Pulmonary System

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Chapter 24 Pulmonary System

Beta 2 (β2) Agonists (Bronchodilators)

Description

β2 Agonists are selective agonists for the β2-adrenergic receptor. They are relatively selective and therefore also stimulate the β1 receptor, but to a far lesser degree.

Prototype and Common Drugs

Short-Acting (Duration 3 to 4 Hours) β2 Agonists (SABAs)

image Prototype: salbutamol (albuterol)
image Others: terbutaline, levalbuterol, pirbuterol

Long-Acting (Duration >12 Hours) β2 Agonists (LABAs)

image Prototype: salmeterol
image Others: formoterol

MOA (Mechanism of Action)

image Bronchoconstriction is one of the hallmarks of asthma.
image Stimulation of β2 receptors in bronchial smooth muscle results in relaxation of bronchial smooth muscle. This results in a larger diameter airway, resulting in lower resistance to airflow in and out of the lungs (Figure 24-1).
image On a cellular level, the binding of an agonist to the β2 receptors on bronchial smooth muscle activates an enzyme, adenylate cyclase, which converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). It is these elevated levels of cAMP that lead to bronchodilation.
image β2 Receptors are also found on other cells in the lung, including inflammatory cells.
image

Figure 24-1

Pharmacokinetics

image These drugs are all typically administered via inhalation: via metered dose inhaler (MDI), dry powder inhaler, or nebulizer (atomizes liquid drug into a mist). Inhalation delivers the drug to the lungs, where the highest concentrations are desired, thereby reducing the probability of side effects.
image Salbutamol is sometimes given as an intravenous infusion and is also available in oral form.
image Response to SABAs is rapid (response time 5 minutes) compared with inhaled anticholinergics (30 minutes).
image For LABAs, the response time of formoterol is similar to that of SABAs (5 minutes), but the onset of action of salmeterol is longer (15 to 20 minutes).
image Systemic uptake of inhaled drugs is significant, and sympathetic stimulation limits the maximum dose.
image Swallowing of drug that is deposited in the mouth and saliva will contribute to systemic absorption.

Indication

image Relief of bronchospasm from any cause:

image Asthma
image Emphysema (chronic obstructive pulmonary disease [COPD])
image Anaphylaxis
image Aspiration (inhalation of liquid or solid matter)

Contraindications

image Severe bronchospasm is life-threatening. Therefore the indication for a β2 agonist would outweigh most reasons not to give it.
image β2 Agonists and (more accurately) β1 agonists must be given with caution to patients in whom tachycardia is undesirable. These conditions include (but are not limited to) patients with severe coronary artery disease and aortic stenosis.

Side Effects

image All side effects are related to overstimulation of β2 and β1 receptors and include primarily:

image Tachycardia and palpitations
image Tremor
image β Stimulation is involved with shifting K+ ions into cells. Therefore blood levels of K+ can be abnormally low (hypokalemia).
image β Stimulation is also involved with glucose metabolism, and excessive stimulation can result in hyperglycemia.

Important Notes

image SABAs as required may be used as sole therapy in mild episodic asthma. Neither SABAs nor LABAs should be used as sole therapy in persistent asthma but should be combined with antiinflammatory therapy.
image The combination of LABAs and ICSs has become standard therapy in the management of asthma. There are two reasons why this combination is believed to be so effective. First, the use of a bronchodilator is believed to open up the airways to improve distribution of the steroid. Second, it appears that chronic ICS use up-regulates β2 receptors in the lungs. This is important because chronic use of β2 agonists is believed to lead to a down-regulation of β2 receptors in the lungs. Some available drugs are combinations of a bronchodilator and steroid together in one inhaler (Table 24-1).
image Although use of ICS-LABA combinations is now a routine practice, the use of LABAs as monotherapy has prompted a lingering safety concern that has plagued these agents since their introduction into the market.
image Pirbuterol is available in a breath-actuated MDI, meaning that the inhaler releases drug in response to patient inhalation.

