CLINICAL PHARMACOLOGY OF DRUGS FOR ASTHMA AND OTHER BRONCHOCONSTRICTIVE DISORDERS

CLINICAL PHARMACOLOGY OF DRUGS ACTING ON THE RESPIRATORY ORGANS FUNCTION

 

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.

 

Classification of severity of chronic stable asthma

 

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.

 

Classification of severity of asthma exacerbations

Adapted from National Asthma Education and Prevention Program. Guidelines for the diagnosis and management of asthma, 2011.

 

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.

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.

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:

 (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 your 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. If you need to use your short acting beta agonist more than 2-3 times a week, you should seek your doctor about management of your asthma.

 (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.

 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

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 b₂-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 b-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 b-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 b stimulation after prolonged treatment with b-agonist drugs, but some studies have shown a loss in the ability of b-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 b-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 b₂-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 b agonists may be greater for some individuals, possibly as a function of genetic variants for the b receptor. Two retrospective and one prospective study have shown differences between patients homozygous for glycine versus arginine at the B-16 locus of the b receptor. Among patients homozygous for arginine, a genotype found in 16% of the Caucasian population in the USA, but more commonly in African Americans, asthma control deteriorated with regular use of albuterol or salmeterol, whereas asthma control improved with this treatment among those homozygous for glycine at the same locus. These findings need to be replicated in larger studies, but it is tempting to speculate that a genetic variant may underlie the report of an increase in asthma mortality from regular use of a long-acting b agonist in studies involving very large numbers of patients.
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.

In low and moderate doses, the methylxanthines¾especially caffeine¾cause mild cortical arousal with increased alertness and deferral of fatigue. The caffeine contained in beverages¾eg, 100 mg in a cup of coffee¾is 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.

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.

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.
The methylxanthines¾especially theophylline¾are 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.

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 agents¾in sufficient concentration¾inhibit antigen-induced release of histamine from lung tissue; their effect on mucociliary transport is unknown.

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 performance¾rather than an effect on the respiratory center¾may 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.

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