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Flashcards in 25 Pharmacology 3: Bronchodilators Deck (23)
1

Asthma

  • The clinical hallmarks of asthma 
  • In mild asthma, symptoms occur...
  • In more severe forms of asthma,...
  • Asthma is characterized physiologically by...
  • Its chronic pathological features 

  • The clinical hallmarks of asthma
    • Recurrent, episodic bouts of coughing
    • Shortness of breath
    • Chest tightness
    • Wheezing
  • In mild asthma, symptoms occur...
    • Only occasionally
  • In more severe forms of asthma,...
    • Frequent attacks of wheezing and dyspnea occur, especially at night
    • Chronic activity limitation is common
  • Asthma is characterized physiologically by...
    • Increased responsiveness of the trachea and bronchi to various stimuli
    • Widespread narrowing of the airways
  • Its chronic pathological features
    • Contraction of airway smooth muscle leading to reversible airflow obstruction
    • Mucosal thickening from edema and cellular infiltration with airway inflammation
    • Persistent airway hyperreactivity (AHR)
    • Airway remodeling

2

The fundamental pathogenesis of asthma

  • Chronic inflammation of the bronchial mucosa is prominent, with infiltration of activated T-lymphocytes and eosinophils
  • This results in subepithelial fibrosis and the release of chemical mediators that can damage the epithelial lining of the airways
  • Many of these mediators are released following activation and degranulation of mast cells in the bronchial tree
  • Some of these mediators act as chemotactic agents for other inflammatory cells
  • They also produce mucosal edema, which narrows the airway and stimulates smooth muscle contraction, leading to bronchoconstriction
  • Excessive production of mucus can cause further airway obstruction by plugging the bronchiolar lumen

3

COPD

  • Characterized by...
  • This process is usually...
  • Consists of...
  • Clinically defined by...
  • The degree of bronchodilatory response at the time of testing,...
  • Bronchodilators 
  • Corticosteroids
  • Anti-inflammatory agents
  • IMPORTANT CONCEPT 1: In contrast to asthma,...

  • Characterized by...
    • Airflow limitation caused by chronic bronchitis
    • Emphysema that is usually caused by tobacco smoking
  • This process is usually...
    • Slowly progressive and largely irreversible
  • Consists of...
    • Increased resistance to airflow
    • Loss of elastic recoil
    • Decreased expiratory flow rate
    • Overinflation of the lung
  • Clinically defined by...
    • A low FEV1 value that fails to respond acutely to bronchodilators, a characteristic that differentiates it from asthma
  • The degree of bronchodilatory response at the time of testing,...
    • Does not predict the degree of clinical benefit to the patient
  • Bronchodilators
    • Given irrespective of the acute response obtained in the pulmonary function laboratory
  • Corticosteroids
    • The inflammatory component of COPD is largely resistant to corticosteroid therapy
  • Anti-inflammatory agents
    • There are currently no effective anti-inflammatory agents to treat COPD
  • IMPORTANT CONCEPT 1: In contrast to asthma,...
    • The airway obstruction in COPD tends to be progressive and not responsive to anti-inflammatory agents

4

Pathogenesis of asthma

  • Mediated by...
  • After re-exposure to the antigen, antigen-antibody interaction on the surface of the mast cells triggers...
  • The agents responsible for the early reactions, such as immediate brochoconstriction 
  • Putative mediators for the more sustained bronchocontriction, cellular infiltration of the airway mucosa, and mucus hypersecretion of the late asthmatic reaction, which occurs 2-8 hours later
  • Some of the features of asthma cannot be readily accounted for by...
  • In many patients, bronchospasm can be provoked by...
  • Bronchoconstriction itself seems to result...

