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Case: agents used to treat asthma. Class

 

Asthma is characterized by acute episodes of bronchoconstriction caused by underlying airway inflammation. A common finding in asthmatics is an increased responsiveness of the bronchi and trachea to exogenous or endogenous stimuli that results in inappropriate contraction of smooth muscle in the airway, and production of thick viscid mucus and mucosal thickening from edema and cellular infiltration. Asthma typically occurs with both an early-phase response lasting approximately 1-2 hours that is triggered by autocoids and inflammatory mediators such as histamine, leukotrienes, and prostaglandins. Immunoglobulin E-sensitized (IgE-sensitized) mast cells play a key role in the early-phase response. The late-phase response that occurs 2-8 hours later is mediated by cytokines from T-helper type 2 (Th2) lymphocytes including granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukins 4, 5, 9, and 13. These mediators attract and activate eosinophils and increase IgE production by B cells. This leads to the chronic bronchoconstriction, continued mucus production, and cellular infiltration that typify the underlying inflammation in asthma.

There are currently six classes of drugs used to treat asthma: β-adrenoreceptor agonists, acetylcholine antagonists, glucocorticoids, leukotriene modifiers, chromones, and anti-IgE monoclonal antibodies. The National Asthma Education and Prevention Program has revised its 1997 guidelines on the treatment of asthma as illustrated in Table Recommendations for pharmacologic management of asthma.

Table: Recommendations for pharmacologic management of asthma in adults and children older than 5

Asthma Severity Symptom Frequency Medications
Mild intermittent <2 days/week,<2 nights/month None; course of systemic glucocorticoids for occasional, severe exacerbations
Mild persistent >2 per week but<once per day

>2 nights/month

Low-dose inhaled glucocorticoids. Alternate: cromolyn, nedocromil, leukotriene modifier, or sustained release theophylline
Moderate persistent Daily,>1 night/week Low- to medium-dose glucocorticoids and long-acting inhaled P2-agonists. Alternate: leukotriene modifier or theophylline
Severe persistent Continual during day, frequent at night High-dose glucocorticoids and long-acting inhaled β2-agonist and (if needed) systemic glucocorticoids

The recommendation for quick relief in all patients regardless of severity is two to four puffs of a short-acting inhaled β2-agonist one to three times per occurrence. Use of short-acting β2-agonists more than two times a week may indicate the need to initiate long-term therapy. Short-acting β2-selective drugs for use in asthma include albuterol, terbutaline, metaproterenol, and pirbuterol. These agents bind specifically to the β2-adrenergic receptor and avoid the cardiovascular effects of β1-activation. Activation of β2-receptors causes bron-chodilation. Onset of action occurs in minutes and lasts for 4-6 hours. Albuterol and terbutaline can be administered orally; terbutaline is available for subcutaneous injection for emergency treatment. Few side effects of short-term use of β2-agonist have been reported. Excessive use or the oral preparations may result in cardiovascular effects such as tachycardia.

Case_agents_used_to_treat_asthma

Long-acting inhaled β2-agonists, such as salmeterol and formoterol, have a much longer half-life (up to 12 hours). These agents are available in metered-dose inhalers that produce fewer side effects than systemic administration. Use of long-acting agents produces the same relaxation in airway smooth muscles and also appears to decrease the release of mediators from mast cells and lymphocytes. The long-acting agents should not be used to reverse an acute attack.

Glucocorticoids are an important treatment for mild persistent and more severe asthma. Glucocorticoids are potent anti-inflammatory agents and reduce the production of inflammatory mediators and cause apoptosis of leukocytes and decrease vascular permeability. They do not cause relaxation of bronchial smooth muscle. The glucocorticoids are used for the prophylactic treatment of asthma; they have no appreciable effect on an acute event. Glucocorticoids administered by inhalation provide a high concentration of drug where needed and minimizes the amount in the systemic circulation. However, some drug is swallowed during inhalation and some drug is absorbed into the systemic circulation through the lung. Adverse effects are attributable to local effects of the glucocorticoids or the drug entering the systemic circulation. These include oral candidiasis, increased loss of calcium from bone, and rarely, suppression of the hypothalamic-pituitary-adrenal axis. Systemic use of glucocorticoids is recommended in patients with severe persistent asthma (see Table Recommendations for pharmacologic management of asthma).