TABLE 24-1 Fixed-Dose Combinations of Inhalers

Salmeterol + fluticasone Advair
Formoterol + budesonide Symbicort
Salbutamol + ipratropium Combivent

Evidence

Long-Acting β Agonists with or without Inhaled Corticosteroids in Adults or Children with Asthma

image A 2007 Cochrane review (67 studies, 42,333 participants) examined the use of LABAs (salmeterol, 50 studies; formoterol, 17 studies) versus placebo. In these studies, patients were followed for 4 to 52 weeks. Patients were allowed to combine inhaled corticosteroids (ICSs) with LABAs in 40 studies, 24 studies did not permit ICSs, and three studies were unclear about ICS use. Use of LABAs, with or without ICSs, was associated with improvements in pulmonary function, symptoms, rescue medication use, and quality-of-life scores.

Formoterol Plus Inhaled Corticosteroids in Asthma

image A 2009 Cochrane review (3 studies, N = 5905 patients) compared combinations of formoterol and ICSs with SABAs alone for relief of asthma symptoms. No clinically important advantages were found for the combination in patients with mild asthma. However, in more severe asthma, one study found that patients not well controlled on high-dose ICSs and who had had an exacerbation in the prior year had a reduced risk of exacerbations requiring oral steroids when using the combination versus terbutaline or formoterol monotherapy for relief. A study in children also found less serious adverse events with the combination of budesonide and formoterol for maintenance and relief.

Regular Formoterol versus Placebo or Short-Acting β Agonists in Chronic Asthma

image A 2008 Cochrane review (22 studies, 8032 patients) compared serious adverse event rates for regular formoterol use with placebo or SABAs in chronic asthma. Nonfatal serious adverse events were increased versus placebo (odds ratio [OR] 1.57), but no increase was detected versus salbutamol or terbutaline. The increased risk over placebo was also seen in patients taking ICSs.

FYI

image Levalbuterol is a purified isomer of albuterol, a formulation that was supposed to result in fewer side effects. However, this has yet to be established in clinical trials.

Inhaled Anticholinergics

Description

Inhaled anticholinergics antagonize the muscarinic receptor.

Prototype and Common Drugs

image Prototype: Ipratropium
image Others: tiotropium

MOA (Mechanism of Action)

image Parasympathetic stimulation of muscarinic receptors of the bronchioles results in bronchoconstriction and also increased bronchial secretions. These actions are largely mediated through M3 receptors, and to a lesser extent, M1 (Figure 24-2).
image Antagonism of these muscarinic receptors prevents bronchoconstriction and reduces secretions. Tiotropium has greater selectivity for M3 receptors than ipratropium, which is considered to be relatively nonspecific for M1, M2, and M3 receptors. The clinical significance of this increased specificity has not been established.
image

Figure 24-2

Pharmacokinetics

image Ipratropium and tiotropium are inhaled. They are quaternary compounds (therefore polarized and not apt to cross hydrophobic cell membranes). They do not readily cross the pulmonary membranes into the blood. Therefore, systemic absorption is low.
image A lot of the drug ends up being swallowed. However, absorption from the gastrointestinal (GI) tract is also very low.
image Compared with salbutamol, onset and duration of action are prolonged, likely because of minimal absorption from the lung.
image Peak effect occurs at 30 to 90 minutes (slightly later than salbutamol). Duration is approximately 6 hours.
image The duration of tiotropium is further prolonged (24 hours), because of its slow dissociation from receptors.

Indications

image Acute asthma, but not as a first-line drug
image COPD: both in acute exacerbations and also for chronic maintenance

Contraindications

image None of major significance
image When anticholinergics are used, caution should be exercised in patients who have conditions that would be exacerbated by cholinergic antagonism, such as glaucoma and urinary retention. However, because inhaled anticholinergics have low systemic absorption, this is typically not an issue in most patients.

Side Effects

image Side effects are minimal because of minimal systemic absorption. Side effects would include the predictable effects of muscarinic antagonism in various organs.
image Local reactions such as dry mouth, nasal irritation, and nose bleeds are not uncommon.

Important Notes

image Ipratropium is slightly slower to act and possibly less effective than β2 agonists for treatment of bronchial asthma.
image Tiotropium is administered once daily, therefore providing a potential convenience advantage over ipratropium.

Evidence

Cardiovascular Safety

image A 2008 meta-analysis (17 trials, N = 14,783 patients) found an increased risk of the composite of cardiovascular death, myocardial infarction (MI), and stroke in patients on inhaled anticholinergics (1.8%) versus control therapy (1.2%). Specifically, risk of MI and cardiovascular death was increased, whereas risk of stroke was not.

