25 Pharmacology 3: Bronchodilators Flashcards
1
Q
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
A
- 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
Q
The fundamental pathogenesis of asthma
A
- 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
Q
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,…
A
- 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
Q
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…
A
- 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
Q
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
A
- 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)
- Drugs that inhibit smooth muscle contraction
- 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
Q
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
A
- 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
Q
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
A
- 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
Q
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…
A
- 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
- Activation of adenyl cyclase via…
- 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
Q
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
A
- 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
Q
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…
A
- 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
Q
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…
A
- 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
Q
Bronchodilators:
Beta-adrenergic agonists:
Alternative signaling
- ß2 adrenergic receptors may also undergo…
- This could be responsible for…
- Nadolol
A
- 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
Q
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
A
- 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
Q
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
A
- 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
Q
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…
A
- 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
Q
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
A
- 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
- M1 receptors
- 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
Q
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,…
A
- 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
Q
Bronchodilators:
Anti-cholinergic drugs
- Anticholinergic therapy in asthma
- Anticholinergic therapy in COPD
- IMPORTANT CONCEPT 8: Anticholinergic agents
A
- 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
