VA Class:RE102
Metaproterenol sulfate is a synthetic sympathomimetic amine that stimulates β-adrenergic receptors less selectively than relatively selective β2-agonists (e.g., albuterol).148, 151, 152, 153, 155, 159
Metaproterenol sulfate is used as a relatively short-acting bronchodilator for the symptomatic treatment of bronchial asthma and of reversible bronchospasm that may occur in chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.146 In comparison to isoproterenol, metaproterenol has a more prolonged duration of action, an apparently lower incidence and decreased severity of adverse cardiac effects, and is more effective after oral administration. After prolonged therapy, metaproterenol retains its efficacy to a greater extent than does isoproterenol.
The manufacturers recommend against the use of metaproterenol with other β-adrenergic bronchodilators.148, 151 (See Drug Interactions: Sympathomimetic Amines.)
Metaproterenol has been used generally as an alternative to selective inhaled short-acting β2-adrenergic agonists.159 Use of a selective short-acting inhaled β2-adrenergic agonist (e.g., albuterol, levalbuterol, pirbuterol) on an as-needed basis to control acute symptoms (e.g., cough, wheezing, dyspnea) of short duration is recommended for all patients with asthma.135, 159 Less β2-selective bronchodilators such as metaproterenol generally are not recommended because of their potential to cause excessive cardiac stimulation, particularly at high dosages.159
Metaproterenol sulfate oral inhalation solution is used via nebulization in the management of acute asthmatic episodes.100, 105, 106 In controlled studies, 70% of patients 6-12 years of age receiving 0.1-0.2 mL of a 5% solution by nebulization demonstrated a 15% improvement in FEV1 above baseline.100 In 8% of patients studied, there was a decrease of 10% or greater in FEV1 following such treatment; although data are insufficient to relate these decreases in pulmonary function to the drug, they may have been related to paradoxical bronchospasm.100 A single nebulized dose of metaproterenol sulfate in the treatment of acute asthma may alleviate symptoms and temporarily improve pulmonary function; however, it may not abort the exacerbation completely.100 For information on the stepped-care approach for drug therapy in asthma, see Asthma under Uses: Bronchospasm, in Albuterol 12:12.08.12.
Concerns about the safety of regular use of inhaled β-agonist bronchodilators for maintenance therapy of asthma have been raised by evidence from some studies suggesting increased morbidity and mortality in patients receiving long-term therapy with short-acting, inhaled β-agonists, particularly fenoterol (currently not commercially available in the US).111, 113, 121, 127, 128, 130 Other studies in patients with mild or moderate asthma suggest that while regularly scheduled use of short-acting, inhaled β2-agonists may not cause harm,121, 124, 131, 132, 133 such use does not appear to have demonstrable advantages compared with intermittent use and does not adequately control asthmatic symptoms, peak flow variability, or airway hyperresponsiveness.121, 131, 133, 134, 135 Suggested mechanisms for detrimental effects of regularly scheduled, inhaled β-agonist therapy include down-regulation of β-adrenergic receptors (tolerance)118, 122 (see Cautions: Precautions and Contraindications), increased responsiveness of airways to allergens and exercise,119, 123, 159 genetic changes in β2-agonist receptor gene,159 or increased airway accessibility to inhaled allergens, which may lead to increased airway inflammation and reactivity and worsening of asthma symptoms.107, 110, 120, 159 The validity of the evidence from these studies has been criticized in terms of study design and/or interpretation of study findings114, 115, 116, 117 and a causal relationship between inhaled β2-agonist therapy and asthma mortality has not been proven.112, 118, 121, 124, 128, 129, 130 Current asthma management guidelines and many clinicians recommend anti-inflammatory therapy with an inhaled corticosteroid as first-line therapy for long-term control in patients with persistent asthma, supplemented by as-needed use of a short-acting, inhaled β2-agonist.135, 159 Regular, daily use of a short-acting, inhaled β2-agonist generally is not recommended, and increased chronic use of such β2-agonists more than twice weekly or acute use (repeated use over more than 1-2 days) for asthma deterioration may indicate the need to initiate or increase long-term control therapy for asthma.135 (See Uses: Asthma and see Cautions: Respiratory Effects, in Salmeterol 12:12.08.12.)
