Asthma is a chronic inflammatory condition affecting the airways and involves the production and activity of inflammatory cells such as mast cells, eosinophils, macrophages, and basophils. These inflammatory cells produce leukotrienes that are very potent smooth muscle constrictors.

The leukotrienes produced by the inflammatory cells are called cysteinyl leukotrienes LTC4, LTD4 and LTE4. These leukotrienes are released during the inflammatory process in response to certain antigens which can cause bronchoconstriction, increased mucous production and inflammation. Leukotrienes are 20-carbon units, and are produced in the body from arachidonic acid by enzyme 5-lipoxygenase. These leukotrienes are several thousand times more potent constrictors of bronchial smooth muscle than histamine.
Asthmatic patients are hyperresponsive to the bronchoconstrictor effects of cysteinyl leukotrienes. Their ability (cysteinyl leukotrienes) to impair airflow is augmented by the preexisting airway edema, mucus hypersecretion and reduced mucocillary clearance.

These medications listed below are useful for the treatment of moderate to severe allergic asthma in patients who are poorly controlled by conventional therapy or have increased side effects to secondary high-dose or prolonged corticosteroid treatment.

 
Zileuton:

1. Leukotriene antagonist /orally active inhibitor of 5-lipoxygenase, thus inhibits leukotrienes.
2. Selective inhibitor of 5-lipoxygenase which prevents formation of LTB4 and the cysteinyl leukotrienes.
   Zileuton is indicated for the prophylaxis and chronic treatment of asthma. Zileuton is not indicated for use in the reversal of bronchospasm in acute asthma attacks.

 Zafirlukast:

1. A leukotriene antagonist, is an oral leukotriene receptor antagonist (LTRA) for the maintenance treatment of asthma, often used in conjunction with an inhaled steroid and/or long-acting bronchodilator.
2. Selective, reversible inhibitor of cysteinyl leukotriene 1 receptor thereby blocking the effects of cysteinyl leukotrienes whic results in smooth muscle relaxation.
   

 Montelukast (singulair)

1. Is a leukotriene receptor antagonist (LTRA) used for the maintenance treatment of asthma.
2. Blocks the action of the D4 leukotriene on the cysteinyl leukotriene receptor in the lungs and bronchial tubes.
3. Reduces bronchoconstriction otherwise caused by the leukotrienes and results in less inflammation.

Allergic rhinitis is an allergic inflammation of the nasal airways, characterized by sneezing, itchy nose/eyes, watery rhinorrhea, and nasal congestion. It occurs when an allergen such as pollen or dust is inhaled by an individual with a sensitized immune system, and triggers antibody production. The specific antibody is immunoglobulin E (IgE) which binds to mast cells and basophils. The mast cells release mediators, such as histamine, leukoktrines, and chemotactic factors, which promote bronchiolar spasm and mucosal thickening from edema and cellular infiltration. Symptoms vary in severity between individuals. Very sensitive individuals can experience hives or other rashes. Particulate matter in polluted air and chemicals such as chlorine and detergents, which can normally be tolerated, can greatly aggravate the condition. Combinations of oral antihistamines with decongestants are the first-line therapies for allergic rhinitis. Systemic effects associated with oral preparations (sedation, insomnia, and rarely, cardiac arrhythmias) have prompted interest in topical intranasal delivery of drugs.

Antihistamines- suppress the histamine-induced wheal (swelling) and vasodilation (flare) response by blocking the binding of histamine to its receptors on nerves, vascular smooth muscle, glandular cells, endothelium, and mast cells. They effectively exert competitive antagonism of histamine for H1-receptors. Itching and sneezing are suppressed by antihistamine blockade of H1-receptors on nasal sensory nerves.

Αlpha-adrenergic agonists- like Phenylephrine or Neo-Synephrine are used primarily as a decongestant, and are sold as an oral medicine, as a nasal spray, or as eye drops. Oral Phenylephrine is now the most common (OTC) decongestant in the United States. Pseudoephedrine was historically more common, although its notoriety as a methamphetamine precursor has led some governments to restrict its sale. They are thought to constrict dilated arterioles in the nasal mucosa and reduce airway resistance, although recent studies have suggested that is no more effect as a decongestant than a placebo. The α-adrenergic agonists should be used no longer than several days due to the risk of rebound nasal congestion.

Corticosteroids- like beclomethasone, budesonide, fluticasone, flunisolide, and triamcinolone are effective when administered as nasal sprays to treat allergic rhinitis. (Patients should be educated not to deeply inhale these medications because the target tissue is the nose, not the lungs or throat. Topical steroids may be more effective than systemic antihistamines in relieving the nasal symptoms of both allergic and nonallergic rhinitis. These agents are thought to be relatively safe for long term usage. In the treatment of chronic rhinitis, improvement may not bees seen for 1-2 weeks after starting therapy.

