigger the release of
  mediators (leukotrienes, histamine, and many
  others) that cause
• a bronchospastic response, with
• smooth muscle contraction
• mucus secretion
• recruitment of inflammatory cells such as
  eosinophils, basophils, and macrophages.

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Late-phase response

• may occur in hours or days
• is an inflammatory response
• levels of histamine and other mediators released
  from inflammatory cells rise again and may induce
  bronchospasm and eventually fibrin and collagen
  deposition and tissue destruction.

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• Nonantigenic stimuli
• (cool air, exercise, nonoxidizing pollutants)
• can trigger nonspecific bronchoconstriction after
  early-phase sensitization.

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Chronic bronchitis

• Chronic bronchitis is characterized by pulmonary
  obstruction caused by excessive production of
  mucus due to hyperplasia and hyperfunctioning of
  mucus-secreting goblet cells.
• Chronic bronchitis is often induced by an
  irritant.

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Rhinitis

• Rhinitis is a decrease in nasal airways due to
  thickening of the mucosa and increased mucus
  secretion.
• Rhinitis may be caused by allergy, viruses,
  vasomotor abnormalities, or rhinitis
  medicamentosa.(is a condition of rebound nasal
  congestion brought on by extended use of topical
  decongestants (e.g., oxymetazoline,
  phenylephrine, xylometazoline, and naphazoline
  nasal sprays) that work by constricting blood
  vessels in the lining of the nose.)

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Agents Used to Treat Asthma and Other Bronchial
Disorders

• Treatment of asthma is based on the severity of
  the disease and response to individual agents.

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Adrenergic agonists

• General characteristics
• Adrenergic agonists stimulate ß2-adrenoceptors,
  resulting in
• relaxation of bronchial smooth muscle
• inhibit the release of mediators
• stimulate mucociliary clearance.
• Adrenergic agonists are useful for the treatment
  of the acute bronchoconstriction (exacerbations)
  of asthma.
• These agents are used both for quick relief and
  for long-term control, depending on biologic
  half-life.

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Short-acting ß2-adrenoceptor agonists

• Albuterol, levalbuterol, pirbuterol,
  metaproterenol
• administered by
• Inhalation, onset of action is 15 minutes.
• available for oral administration.
• Long-term use of these agents for the treatment
  of chronic asthma has been associated with
  diminished control, perhaps due to ß-receptor
  down-regulation.

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Long-acting ß2-adrenoceptor agonists

• Salmeterol, formoterol
• administered as inhalants
• have a slower onset of action
• a longer duration of
• These agents are very effective for prophylaxis
  of asthma but should not be used to treat an
  acute attack.

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• Terbutaline
• Terbutaline is a moderately specific ß2-agonist
• currently available for injection or as a tablet.
  

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• Isoproterenol
• nonselective ß-receptor agonist
• a potent bronchodilator.
• Isoproterenol is most effective in asthmatic
  patients when administered as an inhalant.
• During an acute attack, dosing every 12 hours is
  typically required
• oral preparations are administered 4 times daily
  (qid).

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• Epinephrine
• administered as an inhalant or subcutaneously
• onset of action occurs within 510 minutes
• duration is 6090 minutes.

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• Ephedrine.
• Ephedrine is a relatively nonselective ß- and
  a1-adrenoceptor agonist
• rarely used in the treatment of asthma.
• Some preparations combine ephedrine with a
  methylxanthine.

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Adverse effects of adrenergic agonists

• based on receptor occupancy.
• These adverse effects are minimized by inhalant
  delivery of the adrenergic agonists directly to
  the airways.
• Epinephrine, ephedrine, and isoproterenol have
  significant ß1-receptor activity and can cause
  cardiac effects, including tachycardia and
  arrhythmias, and the exacerbation of angina.
• The most common adverse effect of
  ß2-adrenoreceptor agonists is skeletal muscle
  tremor.
• The adverse effects of a-adrenoceptor agonists
  include vasoconstriction and hypertension.
• Tachyphylaxis, a blunting in the response to
  adrenergic agonists on repeated use, can be
  countered by switching to a different agonist or
  by adding a methylxanthine or corticosteroid to
  the regimen.

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Methylxanthines

• For asthma, the most frequently administered
  methylxanthine is theophylline (1,3-dimethylxanthi
  ne).
• Mechanism of action
• Methylxanthines cause bronchodilation by action
  on the smooth muscles in the airways.
• The exact mechanism remains controversial
• adenosine-receptor antagonist (adenosine causes
  bronchoconstriction and promotes the release of
  histamine from mast cells).
• may decrease the entry and mobilization of
  cellular Ca2 stores.
• Theophylline inhibits phosphodiesterase (leading
  to increased cAMP), but this effect requires very
  high doses, and its contribution to
  bronchodilation remains to be established.

