CLINICAL PHARMACOLOGY OF BRONCHODILATORS, ANTICOUGH AND EXPECTORANT. CLINICAL PHARMACOLOGY OF AGENTS INFLUENCING IMMUNOLOGY SYSTEM
Asthma is an airway disorder characterized by bronchoconstriction, inflammation, and hyperreactivity to various stimuli. Resultant symptoms include dyspnea, wheezing, chest tightness, cough, and sputum production. Wheezing is a highpitched, whistling sound caused by turbulent airflow through an obstructed airway. Thus, any condition that produces significant airway occlusion can cause wheezing. However, a chronic cough may be the only symptom for some people.
Symptoms vary in incidence and severity from occasional episodes of mild respiratory distress, with normal functioning between “attacks,” to persistent, daily, or continual respiratory distress if not adequately controlled. Inflammation and damaged airway mucosa are chronically present, even when clients appear symptom free.
Acute symptoms of asthma may be precipitated by numerous stimuli, and hyperreactivity to such stimuli may initiate both inflammation and bronchoconstriction. Viral infections of the respiratory tract are often the causative agents, especially in infants and young children whose airways are small and easily obstructed. Asthma symptoms may persist for days or weeks after the viral infection resolves. In about 25% of patients with asthma, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) can precipitate an attack. Some patients are allergic to sulfites and may experience life-threatening asthma attacks if they ingest foods processed with these preservatives (eg, beer, wine, dried fruit). The Food and Drug Administration (FDA) has banned the use of sulfites on foods meant to be served raw, such as open salad bars. Patients with severe asthma should be cautioned against ingesting food and drug products containing sulfites or metabisulfites. Gastroesophageal reflux disease (GERD), a common disorder characterized by heartburn and esophagitis, is also associated with asthma. Asthma that worsens at night may be associated with nighttime acid reflux. The reflux of acidic gastric contents into the esophagus is thought to initiate a vagally mediated, reflex type of bronchoconstriction. (Asthma may also aggravate GERD, because antiasthma medications that dilate the airways also relax muscle tone in the gastroesophageal sphincter and may increase acid reflux.) Additional precipitants may include allergens (eg, pollens, molds, others), airway irritants and pollutants (eg, chemical fumes, cigarette smoke, automobile exhaust), cold air, and exercise.
Acute episodes of asthma may last minutes to hours. Bronchoconstriction (also called bronchospasm) involves strong muscle contractions that narrow the airways. Airway smooth muscle extends from the trachea through the bronchioles. It is wrapped around the airways in a spiral pattern, and contraction causes a sphincter-type of action that can completely occlude the airway lumen. Bronchoconstriction is aggravated by inflammation, mucosal edema, and excessive mucus and may be precipitated by the numerous stimuli described above.
When lung tissues are exposed to causative stimuli, mast cells release substances that cause bronchoconstriction and inflammation. Mast cells are found throughout the body in connective tissues and are abundant in tissues surrounding capillaries in the lungs. When sensitized mast cells in the lungs or eosinophils in the blood are exposed to allergens or irritants, multiple cytokines and other chemical mediators (eg, acetylcholine, cyclic guanosine monophosphate [GMP], histamine, interleukins, leukotrienes, prostaglandins, and serotonin) are synthesized and released. These chemicals act directly on target tissues of the airways, causing smooth muscle constriction, increased capillary permeability and fluid leakage, and changes in the mucus-secreting properties of the airway epithelium.
Bronchoconstrictive substances are antagonized by cyclic adenosine monophosphate (cyclic AMP). Cyclic AMP is an intracellular substance that initiates various intracellular activities, depending on the type of cell. In lung cells, cyclic AMP inhibits release of bronchoconstrictive substances and thus indirectly promotes bronchodilation. In mild to moderate asthma, bronchoconstriction is usually recurrent and reversible, either spontaneously or with drug therapy. In advanced or severe asthma, airway obstruction becomes less reversible and worsens because chronically inflamed airways undergo structural changes (eg, fibrosis, enlarged smooth muscle cells, and enlarged mucous glands), called “airway remodeling,” that inhibit their function.
DRUG THERAPY
Two major groups of drugs used to treat asthma, acute and chronic bronchitis, and emphysema are bronchodilators and anti-inflammatory drugs. Bronchodilators are used to prevent and treat bronchoconstriction; anti-inflammatory drugs are used to prevent and treat inflammation of the airways. Reducing inflammation also reduces bronchoconstriction by decreasing mucosal edema and mucus secretions that narrow airways and by decreasing airway hyperreactivity to various stimuli.
BRONCHODILATORS
Beta 2 Agonists
Beta 2 Agonists are a group of medications formulated to act on special receptors called beta-2 receptors, located predominantly on smooth muscle and mucous membrane in the lungs and smaller airways. They also act on cells called mast cells to prevent release of substances which play a role in asthma attacks. Additionally, they may help clear mucous from the lungs. As the airways dilate, any mucous present can move more freely and can be coughed out of the airways.
There are two categories of beta 2 agonists used in asthma:
Short/ Intermediate acting agents:
(Salbutamol, Isoproterenol, Albuterol, Metaproterenol and Terbutaline) – these are usually administered via devices, to deliver the medication straight to the lungs (ie puffers, nebulisers, inhaler). They act within 30 minutes and last for about 4-6 hours. They are often used as needed, to control symptoms. They are quick acting agents, relieving asthma symptoms by opening the airways.
They remain first line agents for relief of acute symptoms and can be effective for both exercise and allergens induced asthma. Care must be taken to ensure that beta agonists are combined with other types of treatment to provide the best control of disease and symptoms, in the long run. They only act acutely and have no sustained actions on other factors involved in diseases such as airways inflammation, oedema and mucous secretion. Increasing usage of beta agonists is a sign of unstable asthma, that needs to be better controlled.
Longer acting agents:
(Salmeterol and Formoterol) – these are usually taken via the inhaled route, through the nose and mouth and last for about 12 hours. These medications are best taken on a regular basis, to provide the best control of your symptoms and can be used in conjunction with glucocorticoids to provide additional control.
You can take beta agonists via different delivery systems, ranging from metered dose inhalers, nebulised solutions, oral liquids and tablets to dry powder inhalers. The route of delivery of the medication can play a role in determining how effective it is in treating your symptoms. It has been suggested that bronchodilator medications taken through the mouth or given as an injection into the veins is more effective than inhaled routes of delivery because this allows bypassing of mucous plugs that may block the airways. However, there is an increased risk of side effects associated with these modes of delivery.
There have been clinical studies performed which compare beta agonists given by two different routes – nebulised (inhaled) and intravenously (through the veins). Some earlier studies suggested advantages with giving medications through the veins, but subsequent studies with medications such as terbutaline and albuterol have demonstrated equivalent or superior effects on lung function using the nebulized (inhalation) route.
Another study involving 15 trials and 584 patients compared the outcomes achieved with the use of beta agonist therapy via the veins, for acute asthma. Intravenous therapy was not associated with improved outcomes in the study population or any identified subgroup.
Epinephrine may be injected subcutaneously in an acute attack of bronchoconstriction, with therapeutic effects in approximately 5 minutes and lasting for approximately 4 hours. However, an inhaled selective beta2 agonist is the drug of choice in this situation. Epinephrine is also available without prescription in a pressurized aerosol form (eg, Primatene).
Almost all over-the-counter aerosol products promoted for use in asthma contain epinephrine. These products are often abused and may delay the client from seeking medical attention. Clients should be cautioned that excessive use may produce hazardous cardiac stimulation and other adverse effects.
Albuterol, bitolterol, levalbuterol, and pirbuterol are short-acting beta2-adrenergic agonists used for prevention and treatment of bronchoconstriction. These drugs act more selectively on beta2 receptors and cause less cardiac stimulation than epinephrine. Most often taken by inhalation, they are also the most effective bronchodilators and the treatment of first choice to relieve acute asthma. Because the drugs can be effectively delivered by aerosol or nebulization, even to young children and patients on mechanical ventilation, there is seldom a need to give epinephrine or other nonselective adrenergic drugs by injection.
The beta2 agonists are usually self-administered by metereddose inhalers (MDIs). Although most drug references still list a regular dosing schedule (eg, every 4 to 6 hours), asthma experts recommend that the drugs be used wheeeded (eg, to treat acute dyspnea or prevent dyspnea during exercise). If these drugs are overused, they lose their bronchodilating effects because the beta2-adrenergic receptors become unresponsive to stimulation. This tolerance does not occur with the long-acting beta2 agonists.
Formoterol and salmeterol are long-acting beta2-adrenergic agonists used only for prophylaxis of acute bronchoconstriction. They are not effective in acute attacks because they have a slower onset of action than the shortacting drugs (up to 20 minutes for salmeterol). Effects last exercise-induced asthma. In high doses, metaproterenol loses some of its selectivity and may cause cardiac and central nervous system (CNS) stimulation.
Terbutaline is a relatively selective beta2-adrenergic agonist that is a long-acting bronchodilator. When given subcutaneously, terbutaline loses its selectivity and has little advantage over epinephrine. Muscle tremor is the most frequent side effect with this agent.
The use of sympathomimetic agents by inhalation at first raised fears about possible cardiac arrhythmias and about hypoxemia acutely and tachyphylaxis or tolerance when given repeatedly. It is true that the vasodilating action of 2-agonist treatment may increase perfusion of poorly ventilated lung units, transiently decreasing arterial oxygen tension (PaO2). This effect is usually small, however, and may occur with any bronchodilator drug; the significance of such an effect depends on the initial PaO2 of the patient. Administration of supplemental oxygen, routine in treatment of an acute severe attack of asthma, eliminates any concern over this effect. The other concern, that -agonist treatment may cause lethal cardiac arrhythmias appears unsubstantiated. In patients presenting for emergency treatment of severe asthma, irregularities in cardiac rhythm improve with the improvements in gas exchange effected by bronchodilator treatment.
The concept that -agonist drugs cause worsening of clinical asthma by inducing tachyphylaxis to their own action remains unestablished. Most studies have shown only a small change in the bronchodilator response to stimulation after prolonged treatment with -agonist drugs, but some studies have shown a loss in the ability of -agonist treatment to inhibit the response to subsequent challenge with exercise, methacholine, or antigen challenge (referred to as a loss of bronchoprotective action).
Fears that heavy use of -agonist inhalers could actually increase morbidity and mortality have not been borne out by careful epidemiologic investigations. Heavy use most often indicates that the patient should be receiving more effective prophylactic therapy with corticosteroids.
