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Bronchodilators, Adrenergic (Systemic)

This monograph includes information on the following:

1) Albuterol
2) Ephedrine
3) Epinephrine
4) Isoproterenol
5) Metaproterenol
6) Terbutaline

Note: For information regarding use of sympathomimetics for cardiovascular indications, see the Sympathomimetic Agents—Cardiovascular Use (Parenteral-Systemic) monograph.
For information regarding use of epinephrine in combination with local anesthetics as an adjunct to local or regional anesthesia, see the Anesthetics (Parenteral-Local) monograph.



INN:
Albuterol—Salbutamol

BAN:
Albuterol—Salbutamol
Epinephrine—Adrenaline


JAN:
Albuterol—Salbutamol
Metaproterenol—Orciprenaline

VA CLASSIFICATION
Albuterol
Primary: RE125

Epinephrine
Primary: RE190
Secondary: CN205; AD900; GU900; BL116

Isoproterenol
Primary: RE190

Metaproterenol
Primary: RE125

Terbutaline
Oral
Primary: RE125

Parenteral
Primary: RE190
Secondary: GU650




Note: Ephedrine is categorized as a Schedule V controlled substance in several states in order to help prevent abuse. In addition to being abused as a stimulant, ephedrine also can be chemically manipulated to produce illicit designer drugs, such as methcathinone (cat) and methamphetamine (crank). {46}9 {46}8

Commonly used brand name(s): Adrenalin3; Alupent5; Ana-Guard3; Brethine6; Bricanyl6; EpiPen3; EpiPen Auto-Injector3; EpiPen Jr.3; EpiPen Jr. Auto-Injector3; Isuprel4; Proventil1; Proventil Repetabs1; Ventolin1; Volmax1.

Other commonly used names are:


Adrenaline —Epinephrine



Orciprenaline —Metaproterenol



Salbutamol —Albuterol

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Bronchodilator—Albuterol; Epinephrine; Isoproterenol; Metaproterenol; Terbutaline;

Anesthetic, local and regional, adjunct—Epinephrine;

Antiallergic, systemic—Epinephrine;

Tocolytic—Terbutaline;

Priapism reversal agent—Epinephrine;

Antihemorrhagic, dental—Epinephrine;

Indications

Accepted

Asthma, bronchial (treatment)
Bronchitis (treatment)
Bronchospasm (treatment) or
Emphysema, pulmonary (treatment)—Albuterol, subcutaneous or intramuscular epinephrine, metaproterenol, and terbutaline are indicated for the symptomatic treatment of bronchial asthma and for treatment of reversible bronchospasm that may occur in association with bronchitis, pulmonary emphysema, and other obstructive airway diseases. {46}7 {46}6 {46}5 {46}4 {46}3 {46}2 {46}1 {46}0 {52}9 {52}8 {52}7 {52}6
—Inhaled albuterol and terbutaline are the initial drugs of choice for treatment of acute bronchospasm because they provide faster delivery of medication to the lungs and fewer systemic side effects. The agents that are less selective for the beta 2 receptor (epinephrine, isoproterenol, metaproterenol) generally are not recommended because of their potential for excessive cardiac stimulation, especially at high doses. Use of albuterol oral solution or syrup is not recommended for treatment of acute bronchospasm. {52}5
—Oral beta 2-adrenergic receptor agonists may be useful in children who are unable to handle use of inhalers. {52}4
—Long-acting oral beta 2-adrenergic receptor agonists may be useful for control of nocturnal asthma symptoms {52}3 {52}2 {52}1, however, inhaled long-acting beta 2-adrenergic receptor agonists generally are preferred because they have fewer side effects associated with their use. {52}0 {56}9
—Isoproterenol injection is indicated for treatment of bronchospasm occurring during anesthesia. {56}8 However, use of intravenous isoproterenol is not generally recommended for treatment of asthma because of the danger of myocardial toxicity. {56}7

Allergic reactions (treatment)
Anaphylactic or anaphylactoid reactions (treatment) or
Angioedema (treatment)—Epinephrine injection is indicated for the emergency treatment of severe (Type 1) allergic reactions (anaphylaxis or anaphylactoid reactions) to insect stings or bites, animal sera, foods, drugs, and other allergens, as well as for treatment of idiopathic or exercise-induced anaphylaxis. {56}6 {56}5 {56}4 {56}3 {56}2 {56}1 {56}0 Epinephrine is the treatment of choice for these indications. {46}9 (For additional information regarding use of epinephrine in anaphylactic shock, see the Sympathomimetic Agents— Cardiovascular Use [Parenteral-Systemic] monograph.)
—Epinephrine injection may be self-administered by patients with a history of an anaphylactic reaction as soon as exposure occurs and/or with onset of symptoms (including flushing, apprehension, syncope, tachycardia, thready or unobtainable pulse associated with a fall in blood pressure, convulsions, vomiting, diarrhea and abdominal cramps, involuntary voiding, wheezing, dyspnea due to laryngeal spasm, pruritus, rashes, urticaria, or angioedema)Patients should seek medical attention from a physician or medical facility as soon as possible following the self-administration of epinephrine. {46}8 {46}7

Anesthesia, local, adjunct or
Anesthesia, regional, adjunct—Epinephrine is indicated for concurrent use with a local anesthetic to decrease the rate of vascular absorption in order to localize and prolong the action of the local anesthetic. {46}6 {46}5 The addition of epinephrine to local anesthetics for injection into areas of the body served by end arteries or with otherwise limited blood supply (fingers, toes, nose, ears, penis) usually is not recommended because of the risk that vasoconstriction will cause sloughing of tissue. {46}4 {46}3 (For additional information regarding use of epinephrine in combination with local anesthetics, see the Anesthetics [Parenteral-Local] monograph.)