  • Mediated by...
    • IgE antibodies bound to mast cells in the airway mucosa
  • After re-exposure to the antigen, antigen-antibody interaction on the surface of the mast cells triggers...
    • The release of mediators stored in the cells’ granules
    • The synthesis and release of other mediators
  • The agents responsible for the early reactions, such as immediate brochoconstriction
    • Histamine, tryptase, other neutral proteases, leukotrienes C4 and D4, and prostaglandins
    • Cause muscle contraction and vascular leakage
  • Putative mediators for the more sustained bronchocontriction, cellular infiltration of the airway mucosa, and mucus hypersecretion of the late asthmatic reaction, which occurs 2-8 hours later
    • Cytokines produced by Th2 lymphocytes, especially GM-CSF and IL-4, 5, 9, and 13
    • Attract and activate eosinophils and stimulate IgE production by B lymphocytes
  • Some of the features of asthma cannot be readily accounted for by...
    • The antigen challenge model
  • In many patients, bronchospasm can be provoked by...
    • Non-antigenic stimuli such as distilled water, exercise, cold air, sulfur dioxide, and rapid respiration
  • Bronchoconstriction itself seems to result...
    • Not simply from the direct effect of the released mediators
    • Also from the activation of neural or humoral pathways

5

Pharmacotherapy of asthma and COPD

  • Current therapeutically available agents for the treatment of asthma and COPD can be divided into two general categories
  • IMPORTANT CONCEPT 2: Anti-inflammatory drugs and combination therapy with bronchodilators
  • IMPORTANT CONCEPT 3: Bronchodilators 

  • Current therapeutically available agents for the treatment of asthma and COPD can be divided into two general categories
    • Drugs that inhibit smooth muscle contraction
      • I.e. bronchodilators (β2-adrenergic agonists, methylxanthines, and anticholinergics)
    • Agents that prevent and/or reverse inflammation
      • I.e., the “long-term control medications” (glucocorticoids, leukotriene inhibitors and receptor antagonists, mast cell-stabilizing agents or cromones)
  • IMPORTANT CONCEPT 2: Anti-inflammatory drugs and combination therapy with bronchodilators
    • Anti-inflammatory drugs (e.g. inhaled corticosteroids (ICS)) are effective for the treatment of chronic asthma
    • Combination therapy with bronchodilators can aid in asthma symptom relief.
  • IMPORTANT CONCEPT 3: Bronchodilators
    • Remain the mainstay therapy to manage the airway obstruction in COPD
    • The combination of long-acting ß2-agonists and inhaled corticosteroids (ICS) may enhance relief through unknown mechanisms

6

Aerosol delivery of drugs

  • Topical application of drugs to the lungs can be accomplished by...
  • This approach should in theory produce...
  • The critical delivery determinant of any particulate matter to the lungs
  • The most effective particles 
  • Other important factors for deposition
  • Even under ideal circumstances,...
  • What can improve the ratio of inhaled to swallowed drug

  • Topical application of drugs to the lungs can be accomplished by...
    • Use of aerosols
  • This approach should in theory produce...
    • High local concentrations in the lungs with a low systemic delivery, thus reducing systemic side effects
  • The critical delivery determinant of any particulate matter to the lungs
    • The size of the particle
    • Particles >10 μm are deposited primarily in the mouth and oropharynx
    • Particles
  • The most effective particles
    • Have a diameter of 1-5 μm
  • Other important factors for deposition
    • Rate of breathing
    • Breath-holding after inhalation
  • Even under ideal circumstances,...
    • Only a small fraction of the aerosolized drug (~2-20%) is deposited in the lungs
  • What can improve the ratio of inhaled to swallowed drug
    • A large volume spacer attached to metered-dose inhalers

7

Bronchodilators

  • The bronchial tree is one of the organs that receive...
  • The predominant adrenergic receptors in the bronchial tree 
  • A subtype of muscarinic cholinergic receptor, M3, mediates...
  • Bronchodilators are a group of agents that cause...
  • Three classes of bronchodilators are in current use