Although it is true that 2-adrenoceptor agonists appear to be safe and effective bronchodilators for most patients, there is some evidence that the risk of adverse effects from chronic treatment with long-acting agonists may be greater for some individuals, possibly as a function of genetic variants for the receptor. Two retrospective and one prospective study have shown differences between patients homozygous for glycine versus arginine at the B-16 locus of the receptor. Among patients homozygous for arginine, a genotype found in 16% of the Caucasian population in the
Xanthines
Pharmacodynamics of Methylxanthines
The methylxanthines have effects on the central nervous system, kidney, and cardiac and skeletal muscle as well as smooth muscle. Of the three agents, theophylline is most selective in its smooth muscle effects, whereas caffeine has the most marked central nervous system effects.
A. CENTRAL NERVOUS SYSTEM EFFECTS
In low and moderate doses, the methylxanthinesespecially caffeinecause mild cortical arousal with increased alertness and deferral of fatigue. The caffeine contained in beverageseg, 100 mg in a cup of coffeeis sufficient to cause nervousness and insomnia in sensitive individuals and slight bronchodilation in patients with asthma. The larger doses necessary for more effective bronchodilation commonly cause nervousness and tremor in some patients. Very high doses, from accidental or suicidal overdose, cause medullary stimulation and convulsions and may lead to death.
B. CARDIOVASCULAR EFFECTS
The methylxanthines have positive chronotropic and inotropic effects. At low concentrations, these effects appear to result from inhibition of presynaptic adenosine receptors in sympathetic nerves increasing catecholamine release at nerve endings. The higher concentrations ( 10 umol/L, 2 mg/L) associated with inhibition of phosphodiesterase and increases in cAMP may result in increased influx of calcium. At much higher concentrations ( 100 umol/L), sequestration of calcium by the sarcoplasmic reticulum is impaired.
The clinical expression of these effects on cardiovascular function varies among individuals. Ordinary consumption of coffee and other methylxanthine-containing beverages usually produces slight tachycardia, an increase in cardiac output, and an increase in peripheral resistance, raising blood pressure slightly. In sensitive individuals, consumption of a few cups of coffee may result in arrhythmias. In large doses, these agents also relax vascular smooth muscle except in cerebral blood vessels, where they cause contraction.
Methylxanthines decrease blood viscosity and may improve blood flow under certain conditions. The mechanism of this action is not well defined, but the effect is exploited in the treatment of intermittent claudication with pentoxifylline, a dimethylxanthine agent. However, no evidence suggests that this therapy is superior to other approaches.
C. EFFECTS ON GASTROINTESTINAL TRACT
The methylxanthines stimulate secretion of both gastric acid and digestive enzymes. However, even decaffeinated coffee has a potent stimulant effect on secretion, which means that the primary secretagogue in coffee is not caffeine.
D. EFFECTS ON KIDNEY
The methylxanthinesespecially theophyllineare weak diuretics. This effect may involve both increased glomerular filtration and reduced tubular sodium reabsorption. The diuresis is not of sufficient magnitude to be therapeutically useful.
E. EFFECTS ON SMOOTH MUSCLE
The bronchodilation produced by the methylxanthines is the major therapeutic action in asthma. Tolerance does not develop, but adverse effects, especially in the central nervous system, may limit the dose (see below). In addition to their effect on airway smooth muscle, these agentsin sufficient concentrationinhibit antigen-induced release of histamine from lung tissue; their effect on mucociliary transport is unknown.
F. EFFECTS ON SKELETAL MUSCLE
The respiratory actions of the methylxanthines may not be confined to the airways, for they also strengthen the contractions of isolated skeletal muscle in vitro and improve contractility and reverse fatigue of the diaphragm in patients with COPD. This effect on diaphragmatic performancerather than an effect on the respiratory centermay account for theophylline’s ability to improve the ventilatory response to hypoxia and to diminish dyspnea even in patients with irreversible airflow obstruction.
There are three main active, naturally occurring methylxanthines – theophylline, theobromine and caffeine. Theophylline is the most commonly used xanthine in treatment of asthma, also used as aminophylline. Theophylline has a proven dilatory action on the airways, although it is less effective compared to the beta 2 adrenoceptor agonists. Several studies have shown that theophylline is both effective in relieving the acute attack and in the treatment of chronic asthma. Additional actions to dilating the airways seems to be implicated, as theophylline has effects on the later stages of asthma.
Xanthines are most commonly used in severe airways obstruction, including cases of acute asthma, and also in maintenance treatment of severe asthma and lung diseases such as bronchitis and empysema.
The exact mechanism by which xanthines produce it’s effects in asthmatic patients is still unclear. It is thought that they induce smooth muscle relaxation, via inhibition of a substance called phosphodiesterase. This allows an increase in cyclic AMP which acts to counteract the inflammatory effects that occur in the later stages of asthma.
Note that xanthines also have actions on other bodily systems including: the central nervous system, heart and major vessels, and kidney. These actions on other systems result in many of the side effects of the drugs. They have a stimulant effect on the central nervous system, resulting in increased alertness, tremor and nervousness. All the xanthines also exhibit a stimulant effect on the heart, causing dilation of blood vessels. They can also act on the kidney to increase urine output and flow.
These drugs are only effective if the cause of your symptoms is due to smooth muscle contraction and airways constriction.
Most xanthine medications are given orally, via slow release preparations. Aminophylline can also be given via the veins as a slow infusion, especially if you present in the emergency setting, with an acute, sustained asthma attack (also known as status asthmaticus).
Overall, theophylline is used as a second line drug in asthma therapy, often in addition to steroids and other anti-asthmatic medications in patients whose asthma is not adequately controlled by other bronchodilators.
Muscarinic Receptor Antagonists
The muscarinic receptor antagonists are a group of bronchodilators that includes medications such as ipratropium and oxitropium. The drug used most commonly in treatment of asthmatics is ipratropium.
There are sensory nerve endings present in the lining of our airways – when these are activated, they induce constriction and narrowing of the airways. Muscarinic receptor antagonists act to relax constriction of airways due to activation of these nerves by stimulation of the parasympathetic system. These medications have been shown to be particularly effective in allergic irritant asthma.
As their name suggests, muscarinic receptor antagonists act to block muscarinic receptors, but they do not discriminate between the different types. They can help decrease mucous secretion and may increase the lung’s ability to clear airway secretions.
Muscarinic receptor antagonists are given via inhaled delivery systems, (ie through the nose) because they are not well absorbed into the body’s circulation. Their peak effect occurs about 30 minutes after administration, lasting for about 3-5 hours. Often, these medications are used with the beta 2 adrenoceptor antagonists.
Ipatropium can also be used to dilate the airways in patients with chronic bronchitis and to treat spasm of the airways precipitated by beta 2 adrenoceptor antagonists. It has been shown to be as effective as inhaled beta 2 agonists in the treatment of stable lung disease. These medications are often employed in maintenance treatment of patients with lung disease such as bronchitis, emphysema, and severe asthma.
ANTI-INFLAMMATORY AGENTS
Corticosteroids
Corticosteroids are used in the treatment of acute and chronic asthma and other bronchoconstrictive disorders, in which they have two major actions. First, they suppress inflammation in the airways by inhibiting the following processes: movement of fluid and protein into tissues; migration and function of neutrophils and eosinophils; synthesis of histamine in mast cells; and production of proinflammatory substances (eg, prostaglandins, leukotrienes, several interleukins, and others). Beneficial effects of suppressing airway inflammation include decreased mucus secretion, decreased edema of airway mucosa, and repair of damaged epithelium, with subsequent reduction of airway reactivity. A second action is to increase the number and sensitivity of beta2-adrenergic receptors, which restores or increases the effectiveness of beta2-adrenergic bronchodilators. The number of beta2 receptors increases within approximately 4 hours, and improved responsiveness to beta2 agonists occurs within approximately 2 hours.
In acute, severe asthma, a systemic corticosteroid in relatively high doses is indicated in patients whose respiratory distress is not relieved by multiple doses of an inhaled beta2 agonist (eg, every 20 minutes for 3 to 4 doses). The corticosteroid may be given IV or orally, and IV administration offers no therapeutic advantage over oral administration. Once the drug is started, pulmonary function usually improves in 6 to 8 hours. Most patients achieve substantial benefit within 48 to 72 hours and the drug is usually continued for 7 to 10 days. Multiple doses are usually given because studies indicate that maintaining the drug concentration at steroid receptor sites in the lung is more effective than high single doses.
High single or pulse doses do not increase therapeutic effects; they may increase risks of developing myopathy and other adverse effects, however. In some infants and young children with acute, severe asthma, oral prednisone for 3 to 10 days has relieved symptoms and prevented hospitalization.
In chronic asthma, a corticosteroid is usually taken by inhalation, on a daily schedule. It is often given concomitantly with one or more bronchodilators and may be given with another anti-inflammatory drug such as a leukotriene modifier or a mast cell stabilizer. In some instances, the other drugs allow smaller doses of the corticosteroid. For acute flare-ups of symptoms during treatment of chronic asthma, a systemic corticosteroid may be needed temporarily to regain control.
In early stages of the progressive disease, patients with COPD are unlikely to need corticosteroid therapy. In later stages, however, they usually need periodic short-course therapy for episodes of respiratory distress. Wheeeded, the corticosteroid is given orally or parenterally because effectiveness of inhaled corticosteroids has not been established in COPD. In end-stage COPD, patients often become “steroiddependent” and require daily doses because any attempt to reduce dosage or stop the drug results in respiratory distress. Such patients experience numerous serious adverse effects of prolonged systemic corticosteroid therapy.
Corticosteroids should be used with caution in clients with peptic ulcer disease, inflammatory bowel disease, hypertension, ongestive heart failure, and thromboembolic disorders. However, they cause fewer and less severe adverse effects when taken in short courses or by inhalation than when taken systemically for long periods of time.
Beclomethasone, budesonide, flunisolide, fluticasone, and triamcinolone are topical corticosteroids for inhalation. Topical administration minimizes systemic absorption and adverse effects. These preparations may substitute for or allow reduced dosage of systemic corticosteroids. In people with asthma who are taking an oral corticosteroid, the oral dosage is reduced slowly (over weeks to months) when an inhaled corticosteroid is added. The goal is to give the lowest oral dose necessary to control symptoms. Beclomethasone, flunisolide, and fluticasone also are available iasal solutions for treatment of allergic rhinitis, which may play a role in bronchoconstriction. Because systemic absorption occurs in clients using inhaled corticosteroids (about 20% of a dose), high doses should be reserved for those otherwise requiring oral corticosteroids.
Hydrocortisone, prednisone, and methylprednisolone are given to clients who require systemic corticosteroids. Prednisone is given orally; hydrocortisone and methylprednisolone may be given IV to patients who are unable to take an oral medication.