Chronic Obstructive Pulmonary Disease
Regular use of selective, short-acting inhaled β2-adrenergic agonists in the management of chronic obstructive pulmonary disease (COPD), in contrast to that in asthma, does not appear to be detrimental.141, 160 However, as long-acting β2-adrenergic agonists have become available for maintenance treatment of COPD, short-acting β2-adrenergic agonists are used by some clinicians mainly to relieve acute symptoms of COPD.161
In the stepped-care approach to drug therapy for COPD, mild intermittent symptoms and minimal lung impairment (e.g., FEV1 at least 80% of predicted) can be treated with a short-acting, selective inhaled β2-agonist such as metaproterenol as needed during acute exacerbations, but use should not exceed 8-12 inhalations daily.136, 137, 138 Current guidelines for the management of COPD state that ipratropium can be added to therapy with a short-acting, selective β2-agonist as separate inhalers or in fixed combination136, 137, 138, 141, 142, 143 in patients with mild-to-moderate persistent symptoms of COPD, with the frequency of inhalation with either agent not exceeding 4 times daily.137, 138, 140, 141, 143, 144 Combining bronchodilators from different classes and with differing durations of action may increase the degree of bronchodilation with a similar or lower frequency of adverse effects.143, 160
In patients with moderate (e.g., FEV1 50-80% of predicted) COPD who have persistent symptoms despite as-needed therapy with ipratropium or a selective inhaled β2-agonist, maintenance treatment with a long-acting bronchodilator (e.g., formoterol, salmeterol, tiotropium) can be added and a short-acting, selective inhaled β2-agonist used as needed for immediate symptom relief.141, 160 Maintenance treatment with long-acting bronchodilators is recommended in such patients as this therapy is more effective and convenient than regular use of short-acting bronchodilators.160 For patients not responding adequately to treatment following addition of a long-acting bronchodilator, a combination of several long-acting bronchodilators such as tiotropium and a long-acting β-adrenergic agonist may be used.142, 144 For treatment of severe to very severe COPD (e.g., FEV1 less than 30 to less than 50% of predicted, history of exacerbations), an inhaled corticosteroid may be added to maintenance therapy with one or more long-acting bronchodilators given separately or in fixed combination.142, 143, 144, 160 For additional information on the stepped-care approach to drug therapy in COPD, see Chronic Obstructive Pulmonary Disease under Uses: Bronchospasm, in Albuterol 12:12.08.12.
Management of acute exacerbations of COPD at home is based initially on the same drugs used for management of the stable patient.141, 143, 144 A short-acting β2-adrenergic agonist is the preferred bronchodilator for treatment of acute exacerbations of COPD.144 If response to a short-acting β2-adrenergic agonist is inadequate, the addition of ipratropium is recommended by some clinicians.141, 144 In a severe exacerbation treated at home, administration of these agents by nebulization or metered-dose inhalation with a spacer device may be used as needed for short-term therapy.141, 142, 143, 144 For more severe exacerbations of COPD (e.g., FEV1 less than 50% of predicted), a short (e.g., 7-10 days) course of oral corticosteroids (e.g., equivalent to 30-40 mg of prednisone daily) can be added to bronchodilator therapy.141, 160 If symptoms of COPD continue to deteriorate several hours after administration of oral corticosteroids, the patient should be hospitalized.144 Following initiation of oxygen therapy in hospitalized patients, therapy with a short-acting β2-adrenergic agonist and/or ipratropium (administered separately or in fixed combination) should be used for acute exacerbations of COPD, although the effectiveness of such combination therapy remains controversial.141, 142, 143, 144 Oral or IV corticosteroids are recommended in addition to other therapies for the management of the hospitalized patient.160 If necessary for severe exacerbations, appropriate anti-infective therapy may be initiated if indicated (increase in dyspnea, purulent exacerbations, sputum volume), based on data from a limited number of randomized trials.141, 142, 143, 160