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Pharmacologic effects

• Methylxanthines are most useful in the treatment
  of asthma because of the following
• These agents produce rapid relaxation of
  bronchial smooth muscle.
• Methylxanthines decrease histamine release in
  response to reaginic (immunoglobulin E)
  stimulation.
• These agents stimulate ciliary transport of
  mucus.
• Methylxanthines improve respiratory performance
  by improving the contractility of the diaphragm
  and by stimulating the medullary respiratory
  center.

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• Pharmacologic properties of Methylxanthines
• almost completely absorbed after oral
  administration.
• permeable into all tissue compartments
• cross the placenta and can enter breast milk.
• are metabolized extensively in the liver and are
  excreted by the kidney.

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Prototype drug theophylline

• Theophylline is available in a microcrystalline
  form for inhalation and as a sustained-release
  preparation it can be administered
  intravenously.
• Theophylline has a very narrow therapeutic index
  blood levels should be monitored upon the
  initiation of therapy.
• Theophylline has a variable half-life t1/2 is
  approximately 89 hours in adults, but it is
  shorter in children.
• Clearance of theophylline is affected by diet,
  drugs, and hepatic disease.

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• Therapeutic uses
• Methylxanthines are used to treat acute or
  chronic asthma that is unresponsive to
  ß-adrenoceptor agonists they can be administered
  prophylactically.
• These agents are used to treat chronic
  obstructive lung disease and emphysema.
• Methylxanthines are used to treat apnea in
  preterm infants (based on stimulation of the
  central respiratory center) usually, caffeine is
  the agent of choice for this therapy.

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• Adverse effects
• Arrhythmias, nervousness, vomiting, and
  gastrointestinal bleeding.
• Methylxanthines may cause behavioral problems in
  children.

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Muscarinic antagonists

• Muscarinic antagonists include ipratropium
  bromide and atropine.
• They inhibit ACh-mediated constriction of
  bronchial airways.
• Anticholinergics decrease mucus secretion.
• They are useful in patients who are refractory
  to, or intolerant of, sympathomimetics or
  methylxanthines.
• Ipratropium
• poorly absorbed
• does not cross the bloodbrain barrier
• is administered as an aerosol
• Atropine is readily absorbed into the systemic
  circulation.
• The adverse effects of atropine include
  drowsiness, sedation, dry mouth, and blurred
  vision

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Chromones

• Cromolyn sodium
• they inhibit the release of mediators from mast
  cells
• suppress the activation of neutrophils,
  eosinophiles, and monocytes
• inhibit cough reflexes
• Administered by inhalation
• Cromolyn sodium is used prophylactically in
  asthma
• it does not reverse an established bronchospasm.
• It is the only antiasthmatic that inhibits both
  early- and late-phase responses.
• Localized adverse effects, which include sore
  throat, cough, and dry mouth.
• It may infrequently cause dermatitis,
  gastroenteritis, nausea, and headache.

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• Nedocromil sodium
• Similar in action to cromolyn.
• More effective in blocking bronchospasm induced
  by exercise or cold air.
• Administered as an inhalant.

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Glucocorticoids

• Glucocorticoids include
• beclomethasone
• triamcinolone acetate
• budesonide
• flunisolide
• fluticasone propionate

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• Glucocorticoids produce a significant increase in
  airway diameter, probably by
• attenuating prostaglandin and leukotriene
  synthesis via inhibition of the phospholipase A2
  reaction
• inhibiting the immune response.
• They increase responsiveness to sympathomimetics
  and decrease mucus production.

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• Available as oral, topical, and inhaled agents.
• Use of inhaled glucocorticoids is recommended for
  the initial treatment of asthma, with additional
  agents added as needed. They are used
  prophylactically rather than to reverse an acute
  attack.
• The most common adverse effects of inhaled
  glucocorticoids are hoarseness and oral
  candidiasis
• the most serious adverse effects are adrenal
  suppression and osteoporosis.
• Inhaled glucocorticoids are partially absorbed.
• Because of their systemic adverse effects, oral
  glucocorticoids are usually reserved for patients
  with severe persistent asthma.

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Pharmacokinetics of inhaled glucocorticoids
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Effect of a spacer on the delivery of an inhaled
aerosol.
Spacers A spacer is a large-volume chamber
attached to a metered-dose inhaler. Spacers
decrease the deposition of drug in the mouth
caused by improper inhaler technique
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1. Leukotriene inhibitors

• Zileuton
• Zileuton inhibits 5-lipoxygenase, the
  rate-limiting enzyme in leukotriene biosynthesis.
• This agent relieves bronchoconstriction from
  exercise.
• Zileuton is administered orally, usually 4 times
  per day.
• Zileuton may cause liver toxicity
• Zileuton may cause flulike symptoms chills
  fatigue, fever.
• F. Zileuton inhibits microsomal P-450s and
  thereby decreases the metabolism of terfenadine,
  warfarin, and theophylline.