Leukotriene Modifiers
Leukotrienes are strong chemical mediators of bronchoconstriction and inflammation, the major pathologic features of asthma. They can cause sustained constriction of bronchioles and immediate hypersensitivity reactions. They also increase mucus secretion and mucosal edema in the respiratory tract. Leukotrienes are formed by the lipoxygenase pathway of arachidonic acid metabolism (Fig. 47–1) in response to cellular injury. They are designated by LT, the letter B, C, D, or E, and the number of chemical bonds in their structure (eg, LTB4, LTC4, and LTE4, also called slow releasing substances of anaphylaxis or SRS-A, because they are released more slowly than histamine).
Leukotriene modifier drugs were developed to counteract the effects of leukotrienes and are indicated for long-term treatment of asthma in adults and children. The drugs help to prevent acute asthma attacks induced by allergens, exercise, cold air, hyperventilation, irritants, and aspirin or NSAIDs.
They are not effective in relieving acute attacks. However, they may be continued concurrently with other drugs during acute episodes.
The leukotriene modifiers include three agents with two different mechanisms of action. Zileuton inhibits lipoxygenase and thereby reduces formation of leukotrienes; montelukast and zafirlukast are leukotriene receptor antagonists. Zileuton is used infrequently because it requires multiple daily dosing, may cause hepatotoxicity, and may inhibit the metabolism of drugs metabolized by the cytochrome P450 3A4 enzymes. Zafirlukast and montelukast improve symptoms and pulmonary function tests (PFTs), decrease nighttime symptoms, and decrease the use of beta2 agonist drugs.
They are effective with oral administration, can be taken once or twice a day, can be used with bronchodilators and corticosteroids, and elicit a high degree of patient adherence and satisfaction. However, they are less effective than low doses of inhaled corticosteroids. Montelukast and zafirlukast are well absorbed with oral administration. They are metabolized in the liver by the cytochrome P450 enzyme system and may interact with other drugs metabolized by this system. Most metabolites are excreted in the feces. Zafirlukast is excreted in breast milk and should not be taken during lactation. The most common adverse effects reported in clinical trials were headache, nausea, diarrhea, and infection. Zileuton is well absorbed, highly bound to serum albumin (93%), and metabolized by the cytochrome P450 liver enzymes; metabolites are excreted mainly in urine. It is contraindicated in clients with active liver disease or substantially levated liver enzymes (three times the upper limit of normal values). When used, hepatic aminotransferase enzymes should be monitored during therapy and the drug should be discontinued if enzyme levels reach five times the normal values or if symptoms of liver dysfunction develop. Elevation of liver enzymes was the most serious adverse effect during clinical trials; other adverse effects include headache, pain, and nausea. In addition, zileuton increases serum concentrations of propranolol, theophylline, and warfarin.
Mast Cell Stabilizers
Cromolyn and nedocromil stabilize mast cells and prevent the release of bronchoconstrictive and inflammatory substances when mast cells are confronted with allergens and other stimuli. The drugs are indicated only for prophylaxis of acute asthma attacks in clients with chronic asthma; they are not effective in acute bronchospasm or status asthmaticus and should not be used in these conditions. Use of one of these drugs may allow reduced dosage of bronchodilators and corticosteroids.
The drugs are taken by inhalation. Cromolyn is available in a metered-dose aerosol and a solution for use with a poweroperated nebulizer. A nasal solution is also available for prevention and treatment of allergic rhinitis. Nedocromil is available in a metered-dose aerosol. Mast cell stabilizers are contraindicated in clients who are hypersensitive to the drugs. They should be used with caution in clients with impaired renal or hepatic function. Also, the propellants in the aerosols may aggravate coronary artery disease or dysrhythmias.
Side effects
Some patients have a dry or irritated throat or a dry mouth after using bronchodilators. To help prevent these problems, gargle and rinse the mouth or take a sip of water after each dose.
The most common side effects are nervousness or restlessness and trembling. These problems usually go away as the body adjusts to the drug and do not require medical treatment.
Less common side effects, such as bad taste in the mouth, coughing, dizziness or lightheadedness, drowsiness, headache, sweating, fast or pounding heartbeat, muscle cramps or twitches, nausea, vomiting, diarrhea, sleep problems and weakness also may occur and do not need medical attention unless they do not go away or they interfere with normal activities.
More serious side effects are not common, but may occur. If any of the following side effects occur, check with the physician who prescribed the medicine as soon as possible:
· Chest pain or discomfort
· Irregular or fluttery heartbeat
· Unusual bruising
· Hives or rash
· Swelling
· Wheezing or other breathing problems
· Numbness in the hands or feet
· Blurred vision.
Other side effects are possible. Anyone who has unusual symptoms after using a bronchodilator should get in touch with his or her physician.
OTHER DRUGS IN THE TREATMENT OF ASTHMA
Anti-IgE Monoclonal Antibodies
An entirely new approach to the treatment of asthma exploits advances in molecular biology to target IgE antibody. From a collection of monoclonal antibodies raised in mice against IgE antibody itself, a monoclonal antibody was selected that appeared to be targeted against the portion of IgE that binds to its receptors (FCe-R1 and FCe-R2 receptors) on mast cells and other inflammatory cells. Omalizumab (an anti-IgE monoclonal antibody) inhibits the binding of IgE to mast cells but does not activate IgE already bound to these cells and thus does not provoke mast cell degranulation. It may also inhibit IgE synthesis by B lymphocytes. The murine antibody has been genetically humanized by replacing all but a small fraction of its amino acids with those found in human proteins, and it does not appear to cause sensitization when given to human subjects.
Studies of omalizumab in asthmatic volunteers showed that its administration over 10 weeks lowered plasma IgE to undetectable levels and significantly reduced the magnitude of both the early and the late bronchospastic responses to antigen challenge. Clinical trials have shown that repeated intravenous or subcutaneous injection of anti-IgE MAb lessens asthma severity and reduces the corticosteroid requirement in patients with moderate to severe disease, especially those with a clear environmental antigen precipitating factor, and improves nasal and conjunctival symptoms in patients with perennial or seasonal allergic rhinitis. Omalizumab’s most important effect is reduction of the frequency and severity of asthma exacerbations, even while enabling a reduction in corticosteroid requirements. Combined analysis of several clinical trials has shown that the patients most likely to respond are, fortunately, those with the greatest need, ie, patients with a history of repeated exacerbations, a high requirement for corticosteroid treatment, and poor pulmonary function. Similarly, the exacerbations most prevented are the ones most important to prevent: Omalizumab treatment reduced exacerbations requiring hospitalization by 88%. These benefits justify the high cost of this treatment in selected individuals with severe disease characterized by frequent exacerbations.
The rapid advance in the scientific description of the immunopathogenesis of asthma has spurred the development of many new therapies targeting different sites in the immune cascade. These include monoclonal antibodies directed against cytokines (IL-4, IL-5, IL-13), antagonists of cell adhesion molecules, protease inhibitors, and immunomodulators aimed at shifting CD4 lymphocytes from the TH2 to the TH1 phenotype or at selective inhibition of the subset of TH2 lymphocytes directed against particular antigens. There is evidence that asthma may be aggravatedor even causedby chronic airway infection with Chlamydia pneumoniae or Mycoplasma pneumoniae. This may explain the reports of benefit from treatment with macrolide antibiotics and, if confirmed, would stimulate the development of new diagnostic methods and antimicrobial therapies.
Asthma is best thought of as a disease in two time domains. In the present domain, it is important for the distress it causescough, nocturnal awakenings, and shortness of breath that interferes with the ability to exercise or to pursue desired activities. For mild asthma, occasional inhalation of a bronchodilator may be all that is needed. For more severe asthma, treatment with a long-term controller, like an inhaled corticosteroid, is necessary to relieve symptoms and restore function. The second domain of asthma is the risk it presents of future events, such as exacerbations, or of progressive loss of pulmonary function. A patient’s satisfaction with his or her ability to control symptoms and maintain function by frequent use of an inhaled 2 agonist does not mean that the risk of future events is also controlled. In fact, use of two or more canisters of an inhaled agonist per month is a marker of increased risk of asthma fatality.
The challenges of assessing severity and adjusting therapy for these two domains of asthma are different. For relief of distress in the present domain, the key information can be obtained by asking specific questions about the frequency and severity of symptoms, the frequency of use of an inhaled 2 agonist for relief of symptoms, the frequency of nocturnal awakenings, and the ability to exercise. Estimating the risk for future exacerbations is more difficult. In general, patients with poorly controlled symptoms in the present have a heightened risk of exacerbations in the future, but some patients seem unaware of the severity of their underlying airflow obstruction (sometimes described as “poor perceivers”) and can be identified only by measurement of pulmonary function, as by spirometry. Reductions in the FEV1 correlate with heightened risk of attacks of asthma in the future. Other possible markers of heightened risk are unstable pulmonary function (large variations in FEV1 from visit to visit, large change with bronchodilator treatment), extreme bronchial reactivity, or high numbers of eosinophils in sputum or of nitric oxide in exhaled air. Assessment of these features may identify patients who need increases in therapy for protection against exacerbations.
Bronchodilators, such as inhaled albuterol, are rapidly effective, safe, and inexpensive. Patients with only occasional symptoms of asthma require no more than an inhaled 2-receptor agonist taken on an as-needed basis. If symptoms require this “rescue” therapy more than twice a week, if nocturnal symptoms occur more than twice a month, or if the FEV1 is less than 80% predicted, additional treatment is needed. The treatment first recommended is a low dose of an inhaled corticosteroid, although treatment with a leukotriene receptor antagonist or with cromolyn may be used. Theophylline is now largely reserved for patients in whom symptoms remain poorly controlled despite the combination of regular treatment with an inhaled anti-inflammatory agent and as-needed use of a 2 agonist. If the addition of theophylline fails to improve symptoms or if adverse effects become bothersome, it is important to check the plasma level of theophylline to be sure it is in the therapeutic range (10-20 mg/L).
An important caveat for patients with mild asthma is that although the risk of a severe, life-threatening attack is lower than in patients with severe asthma, it is not zero. All patients with asthma should be instructed in a simple action plan for severe, frightening attacks: to take up to four puffs of albuterol every 20 minutes over 1 hour. If they do not note clear improvement after the first four puffs, they should take the additional treatments while on their way to an Emergency Department or some other higher level of care.
Inhaled muscarinic antagonists have so far earned a limited place in the treatment of asthma. When adequate doses are given, their effect on baseline airway resistance is nearly as great as that of the sympathomimetic drugs. The airway effects of antimuscarinic and sympathomimetic drugs given in full doses have been shown to be additive only in patients with severe airflow obstruction who present for emergency care. Antimuscarinic agents appear to be of greater value in COPDperhaps more so than in asthma. They are also useful as alternative therapies for patients intolerant of 2-adrenoceptor agonists.