[Labor, premature (treatment)]1—Terbutaline is indicated parenterally as initial tocolytic treatment to suppress premature labor and delay premature delivery. {46}2 {46}1 {46}0 {56}9 {56}8 {56}7 {56}6 Although there is a risk of adverse effects (including maternal tachycardia, arrhythmias, hyperglycemia, hypotension, hypokalemia, pulmonary edema, and myocardial ischemia, and fetal tachycardia and reactive neonatal hypoglycemia) and the manufacturer's product labeling states that use during labor is not recommended, {56}5 {56}4 USP DI Advisory Panels agree that use for this indication is safe and effective. {56}3

[Priapism (treatment)]1—Epinephrine is indicated by intracavernosal injection to treat priapism, {56}2 {56}1 {56}0 {29}9 {29}8 {29}7 {29}6 although phenylephrine is considered to be the drug of first choice {29}5 because it has no direct beta-adrenergic effects. {29}4

[Hemorrhage, gingival (treatment) ]1 or
[Hemorrhage, pulpal (treatment)]1—Epinephrine-impregnated retraction cords are used to control minor gingival bleeding in order to facilitate obtaining accurate dental impressions. However, there is a risk of unpredictable systemic absorption, especially from abraded surfaces. {29}3 It is recommended that epinephrine retraction cords be used with caution in patients with cardiovascular disease. {29}2
—Epinephrine also is applied topically, in dilute solutions, directly to gingival or pulpal tissues to control minor local hemorrhage. {29}1 {29}0

[Hyperkalemia (treatment)]1—Albuterol is indicated as a temporary treatment option for hyperkalemia in acute situations in pediatric patients.{30}9{30}8{30}7{30}6{30}5{30}4{30}3{30}2{30}1{30}0

Acceptance not established
The evidence to support use of terbutaline in maintenance treatment of premature labor is limited {32}9 {32}8 {32}7 {32}6 {32}5 {32}4 and conflicting, {32}3 {32}2 {32}1 but seems to indicate that terbutaline administration does not significantly prolong pregnancy. {32}0 {64}9 Despite the routine use of terbutaline as a tocolytic agent, USP DI Advisory Panels agree that safety and efficacy are not established for this indication. {64}8

There is insufficient data to show that albuterol is beneficial for the treatment of hyperkalemia in adults.{64}7 {64}6 {64}5 {64}4 {64}3 {64}2 {64}1 {64}0 {64}9 {64}8

Unaccepted
Although ephedrine has been used as a bronchodilator , a nasal decongestant, and to treat urinary incontinence, it has been generally replaced by safer and more effective medications. {64}7

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Albuterol: 239.32 {64}6
    Albuterol sulfate: 576.7 {64}5
    Ephedrine sulfate: 428.55 {64}4
    Epinephrine: 183.21 {64}3
    Isoproterenol hydrochloride: 247.72 {64}2
    Metaproterenol sulfate: 520.60 {64}1
    Terbutaline sulfate: 548.66 {64}0

Mechanism of action/Effect:

Sympathomimetic agents mimic, to varying degrees, the actions of endogenous catecholamines by stimulating adrenergic receptors. Stimulation of adrenergic receptors may occur directly (e.g., epinephrine) or indirectly via norepinephrine release (e.g., ephedrine), or effects may be mixed. Relative stimulation of alpha- and beta-adrenergic receptors and selectivity of effect (alpha 1, alpha 2, beta 1, beta 2) vary with individual agents, which leads to variation in effects. {64}9

• Albuterol—Primarily stimulates beta 2-adrenergic receptors, with some minor beta 1-adrenergic activity {64}8.


• Ephedrine—Stimulates both alpha- and beta-adrenergic receptors {64}7. Also, stimulates the release of other catecholamines {64}6, specifically norepinephrine {64}5.


• Epinephrine—Potent stimulant of both alpha- and beta-adrenergic receptors. {64}4 {64}3.


• Isoproterenol—Stimulates both beta 2- and beta 1-adrenergic receptors. {64}2


• Metaproterenol—Somewhat selective for beta 2-adrenergic receptors, with some beta 1-adrenergic activity {64}1.


• Terbutaline—Primarily stimulates beta 2-adrenergic receptors, with some minor beta 1-adrenergic activity {64}0.


All of these beta-adrenoceptor agonists have at least one asymmetric carbon atom and as a result exist in two or more stereoisomeric forms. {64}9 The biological activity of racemic sympathomimetics is primarily the result of the (R)-enantiomer, whereas the (S)-enantiomer, though apparently lacking in therapeutic effect, may play a role in the undesirable action observed with adrenergic bronchodilators of inducing airway hyperreactivity or hyperresponsiveness (paradoxical bronchospasm). {64}8 {64}7

Bronchodilator—Adrenergic bronchodilators act by stimulating beta 2-adrenergic receptors in the lungs to relax bronchial smooth muscle, thereby relieving bronchospasm. {64}6

Anesthetic (local) adjunct—Epinephrine acts on alpha-adrenergic receptors in the skin and mucous membranes to produce vasoconstriction. Vasoconstriction decreases the rate of vascular absorption of the local anesthetic used with epinephrine, prolonging the duration of action and possibly decreasing the risk of toxicity due to the anesthetic. {64}5 {64}4

Antiallergic—Epinephrine acts on alpha-adrenergic receptors to counteract vasodilation, particularly peripheral vessel vasodilation {64}3, and on beta-adrenergic receptors to inhibit the release of mediators of immediate hypersensitivity, such as histamine and leukotrienes, from mast cells {64}2 {64}1.