Metaproterenol sulfate may be administered orally or by oral inhalation via a metered-dose inhaler, intermittent positive pressure breathing (IPPB) apparatus, or nebulizer.145, 146, 148, 151
To ensure maximum bronchodilator effects, proper use of metaproterenol sulfate oral aerosol inhaler is important. The oral inhalation aerosol inhaler should be used only with the actuator provided by the manufacturer.149 The aerosol should be shaken well before use.149 The mouthpiece should be placed well into the mouth and the lips closed tightly around it.149 The patient should exhale through the nose as completely as possible and then inhale slowly and deeply through the mouth while actuating the inhaler.149 After holding the breath for a few seconds, the mouthpiece should be removed and the patient should exhale slowly; at least 2 minutes should elapse between inhalations from the aerosol inhaler.149 Patients should avoid spraying metaproterenol sulfate oral inhalation aerosol into the eyes.149
To clean the metered-dose inhaler, the metal canister should be removed and the plastic mouthpiece cleansed by running warm water through the mouthpiece.149 If soap is used to clean the mouthpiece, rinse the mouthpiece thoroughly with plain water.149
Dosage of metaproterenol sulfate must be carefully adjusted according to individual requirements and response.145, 146, 148, 151, 151
For adults and children older than 9 years of age or those weighing more than 27.3 kg, the usual oral dosage of metaproterenol sulfate is 20 mg 3 or 4 times daily.151 For children 6-9 years of age or those weighing less than 27.3 kg, the usual oral dosage is 10 mg 3 or 4 times daily.151 Experience in children younger than 6 years of age is limited, but oral dosages of 1.3-2.6 mg/kg daily in divided doses have been well tolerated.151
The oral aerosol inhaler delivers approximately 0.65 mg of metaproterenol sulfate per metered spray.148 The commercially available aerosol delivers at least 100 or 200 metered sprays from a 7- or 14-g canister, respectively.148, 149
For adults and children 12 years of age or older, the usual dosage of metaproterenol sulfate administered via a metered-dose aerosol inhaler is 1.3 or 1.95 mg (2 or 3 inhalations).148 Doses should usually not be repeated more often than every 3-4 hours.148, 149 If necessary, additional inhalations may be used; no more than 7.8 mg (12 inhalations) should be administered in any 24-hour period.148, 149
For administration via an air-driven nebulizer, the usual dosage of metaproterenol sulfate for adults and children 12 years of age or older is 10 or 15 mg (contents of 1 vial of the 0.4 or 0.6% solution for nebulization, respectively) 3 or 4 times daily.145 To relieve acute attacks of bronchospasm, these doses usually do not need to be repeated more often than every 4 hours.145
The most common adverse effects of metaproterenol sulfate are dose related and characteristic of sympathomimetic agents. Adverse effects usually occur only at high doses, but may persist for a relatively long time because of the drug's considered a “short-acting bronchodilator” duration of action. The principal adverse effects of metaproterenol are tachycardia,145, 146, 151 tremor,145, 146, 148, 151 palpitation,146, 148 hypertension,146 nervousness,146, 151, 148 headache,146, 148, 151 fatigue,146 dizziness,148 nausea,145, 146, 148, 151 vomiting,146, 148 bad taste,146 GI distress,146, 148 throat irritation,148 cough,148 and exacerbation of asthma.146, 148 Other common adverse effects occurring with metaproterenol oral tablets include insomnia,146 diarrhea,146 drowsiness,146 syncope,146 appetite changes,146 dry throat,146 and fever.146 Pruritus also occurs infrequently with metaproterenol oral tablets.146 The adverse effect profile in pediatric patients is similar; however, limited evidence suggests that the incidence of such effects may be higher in this patient population than in adults.
Therapy with metaproterenol potentially may produce hypokalemia in some patients, which has the potential to produce adverse cardiovascular effects.155, 156, 157 It has also been reported that some patients treated with metaproterenol (route unspecified) developed cramps in the muscles of the extremities, which responded to oral administration of potassium salts.