Although it was predicted that muscarinic antagonists would dry airway secretions and interfere with mucociliary clearance, direct measurements of fluid volume secretion from single airway submucosal glands in animals show that atropine decreases baseline secretory rates only slightly. The drugs do, however, inhibit the increase in mucus secretion caused by vagal stimulation. No cases of inspissation of mucus have been reported following administration of these drugs.
If asthmatic symptoms occur frequently or if significant airflow obstruction persists despite bronchodilator therapy, inhaled corticosteroids should be started. For patients with severe symptoms or severe airflow obstruction (eg, FEV1 50% predicted), initial treatment with a combination of inhaled and oral corticosteroid (eg, 30 mg/d of prednisone for 3 weeks) treatment is appropriate. Once clinical improvement is noted, usually after 7-10 days, the oral dose should be discontinued or reduced to the minimum necessary to control symptoms.
An issue for inhaled corticosteroid treatment is patient compliance. Analysis of prescription renewals shows that corticosteroids are taken regularly by a minority of patients. This may be a function of a general “steroid phobia” fostered by emphasis in the lay press over the hazards of long-term oral corticosteroid therapy and by ignorance over the difference between corticosteroids and anabolic steroids, taken to enhance muscle strength by now-infamous athletes. This fear of corticosteroid toxicity makes it hard to persuade patients whose symptoms have improved after starting the treatment that they should continue it for protection against attacks. This context accounts for the interest in a recent report that instructing patients with mild but persistent asthma to initiate inhaled corticosteroid therapy only when their symptoms worsened was as effective in maintaining pulmonary function and preventing attacks as taking it twice each day.
In patients with more severe asthma, whose symptoms are inadequately controlled by a standard dose of an inhaled corticosteroid, two options may be considered: to double the dose of inhaled corticosteroid or to add a long-acting inhaled 2-receptor agonist (salmeterol or formoterol). Many studies have shown this combination therapy to be more effective than doubling the dose of the inhaled corticosteroid, but the FDA has issued a warning that the use of a long-acting agonist is associated with a very small but statistically significant increase in the risk of death or near death from an asthma attack, especially in African Americans. This warning has not so far had much effect on prescriptions for a fixed-dose combination of inhaled fluticasone (a corticosteroid) and salmeterol (a long-acting agonist), probably because their combination in a single inhaler offers several advantages. Combination inhalers are convenient; they ensure that the long-acting agonist will not be taken as monotherapy (knowot to protect against attacks); and they produce prompt, sustained improvements in clinical symptoms and pulmonary function and reduce the frequency of exacerbations requiring oral corticosteroid treatment. In patients prescribed such combination treatment, it is important to provide explicit instructions that a standard, short-acting inhaled 2 agonist, such as albuterol, be used as needed for relief of acute symptoms.
CROMOLYN NEDOCROMIL; LEUKOTRIENE ANTAGONISTS
Cromolyn or nedocromil by inhalation, or a leukotriene-receptor antagonist as an oral tablet, may be considered as alternatives to inhaled corticosteroid treatment in patients with symptoms occurring more than twice a week or who are wakened from sleep by asthma more than twice a month. Neither treatment is as effective as even a low dose of an inhaled corticosteroid, but both prevent the issue of “steroid phobia” described above.
Cromolyn and nedocromil may also be useful in patients whose symptoms occur seasonally or after clear-cut inciting stimuli such as exercise or exposure to animal danders or irritants. In patients whose symptoms are continuous or occur without an obvious inciting stimulus, the value of these drugs can be established only with a therapeutic trial of inhaled drug four times a day for 4 weeks. If the patient responds to this therapy, the dose can then be optimized.
Treatment with a leukotriene-receptor antagonist, particularly montelukast, is widely prescribed, especially by primary care providers. Taken orally, leukotriene-receptor antagonists are easy to use and appear to be taken more regularly than inhaled corticosteroids. They are rarely associated with troublesome side effects. Maintenance therapy with a leukotriene antagonist or with cromolyn or nedocromil appears to be roughly as effective as maintenance therapy with theophylline. Because of concerns over the possible long-term toxicity of systemic absorption of inhaled corticosteroids, this maintenance therapy has become widely used for treating children in the USA.
Treatment with omalizumab, the monoclonal humanized anti-IgE antibody, is reserved for patients with chronic severe asthma inadequately controlled by high-dose inhaled corticosteroid plus long-acting -agonist combination treatment (eg, fluticasone 500 mcg plus salmeterol 50 mcg inhaled twice daily). This treatment reduces lymphocytic, eosinophilic bronchial inflammation and effectively reduces the frequency and severity of exacerbations. It is reserved for patients with demonstrated IgE-mediated sensitivity (by positive skin test or radioallergosorbent test [RAST] to common allergens) and an IgE level within a range that can be reduced sufficiently by twice weekly subcutaneous injection.
OTHER ANTI-INFLAMMATORY THERAPIES
Some reports suggest that agents commonly used to treat rheumatoid arthritis may also be used to treat patients with chronic steroid-dependent asthma. The development of an alternative treatment is important, because chronic treatment with oral corticosteroids may cause osteoporosis, cataracts, glucose intolerance, worsening of hypertension, and cushingoid changes in appearance. Initial studies suggested that oral methotrexate or gold salt injections were beneficial in prednisone-dependent asthmatics, but subsequent studies did not confirm this promise. In contrast, the benefit from treatment with cyclosporine seems real. However, this drug’s great toxicity makes this finding only a source of hope that other immunomodulatory therapies will ultimately be developed for the small proportion of patients whose asthma can be managed only with high oral doses of prednisone. An immunomodulatory therapy recently reported to improve asthma is injection of etanercept, a TNF- antagonist used for treatment of ankylosing spondylitis and severe rheumatoid arthritis.
The treatment of acute attacks of asthma in patients reporting to the hospital requires close, continuous clinical assessment and repeated objective measurement of lung function. For patients with mild attacks, inhalation of a 2-receptor agonist is as effective as subcutaneous injection of epinephrine. Both of these treatments are more effective than intravenous administration of aminophylline (a soluble salt of theophylline). Severe attacks require treatment with oxygen, frequent or continuous administration of aerosolized albuterol, and systemic treatment with prednisone or methylprednisolone (0.5 mg/kg every 6 hours). Even this aggressive treatment is not invariably effective, and patients must be watched closely for signs of deterioration. General anesthesia, intubation, and mechanical ventilation of asthmatic patients cannot be undertaken lightly but may be lifesaving if respiratory failure supervenes.
The high prevalence of asthma in the developed world and its rapid increases in the developing world call for a strategy for primary prevention. Strict antigen avoidance during infancy, once thought to be sensible, has now been shown to be ineffective. In fact, growing up in a household where cats and dogs are kept as pets may protect against developing asthma. The best hope seems to lie in understanding the importance of microbial exposures during infancy in shaping a balanced immune response, and one study showing that feeding Lactobacillus caseii to infants born to allergic parents reduced the rate of allergic dermatitis at age 2 years offers reason for hope.
The immune response occurs when immunologically competent cells are activated in response to foreign organisms or antigenic substances liberated during the acute or chronic inflammatory response. The outcome of the immune response for the host may be beneficial, as when it causes invading organisms to be phagocytosed or neutralized. On the other hand, the outcome may be deleterious if it leads to chronic inflammation without resolution of the underlying injurious process. Chronic inflammation involves the release of a number of mediators that are not prominent in the acute response. One of the most important conditions involving these mediators is rheumatoid arthritis, in which chronic inflammation results in pain and destruction of bone and cartilage that can lead to severe disability and in which systemic changes occur that can result in shortening of life.
The immune system has evolved to protect the host from invading pathogens and to eliminate disease. At its functioning best, the immune system is exquisitely responsive to invading pathogens while retaining the capacity to recognize self antigens to which it is tolerant. Protection from infection and disease is provided by the collaborative efforts of the innate and adaptive immune systems.
Immunodeficiency diseases result from inadequate function in the immune system; the consequences include increased susceptibility to infections and prolonged duration and severity of disease. Immunodeficiency diseases are either congenitally acquired or arise from extrinsic factors such as bacterial or viral infections or drug treatment. Affected individuals frequently succumb to infections caused by opportunistic organisms of low pathogenicity for the immunocompetent host. Examples of congenitally acquired immunodeficiency disease include X-linked agammaglobulinemia, DiGeorge’s syndrome, and severe combined immunodeficiency disease (SCID) due to adenosine deaminase (ADA) deficiency.
X-linked agammaglobulinemia is a disease affecting males that is characterized by a failure of immature B-lymphocytes to mature into antibody-producing plasma cells. These individuals are susceptible to recurrent bacterial infections, although the cell-mediated responses directed against viruses and fungi are preserved. DiGeorge’s syndrome is due to failure of the thymus to develop, resulting in diminished T-cell responses (TDTH, CTL), while the humoral response is unaffected.
The ADA enzyme normally prevents the accumulation of toxic deoxy-ATP in cells. Deoxy-ATP is particularly toxic to lymphocytes, and leads to death of T and B cells. Absence of the enzyme therefore results in SCID. Infusion of the purified enzyme (pegademase, from bovine sources) and transfer of ADA gene-modified lymphocytes have both been used successfully to treat this disease.
AIDS represents the classic example of immunodeficiency disease caused by extrinsic factors, in this instance the human immunodeficiency virus (HIV). This virus exhibits a strong tropism for CD4 T helper cells; these become depleted, giving rise to increased frequency of opportunistic infections and malignancies in infected individuals. AIDS is also characterized by an imbalance in TH1 and TH2 cells, and the ratios of cells and their functions are skewed toward TH2. This results in hypergammaglobulinemia, loss of cytotoxic lymphocyte activity, and delayed hypersensitivity.
Immunosuppressive agents have proved very useful in minimizing the occurrence or impact of deleterious effects of exaggerated or inappropriate immune responses. Unfortunately, these agents also have the potential to cause disease and to increase the risk of infection and malignancies.
Glucocorticoids (corticosteroids) were the first hormonal agents recognized as having lympholytic properties. Administration of any glucocorticoid reduces the size and lymphoid content of the lymph nodes and spleen, although it has no toxic effect on proliferating myeloid or erythroid stem cells in the bone marrow.
Glucocorticoids are thought to interfere with the cell cycle of activated lymphoid cells. Glucocorticoids are quite cytotoxic to certain subsets of T cells, but their immunologic effects are probably due to their ability to modify cellular functions rather than to direct cytotoxicity. Although cellular immunity is more affected than humoral immunity, the primary antibody response can be diminished, and with continued use, previously established antibody responses are also decreased. Additionally, continuous administration of corticosteroid increases the fractional catabolic rate of IgG, the major class of antibody immunoglobulins, thus lowering the effective concentration of specific antibodies. Contact hypersensitivity mediated by DTH T cells, for example, is usually abrogated by glucocorticoid therapy.