Tocolytic—Beta-adrenergic stimulation by terbutaline relaxes uterine muscle {64}0, decreasing uterine contractibility and inhibiting preterm labor {64}9.

Priapism reversal agent—Epinephrine-induced vasoconstriction reverses priapism.

Antihemorrhagic, dental—Vasoconstriction by epinephrine reduces minor bleeding during dental procedures. {64}8


Other actions/effects:

Stimulation of beta 1 {64}7 {64}6 and beta 2-adrenergic receptors in the heart produces tachycardia {64}5 {64}4 {64}3 and causes an increase in the rate and force of cardiac contractions {64}2.

Stimulation of beta 2 receptors located in skeletal muscle causes muscle tremor {64}1 {64}0and the dilation of skeletal muscle vasculature, which may result in decreased peripheral resistance {29}9 {29}8 {29}7.

Beta-adrenergic stimulation may inhibit contractions of the pregnant uterus {29}6.

Beta 2-adrenergic stimulation also enhances glycogenolysis and gluconeogenesis, which may lead to hyperglycemia {29}5 {29}4.

Beta 2-adrenergic stimulation of Na +/K +-ATPase may cause an intracellular potassium shift, leading to hypokalemia {29}3.

Alpha-adrenergic stimulation causes vasoconstriction that can lead to hypertension. {29}2


Albuterol:

Albuterol primarily stimulates beta 2-adrenergic receptors, although it has some minor beta 1-adrenergic activity {29}1 {29}0.



Ephedrine:

Ephedrine stimulates both alpha- and beta-adrenergic receptors and enhances the release of endogenous norepinephrine from sympathetic neurons, resulting in increased systolic and diastolic blood pressure and increased cardiac output. Ephedrine also stimulates the central nervous system (CNS), although to a lesser extent than does amphetamine.



Epinephrine:

Epinephrine is a potent non-selective stimulant of both alpha- and beta-adrenergic receptors. {29}9 {29}8 At very low doses (less than 0.01 mcg per kg of body weight per minute [mcg/kg/minute]), epinephrine may stimulate beta 2-adrenergic receptors and decrease blood pressure through dilatation of skeletal muscle vasculature. At doses of 0.04 to 0.1 mcg/kg/minute, stimulation of beta 1- and beta 2-adrenergic {29}7 receptors predominates, increasing heart rate, cardiac output, and stroke volume and decreasing peripheral vascular resistance. At doses exceeding 0.2 mcg/kg/minute, stimulation of alpha-adrenergic receptors produces vasoconstriction and increased total peripheral resistance. Doses exceeding 0.3 mcg/kg/minute decrease renal blood flow, gastrointestinal motility, pyloric tone, and splanchnic vascular bed perfusion.

Epinephrine has significant beta-adrenergic activity in the heart, resulting in an increased rate and force of cardiac contractions. Epinephrine increases conduction velocity in the myocardium and increases ectopic pacemaker activity. Myocardial oxygen demand also is increased. {29}6



Isoproterenol:

Isoproterenol is a nonselective beta-adrenergic receptor agonist. It is a potent inotrope and chronotrope (beta 1-adrenergic effects produce increased rate and force of cardiac contractions), increasing cardiac output despite a reduction in mean blood pressure due to peripheral vasodilation. {29}5



Metaproterenol:

Metaproterenol stimulates both beta 1- and beta 2-adrenergic receptors. Metaproterenol has significant beta 1-adrenergic activity in the heart, resulting in an increased rate and force of cardiac contractions.



Terbutaline:

Terbutaline primarily stimulates beta 2-adrenergic receptors, although it also has some minor beta 1-adrenergic activity {29}4 {29}3.


Absorption:


Albuterol:

Rapidly and well absorbed following oral administration {29}2 {29}1 {29}0.

Extended-release tablets: Availability is approximately 80% of that for tablets after a single dose, regardless of whether or not taken with food, but is 100% of that for immediate-release tablets at steady-state {29}9. Food decreases the rate of absorption without affecting bioavailability {29}8.



Ephedrine:

Rapidly and completely absorbed following parenteral administration {29}7.



Epinephrine:

Well absorbed following subcutaneous or intramuscular administration {29}6. Absorption is slower after subcutaneous administration, but vigorous massage of the injection site will speed absorption {29}5. Rapidly absorbed through the lung capillary bed after injection into the endotracheal tube directly into the bronchial tree {29}4.



Isoproterenol:

Rapidly absorbed following parenteral administration {29}3.



Metaproterenol:

Oral: Less than 10% absorbed intact {29}2 {29}1.



Terbutaline:

Oral: 30 to 70% {29}0; food reduces bioavailability by one third {28}.