Cromolyn-is a mast cell stabilizer, it blocks a calcium channel essential for mast cell degranulation, stabilizing the cell and thereby preventing the release of histamine and related mediators. One suspected pharmacodynamic mechanism is the blocking of IgE-regulated calcium channels. Without intracellular calcium, the histamine vesicles cannot fuse to the cell membrane and degranulate. Put simply this drug prevents the release of inflammatory chemicals such as histamine from mast cells. This drug may be useful, particularly when administered before contact with an allergen. For best results dosing should occur at least 1-2 weeks prior to allergen exposure. Side note-this drug does have a short duration of action requiring multiple daily doses which may impact adherence to therapy as well as therapeutic efficacy.

Antitussive agents: are cough suppressants. Codeine is the gold standard. Codeine decreases the sensitivity of cough centers in the central nervous system to peripheral stimuli and decreases mucosal secretion. Doses for cough suppressant does not provide analgesia but still have side effects such as constipation, dysphoria and fatigue. Dextromethorphan is a synthetic derivative of morphine that is used as a cough depressant. It has no analgesic action and shows some of the actions of codeine. It suppresses the response of the central cough center. Dextromethorphan has less side effects than codeine.

Expectorants: loosen mucus and help expel it from the respiratory tract.

N-acetylcysteine: is used as a mucolytic agent. It is a derivative of cysteine; an acetyl group is attached to the nitrogen atom. It is used as a cough medicine because it breaks disulfide bonds in mucus and liquefies it, making it easier to cough up. It is also this action of breaking disulfide bonds that makes it useful in thinning the abnormally thick mucus in Cystic Fibrosis patients.

Guaifenesin: is an expectorant. Guaifenesin is thought to act as an expectorant by increasing the volume and reducing the viscosity of secretions in the trachea and bronchi. It also stimulates the flow of respiratory tract secretions allowing ciliary movement to carry the loosened secretions upward toward the pharynx.

                                    Beta agonists:

Interact with beta receptors on the surface of a variety of cells that may play a role in asthma pathogenesis. Beta agonists have the potential to relax bronchial smooth muscle, decrease mast cell mediator release, inhibit neutrophil, eosinophil, and lymphocyte functional responses, increase mucociliary transport, and affect vascular tone and edema formation

Short-acting beta agonists: remain first-line therapy for the relief of acute symptoms and are effective for the prophylaxis of both exercise- and allergen-induced asthma. However, reliance on beta agonists to relieve symptoms chronically may result in the paradoxical situation in which symptom control becomes progressively more difficult to achieve due to delays in the use of other therapeutic agents (such as antiinflammatory drugs) that can reverse or attenuate other important pathophysiologic factors, including airway edema, mucus secretion, and inflammation.

The currently available inhaled SABAs have a rapid onset of action (within five minutes), an intermediate duration of effect (approximately four to six hours), and relative beta-2 selectivity The inhaled route of administration is preferred over oral administration because of the shorter time to relief, greater potency of bronchodilation, and fewer side effects. Patients who develop asthmatic symptoms as a result of predictable triggers (eg, exercise-induced bronchoconstriction) are encouraged to use their SABA approximately 10 minutes prior to exposure in order to prevent the development of symptoms.

Corticosteroids:

Patients with continued wheezing and shortness of breath despite intensive bronchodilator therapy most likely have persistent airflow obstruction on the basis of airway inflammation and intraluminal mucus plugging. Their rate of improvement typically slows after the first hour of treatment, since airway edema, cellular infiltration, and mucus hypersecretion resolve with a tempo far slower than smooth muscle constrictio]. Among patients with significant airflow obstruction despite intensive treatment with bronchodilators, systemic glucocorticoids speed the rate of improvement.

Current guidelines encourage early systemic glucocorticoids for all patients who have a moderate (peak expiratory flow <70 percent of baseline) or severe exacerbation (peak expiratory flow <40 percent of baseline; in the urgent care setting, the criterion for a severe asthmatic attack changes from the <50 percent used for decision-making at home to <40 percent), or in whom inhaled short-acting beta agonists do not fully correct the decrement in peak flow. In the past, systemic glucocorticoids were commonly withheld for many hours and even days, while treating with bronchodilators and awaiting gradual spontaneous improvement in airway inflammation. Supplemental systemic glucocorticoids should be administered promptly to any patient who develops an asthma exacerbation despite daily or alternate day oral glucocorticoid therapy.

In general, the onset of action of systemic glucocorticoids is not clinically apparent until as long as six hours after administration. Thus, the beneficial effect is not likely to be observed during the few hours that the patient spends in the medical office or emergency department. Early administration helps to minimize the delay in improvement anticipated with systemic glucocorticoids.