Glucocorticoids are used in a wide variety of conditions. It is thought that the immunosuppressive and anti-inflammatory properties of corticosteroids account for their beneficial effects in diseases like idiopathic thrombocytopenic purpura and rheumatoid arthritis. Glucocorticoids modulate allergic reactions and are useful in the treatment of diseases like asthma or as premedication for other agents (eg, blood products, chemotherapy) that might cause undesirable immune responses. Glucocorticoids are first-line immunosuppressive therapy for both solid organ and hematopoietic stem cell transplant recipients, with variable results. The toxicities of long-term glucocorticoid therapy can be severe.
Cyclosporine (cyclosporin A, CSA) is an immunosuppressive agent with efficacy in human organ transplantation, in the treatment of graft-versus-host disease after hematopoietic stem cell transplantation, and in the treatment of selected autoimmune disorders. Cyclosporine is a peptide antibiotic that appears to act at an early stage in the antigen receptor-induced differentiation of T cells and blocks their activation. Cyclosporine binds to cyclophilin, a member of a class of intracellular proteins called immunophilins. Cyclosporine and cyclophilin form a complex that inhibits the cytoplasmic phosphatase, calcineurin, which is necessary for the activation of a T-cell-specific transcription factor. This transcription factor, NF-AT, is involved in the synthesis of interleukins (eg, IL-2) by activated T cells. In vitro studies have indicated that cyclosporine inhibits the gene transcription of IL-2, IL-3, IFN-, and other factors produced by antigen-stimulated T cells, but it does not block the effect of such factors on primed T cells nor does it block interaction with antigen.
Cyclosporine may be given intravenously or orally, though it is slowly and incompletely absorbed (20-50%). The absorbed drug is primarily metabolized by the P450 3A enzyme system in the liver with resultant multiple drug interactions. This propensity for drug interaction contributes to significant interpatient variability in bioavailability, such that cyclosporine requires individual patient dosage adjustments based on steady-state blood levels and the desired therapeutic ranges for the drug. Cyclosporine ophthalmic solution is now available for severe dry eye syndrome, as well as ocular graft-versus-host disease. Inhaled cyclosporine is being investigated for use in lung transplantation.
Toxicities are numerous and include nephrotoxicity, hypertension, hyperglycemia, liver dysfunction, hyperkalemia, altered mental status, seizures, and hirsutism. Cyclosporine causes very little bone marrow toxicity. While an increased incidence of lymphoma and other cancers (Kaposi’s sarcoma, skin cancer) have been observed in transplant recipients receiving cyclosporine, other immunosuppressive agents may also predispose recipients to cancer. Some evidence suggests that tumors may arise after cyclosporine treatment because the drug induces TGF-, which promotes tumor invasion and metastasis.
Cyclosporine may be used alone or in combination with other immunosuppressants, particularly glucocorticoids. It has been used successfully as the sole immunosuppressant for cadaveric transplants of the kidney, pancreas, and liver, and it has proved extremely useful in cardiac transplants as well. In combination with methotrexate, cyclosporine is a standard prophylactic regimen to prevent graft-versus-host disease after allogeneic stem cell transplants. Cyclosporine has also proved useful in a variety of autoimmune disorders, including uveitis, rheumatoid arthritis, psoriasis, and asthma. Its combination with newer agents is showing considerable efficacy in clinical and experimental settings where effective and less toxic immunosuppression is needed. Newer formulations of cyclosporine have been developed that are improving patient compliance (smaller, better tasting pills), and increasing bioavailability.
Tacrolimus (FK 506) is an immunosuppressant macrolide antibiotic produced by Streptomyces tsukubaensis. It is not chemically related to cyclosporine, but their mechanisms of action are similar. Both drugs bind to cytoplasmic peptidyl-prolyl isomerases that are abundant in all tissues. While cyclosporine binds to cyclophilin, tacrolimus binds to the immunophilin FK-binding protein (FKBP). Both complexes inhibit calcineurin, which is necessary for the activation of the T-cell-specific transcription factor NF-AT.
On a weight basis, tacrolimus is 10-100 times more potent than cyclosporine in inhibiting immune responses. Tacrolimus is utilized for the same indications as cyclosporine, particularly in organ and stem cell transplantation. Multicenter studies in the USA and in Europe indicate that both graft and patient survival are similar for the two drugs. Tacrolimus has been proven to be effective therapy for preventing rejection in solid-organ transplant patients even after failure of standard rejection therapy, including anti-T-cell antibodies. It is now considered a standard prophylactic agent (usually in combination with methotrexate or mycophenolate mofetil) for graft-versus-host disease.
Tacrolimus can be administered orally or intravenously. The half-life of the intravenous form is approximately 9-12 hours. Like cyclosporine, tacrolimus is metabolized primarily by P450 enzymes in the liver, and there is potential for drug interactions. The dosage is determined by trough blood level at steady state. Its toxic effects are similar to those of cyclosporine and include nephrotoxicity, neurotoxicity, hyperglycemia, hypertension, hyperkalemia, and gastrointestinal complaints.
Because of the effectiveness of systemic tacrolimus in some dermatologic diseases, a topical preparation is now available. Tacrolimus ointment is currently used in the therapy of atopic dermatitis and psoriasis.
Sirolimus (rapamycin) is derived from Streptomyces hygroscopicus and binds immunophilins and inhibits calcineurin, as do cyclosporine and tacrolimus. However, it does not block interleukin production by activated T cells but instead blocks the response of T cells to cytokines. In vitro, it antagonizes tacrolimus-induced T-cell responses but seems to be synergistic with cyclosporine. Furthermore, it is a potent inhibitor of B-cell proliferation and immunoglobulin production. Sirolimus also inhibits the mononuclear cell proliferative response to colony-stimulating factors and suppresses hematopoietic recovery after myelotoxic treatment in mice.
Sirolimus is available only as an oral drug. It is rapidly absorbed and its elimination is similar to that of cyclosporine and tacrolimus, being a substrate for both cytochrome P450 3A and P-glycoprotein. Significant drug interactions can occur, and the drug level in the blood may need to be monitored.
Sirolimus has been used effectively alone and in combination with other immunosuppressants (corticosteroids, cyclosporine, tacrolimus, and mycophenolate mofetil) to prevent rejection of solid organ allografts. Sirolimus is being investigated as therapy for steroid-refractory acute and chronic graft-versus-host disease in hematopoietic stem cell transplant recipients. Topical sirolimus is also used in some dermatologic disorders and, in combination with cyclosporine, in the management of uveoretinitis. Recently, sirolimus-eluting coronary stents have been shown to reduce restenosis and additional adverse cardiac events in patients with severe coronary artery disease, due to its antiproliferative effects. A derivative of sirolimus, everolimus, is a proliferation-signal inhibitor that may be of benefit in decreasing rejection in cardiac transplantation.
Toxicities of sirolimus can include profound myelosuppression (especially thrombocytopenia), hepatotoxicity, diarrhea, hypertriglyceridemia, and headache.
Mycophenolate mofetil (MMF) is a semisynthetic derivative of mycophenolic acid, isolated from the mold Penicillium glaucum. In vitro, it inhibits T- and B-lymphocyte responses, including mitogen and mixed lymphocyte responses, probably by inhibition of de novo synthesis of purines. Mycophenolate mofetil is hydrolyzed to mycophenolic acid, the active immunosuppressive moiety; it is synthesized and administered as MMF to enhance bioavailability. Mycophenolate mofetil is used in solid organ transplant patients for refractory rejection and, in combination with prednisone, as an alternative to cyclosporine or tacrolimus in patients who do not tolerate those drugs. Mycophenolate mofetil is used to treat steroid-refractory graft-versus-host disease in hematopoietic stem cell transplant patients. It is also used in combination with tacrolimus or other immunosuppressants as prophylaxis to prevent graft-versus-host disease. Newer immunosuppressant applications for MMF include lupus nephritis, rheumatoid arthritis, and some dermatologic disorders.
Mycophenolate mofetil is available in both oral and intravenous forms. The oral form is rapidly metabolized to mycophenolic acid but not by the cytochrome P450 3A system, though some drug interactions still occur.
Toxicities include gastrointestinal disturbances (nausea and vomiting, diarrhea, abdominal pain) headache, hypertension and reversible myelosuppression (primarily neutropenia).
Thalidomide is a sedative drug that was withdrawn from the market in the 1960s because of its disastrous teratogenic effects when used during pregnancy. Nevertheless, it has significant immunomodulatory actions and is currently in active use or in clinical trials for over 40 different illnesses. Thalidomide inhibits angiogenesis and has anti-inflammatory and immunomodulatory effects. It inhibits TNF-, reduces phagocytosis by neutrophils, increases production of IL-10, alters adhesion molecule expression, and enhances cell-mediated immunity via interactions with T cells. The complex actions of thalidomide continue to be studied as its clinical use evolves.
Thalidomide is currently used in the treatment of multiple myeloma at initial diagnosis and for relapsed-refractory disease. Patients generally show signs of response within 2-3 months of starting the drug, with response rates from 20 to 70%. When combined with dexamethasone, the response rates in myeloma are 90% or more in some studies. Many patients have durable responsesup to 12-18 months in refractory disease and even longer in some patients treated at diagnosis. The success of thalidomide in myeloma has lead to numerous clinical trials in other diseases such as myelodysplastic syndrome, acute myelogenous leukemia, and graft-versus-host disease, as well as in solid tumors like colon cancer, renal cell carcinoma, melanoma, and prostate cancer, with variable results to date. Thalidomide has been used for many years in the treatment of some manifestations of leprosy and has been reintroduced in the USA for erythema nodosum leprosum; it is also useful in management of the skin manifestations of lupus erythematosus.
The adverse effect profile of thalidomide is extensive. The most important toxicity is teratogenesis. Because of this effect, thalidomide prescription and use is closely regulated by the manufacturer. Other adverse effects of thalidomide include peripheral neuropathy, constipation, rash, fatigue, hypothyroidism, and increased risk of deep vein thrombosis. Thrombosis is sufficiently frequent, particularly in the myeloma population, that most patients are placed on warfarin when thalidomide treatment is initiated.
Owing to thalidomide’s serious toxicity profile, considerable effort has been expended in the development of analogs. Immunomodulatory derivatives of thalidomide are termed IMiDs. Some IMiDs are much more potent than thalidomide in regulating cytokines and affecting T-cell proliferation. Lenalidomide is an IMiD that in animal and in vitro studies has been shown to be similar to thalidomide in action, but with less toxicity, especially teratogenicity. Lenalidomide was approved by the Food and Drug Administration in late 2005 as a consequence of trials that showed its effectiveness in the treatment of the myelodysplastic syndrome with the chromosome 5q31 deletion. Several clinical trials using lenalidomide to treat relapsed or refractory myeloma are showing benefits and it is likely to be approved by the FDA for that indication as well.