  • The bronchial tree is one of the organs that receive...
    • Dual sympathetic and parasympathetic innnervation
  • The predominant adrenergic receptors in the bronchial tree
    • β2, which cause relaxation
  • A subtype of muscarinic cholinergic receptor, M3, mediates...
    • Smooth muscle contraction in the lungs
  • Bronchodilators are a group of agents that cause...
    • Rapid relaxation of bronchial smooth muscle
  • Three classes of bronchodilators are in current use
    • β-adrenergic agonists
    • Theophylline
    • Anticholinergic drugs

8

Bronchodilators:
Beta-adrenergic agonists:
Mechanism of action

  • β-agonists produce bronchodilation by...
  • Activation of β2 receptors results in...
  • For example, PKA phosphorylation of Ca2+-activated K+ channels (BKCa)...
  • β2 agonists have other beneficial effects including...
  • The inhibitory effects on mast cell mediator release and microvascular leakage suggests that ß2 agonists may...

  • β-agonists produce bronchodilation by...
    • Directly stimulating β2- receptors in airway smooth muscle
  • Activation of β2 receptors results in...
    • Activation of adenyl cyclase via...
      • A stimulatory guanine-nucleotide binding protein [G protein (Gs)]
      • Increases intracellular cyclic 3′5′-adenosine monophosphate (cAMP)
    • This activates protein kinase A, which then phosphorylates several target proteins within the cell leading to relaxation of bronchial smooth muscle
  • For example, PKA phosphorylation of Ca2+-activated K+ channels (BKCa)...
    • Increases K+ efflux
    • Facilitates repolarization
    • Stimulates Ca2+ sequestration into intracellular stores
  • β2 agonists have other beneficial effects including...
    • Inhibition of mast cell mediator release
    • Prevention of microvascular leakage and airway edema
    • Enhanced mucociliary clearance
  • The inhibitory effects on mast cell mediator release and microvascular leakage suggests that ß2 agonists may...
    • Modify acute inflammation
    • β2 agonists, however, have no effect on chronic inflammation

9

Bronchodilators:
Beta-adrenergic agonists:
Long and short acting ß2-agonists

  • β2 agonists were developed through...
  • NE differs from epinephrine in the...
  • Modification at this site confers...
  • The selectivity of β2 agonists is...
  • Inhalation of the drug aids...
  • β2 agonists are generally divided into...
  • IMPORTANT CONCEPT 4: Short-acting β 2 adrenergic receptor agonists

  • β2 agonists were developed through...
    • Substitutions in the catecholamine structure of norepinephrine (NE)
  • NE differs from epinephrine in the...
    • Terminal amine group
  • Modification at this site confers...
    • ß receptor selectivity
    • Further substitutions have resulted in β2 selectivity
  • The selectivity of β2 agonists is...
    • Obviously dose dependent
  • Inhalation of the drug aids...
    • Selectivity since it delivers small doses to the airways and minimizes systemic exposure
  • β2 agonists are generally divided into...
    • Short (4-6 h) and long (>12 h) acting agents
  • IMPORTANT CONCEPT 4: Short-acting β 2 adrenergic receptor agonists
    • Such as albuterol
    • The preferred treatment for rapid symptomatic relief of dyspnea associated with asthmatic bronchoconstriction

10

Bronchodilators:
Beta-adrenergic agonists:
Safety

  • Side effects with topical delivery
  • IMPORTANT CONCEPT 5: The development of more selective ß2-agonists for the treatment of asthma or COPD...

  • Side effects with topical delivery
    • There are relatively few side effects with these agents at therapeutic doses
    • At higher doses, these agents may lead to increased heart rate, cardiac arrhythmias, muscle tremors, metabolic disturbances and CNS effects associated with β2-adrenergic receptor activation
  • IMPORTANT CONCEPT 5: The development of more selective ß2-agonists for the treatment of asthma or COPD...
    • Is not warranted since the side effects of these compounds are largely due to activation of ß2-adrenergic receptors in peripheral tissues

11

Bronchodilators:
Beta-adrenergic agonists:
Safety

  • Tolerance to long-acting ß agonists (LABA)
  • This is likely due to...
  • >90% of ß2- adrenergic receptors...
  • The long-term safety of LABA
  • IMPORTANT CONCEPT 6: Although evaluations of the long-term safety of LABA continue, it is now recommended that LABA be used only...