Adverse reactions from β-agonist oral inhalation solutions for nebulization may occur with a new container of a preparation in patients who previously have tolerated that same preparation without adverse effect. Reports indicate that such patients subsequently may tolerate replacement containers of the same preparation without adverse effect.
Precautions and Contraindications
Excessive or prolonged use of sympathomimetic amine aerosols can lead to decreased effectiveness. Failure to respond to a previously effective dosage of metaproterenol may indicate seriously worsening asthma that requires reevaluation and possible institution of alternative regimens or therapy.112, 126, 135, 159 Patients should be instructed to contact their clinician if decreased effectiveness of metaproterenol occurs145, 151 rather than increasing the dose or frequency of administration.148, 151 Fatalities, sometimes associated with cardiac arrest, have occurred following excessive use of metaproterenol inhalation.145, 148 Patients should be instructed to contact their clinician if asthmatic symptoms worsen or adverse reactions occur with usual dosages of metaproterenol.145, 151 In an open-label clinical trial evaluating the effects of potential tolerance to metaproterenol on lung function, metaproterenol (given 4 times daily by a nebulizer) continued to produce appreciable improvement in lung function throughout the study period of 60-90 days.145
Although the mechanism(s) has not been fully elucidated, paradoxical bronchoconstriction has occasionally occurred after repeated or excessive use of sympathomimetic amine oral inhalations (especially isoproterenol); rarely, a patient may develop acute bronchospasm immediately upon inhalation of a sympathomimetic drug preparation.148 Acute bronchospasm probably represents a hypersensitivity reaction to the active drug or an ingredient in the commercial product. Although it may not be possible to distinguish paradoxical bronchoconstriction or that associated with hypersensitivity to the drug or an ingredient in the formulation from worsening of the asthma, metaproterenol should be discontinued immediately if bronchoconstriction occurs and alternative therapy instituted.148
Patients should also be advised that following administration of the drug, a sufficient interval of time should elapse before administering another sympathomimetic agent. In addition, the effects of metaproterenol may last for 6 hours or longer. The drug should not be used more often than is recommended and the patient should not increase the number of inhalations or frequency of use without first consulting a physician. If asthmatic symptoms worsen, adverse reactions occur, or if the patient does not respond to the usual dose, the patient should be advised to contact the physician immediately. A single nebulized dose of metaproterenol sulfate in the treatment of acute asthma may not abort the exacerbation completely. Safety of metaproterenol sulfate oral inhalation aerosol for self-medication (not supervised by a physician) has not been fully determined.
Metaproterenol should be used with particular caution in patients with cardiovascular disorders such as ischemic heart disease, hypertension, cardiac arrhythmias, coronary artery disease, or congestive heart failure; hyperthyroidism; diabetes mellitus; seizure disorders; and in those who are sensitive to the actions of sympathomimetic agents.145, 146, 148, 151
Metaproterenol is contraindicated in patients with preexisting cardiac arrhythmias associated with tachycardia.145, 146, 148, 151 Certain immediate hypersensitivity reactions have occurred rarely following metaproterenol therapy;146, 148, 151 therefore, the drug is also contraindicated in those with a history of hypersensitivity to the drug or other ingredients in the commercially available formulations.145, 146, 148, 151
Studies on the use of metaproterenol sulfate in asthmatic children have shown that the drug is a useful alternative to isoproterenol. Most manufacturers state that safety and efficacy of metaproterenol oral inhalation in children younger than 12 years of age have not been established.140, 145, 148 The manufacturers also state that safety and efficacy of orally administered metaproterenol tablets in children younger than 6 years of age have not been established.146 Safety and efficacy of metaproterenol oral solution have been demonstrated in a limited number of pediatric patients younger than 6 years of age.151
Mutagenicity and Carcinogenicity
Studies to determine the mutagenic potential of metaproterenol sulfate have not been performed to date. Long-term studies in mice and rats to evaluate the carcinogenic potential of orally administered metaproterenol sulfate have not been completed.145
Pregnancy, Fertility, and Lactation
Although there are no adequate and controlled studies to date in humans, metaproterenol sulfate has been shown to be teratogenic and embryocidal in rabbits when given orally at 620 times the usual human inhalation dosage or 62 times the usual human oral dosage. Teratogenic effects included skeletal abnormalities and hydrocephalus with bone separation. Reproduction studies in rats, mice, and rabbits showed no teratogenic or embryocidal effect at 310 times the usual human inhalation dosage or 31 times the usual human oral dosage. Metaproterenol sulfate should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.