CC-4047 (Actimid) is another IMiD that is being investigated for the treatment of myelodysplastic syndrome, myeloma, and prostate cancer.
Another group of thalidomide analogs, selective cytokine inhibitory drugs (SelCIDs), are phosphodiesterase type 4 inhibitors with potent anti-TNF- activity but no T-cell co-stimulatory activity. Several SelCIDs are currently under investigation for clinical use.
Azathioprine is a prodrug of mercaptopurine and, like mercaptopurine, functions as an antimetabolite. Although its action is presumably mediated by conversion to mercaptopurine and further metabolites, it has been more widely used than mercaptopurine for immunosuppression in humans. These agents represent prototypes of the antimetabolite group of cytotoxic immunosuppressive drugs, and many other agents that kill proliferative cells appear to work at a similar level in the immune response.
Azathioprine is well absorbed from the gastrointestinal tract and is metabolized primarily to mercaptopurine. Xanthine oxidase splits much of the active material to 6-thiouric acid prior to excretion in the urine. After administration of azathioprine, small amounts of unchanged drug and mercaptopurine are also excreted by the kidney, and as much as a twofold increase in toxicity may occur in anephric or anuric patients. Since much of the drug’s inactivation depends on xanthine oxidase, patients who are also receiving allopurinol for control of hyperuricemia should have the dose of azathioprine reduced to one-fourth to one-third the usual amount to prevent excessive toxicity.
Azathioprine and mercaptopurine appear to produce immunosuppression by interfering with purine nucleic acid metabolism at steps that are required for the wave of lymphoid cell proliferation that follows antigenic stimulation. The purine analogs are thus cytotoxic agents that destroy stimulated lymphoid cells. Although continued messenger RNA synthesis is necessary for sustained antibody synthesis by plasma cells, these analogs appear to have less effect on this process than oucleic acid synthesis in proliferating cells. Cellular immunity as well as primary and secondary serum antibody responses can be blocked by these cytotoxic agents.
Azathioprine and mercaptopurine appear to be of definite benefit in maintaining renal allografts and may be of value in transplantation of other tissues. These antimetabolites have been used with some success in the management of acute glomerulonephritis and in the renal component of systemic lupus erythematosus. They have also proved useful in some cases of rheumatoid arthritis, Crohn’s disease, and multiple sclerosis. The drugs have been of occasional use in prednisone-resistant antibody-mediated idiopathic thrombocytopenic purpura and autoimmune hemolytic anemias.
The chief toxic effect of azathioprine and mercaptopurine is bone marrow suppression, usually manifested as leukopenia, although anemia and thrombocytopenia may occur. Skin rashes, fever, nausea and vomiting, and sometimes diarrhea occur, with the gastrointestinal symptoms seen mainly at higher dosages. Hepatic dysfunction, manifested by very high serum alkaline phosphatase levels and mild jaundice, occurs occasionally, particularly in patients with preexisting hepatic dysfunction.
The alkylating agent cyclophosphamide is one of the most efficacious immunosuppressive drugs available. Cyclophosphamide destroys proliferating lymphoid cells but also appears to alkylate some resting cells. It has been observed that very large doses (eg, 120 mg/kg intravenously over several days) may induce an apparent specific tolerance to a new antigen if the drug is administered simultaneously with, or shortly after, the antigen. In smaller doses, it has been effective against autoimmune disorders (including systemic lupus erythematosus) and in patients with acquired factor XIII antibodies and bleeding syndromes, autoimmune hemolytic anemia, antibody-induced pure red cell aplasia, and Wegener’s granulomatosis.
Treatment with large doses of cyclophosphamide carries considerable risk of pancytopenia and hemorrhagic cystitis and therefore is generally combined with stem cell rescue (transplant) procedures. Although cyclophosphamide appears to induce tolerance for marrow or immune cell grafting, its use does not prevent the subsequent graft-versus-host disease syndrome, which may be serious or lethal if the donor is a poor histocompatibility match (despite the severe immunosuppression induced by high doses of cyclophosphamide). Other adverse effects of cyclophosphamide include nausea, vomiting, cardiac toxicity, and electrolyte disturbances.
Leflunomide is a prodrug of an inhibitor of pyrimidine synthesis (rather than purine synthesis). It is orally active, and the active metabolite has a long half-life of several weeks. Thus, the drug should be started with a loading dose, but it can be taken once daily after reaching steady state. It is approved only for rheumatoid arthritis at present, though studies are underway combining leflunomide with mycophenolate mofetil for a variety of autoimmune and inflammatory skin disorders, as well as preservation of allografts in solid organ transplantation. Leflunomide also appears (from murine data) to have antiviral activity.
Toxicities include elevation of liver enzymes with some risk of liver damage, renal impairment, and teratogenic effects. A low frequency of cardiovascular effects (angina, tachycardia) was reported in clinical trials of leflunomide.
Hydroxychloroquine is an antimalarial agent with immunosuppressant properties. It is thought to suppress intracellular antigen processing and loading of peptides onto MHC class II molecules by increasing the pH of lysosomal and endosomal compartments, thereby decreasing T-cell activation.
Because of these immunosuppressant activities, hydroxychloroquine is used to treat some autoimmune disorders, eg, rheumatoid arthritis and systemic lupus erythematosus. It has also been used to both treat and prevent graft-versus-host disease after allogeneic stem cell transplantation.
Other cytotoxic agents, including vincristine, methotrexate, and cytarabine, also have immunosuppressive properties. Methotrexate has been used extensively in rheumatoid arthritis and in the treatment of graft-versus-host disease. Although the other agents can be used for immunosuppression, their use has not been as widespread as the purine antagonists, and their indications for immunosuppression are less certain. The use of methotrexate (which can be given orally) appears reasonable in patients with idiosyncratic reactions to purine antagonists. The antibiotic dactinomycin has also been used with some success at the time of impending renal transplant rejection. Vincristine appears to be quite useful in idiopathic thrombocytopenic purpura refractory to prednisone. The related vinca alkaloid vinblastine has been shown to prevent mast cell degranulation in vitro by binding to microtubule units within the cell and to prevent release of histamine and other vasoactive compounds. Pentostatin is an adenosine deaminase inhibitor primarily used as an antineoplastic agent for lymphoid malignancies, and produces a profound lymphopenia. It is now frequently used for steroid-resistant graft-versus-host disease after allogeneic stem cell transplantation, as well as in preparative regimens prior to those transplants to provide severe immunosuppression to prevent allograft rejection.
IMMUNOSUPPRESSIVE ANTIBODIES
The development of hybridoma technology by Milstein and Kohler in 1975 revolutionized the antibody field and radically increased the purity and specificity of antibodies used in the clinic and for diagnostic tests in the laboratory. Hybridomas consist of antibody-forming cells fused to immortal plasmacytoma cells. Hybrid cells that are stable and produce the required antibody can be subcloned for mass culture for antibody production. Large-scale fermentation facilities are now used for this purpose in the pharmaceutical industry.
More recently, molecular biology has been used to develop monoclonal antibodies. Combinatorial libraries of cDNAs encoding immunoglobulin heavy and light chains expressed on bacteriophage surfaces are screened against purified antigens. The result is an antibody fragment with specificity and high affinity for the antigen of interest. This technique has been used to develop antibodies specific for viruses (eg, HIV), bacterial proteins, tumor antigens, and even cytokines. Several antibodies developed in this manner are in clinical trials.
Other genetic engineering techniques involve production of chimeric and humanized versions of murine monoclonal antibodies in order to reduce their antigenicity and increase the half-life of the antibody in the patient. Murine antibodies administered as such to human patients evoke production of human antimouse antibodies (HAMA), which clear the original murine proteins very rapidly. Humanization involves replacing most of the murine antibody with equivalent human regions while keeping only the variable, antigen-specific regions intact. Chimeric mouse-human antibodies have similar properties with less complete replacement of the murine components. The current naming convention for these engineered substances uses the suffix “umab” or “zumab” for humanized antibodies, and “imab” or “ximab” for chimeric products. These procedures have been successful in reducing or preventing HAMA production for many of the antibodies discussed below.
1. Antilymphocyte Antithymocyte Antibodies
Antisera directed against lymphocytes have been prepared sporadically for over 100 years. With the advent of human organ transplantation as a therapeutic option, heterologous antilymphocyte globulin (ALG) took oew importance. ALG and antithymocyte globulin (ATG) are now in clinical use in many medical centers, especially in transplantation programs. The antiserum is usually obtained by immunization of large animals such as horses or sheep with human lymphoid cells.
Antilymphocyte antibody acts primarily on the small, long-lived peripheral lymphocytes that circulate between the blood and lymph. With continued administration, “thymus-dependent” lymphocytes from lymphoid follicles are also depleted, as they normally participate in the recirculating pool. As a result of the destruction or inactivation of T cells, an impairment of delayed hypersensitivity and cellular immunity occurs while humoral antibody formation remains relatively intact. ALG and ATG are useful for suppressing certain major compartments (ie, T cells) of the immune system and play a definite role in the management of solid organ and bone marrow transplantation.
Monoclonal antibodies directed against specific antigens such as CD3, CD4, CD25, CD40, IL-2 receptor, and TNF (discussed below) much more selectively influence T-cell subset function. The high specificity of these antibodies improves selectivity and reduces toxicity of the therapy and alters the disease course in several different autoimmune disorders.
In the management of transplants, ALG and monoclonal antibodies can be used in the induction of immunosuppression, in the treatment of initial rejection, and in the treatment of steroid-resistant rejection. There has been some success in the use of ALG and ATG plus cyclosporine to prepare recipients for bone marrow transplantation. In this procedure, the recipient is treated with ALG or ATG in large doses for 7-10 days prior to transplantation of bone marrow cells from the donor. Residual ALG appears to destroy the T cells in the donor marrow graft, and the probability of severe graft-versus-host syndrome is reduced.
The adverse effects of ALG are mostly those associated with injection of a foreign protein obtained from heterologous serum. Local pain and erythema often occur at the injection site (type III hypersensitivity). Since the humoral antibody mechanism remains active, skin-reactive and precipitating antibodies may be formed against the foreign IgG. Similar reactions occur with monoclonal antibodies of murine origin, and reactions thought to be caused by the release of cytokines by T cells and monocytes have also been described.