  • Tolerance to long-acting ß agonists (LABA)
    • Despite the tendency of ß2-adrenergic receptors to be desensitized upon chronic agonist treatment, tolerance to long-acting ß agonists (LABA) is generally not observed
  • This is likely due to...
    • The presence of “spare” ß2-adrenergic receptors in airway smooth muscle cells
    • The relatively low expression of GRK2, the kinase that phosphorylates and inactivates these receptors
  • >90% of ß2- adrenergic receptors...
    • Can be lost without any physiological consequences on airway function
  • The long-term safety of LABA
    • Increased frequency of deaths or near deaths reported with chronic salmeterol use was shown later to be mainly confined to African-American patients living in the inner city who were not taking ICS
    • Approved LABA in the US carry a black box warning cautioning against overuse
    • The long-term safety profile of LABA in children is currently being evaluated
    • To date, no major adverse events have been reported in COPD patients taking LABA
  • IMPORTANT CONCEPT 6: Although evaluations of the long-term safety of LABA continue, it is now recommended that LABA be used only...
    • In combination with ICS

12

Bronchodilators:
Beta-adrenergic agonists:
Alternative signaling

  • ß2 adrenergic receptors may also undergo...
  • This could be responsible for...
  • Nadolol

  • ß2 adrenergic receptors may also undergo...
    • An alternative coupling through Gq or Gßγ to activate phospholipase C and thereby enhance inflammatory responses
    • Coupling of ß2 adrenergic receptors to p38 MAPK and PI3- kinase via ß-arrestin-2 may have similar proinflammatory effects in asthma patients
  • This could be responsible for...
    • Some rare adverse events associated with LABA use
  • Nadolol
    • A ß-blocker that acts as an inverse agonist (i.e. selective inhibition of constitutively active ß2 adrenergic receptor coupled to ß-arrestin-2 or Gq)

13

Bronchodilators:
Theophylline

  • The methylxanthine theophylline shares a similar structure to...
  • Many salts of theophylline have been marketed, the most common being...
  • Theophylline is now mainly used...
  • PDE inhibition
  • Another hypothesized mechanism of action of theophylline
  • The dose of theophylline required to yield therapeutic concentrations

  • The methylxanthine theophylline shares a similar structure to...
    • The dietary xanthine caffeine
  • Many salts of theophylline have been marketed, the most common being...
    • Aminophylline, which is the ethylenediamine salt
  • Theophylline is now mainly used...
    • In developing countries since it is relatively inexpensive
  • PDE inhibition
    • Theophylline is a weak, non-selective inhibitor of phosphodiesterase (PDE)
    • There are at least 10 PDE family members, all of which catabolize cyclic nucleotides in the cell
    • PDE inhibition results in increased concentrations of cAMP and cGMP
  • Another hypothesized mechanism of action of theophylline
    • Adenosine receptor inhibition, which may prevent the release of mediators from mast cells.
  • The dose of theophylline required to yield therapeutic concentrations
    • Varies among subjects, largely because of differences in clearance and its therapeutic range is rather narrow (plasma concentrations, 5-15 mg/L)

14

Bronchodilators:
Theophylline

  • Increased clearance is seen in...
  • Concurrent administration of phenobarbitol or phenytoin...
  • Reduced clearance is also seen with...
  • Unwanted side effects
  • The most common side effects 
  • IMPORTANT CONCEPT 7: Methylxanthines