Subcutaneous: More rapidly absorbed than with oral administration. {90} Systemic availability is approximately 100%. {90}


Biotransformation:


Albuterol:

Metabolized through sulfate conjugation to its inactive 4'- O-sulphate ester by phenol sulphotransferase (PST). {79} {88} {90} The (R)-enantiomer of albuterol is preferentially metabolized (ten fold) by PST compared to the (S)-enantiomer of albuterol. {87} {88}



Ephedrine:

Hepatic, slow (small amounts). Metabolites include p-hydroxyephedrine, p-hydroxynorephedrine, norephedrine, and their conjugates. {81}



Epinephrine:

Hepatic and other tissues, rapid, by monoamine oxidase (MAO) and COMT {22}. After becoming fixed in tissues, epinephrine is enzymatically inactivated to metanephrine or 3,4-dihydroxyphenylglycoaldehyde (DOPGAL), both of which undergo further metabolism and/or sulfate or glucuronide conjugation and are eliminated in the urine in the form of sulfates and glucuronides. {65} {91} Vanillylmandelic acid (VMA) formation results from the combined action of MAO and COMT; VMA also is detectable in the urine. {19} Any circulating epinephrine not enzymatically deactivated is deactivated by reuptake at synaptic receptor sites {22}.



Isoproterenol:

Hepatic and other tissues, by COMT {24} as well as PST {90}. The 3'- O-methyl metabolite is a weak beta-adrenergic receptor antagonist. {90}



Metaproterenol:

By sulfate conjugation in the gastrointestinal tract {25} {26}.



Terbutaline:

Oral: Gastrointestinal and hepatic, 60% metabolized by first-pass metabolism; no known active metabolites {28}.

Subcutaneous: Approximately one third metabolized, to inactive metabolites {29}.


Half-life:


Elimination:

Albuterol: 3.8 to 6 hours {92}.

Ephedrine: About 3 hours at urinary pH 5 and about 6 hours at urinary pH 6.3 {81}.

Isoproterenol: 0.05 hour {90}.

Terbutaline: 3 to 4 hours {28} {29}.


Onset of action:


Albuterol:

Tablets: Within 30 minutes {02}.



Epinephrine:

Intravenous: Immediate {19} {21}.

Subcutaneous: Bronchodilation—Within 5 to 10 minutes {18}.



Metaproterenol:

Within 30 minutes {25}.



Terbutaline:


Oral—

Measurable change in flow rate—Within 30 minutes {27} {28} {30}.

Improvement in pulmonary function—Within 60 to 120 minutes {30}



Subcutaneous—

Measurable change in flow rate—Within 5 minutes {29}.

Improvement in pulmonary function—Within 15 minutes {29}.



Time to peak concentration:


Albuterol:

Syrup: Within 2 hours {01} {03}.

Tablets: 2 to 3 hours {02}.



Terbutaline:

Oral: Serum—After single dose: 30 minutes to 5 hours {28}.

Subcutaneous: Plasma—15 to 30 minutes {29} {90}.


Peak plasma concentration


Albuterol:

Syrup: 18 nanograms per mL after a 4 mg dose {01} {03}.

Tablets: 18 nanograms per mL after a single 4 mg dose {11}; 6.7 nanograms per mL after dosing with 2 mg every 6 hours; 14.8 nanograms per mL after dosing with 4 mg every 6 hours {02}.

Extended-release tablets: 6.5 nanograms per mL after dosing with 4 mg every 12 hours {05}.



Terbutaline:

Oral: Average of approximately 1 nanogram per mL after each 1 mg administered to fasting adults {28}.

Subcutaneous: Mean, 7.6 nanograms per mL after a 0.5 mg dose {29}.


Time to peak effect:


Albuterol:

Tablets: 2 to 3 hours {02}.



Epinephrine:

Bronchodilation: Within 20 minutes following subcutaneous administration {18}.



Terbutaline:

Oral: 120 to 180 minutes {27} {30}.

Subcutaneous: Within 30 to 60 minutes {29}.


Duration of action:


Albuterol:

Oral solution: 4 to 6 hours {83}.

Extended-release tablets: Up to 12 hours {05}.



Ephedrine:

Pressor and cardiac effects: 1 hour following intramuscular or subcutaneous administration {81}.



Epinephrine:

Injection: Short, following subcutaneous or intramuscular administration {18}.



Isoproterenol:

1 to 2 hours {83}.



Metaproterenol:

Approximately 4 hours {26}.



Terbutaline:


Oral—

Clinically significant decrease in airway and pulmonary resistance—At least 4 hours {27}.

Significant bronchodilator activity, as measured by various pulmonary function determinations (airway resistance, MMEFR, PEFR)—Up to 8 hours {27} {28}.



Subcutaneous—

Clinically significant bronchodilator activity—90 minutes to 4 hours. The duration is comparable to that found with equimilligram doses of epinephrine. {29}



Elimination:


Albuterol—
        Renal, 69 to 90% (60% as the metabolite) {01} {03}.
        Fecal, 4% {01} {03}.



Ephedrine—
        Renal, mostly unchanged. Rate of urinary excretion is dependent on urinary pH; percentage of drug and metabolites excreted is increased by acidification of urine and decreased by alkalinization of urine. {81}



Epinephrine—
        Renal, largely as inactivated compounds, with the remainder either partly unchanged or as sulfate or glucuronide conjugates {19} {22}. VMA is also detected in urine {19}.



Metaproterenol—
        Fecal {25} {26}.