Anaphylactic and serum sickness reactions to ALG and murine monoclonal antibodies have been observed and usually require cessation of therapy. Complexes of host antibodies with horse ALG may precipitate and localize in the glomeruli of the kidneys. Even more disturbing has been the development of histiocytic lymphomas in the buttock at the site of ALG injection. The incidence of lymphoma as well as other forms of cancer is increased in kidney transplant patients. It appears likely that part of the increased risk of cancer is related to the suppression of a normally potent defense system against oncogenic viruses or transformed cells. The preponderance of lymphoma in these cancer cases is thought to be related to the concurrence of chronic immune suppression with chronic low-level lymphocyte proliferation.
Monoclonal antibodies against T-cell surface proteins are increasingly being used in the clinic for autoimmune disorders and in transplantation settings. Clinical studies have shown that the murine monoclonal antibody muromonab-CD3 (OKT3) directed against the CD3 molecule on the surface of human thymocytes and mature T cells can also be useful in the treatment of renal transplant rejection. In vitro, muromonab-CD3 blocks killing by cytotoxic human T cells and several other T-cell functions. In a prospective randomized multicenter trial with cadaveric renal transplants, use of muromonab-CD3 (along with lower doses of steroids or other immunosuppressive drugs) proved more effective at reversing acute rejection than did conventional steroid treatment. Muromonab-CD3 is approved for the treatment of renal allograft rejection crises. Several other monoclonal antibodies directed against surface markers on lymphocytes are approved for certain indications (see monoclonal antibody section below), while others are in various stages of development and clinical trials.
3. Immune Globulin Intravenous (IGIV)
A quite different approach to immunomodulation is the intravenous use of polyclonal human immunoglobulin. This immunoglobulin preparation (usually IgG) is prepared from pools of thousands of healthy donors, and no specific antigen is the target of the “therapeutic antibody.” Rather, one expects that the pool of different antibodies will have a normalizing effect upon the patient’s immune networks.
IGIV in high doses (2 g/kg) has proved effective in a variety of different conditions ranging from immunoglobulin deficiencies to autoimmune disorders to HIV disease to bone marrow transplants. In patients with Kawasaki’s disease, it has been shown to be safe and effective, reducing systemic inflammation and preventing coronary artery aneurysms. It has also brought about good clinical responses in systemic lupus erythematosus and refractory idiopathic thrombocytopenic purpura. Possible mechanisms of action of IGIV include a reduction of T helper cells, increase of suppressor T cells, decreased spontaneous immunoglobulin production, Fc receptor blockade, increased antibody catabolism, and idiotypic-anti-idiotypic interactions with “pathologic antibodies.” Although its precise mechanism of action is still controversial, IGIV brings undeniable clinical benefit to many patients with a variety of immune syndromes.
5. Hyperimmune Immunoglobulins
Hyperimmune immunoglobulin preparations are IGIV preparations made from pools of selected human or animal donors with high titers of antibodies against particular agents of interest such as viruses or toxins. Various hyperimmune IGIVs are available for treatment of respiratory syncytial virus, cytomegalovirus, varicella zoster, human herpesvirus 3, hepatitis B virus, rabies, tetanus, and digoxin overdose. Intravenous administration of the hyperimmune globulins is a passive transfer of high titer antibodies that either reduces risk or reduces the severity of infection. Rabies hyperimmune globulin is injected around the wound and given intravenously. Tetanus hyperimmune globulin is administered intravenously when indicated for prophylaxis. Rattlesnake and coral snake hyperimmune globulins (antivenins) are of equine origin and are effective for North and South American rattlesnakes and some coral snakes (but not Arizona coral snake). Equine and ovine antivenins are available for rattlesnake envenomations, but only equine antivenin is available for coral snake bite. The ovine antivenin is a Fab preparation and is less immunogenic than whole equine IgG antivenins, but retains the ability to neutralize the rattlesnake venom.
MONOCLONAL ANTIBODIES (MABS)
Recent advances in the ability to manipulate the genes of immunoglobulins have resulted in development of a wide array of humanized and chimeric monoclonal antibodies directed against therapeutic targets. The only murine elements of humanized monoclonal antibodies are the complementarity-determining regions in the variable domains of immunoglobulin heavy and light chains. Complementarity-determining regions are primarily responsible for the antigen-binding capacity of antibodies. Chimeric antibodies typically contain antigen-binding murine variable regions and human constant regions. The following are brief descriptions of the engineered antibodies that have been approved by the FDA.
Alemtuzumab is a humanized IgG1 with a kappa chain that binds to CD52 found oormal and malignant B and T lymphocytes, NK cells, monocytes, macrophages, and a small population of granulocytes. Currently, alemtuzumab is approved for the treatment of B-cell chronic lymphocytic leukemia in patients who have been treated with alkylating agents and have failed fludarabine therapy. Alemtuzumab appears to deplete leukemic and normal cells by direct antibody-dependent lysis. Patients receiving this antibody become lymphopenic and may also become neutropenic, anemic, and thrombocytopenic. As a result patients should be closely monitored for opportunistic infections and hematologic toxicity.
Bevacizumab is a humanized IgG1 monoclonal antibody that binds to vascular endothelial growth factor (VEGF) and inhibits VEGF from binding to its receptor, especially on endothelial cells. It is an antiangiogenic drug that has been shown to inhibit growth of blood vessels (angiogenesis) in tumors. It is approved for first-line treatment of patients with metastatic colorectal cancer alone or in combination with 5-FU-based chemotherapy. Since bevacizumab is antiangiogenic, it should not be administered until patients heal from surgery. Patients taking the drug should be watched for hemorrhage, gastrointestinal perforations, and wound healing problems.
Cetuximab is a human-mouse chimeric monoclonal antibody that targets epidermal growth factor receptor (EGFR). Binding of cetuximab to EGFR inhibits tumor cell growth by a variety of mechanisms, including decreases in kinase activity, matrix metalloproteinase activity, and growth factor production, and increased apoptosis. It is indicated for use in patients with metastatic colorectal cancer whose tumors overexpress EGFR. Cetuximab may be administered in combination with irinotecan or alone in patients who cannot tolerate irinotecan.
Gemtuzumab is a humanized IgG4 monoclonal antibody with a kappa light chain specific for CD33, a sialoadhesion protein found on leukemic blast cells in 80-90% of patients with acute myelogenous leukemia (AML). Gemtuzumab alone has some antiblast activity. In the clinical formulation, gemtuzumab is coupled to the cytotoxic agent, ozogamicin, which is a semisynthetic derivative of calicheamicin, an antibiotic with antitumor activity. Internalization of gemtuzumab-ozogamicin by the tumor cell results in release of the cytotoxin from the antibody in the lysosome. Ozogamicin then binds to the minor groove in DNA, causing double-strand breaks and cell death.
Gemtuzumab is approved for the treatment of patients 60 years and older in first relapse with CD33 acute myelogenous leukemia who are not considered candidates for other types of cytotoxic chemotherapy. Adverse events due to the administration of gemtuzumab-ozogamicin include severe myelosuppression, especially neutropenia, requiring careful hematologic monitoring. Other adverse events associated with gemtuzumab are significant hepatotoxicity and various hypersensitivity reactions.
Rituximab is a chimeric murine-human monoclonal IgG1 (human Fc) that binds to the CD20 molecule oormal and malignant B lymphocytes and is approved for the therapy of patients with relapsed or refractory low-grade or follicular, B-cell non-Hodgkin’s lymphoma. The mechanism of action includes complement-mediated lysis, antibody-dependent cellular cytotoxicity, and induction of apoptosis in the malignant lymphoma cells. This drug appears to be synergistic with chemotherapy (eg, fludarabine, CHOP) for lymphoma.
Trastuzumab is a recombinant DNA-derived, humanized monoclonal antibody that binds to the extracellular domain of the human epidermal growth factor receptor HER-2/neu. This antibody blocks the natural ligand from binding and down-regulates the receptor. Trastuzumab is approved for the treatment of metastatic breast cancer in patients whose tumors overexpress HER-2/neu. As a single agent it induces remission in about 15-20% of patients; in combination with chemotherapy, it increases response rate and duration as well as 1-year survival. Trastuzumab is under investigation for other tumors that express HER-2.
MABs Used to Deliver Isotopes to Tumors
Arcitumomab is a murine F(ab)2 fragment from an anti-carcinoembryonic antigen (CEA) antibody labeled with technetium 99m (99mTc) that is used for imaging patients with metastatic colorectal carcinoma (immunoscintigraphy) to determine extent of disease. CEA is often upregulated on tumor in patients with gastrointestinal carcinomas. The use of the F(ab)2 fragment decreases the immunogenicity of the agent so that it can be given more than once, unlike other intact murine monoclonal antibodies.
Capromab pendetide is a murine monoclonal antibody specific for prostate specific membrane antigen. It is coupled to isotopic indium (111In) and is used in immunoscintigraphy for patients with biopsy-confirmed prostate cancer and post-prostatectomy in patients with rising prostate specific antibody level to determine extent of disease.
Ibritumomab tiuxetan is an anti-CD20 murine monoclonal antibody labeled with isotopic yttrium (90Y) or 111In. The radiation of the isotope provides the major antitumor activity. Ibritumomab is approved for use in patients with relapsed or refractory low-grade, follicular, or B-cell non-Hodgkin’s lymphoma, including patients with rituximab-refractory follicular disease. It is used in conjunction with rituximab in a two-step therapeutic regimen.
Nofetumomab is a mouse monoclonal antibody coupled to 99mTc that is used for diagnostic purposes to determine extent of disease and to stage patients with small cell lung cancer. It binds a 40 kD antigen found on many tumor cell types, but also on some normal cells. It is an accurate indicator of extent of disease in biopsy-confirmed small cell lung cancer except in those patients with brain or adrenal metastases.
Tositumomab is another anti-CD20 monoclonal antibody and is complexed with iodine 131 (131I). Tositumomab is used in two-step therapy in patients with CD20-positive, follicular non-Hodgkin’s lymphoma whose disease is refractory to rituximab and standard chemotherapy. Toxicities are similar to those for ibritumomab and include severe cytopenias such as thrombocytopenia and neutropenia. Tositumomab should not be administered to patients with greater than 25% bone marrow involvement.
MABs Used as Immunosuppressants and Anti-Inflammatory Agents
A. ANTI-TNF-ALPHA MABS
Adalimumab, etanercept, and infliximab are antibodies that bind TNF-, a proinflammatory cytokine. Blocking TNF- from binding to TNF receptors on inflammatory cell surfaces results in suppression of downstream inflammatory cytokines such as IL-1 and IL-6 and adhesion molecules involved in leukocyte activation and migration. An increased risk of lymphoma is common to each of these agents.