  • Increased clearance is seen in...
    • Children 
    • Cigarette and marijuana smokers
  • Concurrent administration of phenobarbitol or phenytoin...
    • Increases activity of cytochrome P-450 (CYP), which results in increased metabolic breakdown
  • Reduced clearance is also seen with...
    • Certain drugs that interfere with the CYP system, such as cimetidine, erythromycin, ciprofloxacin, allopurinol, zileuton, and zafirlukast
    • Viral infections and vaccinations may also reduce clearance
  • Unwanted side effects
    • May be seen at higher plasma concentrations, although they may occur in some patients even at low concentrations
  • The most common side effects 
    • Anorexia, nausea and vomiting, headache, abdominal discomfort, and restlessness.
  • IMPORTANT CONCEPT 7: Methylxanthines
    • Infrequently used in developed countries due to the existence or more effective bronchodilators and difficulty in attaining its narrow therapeutic range
    • Remains a useful drug in some patients with severe asthma or COPD, particularly those that are not responsive to ß2-agonists

15

Bronchodilators:
Anti-cholinergic drugs

  • Human airways are innervated by a supply of...
  • Motor nerves 
    • Derived from...
    • Form...
  • This vagally derived innervation
    • Extends along...
    • Predominates in...
  • Postganglionic fibers 
    • Derived from...
    • Supply...
  • Release of acetylcholine (ACh) at these sites results in...

  • Human airways are innervated by a supply of...
    • Efferent, cholinergic, parasympathetic autonomic nerves
  • Motor nerves
    • Derived from the vagus
    • Form ganglia within and around the walls of the airways
  • This vagally derived innervation
    • Extends along the length of the bronchial tree
    • Predominates in the large and medium-sized airways
  • Postganglionic fibers
    • Derived from the vagal ganglia
    • Supply the smooth muscle and submucosal glands of the airways as well as the vascular structures
  • Release of acetylcholine (ACh) at these sites results in...
    • Stimulation of muscarinic receptors
    • Subsequent airway smooth muscle contraction
    • Release of secretions from the submucosal airway glands

16

Bronchodilators:
Anti-cholinergic drugs

  • Three pharmacologically distinct subtypes of muscarinic receptors exist within the airways
    • M1 receptors 
    • M2 receptors 
    • M3 receptors 
  • Atropine 
  • Ipratropium 
  • Atropine and ipratropium 

  • Three pharmacologically distinct subtypes of muscarinic receptors exist within the airways
    • M1 receptors
      • Present on peribronchial ganglion cells where the preganglionic nerves transmit to the postganglionic nerves
    • M2 receptors
      • Present on pre-ganglionic sites and function to inhibit acetylcholine release
    • M3 receptors
      • Present on smooth muscle and coupled to Gq
      • Activation leads to increases in intracellular Ca2+ levels resulting in contraction of airway smooth muscle and bronchoconstriction
  • Atropine
    • The prototype anticholinergic bronchodilator
  • Ipratropium
    • A quaternary amine, which is poorly absorbed across biologic membranes
  • Atropine and ipratropium 
    • Antagonize the actions of Ach at parasympathetic, postganglionic, effector cell junctions by competing with Ach for M3 receptor sites
    • This antagonism of Ach results in airway smooth muscle relaxation and bronchodilation

17

Bronchodilators:
Anti-cholinergic drugs

  • Ipratropium is given exclusively by...
  • Tiotropium (Spiriva ®)
  • Tiotropium vs. ipratropium
  • Despite some concern about the safety of distinct delivery methods for tiotropium,...