Studies to evaluate the effects of metaproterenol sulfate on fertility in animals have not been performed to date.
It is not known if metaproterenol is distributed into milk.145, 148, 151 Metaproterenol oral inhalation solution should be used with caution in nursing women.145 Metaproterenol oral solution or inhalation aerosol should be used in nursing women only if potential benefits to the woman outweigh the possible risk to the infant.148, 151
Metaproterenol sulfate should not be administered concurrently with other sympathomimetic agents because of the possibility of additive effects and possible toxicity.148, 151 Extreme care should be exercised; a sufficient length of time should elapse after the administration of metaproterenol before another sympathomimetic agent is administered.146, 148
There is some evidence from animal studies that concomitant administration of a sympathomimetic agent (e.g., isoproterenol) and a theophylline derivative (e.g., aminophylline) may produce increased cardiotoxic effects.100, 101, 102, 145, 146, 148 Although such an interaction has not been established in humans, a few reports have suggested that such a combination may have the potential for producing cardiac arrhythmias.101, 102 Further accumulation of clinical data is needed to determine whether this potential interaction occurs in humans.101, 102 However, pharmacokinetic interactions between theophylline and metaproterenol are unlikely.150
The manufacturers state that the effects of metaproterenol on the vascular system may be potentiated in patients receiving monoamine oxidase inhibitors or tricyclic antidepressants; metaproterenol should be administered with caution in patients receiving these drugs.146, 148, 151
Metaproterenol sulfate and β-adrenergic blocking agents (e.g., propranolol hydrochloride) have been shown to be mutually antagonistic when they are administered concomitantly.158β-Adrenergic blocking agents not only block the pulmonary effects of β-agonists, but may produce severe bronchospasm in asthmatic patients.158 However, under certain circumstances (e.g., prophylaxis after myocardial infarction), there may be no acceptable alternatives to the use of β-adrenergic blocking agents in patients with asthma; cardioselective β-adrenergic blocking agents without intrinsic sympathomimetic activity (e.g., metoprolol, atenolol, esmolol) should be used with caution in these patients.158 Low dosages of a cardioselective β-adrenergic blocker should be used initially, and dosage of such agents should be titrated upward with caution in patients receiving concurrent metaproterenol.158
Metaproterenol sulfate stimulates β-adrenergic receptors of the sympathetic nervous system and has little or no effect on α-adrenergic receptors. Metaproterenol has a greater stimulating effect on the β-receptors of the bronchial and vascular smooth muscles (β2-receptors) and a lesser effect on the β-receptors of the heart (β1-receptors) than does isoproterenol. Metaproterenol has a less selective action on β2-receptors than does albuterol.159
β-adrenergic agonists stimulate the production of cyclic adenosine-3',5'-monophosphate (AMP) by activation of the enzyme adenyl cyclase,146, 151 which mediates bronchial smooth muscle relaxation and inhibition of the release of proinflammatory mediators from mast cells in the airways.146, 148, 151 The main effect of metaproterenol is relaxation of smooth muscle of the bronchial tree and the peripheral vasculature. The drug decreases resistance of the airways as measured by pulmonary function tests such as the forced expiratory volume in 1 second (FEV1).145, 148, 151 Metaproterenol may have a lesser tendency to decrease arterial oxygen tension than does isoproterenol. Metaproterenol may cause CNS stimulation and some cardiostimulatory effects, which may result in tachycardia and hypertension.
Metaproterenol sulfate is well absorbed from the GI tract, but only about 40% of an oral dose reaches systemic circulation as unchanged drug since it undergoes extensive metabolism on first pass through the liver. Oral bioavailability of metaproterenol is about 10%.151, 152
The onset of action usually occurs within 1 minute following oral inhalation of the aerosol, within 5-30 minutes following nebulization,145 and within 15-30 minutes after oral administration.146 The peak effect is achieved within about 1 hour following oral inhalation or oral administration.