Adalimumab is a completely human IgG1 approved for use in rheumatoid arthritis. Like the other anti-TNF- biologicals, adalimumab blocks the interaction of TNF- with TNF receptors on cell surfaces; it does not bind TNF-. Pharmacodynamic studies showed that administration of adalimumab reduced levels of Creactive protein, erythrocyte sedimentation rate, serum IL-6 and matrix metalloproteinases MMP-1 and MMP-
Etanercept is a dimeric fusion protein composed of human IgG1 constant regions (CH2, CH3, and hinge, but not CH1) fused to the TNF receptor. Etanercept binds to both TNF- and TNF- and appears to have effects similar to that of infliximab, ie, inhibition of TNF--mediated inflammation, but its half-life is shorter due to its physical form (fusion protein) and the route of injection (subcutaneously, twice weekly). Etanercept is approved for adult RA, polyarticular-course juvenile RA, and psoriatic arthritis. It may be used in combination with methotrexate.
Infliximab is a human-mouse chimeric IgG1 monoclonal antibody possessing human constant (Fc) regions and murine variable regions. Infliximab is currently approved for use in Crohn’s disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis.
B. ABATACEPT
Abatacept is a recombinant fusion protein composed of the extracellular domain of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) fused to human IgG Fc. CTLA-4 is a costimulatory molecule found on T cells that binds to CD80 and CD86 on antigen presenting cells. This fusion protein blocks activation of T cells by binding to CD80 or 86 so that CD28 on T cells cannot bind and stimulate the T cell and lead to cytokine release. Abatacept is approved for patients with severe rheumatoid arthritis who have failed other DMARDS. Patients should not take other anti-TNF drugs or anakinra while taking abatacept.
C. ALEFACEPT
Alefacept is an engineered protein consisting of the CD2-binding portion of leukocyte-function-associated antigen-3 (LFA-3) fused to a human IgG1 Fc region (hinge, CH1, and CH2), approved for the treatment of plaque psoriasis. It inhibits activation of T cells by binding to cell surface CD2, inhibiting the normal CD2/LFA-3 interaction. Treatment of patients with alefacept also results in a dose-dependent reduction of the total number of circulating T cells, including those that predominate in psoriatic plaques. Therefore, T-cell counts of patients receiving alefacept must be monitored, and the drug discontinued if CD4 lymphocyte levels fall below 250 cells/uL.
D. BASILIXIMAB
Basiliximab is a chimeric mouse-human IgG1 that binds to CD25, the IL-2 receptor alpha chain on activated lymphocytes. It functions as an IL-2 antagonist, blocking IL-2 from binding to activated lymphocytes, and is therefore immunosuppressive. It is indicated for prophylaxis of acute organ rejection in renal transplant patients and is usually used as part of an immunosuppressive regimen that also includes glucocorticoids and cyclosporine A.
E. DACLIZUMAB
Daclizumab is a humanized IgG1 that binds to the alpha subunit of the IL-2 receptor. Its indications are identical to that of basiliximab, but the mode of administration differs.
F. EFALIZUMAB
Efalizumab is a recombinant humanized anti-CD11a monoclonal antibody approved for the treatment of adult patients with severe psoriasis. Binding of efalizumab to CD11a (the alpha subunit of LFA-1) inhibits the interaction of LFA-1 on all lymphocytes with intercellular adhesion molecule-1 (ICAM-1), thereby inhibiting the adhesion, activation, and migration of lymphocytes into skin. Efalizumab is administered by subcutaneous injection.
G. OMALIZUMAB
Omalizumab is an anti-IgE recombinant humanized monoclonal antibody that is approved for the treatment of allergic asthma in adult and adolescent patients whose symptoms are refractory to inhaled corticosteroids. The antibody blocks the binding of IgE to the high-affinity Fc receptor on basophils and mast cells, which suppresses IgE-mediated release of type I allergy mediators such as histamine and leukotrienes. Total serum IgE levels may remain elevated in patients for up to 1 year after administration of this antibody.
Abciximab is a Fab fragment of a murine-human monoclonal antibody that binds to the integrin GPIIb/IIIa receptor on activated platelets and inhibits fibrinogen, von Willebrand factor, and other adhesion molecules from binding to activated platelets, thus preventing their aggregation.
Palivizumab is a monoclonal antibody that binds to the fusion protein of respiratory syncytial virus, preventing infection in susceptible cells in the airways. It is used ieonates at risk for this viral infection and reduces the frequency of infection and hospitalization by about 50%.
CLINICAL USES OF IMMUNOSUPPRESSIVE DRUGS
Immunosuppressive agents are commonly used in two clinical circumstances: transplantation and autoimmune disorders. The agents used differ somewhat for the specific disorders treated, as do administration schedules. Because autoimmune disorders are very complex, optimal treatment schedules have yet to be established in many clinical situations.
The effectiveness of immunosuppressive drugs in autoimmune disorders varies widely. Nonetheless, with immunosuppressive therapy, remissions can be obtained in many instances of autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, type 1 diabetes, Hashimoto’s thyroiditis, and temporal arteritis. Improvement is also often seen in patients with systemic lupus erythematosus, acute glomerulonephritis, acquired factor VIII inhibitors (antibodies), rheumatoid arthritis, inflammatory myopathy, scleroderma, and certain other autoimmune states.
Immunosuppressive therapy is utilized in chronic severe asthma, where cyclosporine is often effective and sirolimus is another alternative. Omalizumab (anti-IgE antibody) has recently been approved for the treatment of severe asthma (see previous section). Tacrolimus is currently under clinical investigation for the management of autoimmune chronic active hepatitis and of multiple sclerosis, where IFN- has a definitive role.
The development of agents that modulate the immune response rather than suppress it has become an important area of pharmacology. The rationale underlying this approach is that such drugs may increase the immune responsiveness of patients who have either selective or generalized immunodeficiency. The major potential uses are in immunodeficiency disorders, chronic infectious diseases, and cancer. The AIDS epidemic has greatly increased interest in developing more effective immunomodulating drugs.
The cytokines are a large and heterogeneous group of proteins with diverse functions. Some are immunoregulatory proteins synthesized within lymphoreticular cells and play numerous interacting roles in the function of the immune system and in the control of hematopoiesis. In most instances, cytokines mediate their effects through receptors on relevant target cells and appear to act in a manner similar to the mechanism of action of hormones. In other instances, cytokines may have antiproliferative, antimicrobial, and antitumor effects.
The first group of cytokines discovered, the interferons (IFNs), were followed by the colony-stimulating factors (CSFs). The latter regulate the proliferation and differentiation of bone marrow progenitor cells. Most of the more recently discovered cytokines have been classified as interleukins (ILs) and numbered in the order of their discovery. Cytokines are produced using gene cloning techniques.
Most cytokines (including TNF-, IFN-, IL-2, granulocyte colony-stimulating factor [G-CSF], and granulocyte-macrophage colony-stimulating factor [GM-CSF]) have very short serum half-lives (minutes). The usual subcutaneous route of administration provides slower release into the circulation and a longer duration of action. Each cytokine has its own unique toxicity, but some toxicities are shared. For example, IFN-, IFN-, IFN-, IL-2, and TNF- all induce fever, flulike symptoms, anorexia, fatigue, and malaise.
Interferons are proteins that are currently grouped into three families: IFN-, IFN-, and IFN-. The IFN- and IFN- families comprise type I IFNs, ie, acid-stable proteins that act on the same receptor on target cells. IFN-, a type II IFN, is acid-labile and acts on a separate receptor on target cells. Type I IFNs are usually induced by virus infections, with leukocytes producing IFN-. Fibroblasts and epithelial cells produce IFN-. IFN- is usually the product of activated T lymphocytes.
IFNs interact with cell receptors to produce a wide variety of effects that depend on the cell and IFN types. IFNs, particularly IFN-, display immune-enhancing properties, which include increased antigen presentation and macrophage, NK cell, and cytotoxic T-lymphocyte activation. IFNs also inhibit cell proliferation. In this respect, IFN- and IFN- are more potent than IFN-. Another striking IFN action is increased expression of MHC molecules on cell surfaces. While all three types of IFN induce MHC class I molecules, only IFN- induces class II expression. In glial cells, IFN- antagonizes this effect and may, in fact, decrease antigen presentation within the nervous system.
IFN- is approved for the treatment of several neoplasms, including hairy cell leukemia, chronic myelogenous leukemia, malignant melanoma, and Kaposi’s sarcoma, and for use in hepatitis B and C infections. It has also shown activity as an anticancer agent in renal cell carcinoma, carcinoid syndrome, and T cell leukemia. IFN- is approved for use in relapsing-type multiple sclerosis. IFN- is approved for the treatment of chronic granulomatous disease and IL-2, for metastatic renal cell carcinoma and malignant melanoma. Numerous clinical investigations of the other cytokines, including IL-1, -3, -4, -6, -11, and -12, are still in progress. Toxicities of IFNs, which include fever, chills, malaise, myalgias, myelosuppression, headache, and depression, can severely restrict their clinical use.
TNF- has been extensively tested in the therapy of various malignancies, but results have been disappointing due to dose-limiting toxicities. One exception is the use of intra-arterial high-dose TNF- for malignant melanoma and soft tissue sarcoma of the extremities. In these settings, response rates greater than 80% have beeoted.
Cytokines have been under clinical investigation as adjuvants to vaccines, and IFNs and IL-2 have shown some positive effects in the response of human subjects to hepatitis B vaccine. IL-12 and GM-CSF have also shown adjuvant effects with vaccines. GM-CSF is of particular interest because it promotes recruitment of professional antigen-presenting cells such as the dendritic cells required for priming naive antigen-specific T-lymphocyte responses. There are some claims that GM-CSF can itself stimulate an antitumor immune response, resulting in tumor regression in melanoma and prostate cancer.
It is important to emphasize that cytokine interactions with target cells often result in the release of a cascade of different endogenous cytokines, which exert their effects sequentially or simultaneously. For example, IFN- exposure increases the number of cell surface receptors on target cells for TNF-. Therapy with IL-2 induces the production of TNF-, while therapy with IL-12 induces the production of IFN-.
Cytokine Inhibitors
A more recent application of immunomodulation therapy involves the use of cytokine inhibitors for inflammatory diseases and septic shock, conditions in which cytokines such as IL-1 and TNF- are involved in the pathogenesis. Drugs now under investigation include anticytokine monoclonal antibodies, soluble cytokine receptors (soluble forms of IL-1 and TNF- receptors occur naturally in humans), and the IL-1 receptor antagonist (IL-1R), anakinra. Anakinra is a recombinant form of the naturally occurring IL-1 receptor antagonist that prevents IL-1 from binding to its receptor, stemming the cascade of cytokines released if IL-1 were to bind to the IL-1R. Anakinra is approved for use in adult rheumatoid arthritis patients who have failed treatment with one or more disease-modifying antirheumatic drugs. Patients must be carefully monitored if they are also taking an anti-TNF- drug, have chronic infections, or are otherwise immunosuppressed.