Inhaled anticholinergics:

 At present, the use of inhaled ipratropium is usually reserved for patients with severe airflow obstruction failing to improve despite repeated administration of inhaled beta agonists. Other special circumstances in which such parasympatholytic therapy may be of particular benefit include treatment of patients on monoamine oxidase inhibitor therapy (who may have increased toxicity from sympathomimetic therapy due to impaired drug metabolism), patients with chronic obstructive pulmonary disease with an asthmatic component, and patients whose asthma has been triggered by beta-blocker therapy.

                          Leukotriene antagonists:

The sulfidopeptide leukotrienes: (leukotriene C4, D4 and E4) are potent chemical mediators of the allergic response in asthma. Their actions include stimulation of bronchoconstriction (1000-fold more potent than histamine), mucus hypersecretion, microvascular leakage with edema formation, and eosinophil chemoattraction. Two types of medications that block these leukotriene effects are now available: a 5-lipoxygenase enzyme inhibitor that blocks production of leukotrienes, and leukotriene receptor antagonists that competitively inhibit the action of leukotrienes at their receptor.

The leukotriene modifying drugs in use in the United States include: zafirlukast, montelukast, and zileuton All are orally administered. Zileuton currently requires monitoring for liver function abnormalities and is not recommended for routine use in mild persistent asthma.
• Zafirlukast (Accolate) was the first drug available in the category of leukotriene receptor antagonists (LTRAs). In adolescents and adults, the dosing for zafirlukast is 20 mg administered twice daily. Absorption is optimized by ingestion of the medication on an empty stomach. Zafirlukast is metabolized in the liver by CYP2C9. The only significant drug interaction is with warfarin, resulting in an increase in the prothrombin time.
• Montelukast (Singulair) is also a LTRA. The dose in adolescents and adults is 10 mg once daily . No significant drug interactions have been reported. In most clinical trials montelukast was administered in the evening; however, there is no clinical evidence that favors evening versus morning dosing.

The leukotriene modifying drugs, however, are generally less effective than inhaled glucocorticoids. It appears that some people with asthma respond well to the leukotriene-blocking drugs, whereas others do not. These differences likely relate to variability among patients in the relative contribution of leukotriene over-expression to the pathogenesis of their asthma. Anti-leukotriene agents may also be helpful in the setting of mild persistent asthma in which exercise-induced bronchospasm is a prominent feature . Leukotriene receptor antagonists inhibit exercise-induced bronchoconstriction and chronic use is not associated with tachyphylaxis, unlike long-acting inhaled beta agonists.

Cromolyn:

 is an alternative medications for prevention of exercise-induced bronchoconstriction or prevention of asthma symptoms caused by predictable allergic exposures (eg, visiting a home with a cat) Ccromolyn is not available in the United States, in a metered dose inhaler; the only remaining formulation for asthma is the solution of cromolyn for nebulization. HFA-based and dry powder inhaler formulations for cromolyn and nedocromil are available in many other countries.

These agents prevent bronchospasm through mast-cell stabilizing and other properties, although they DO NOT have acute bronchodilating capacity. They have the advantage of being virtually devoid of adverse side effects, aside from a mildly unpleasant taste with nedocromil that is experienced by some individuals.
efficacy — Two inhalations of either cromolyn taken approximately 10 to 20 minutes prior to exercise or other trigger exposure have been shown to be effective preventive treatment in blinded, placebo-controlled studies. This medication provides additive protection when used in combination with an inhaled beta agonist prior to exercise.

The prescription of inhaled beta agonists as monotherapy for intermittent asthma has the advantage of providing both prevention and relief of symptoms, compared to the cromoglycates, which are preventive only.

Theophylline:

The use of theophylline to treat asthma has undergone several cycles of enthusiasm and unpopularity over the past 50 years. The dissemination of clinical practice guidelines that list theophylline as a "not preferred" alternative, the availability of newer agents, and concerns regarding the risk-benefit ratio of the drug have resulted in infrequent prescribing of theophylline. Nevertheless, its low cost offers an advantage over other long-term maintenance medications that are added to inhaled glucocorticoids, such as montelukast and long-acting beta agonists.

Therapeutic actions: Though traditionally classified as a bronchodilator, the ability of theophylline to control chronic asthma appears disproportionately greater than is explainable by its modest degree of bronchodilator activity alone. Theophylline has antiinflammatory, immunomodulatory, and bronchoprotective effects that potentially contribute to its efficacy as a prophylactic anti-asthma drug.