Terbutaline—
        Oral: Renal {28}.
        Subcutaneous: Renal, unchanged (majority of drug) {29}.



In dialysis—


Albuterol—
        There is insufficient evidence to determine whether albuterol is removable by dialysis {02}.



Ephedrine—
        It is not known whether ephedrine is removable by dialysis {13}.



Isoproterenol—
        It is not known whether isoproterenol is removable by dialysis {24}.



Terbutaline—
        It is not known whether terbutaline is removable by dialysis {28}.




Precautions to Consider

Carcinogenicity/Tumorigenicity

Albuterol—Studies in Sprague-Dawley rats for 2 years at dietary doses of 2, 10, and 50 mg per kg of body weight (mg/kg) (corresponding to 1/2, 3, and 15 times, respectively, the maximum recommended daily oral dose for adults on a mg per square meter of body surface area basis (mg/m 2) or 2/5, 2, and 10 times, respectively, the maximum recommended daily oral dose for children on a mg/m 2 basis) found significant dose-related increases in the incidence of benign leiomyomas of the mesovarium. Studies in CD-1 mice for 18 months at dietary doses of up to 500 mg/kg (approximately 65 times the maximum recommended daily oral dose for adults on a mg/m 2 basis or approximately 50 times the maximum recommended daily oral dose for children on a mg/m 2 basis) and in Golden hamsters for 22 months at dietary doses of up to 50 mg/kg (approximately 7 times the maximum recommended daily oral dose for adults and children on a mg/m 2 basis) found no evidence of tumorigenicity. {95}


Epinephrine—Studies have not been done. {15} {22}


Isoproterenol—Long-term studies have not been done. However, there are no reports of carcinogenic effects in humans. {24}


Metaproterenol—Studies in mice for 18 months at doses corresponding to 31 and 62 times the maximum recommended human dose (MRHD) (based on a 50 kg individual) found a significant increase in benign hepatic adenomas in males and benign ovarian tumors in females. A study in rats for 2 years at doses 62 times the MRHD found a nonsignificant incidence of benign leiomyomata of the mesovarium. {25} {26}


Terbutaline—Two-year studies in Sprague-Dawley rats at doses of 50, 500, 1000, and 2000 mg/kg (corresponding to 167, 1667, 3333, and 6667 times the recommended daily human adult oral dose, respectively) found drug-related changes in the female genital system, including dose-related increases in leiomyomas of the mesovarium. In addition, dose-related increases in the incidence of ovarian cysts were seen at all dose levels except 2000 mg/kg. A 21-month study in mice at oral doses of 5, 50, and 200 mg/kg (corresponding to 17, 167, and 667 times the recommended daily adult oral dose, respectively) found no evidence of carcinogenicity. {28} {29}


Mutagenicity

Albuterol—No evidence of mutagenicity was found in the Ames test with or without metabolic activation using tester strains Salmonella typhimurium TA1537, TA1538, and TA98 or Escherichia coli WP2, WP2uvrA, and WP67. No forward mutation occurred in yeast strain Saccharomyces cerevisiae S9 nor any mitotic gene conversion in yeast S. cerevisiae JD1 with or without metabolic activation. Results of fluctuation assays in S. typhimurium TA98 and E. coli WP2, both with metabolic activation, were negative. Albuterol was not found to be clastogenic in a human peripheral lymphocyte assay or in an AH1 strain mouse micronucleus assay at intraperitoneal doses of up to 200 mg/kg. {95}


Epinephrine—Studies have not been done {15} {22}.


Isoproterenol—Studies have not been done {24}.


Metaproterenol—Studies have not been done {25} {26}.


Terbutaline—Studies have not been done {28} {29}.


Pregnancy/Reproduction

Pregnancy—

Albuterol

Adequate and well-controlled studies in humans have not been done {01} {02}. Albuterol crosses the placenta. In a surveillance study of 1090 Michigan Medicaid recipients whose newborns were exposed to albuterol during the first trimester, 43 major defects were expected and 48 were observed (including cardiovascular defects, oral clefts, spina bifida, limb reduction defects, hypospadias, and polydactyly). Only with the occurrence of polydactyly was there a suggestion of a possible association; however, the mother's disease severity and concurrent medication use may also have been a factor. {54}

Albuterol may delay preterm labor. Caution is recommended with use for bronchospasm in pregnant patients because of possible interference with uterine contractility. {01} {02}

Albuterol also has been reported to cause maternal and fetal tachycardia and hyperglycemia (especially in patients with diabetes), as well as maternal hypotension, acute congestive heart failure, pulmonary edema, and death {54}.

Studies in mice at subcutaneous doses corresponding to 0.2 times the maximum human (child weighing 21 kg) oral dose found teratogenicity. In CD-1 mice, cleft palate occurred in 5 of 111 fetuses (4.5%) at a dose of 0.25 mg/kg and in 10 of 108 fetuses (9.3%) at a dose of 2.5 mg/kg (approximately 3/100 and 3/10 the maximum recommended daily oral dose for adults on a mg/m 2 basis, respectively). Cleft palate also occurred in 22 of 72 fetuses (30.5%) in a control group treated with isoproterenol 2.5 mg/kg subcutaneously (approximately 3/10 the maximum recommended daily oral dose for adults on a mg/m 2 basis) {01} {02} {03}

A study in Stride Dutch rabbits at oral doses of 50 mg/kg (approximately 25 times the maximum recommended daily oral dose for adults on a mg/m 2 basis) found cranioschisis in 7 of 19 (37%) fetuses {01} {02}.