Metaproterenol appears to be less rapidly metabolized than is isoproterenol, and its bronchodilating effect persists for at least 1 hour longer than that of equipotent doses of isoproterenol. Effects may persist for 4 hours or longer after a single dose of metaproterenol administered by inhalation via nebulization or orally,145, 146, 151 but after long-term use the drug may have a shorter duration of action. In single-dose studies in patients receiving metaproterenol inhalation aerosol, the duration of bronchodilating effect varied from 1-5 hours.148 In multiple-dose studies in which metaproterenol was administered by oral inhalation aerosol via a metered-dose inhaler, the duration of action was 1-2.5 hours;148 the reasons for the differences in duration of action are not known.148 In single-dose studies in which the drug was administered via an IPPB apparatus or hand-bulb nebulizer, the duration of action was up to 6 hours or 2-3 hours, respectively; in multiple-dose studies, the duration of action was 4-6 hours after either method of administration.145 The reasons for the differences in duration of action are not known.
It is not known if metaproterenol is distributed into milk.148 Approximately 10-15% of metaproterenol is bound to plasma proteins.153
In contrast to isoproterenol, metaproterenol sulfate is not metabolized by catechol- O -methyltransferase (COMT).140, 145, 146, 147 In a study in healthy individuals receiving a single dose of metaproterenol tablets (20 mg), approximately 40% of the drug was eliminated in urine as unchanged drug and metaproterenol- O -sulfate, its major metabolite.140, 146, 147 However, following oral inhalation, metaproterenol has been reported also to be metabolized to glucuronic acid conjugates.145
Following oral administration of metaproterenol, elimination of the drug was biphasic with a terminal half-life of 1.5-6 hours.152, 153
Metaproterenol sulfate is a synthetic sympathomimetic amine that is similar to isoproterenol in chemical structure and in pharmacologic action. The drug occurs as a white, crystalline powder with a bitter taste. The commercially available drug is a racemic mixture of 2 optical isomers. Metaproterenol sulfate is freely soluble in water. A 10% solution of the drug has a pH of 4-5.5. The commercially available oral solution has a pH of 2.5-4.
Metaproterenol is heat-stable and may be autoclaved, but is oxidized in air, especially in neutral or alkaline solution or in the presence of light or of heavy metal ions.
Oral preparations of metaproterenol sulfate should be protected from light and moisture.146, 151 Metaproterenol sulfate tablets and oral solution should be stored in tight, light-resistant containers at 15-30°C; freezing of the oral solution should be avoided.146, 151
Metaproterenol sulfate oral inhalation aerosol should be stored at 15-25°C.148 At temperatures below this range, cooling of the propellants can decrease internal pressure of the canister, which may result in delivery of particles too large to provide full therapeutic effect.103, 104 A 5-minute cooling of inhalers to 0°C produced a mean decrease in peak propellant pressure of 28% (range: 20-38%); however, this effect was reversed when the canisters were warmed to room temperature.103 Exposure of metaproterenol sulfate oral inhalation aerosol to excessive humidity should be avoided.148
Metaproterenol sulfate solutions for nebulization should be stored at temperatures not exceeding 25°C and should be protected from light.145 The solutions for nebulization should not be used if they are pinkish or darker than slightly yellow in color or contain a precipitate.145
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Solution | 10 mg/5 mL* | Metaproterenol Sulfate Syrup | |
Tablets | 10 mg* | Metaproterenol Sulfate Tablets | ||
20 mg* | Metaproterenol Sulfate Tablets | |||
Oral Inhalation | Aerosol | 0.65 mg/metered spray | Alupent® (with chlorofluorohydrocarbon propellants) | |
Solution, for nebulization | 0.4%* | Metaproterenol Sulfate Inhalation Solution | ||
0.6%* | Metaproterenol Sulfate Inhalation Solution |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
AHFS® Drug Information. © Copyright, 1959-2022, Selected Revisions January 1, 2009. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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