In patients with allergic asthma, it attenuates the late phase increase in airway obstruction and airway responsiveness to histamine, decreases allergen-induced migration of activated eosinophils into the bronchial mucosa, and decreases the sputum eosinophil count . Moreover, withdrawal of theophylline from patients with severe chronic asthma receiving high-doses of inhaled glucocorticoid therapy results in increased symptoms of asthma accompanied by an increase in the number of activated cytotoxic T-lymphocytes in the bronchial mucosa and an increase in helper T-lymphocytes in the airway epithelium.
Although several molecular mechanisms have been proposed to explain the actions of theophylline, the non-specific inhibition of phosphodiesterase that occurs at clinically relevant drug concentrations appears to be the most important. Theophylline increases the intracellular concentration of cyclic nucleotides in airway smooth muscle and inflammatory cells by inhibiting phosphodiesterase-mediated hydrolysis. However, inhibition of specific isozymes may also be important; inhibition of phosphodiesterase type III and type IV relaxes smooth muscles in pulmonary arteries and in airways , while antiinflammatory and/or immunomodulatory actions probably result from inhibition of the type IV isozymes . 

There are four common clinical circumstances in which theophylline may be indicated :
• Additive maintenance therapy in a patient whose asthma is not adequately controlled with conventional doses of inhaled glucocorticoids
• Primary maintenance therapy in a patient who is more likely to adhere to an oral than an inhaled regimen
• Primary maintenance therapy when the administration of an inhaled glucocorticoid is difficult or cumbersome, as in toddlers and preschool-age children
• Additive acute therapy in the intensive care unit for patients failing to respond to vigorous use of inhaled ß2-selective agonists and systemically administered glucocorticoids

Omalizumab:

Is a recombinant humanized IgG1 monoclonal antibody that binds IgE with high affinity and has been developed for the treatment of allergic diseases. In the United States, omalizumab is approved for use in patients 12 and older with moderate to severe persistent asthma, allergic sensitization to an allergen that is present year round (a perennial allergen), and symptoms that are inadequately controlled with inhaled glucocorticoids.

Mechanisms of action — Omalizumab binds to the third constant domain of the IgE heavy chain (C-epsilon-3), forming complexes that are subsequently cleared by the hepatic reticuloendothelial system. This binding inhibits interaction of circulating IgE with both high and low-affinity IgE receptors on mast cells, basophils, and other cell types. The antibody is specific to IgE and does not bind to IgG or IgA. An important property of omalizumab is that it cannot bind to IgE receptors or to IgE already attached to Fc-epsilon-RI, and therefore does not activate mast cells or basophils in this manner .Free IgE must be must be reduced to extremely low levels in order to achieve clinical efficacy. This is because there are 10,000 to 1,000,000 Fc-epsilon-RI on mast cells and basophils and nearly all are occupied by IgE. Only 2000 IgE molecules are needed for half-maximal release of histamine from basophils; therefore, a marked reduction in IgE is needed to prevent mast cell and basophil activation

Omalizumab therapy causes a marked down-regulation of Fc-epsilon-RI on the surface of basophils and mast cells

Route of administration — Omalizumab is approved for administration by subcutaneous injection. Initial trials demonstrated that aerosolized omalizumab was ineffective in protecting against allergen challenge and had no effect on circulating IgE .In contrast, parenteral use of the antibody significantly reduced the concentration of circulating free IgE and affected markers of asthma severity.
In patients receiving inhaled glucocorticoids therapy, treatment with omalizumab (compared to placebo) can result in a significant reduction in the dose of inhaled glucocorticoids required to control symptoms, and reduces the risk of exacerbations .

Approved indications in asthma — The Food and Drug Administration in the United States approved omalizumab for subcutaneous use in patients with moderate-to-severe persistent asthma, demonstrable sensitivity to a perennial aeroallergen, and incomplete symptom control with inhaled corticosteroid treatment in 2003 The 2007 National Asthma Education and Prevention Program (NAEPP) asthma guidelines recommended that omalizumab be considered as adjunctive therapy in step 5 or 6 care for patients with allergies and severe persistent asthma .

Dosing and administration — Omalizumab is administered by subcutaneous injection every two to four weeks in a dose that is determined by body weight and the levels of serum IgE (0.016 mg/kg per IU/mL of IgE per month). It should not be initiated in the setting of an acute exacerbation of asthma, nor should it be self-administered.

Therapy requires: a dose of 150 to 375 mg injected subcutaneously every two to four weeks. No more than 150 mg should be administered at a single site, to prevent local reactions. The elimination half-life of the drug is one to four weeks after subcutaneous administration.

Pretreatment testing — Total serum IgE levels should be between 30 and 700 international units/mL (IU/mL). Sensitization to a perennial aeroallergen (eg, dust mite, animal danders, cockroach, molds) must be demonstrated by positive skin testing or in vitro IgE testing.