Leukotrienes B4, C4, and D4 play an important role in the pathogenesis of asthma. LCB4 is a potent neutrophile chemoattractant, and LTC4 and LTD4 are involved in bronchoconstriction and overproduction of airway mucus. These mediators are derived from arachidonic acid via the enzyme 5-lipoxygenase. Two classes of drugs have been developed that interfere with leukotrienes. Zileuton is an inhibitor of 5-lipoxygenase and thereby decreases the biosynthesis of leukotrienes. Zafirlukast and montelukast are specific, competitive, Cys-LTl receptor antagonists. The Cys-LTl receptor is responsible for mediating the bronchoconstrictor activity of all leukotrienes. The two classes of drugs are equally effective in the treatment of mild-to-moderate persistent asthma and appear to be about as effective as low-dose inhaled glucocorticoids. All of the leukotriene modifiers are administered orally; the receptor antagonists may be taken once or twice a day, zileuton is taken four times a day. Zileuton has been associated with liver toxicity, and monitoring liver enzymes is recommended.

The methylxanthines include theophylline, theobromine, and caffeine; theophylline is used as a second-line agent to treat asthma. Theophylline was originally thought to act by inhibiting cyclic nucleotide phosphodiesterases, thereby increasing intracellular cAMP and cyclic guanosine monophosphate (cGMP). Theophylline is also an antagonist of adenosine receptors, and this mechanism of action might be especially important in asthma because activation of pulmonary adenosine receptors results in bronchoconstriction. However, the precise mechanism of action of theophylline in the lung remains controversial. Theophylline produces bronchodilation and improves long-term control of asthma. Theophylline is available for oral administration, as a suppository, and for parenteral use. Plasma levels of theophylline show considerable variability between patients, and the drug has a narrow therapeutic window; blood levels need to be monitored. Infants and neonates have the slowest rates of clearance.

The chromones, cromolyn and nedocromil, are unique drugs used for the prophylaxis of mild-to-moderate persistent asthma. A variety of mechanisms of action have been proposed for these agents including inhibition of mediator release from mast cells and suppression of activation of leukocytes. These various effects are now thought to be mediated by inhibition of various chloride channels that are responsible for secretion and cellular activation. They have no effect on airway smooth muscle tone and are ineffective in reversing bronchospasm; thus they are truly for prevention. Both agents are administered by inhalation and are effective in reducing both antigen and exercise-induced asthma. They are poorly absorbed into the systemic circulation and have mild adverse effects including throat irritation, cough, and nasal congestion. More serious adverse reactions including ana-phylaxis, anemia, and pulmonary infiltration are rare.

Inhaled acetylcholine muscarinic cholinoreceptor antagonists have a use in treatment of asthma, but they have been somewhat superseded by other agents. Muscarinic antagonists can effectively block the bronchoconstriction, and the increase in mucus secretion that occurs in response to vagal discharge. Ipratropium bromide is a quaternary ammonium derivative of atropine that can be administered by inhalation and that is poorly absorbed into the systemic circulation. Ipratropium bromide causes variable degrees of bronchodilation in patients; this may reflect the variable degree that parasympa-thetic stimulation contributes to asthma in individual patients. Ipratropium bromide is useful in patients that are unresponsive or cannot tolerate β2-receptor agonists and in COPD. In addition, ipratropium bromide increases the bron-chodilator activity of albuterol in the treatment of severe acute attacks.

IgE bound to mast cells plays an important role in antigen-induced asthma. A newly developed monoclonal antibody that targets circulating IgE and prevents its interaction with mast cells has recently been approved for the treatment of asthma. By decreasing the amount of IgE antibodies available to bind mast cells, IgE cross-linking is less likely and subsequently, the mast cell release of those mediators is decreased. In clinical trials, omalizumab significantly reduced IgE levels and reduced the magnitude of both the early- and late-phase responses to antigen. Omalizumab is indicated for adults and children older than 12 years with moderate-to-severe persistent asthma who have a positive skin test or in vitro reactivity to a perennial aeroaller-gen and whose symptoms are inadequately controlled with inhaled corticosteroids. The most frequent adverse events included injection site reaction, viral infections, upper respiratory tract infection (20%), sinusitis, headache, and pharyngitis. These events were observed at similar rates in omalizumab-treated patients and control patients. More serious adverse effects include malignancy (0.5%) and anaphylaxis.

 

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