FDA Pregnancy Category C. {05}



Ephedrine

Although adequate and well-controlled studies in humans have not been done, the Collaborative Perinatal Project monitored 373 and 873 mother-child pairs exposed to ephedrine during their first trimester and any time during pregnancy, respectively. For use in the first trimester, an association was found between sympathomimetic drugs as a class and minor malformations, inguinal hernia, and clubfoot. {54}

Studies in animals have not been done {13} {81}.

{14}. Ephedrine is contraindicated when maternal blood pressure exceeds 130/80 mmHg {81}.

FDA Pregnancy Category C. {13} {81}



Epinephrine

Epinephrine crosses the placenta {18} {22} {54}. Although adequate and well-controlled studies in humans have not been done {15}, the Collaborative Perinatal Project monitored 189 mother-child pairs having first trimester exposure to epinephrine. A statistically significant association was found between first trimester use and both major and minor malformations. An association also was found with inguinal hernia after both first trimester use and use any time during pregnancy. Although not specified, these data may reflect the mother's asthma severity. {54} {59}

A surveillance study of 35 Michigan Medicaid recipients whose newborns were exposed to epinephrine during the first trimester showed no association between use of the drug and the development of congenital defects {54}.

Theoretically, the alpha-adrenergic effects of epinephrine could cause a decrease in uterine blood flow, {18} {54} {59} and one case of fetal anoxic damage has been reported after intravenous administration {54}.

Studies in rats at doses of 25 times the human dose have found that epinephrine causes teratogenicity {19}.

. Epinephrine is contraindicated when maternal blood pressure exceeds 130/80 mm Hg {19}.

Epinephrine, administered subcutaneously, may be considered in acute, severe exacerbations of asthma, following the unsuccessful use of other therapies. {55}

FDA Pregnancy Category C. {15}



Isoproterenol

Adequate and well-controlled studies in humans have not been done {24}. In a surveillance study of 16 Michigan Medicaid recipients whose newborns were exposed to isoproterenol during the first trimester, 0.7 major defects were expected and one major defect (oral cleft) was observed. The Collaborative Perinatal Project monitored 31 mother-child pairs who had first trimester exposure to isoproterenol. No association was found between use of the drug and subsequent development of congenital defects. For use in the first trimester, an association was found between sympathomimetic drugs as a class and minor malformations, inguinal hernia, and clubfoot. {54}

The beta-adrenergic effects of isoproterenol may result in inhibition of contractions of the pregnant uterus {54}.

Studies in animals found evidence of teratogenicity {59}.

FDA Pregnancy Category C. {24}



Metaproterenol

Adequate and well-controlled studies in humans have not been done {25} {26}. In a surveillance study of 361 Michigan Medicaid recipients whose newborns were exposed to metaproterenol during the first trimester, 15 major birth defects were expected and 17 were observed. Only with the occurrence of polydactyly was there a suggestion of a possible association; however, the mother's disease severity and concurrent medication use may also have been a factor. {54}

Metaproterenol can also cause maternal and fetal tachycardia, as well as maternal hyperglycemia and hypotension and fetal hypoglycemia {54}.

Studies in rabbits at oral doses of 100 mg/kg, corresponding to 62 times the MRHD, found teratogenicity and embryotoxicity (including skeletal abnormalities, hydrocephalus, and skull bone separation). Studies in mice at oral doses of 50 mg/kg (31 times the MRHD) also found embryotoxicity. Other studies in rabbits, rats, and mice found no teratogenic, embryotoxic, or fetotoxic effects. {25} {26}

FDA Pregnancy Category C {25} {26}.



Terbutaline

Adequate and well-controlled studies in humans have not been done {28} {29}.

Terbutaline crosses the placenta. Studies using single intravenous doses found umbilical blood concentrations ranging from 11 to 48% of maternal blood concentrations. {28} {29}

In a surveillance study of 149 Michigan Medicaid recipients whose newborns were exposed to terbutaline during the first trimester, six major defects were expected and seven occurred (including three cardiovascular defects and one oral cleft). The data did not support an association between the medication and congenital defects. {54}

Terbutaline can cause transient maternal and fetal tachycardia, as well as maternal hyperglycemia (followed by an increase in serum insulin concentrations) and hypotension and fetal hypoglycemia {54}. There has been a single report of myocardial necrosis in an infant, possibly caused by catecholamine excess, and one unexplained intrapartum fetal death {54}.

Studies in mice at subcutaneous doses of up to 1.1 mg/kg (corresponding to 4 times the human oral dose or 110 times the human subcutaneous dose) and in rats at oral doses of up to 50 mg/kg (corresponding to 167 times the human oral dose) found no harmful effects on the fetus {28} {29}.

FDA Pregnancy Category B {28} {29}.


Labor and delivery—


Albuterol

There have been reports of delayed preterm labor after administration of albuterol {01} {05} {06} {07} {08} {09}. Although albuterol has been used for initial treatment to suppress premature labor and delay premature delivery, caution is recommended because of the potential for adverse effects (including maternal tachycardia, hyperglycemia, and hypotension and fetal tachycardia and hypoglycemia) {54}.



Epinephrine

May delay the second stage of labor {22}. Doses sufficient to reduce uterine contractions may cause prolonged uterine atony with hemorrhage {22}.