  • Ipratropium is given exclusively by...
    • Inhalation from a metered-dose inhaler or a nebulizer
    • Inhaled ipratropium has a slow onset (about 30 minutes) and a relatively long duration of action (about 6 hours)
  • Tiotropium (Spiriva ®)
    • A structural analog of ipratropium
    • Approved for treatment of COPD
  • Tiotropium vs. ipratropium
    • Like ipratropium, tiotropium has high affinity for all muscarinic receptor subtypes
    • It dissociates from some receptors (i.e. M3) much more slowly than ipratropium
      • However, the rapid dissociation of tiotropium from M2 receptors limits its antagonism of these pre-junctional receptors and therefore does not interfere with pre-junctional inhibition of acetylcholine release
    • It is formulated for use with an oral inhalator with an once/day dosing
  • Despite some concern about the safety of distinct delivery methods for tiotropium,...
    • I.e. dry powder [Handi-Haler®] versus aqueous [Respimat®] inhaler
    • No differences in safety profile and exacerbation profile between the two inhalation methods

18

Bronchodilators:
Anti-cholinergic drugs

  • Anticholinergic therapy in asthma
  • Anticholinergic therapy in COPD
  • IMPORTANT CONCEPT 8: Anticholinergic agents

  • Anticholinergic therapy in asthma
    • Generally failed to show significant benefit in asthma
    • Improvement in post-bronchodilator forced expiratory volume in 1 second (FEV1) and reduced incidence of severe exacerbation in poorly controlled asthma patients taking once daily tiotropium (Spiriva®) as an add-on to their pretrial asthma medications
  • Anticholinergic therapy in COPD
    • This relative lack of efficacy in asthma contrasts with COPD, in which anticholinergic agents are among the most effective treatments
  • IMPORTANT CONCEPT 8: Anticholinergic agents
    • Effective for treatment of airway obstruction in COPD
    • Due to their inhibition of the reflex increases in parasympathetic activity that contributes to bronchoconstriction

19

Future pharmacological directions for asthma and COPD:
Vasoactive intestinal peptide analogs

  • Vasoactive intestinal peptide (VIP) 
  • A more stable cyclic analogue of VIP (Ro-25-1553) 

  • Vasoactive intestinal peptide (VIP)
    • Potent relaxant of constricted human airways in vitro
    • Degraded in the airway epithelium and ineffective in asthmatic patients
  • A more stable cyclic analogue of VIP (Ro-25-1553)
    • Has a more prolonged effect in vitro ad in vivo and is effective in asthmatic patients by inhalation

20

Future pharmacological directions for asthma and COPD:
Prostaglandin E2

  • PGE agonists that are selective for lung receptor subtypes are being considered for exploration as bronchodilator/anti-inflammatory drugs

21

Future pharmacological directions for asthma and COPD:
Atrial natriuretic peptides (ANP)

  • Intravenous infusion of ANP 
  • ANP
  • Urodilatin

  • Intravenous infusion of ANP
    • Produces a significant bronchodilator response
    • Protects against bronchoconstriction induced by inhaled bronchoconstrictors such as methacholine
  • ANP
    • A peptide and subject to rapid enzymatic degradation
  • Urodilatin
    • A related peptide
    • Less susceptible to degradation
    • Has a longer duration of action
    • As potent as salmeterol when given intravenously

22

Future pharmacological directions for asthma and COPD:
Phosphodiesterase 4 (PDE4) inhibitors

  • In animal models of asthma, PDE4 inhibitors...
  • The PDE4 inhibitor cilomilast 
  • PDE4B

  • In animal models of asthma, PDE4 inhibitors...
    • Reduce eosinophil infiltration and airway hyperresponsiveness to allergens
  • The PDE4 inhibitor cilomilast
    • Has been clinically tested in COPD
    • Causes emesis, which is a common side effect with this drug class (this could be due to inhibition of PDE4D)
  • PDE4B
    • There is hope that selective inhibitors of PDE4B might have more therapeutic potential

23

Future pharmacological directions for asthma and COPD:
Pharmacogenomics

  • The 16th amino acid position of the β2 adrenergic receptor
    • Associated with a major, clinically significant pharmacogenomic effect, namely down regulation of the receptor and responsiveness of patients using β-agonists
  • Investigations of the effect of this and other polymorphisms on the response to LABA are currently being conducted

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