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• Zafirlukast and montelukast
• Zafirlukast and montelukast are antagonists of
  the leukotriene receptor LT1. This blocks the
  action of the cys-leukotrienes C4, D4, and E4
  (LTC4, LTD4, LTE4, respectively)
• These drugs are recommended as an alternative to
  medium-dose inhaled glucocorticoids.
• Adverse effects of zafirlukast include headache
  and elevation in liver enzymes.
• Zafirlukast and montelukast are administered
  orally, 12 times per day
• Zafirlukast inhibits the metabolism of warfarin.

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G. Anti-IgE antibody

• Omalizumab binds to human IgE's high-affinity Fc
  receptor (FceRI), blocking the binding of IgE to
  mast cells and basophils and other cells
  associated with the allergic response.
• Omalizumab is approved for treatment of asthma in
  patients over 12 years old who are refractory to
  inhaled glucocorticoids.
• The drug is administered by subcutaneous
  injection every 24 weeks.

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Drugs Used to Treat Rhinitis and Cough
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Rhinitis

• Characteristics of Rhinitis
• Congestion is caused by increased mucus
  production, vasodilation, and fluid accumulation
  in mucosal spaces.
• Mucus production, vasodilation, and
  parasympathetic stimulation and airway widening
  are produced by inflammatory mediators
  (histamine, leukotrienes, prostaglandins, and
  kinins).

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Selected Drugs

• Antihistamines
• Antihistamines are histamine1 (H1)-receptor
  antagonists they include diphenhydramine,
  brompheniramine, chlorpheniramine, and
  loratadine, which are useful in allergic rhinitis
  but have little effect on rhinitis associated
  with colds.
• Antihistamines reduce the parasympathetic tone of
  arterioles and decrease secretion through their
  anticholinergic activity.
• Anticholinergics might be more effective in
  rhinitis, but the doses required produce systemic
  adverse effects.
• Ipratropium bromide, a poorly absorbed ACh
  antagonist administered by nasal spray, is
  approved for rhinorrhea associated with the
  common cold or with allergic or nonallergic
  seasonal rhinitis.

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• a-Adrenoceptor agonists
• a-Adrenoceptor agonists act as nasal
  decongestants.
• Administration
• Nasal aerosols epinephrine and oxymetazoline
• Oral pseudoephedrine
• Orally or as a nasal aerosol phenylephrine.

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• Oral administration results in
• longer duration of action
• increased systemic effects
• less potential for rebound congestion and
  dependence.
• These agents reduce airway resistance by
  constricting dilated arterioles in the nasal
  mucosa.
• a-Adrenoceptor agonists produce adverse effects
  that include nervousness, tremor, insomnia,
  dizziness, and rhinitis medicamentosa

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• Inhaled corticosteroids
• beclomethasone
• flunisolide.
• Topical corticosteroids are administered as nasal
  sprays to reduce systemic absorption and adverse
  effects.
• These agents require 12 weeks for full effect.

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• Cromolyn and nedocromil
• These drugs are administered several times daily
  by aerosol spray or nebulizer.

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Cough

• Cough is produced by the cough reflex, which is
  integrated in the cough center in the medulla.
• The initial stimulus for cough probably arises in
  the bronchial mucosa, where irritation results in
  bronchoconstriction.
• Cough receptors, specialized stretch receptors
  in the trachea and bronchial tree, send vagal
  afferents to the cough center and trigger the
  cough reflex.

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B. selected drugs

• Antitussive agents
• Codeine, hydrocodone, and hydromorphone
• are opiates that decrease sensitivity of the
  central cough center to peripheral stimuli and
  decrease mucosal secretions.
• Antitussive actions occur at doses lower than
  those required for analgesia.
• These agents produce constipation, nausea, and
  respiratory depression.
• Dextromethorphan
• Dextromethorphan is the L-isomer of an opioid it
  is active as an antitussive, but it is devoid of
  analgesic action or addictive liability.
• Dextromethorphan is less constipating than
  codeine.

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• 3. Benzonatate
• Benzonatate is a glycerol derivative chemically
  similar to procaine.
• Benzonatate reduces the activity of peripheral
  cough receptors and also appears to reduce the
  threshold of the central cough center.
• 4. Diphenhydramine
• Diphenhydramine is an H1-receptor antagonist
  however, antitussive activity is probably not
  mediated at this receptor.
• Diphenhydramine acts centrally to decrease the
  sensitivity of the cough center to afferents.

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• Expectorants stimulate the production of a
  watery, less-viscous mucus they include
  guaifenesin.
• Guaifenesin acts directly via the
  gastrointestinal tract to stimulate the vagal
  reflex.
• Near-emetic doses of guaifenesin are required for
  beneficial effect these doses are not attained
  in typical OTC preparations.

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• Mucolytics
• Acetylcysteine
• Acetylcysteine reduces the viscosity of mucus and
  sputum by cleaving disulfide bonds.
• Acetylcysteine is delivered as an inhalant and
  modestly reduces chronic obstructive pulmonary
  disease exacerbation rates by roughly 30.