Ipratropium versus Short-Acting β2 Agonists in Chronic Obstructive Pulmonary Disease

image A 2006 Cochrane review (11 studies, N = 3912 patients) found small benefits of ipratropium over SABAs on measures of lung function, quality of life, and the requirement for oral steroids. The combination of ipratropium and SABAs was better than a β2 agonist alone with respect to postbronchodilator lung function and a reduction in the need for oral steroids.

FYI

image Ipratropium (Atrovent) was derived from atropine.
image Asthma cigarettes, containing alkaloids from the belladonna plant, were an early and controversial treatment for asthma. These were the earliest inhaled anticholinergics and were used until the mid-twentieth century.

Leukotriene Receptor Antagonists

Description

Leukotriene receptor antagonists (LTRAs) are a newer class of drug used to treat bronchoconstriction. As the name implies, they antagonize leukotriene (LT) receptors. These drugs are taken orally (not inhaled).

Prototype and Common Drugs

image Prototype: montelukast
image Others: zafirlukast

MOA (Mechanism of Action)

image Leukotrienes are biologically active fatty acids derived from the oxidative metabolism of arachidonic acid, via the enzyme 5-lipoxygenase.
image LT receptors such as LTC4 and LTD4 exert several effects that are commonly associated with asthma:

image Bronchoconstriction
image Hyperresponsive airways
image Mucosal edema
image Mucous hypersecretion

image Leukotriene receptor antagonists competitively and selectively block the LTD4 receptor (Figure 24-3).
image

Figure 24-3

Pharmacokinetics

image Zafirlukast inhibits liver enzymes (CYP3A4) and therefore can increase the effects of warfarin.

Indications

image These drugs are not indicated for acute exacerbations of the disease. They are recommended for prophylaxis and chronic treatment of asthma.
image LTRAs can be tried when an inhaled steroid cannot be used, or if the inhaled steroid dose cannot be increased.

Contraindications

image None of major significance

Side Effects

Common and Not Serious

image Headache, vomiting, diarrhea

Rare and Serious

image Churg-Strauss syndrome (allergic granulomatosis) may occur. Rare in this case means 34.6 per million person-years. If 1 million people took the drug for 1 year, 35 patients would develop Churg-Strauss syndrome.

Evidence

LRTAs versus Inhaled Corticosteroids (ICSs) for Chronic Asthma

image A 2000 Cochrane review (27 trials) compared the safety and efficacy of antileukotrienes to ICS in mild to moderate asthma. Patients treated with antileukotrienes were more likely to have an exacerbation requiring systemic steroids (NNH = 26). ICS also improved pulmonary functions (FEV1), symptoms, nocturnal awakenings, rescue medication use, and quality of life to a greater extent than did antileukotrienes. More patients treated with antileukotrienes withdrew due to poor asthma control. The risk of side effects was no different between groups.

LTRAs Plus ICSs versus ICSs Alone for Chronic Asthma

image A 2002 Cochrane review (27 studies) evaluated the effect of adding LTRAs to patients already treated with ICS for chronic asthma. The findings supported a modest improvement to lung function tests. There were statistically non-significant improvements in the need for rescue β2 agonists.

LTRAs Plus ICSs versus Long-Acting β2 Agonists (LABAs) Plus ICSs for Chronic Asthma

image A 2006 Cochrane review (16 studies) evaluated the effect of adding LTRAs vs. LABAs to ICS in patients with chronic asthma. The findings showed a lower rate of requiring systemic steroids (RR = 0.83) with LABAs. Other endpoints including lung function tests, symptoms, and use of rescue β2 agonists were also superior with LABAs. Withdrawals from treatment and side effects were similar in both groups.

FYI

image Zileuton is a 5-lipoxygenase inhibitor approved for use in the United States but not in some other jurisdictions, due to safety concerns.
image LTs were originally discovered in leukocytes, hence their prefix.
image An ene bond is one in which there are two bonds between two carbon atoms (C=C). Leuktrienes have three of these bonds. The ane bond is a single bond (C–C).
image Zafirlukast is administered twice a day. Montelukast is administered once a day.

Methylxanthines

Description

Xanthine is a purine base that can be found in both plants and animals. Methylxanthine is a methylated derivative of xanthine. A class of drug that has been around for a very long time, methylxanthines are administered orally but can have significant toxicities.

Prototype and Common Drugs

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