Isoproterenol

Decreases uterine contractility in humans and animals {59}.



Metaproterenol

Decreases uterine contractility {59}.



Terbutaline

Terbutaline delays preterm labor. Although terbutaline is being used for initial treatment to suppress premature labor and delay premature delivery, caution is recommended because of the potential for adverse effects (including maternal tachycardia, hyperglycemia, and hypotension and fetal tachycardia and hypoglycemia). {54}


Breast-feeding

Albuterol—It is not known whether albuterol is distributed into human breast milk. {01} {02} {03} {05}


Ephedrine—It is not known whether ephedrine is distributed into human breast milk {13} {14}. Irritability, excessive crying, and disturbed sleeping pattern were reported in the breast-fed infant of a mother taking a long-acting preparation containing d-isoephedrine and dexbrompheniramine; the symptoms resolved when breast-feeding was discontinued. {54} {59}


Epinephrine—Epinephrine is distributed into human breast milk {22}. Risk-benefit should be considered because of potential adverse effects in the nursing infant {22}.


Isoproterenol—It is not known whether isoproterenol is distributed into human breast milk. However, risk-benefit should be considered. {24}


Metaproterenol—It is not known whether metaproterenol is distributed into human breast milk. However, risk-benefit should be considered. {25} {26}


Terbutaline—Terbutaline is distributed into breast milk {27} {28} {29} {30} {54} {59}, although no adverse effects have been reported in nursing infants {54} {59}. Risk-benefit should be considered before breast-feeding during treatment with terbutaline {27} {28} {29} {30}.


Pediatrics

In infants with asthma, response to beta 2-adrenergic receptor agonist therapy can be variable and may not be a reliable predictor of satisfactory outcome {32}.

Albuterol—The safety and efficacy of albuterol tablets in children younger than 6 years of age have not been established. {02} {05} The safety and efficacy of albuterol oral solution or syrup in children under 2 years of age have not been established. {01} {03} {06}The incidence of excitement and nervousness may be increased in children 2 to 6 years of age {03} {10}.


Ephedrine—Use has been replaced by safer and more effective agents. {53}


Isoproterenol—Appropriated studies on the relationship of age to the effects of isoproterenol have not been performed in the pediatric population. However, no pediatrics-specific problems have been documented to date.


Metaproterenol—Safety and efficacy of the tablets in children younger than 6 years of age have not been established. Safety and efficacy of the syrup in children younger than 6 years of age have been established in only a limited number of patients {26}.


Terbutaline—Safety and efficacy in children younger than 6 years of age have not been established {30}.



Geriatrics


Older adults, especially those with pre-existing ischemic heart disease, may be more sensitive to the effects of beta-adrenergic receptor agonists, including tremor, hypertension, hypokalemia, and tachycardia {05} {32} {60} {67}. In general, use of inhaled beta 2-adrenergic receptor agonists is preferred because they cause fewer systemic side effects than beta 2-adrenergic receptor agonists delivered by other routes of administration {60} {67}.

Because of the risk of cardiac stimulation, use of subcutaneous bronchodilators is recommended only in life-threatening situations, with careful electrocardiogram (ECG) monitoring {67}.

Ephedrine—The possibility of urinary retention, especially in elderly males with prostatism, as a result of contraction of the bladder sphincter should be kept in mind {13} {14}.


Dental

Unpredictable systemic absorption can occur with topical application of epinephrine to the gingival or pulpal tissues..

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications depending on the amount present, may also interact with this medication.

Acidifiers, urinary    (may decrease the half-life of ephedrine by decreasing tubular reabsorption, which may lead to decreased effects {57})


Alkalizers, urinary    (may increase the half-life and decrease elimination of ephedrine by increasing tubular reabsorption, which may lead to increased effects {57})


Alpha-adrenergic blocking agents{13}{81} , such as:
Doxazosin
Labetalol
Phenoxybenzamine
Phentolamine
Prazosin
Terazosin
Tolazoline or
Other medications with alpha-adrenergic blocking action, such as:
Haloperidol
Phenothiazines
Thioxanthenes    (concurrent use may antagonize the peripheral vasoconstriction and hypertensive effects of sympathomimetic agents {13} {81}; phentolamine may be used for therapeutic benefit, such as in ephedrine overdose {13})


» Anesthetics, hydrocarbon inhalation, such as:
Chloroform
Enflurane
Halothane
Methoxyflurane    (administration of sympathomimetic agents, especially ephedrine, epinephrine, or isoproterenol, to patients receiving these anesthetics may increase the risk of severe atrial and ventricular arrhythmias because these anesthetics greatly sensitize the myocardium to the effects of sympathomimetic agents {19} {24} {81}; arrhythmias may respond to administration of a beta-blocking agent {19} {81} {21}; use of a pressor drug with less severe cardiac-stimulating effects should be considered {81})


» Antidepressants, tricyclic{01}{15}{25}    (tricyclic antidepressants block reuptake of sympathomimetic agents in the neuron, which may increase the pressor response to direct-acting sympathomimetic agents and decrease sensitivity to indirect-acting sympathomimetic agents; caution is recommended with concurrent use {01} {15} {25} {57})

    (may add to the QTc interval prolongation caused by beta-adrenergic receptor agonists {67})


Antidiabetic agents, oral or
Insulin    (concurrent use with epinephrine may result in decreased effects of these medications because epinephrine increases blood glucose by inhibiting glucose uptake by peripheral tissues and promotes glycogenolysis; increased doses of these medications may be required {22})


Antihypertensives    (sympathomimetic agents may increase blood pressure and interfere with the hypotensive effects of these medications; the patient should be carefully monitored to confirm that the desired effect is being obtained {14})

    (concurrent use of epinephrine with guanadrel or guanethidine may increase the pressor effect of epinephrine {19} {57} as a result of inhibition of sympathomimetic uptake by adrenergic neurons, possibly resulting in hypertension and cardiac arrhythmias {19})

    (ephedrine may decrease the hypotensive effects of guanadrel or guanethidine by causing displacement from and inhibiting uptake by adrenergic neurons {13} {14} {57})

    (concurrent use with methyldopa may decrease the hypotensive effect of methyldopa and potentiate the pressor effect of sympathomimetic agents {57})

    (guanethidine, methyldopa, or reserpine may reduce the pressor response to indirectly-acting sympathomimetic agents such as ephedrine by reducing the amount of norepinephrine in sympathetic nerve endings {14} {57})


Astemizole or
Cisapride or
Terfenadine or
Medications that prolong the QTc interval, other    (may add to the QTc interval prolongation caused by beta-adrenergic receptor agonists {67})


» Beta-adrenergic blocking agents, ophthalmic    (ophthalmic beta-adrenergic blocking agents are absorbed systemically via the nasolacrimal duct; respiratory complications associated with the use of timolol have been reported and include bronchospasm, dyspnea, wheezing, decreased pulmonary function, and respiratory failure {67}; therefore, concurrent use may result in inhibition of the beta-adrenergic effects of the adrenergic bronchodilators and worsening of bronchospasm {67})


» Beta-adrenergic blocking agents, systemic    (may block the cardiostimulating and bronchodilating effects of sympathomimetic agents {01} {28} {60} {81} and can cause bronchospasm on their own {28} {67}; concurrent use in asthmatic patients can lead to severe asthmatic attacks and is not recommended {95}; it is recommended that patients receiving treatment for both bronchospastic disease and hypertension receive an alternative medication to a beta-blocker for the hypertension {28} {60})

    (the use of epinephrine may be hazardous in patients who are receiving nonselective beta-adrenergic blocking agents since its unopposed actions on vascular alpha 1-adrenergic receptors may lead to severe hypertension and cerebral hemorrhage {65}; epinephrine retraction cords, used in the treatment of gingival or pulpal hemorrhage, should be avoided in patients taking beta-adrenergic blocking agents due to the potential systemic vasoconstriction {94})


» Cocaine, mucosal-local    (in addition to increasing CNS stimulation, concurrent use with sympathomimetic agents may increase the cardiovascular effects of either or both medications and the risk of adverse effects {65} {73})

    (concurrent use of epinephrine with cocaine [especially intranasal application of epinephrine and cocaine, which is potentially lethal] is not recommended because of the high risk of hypertensive episodes and cardiac arrhythmias {75}; also, concurrent topical use of cocaine and epinephrine is unnecessary because epinephrine does not provide additional local vasoconstriction, slow absorption of cocaine from the mucosa, or prolong cocaine's duration of action {65})


» Diatrizoates or
» Iothalamate or
» Ioversol or
» Ioxaglate    (neurologic effects, including paraplegia, may increase during aortography when these agents are administered after vasopressor agents used to increase contrast; this increase is due to contraction of vessels in the splanchnic circulation, which forces more of the contrast material into the vessels leading to the spine and spinal cord {76})


Digitalis glycosides    (a single dose of albuterol has been reported to result in a 16 to 22% decrease in serum digoxin concentrations in patients who have received digoxin for 10 days; although the clinical significance in obstructive airway disease has not been established, monitoring of serum digoxin concentrations is recommended {01})

    (beta 2-adrenergic–induced hypokalemia could lead to digitalis toxicity {60})

    (concurrent use with sympathomimetic agents possessing beta 1-adrenergic activity may increase the risk of cardiac arrhythmias {14}; caution and close ECG monitoring are very important if concurrent use is necessary {14} {15})


Ergot alkaloids    (concurrent use with sympathomimetic agents may result in enhanced vasoconstriction and pressor effects {65}; concurrent use of ergotamine may produce peripheral vascular ischemia and gangrene and is not recommended {72})


Hypokalemia-causing medications, other{01}{02}{67} (see Appendix II)    (possibility of increased effects {01} {02} {67}, especially with high doses of sympathomimetic agents; monitoring of serum potassium concentrations and cardiac function is recommended with concurrent use {67})


» Medications that sensitize the myocardium to the actions of sympathomimetic agents (e.g., digitalis glycosides, quinidine)    (caution is recommended with concurrent use because sympathomimetic agents can cause arrhythmias; caution and close ECG monitoring are very important if concurrent use is necessary {15} {81})


» Monoamine oxidase (MAO) inhibitors{01}{15}{25}{67} , including furazolidone, procarbazine, and selegiline    (pressor effects of indirect-acting sympathomimetic agents may be potentiated {15} {25} {26} {28} {57} {67}; indirect-acting sympathomimetics cause the release of catecholamines, which accumulate in intraneuronal storage sites during MAO inhibitor therapy, and may result in severe hypertension, headache, and hyperpyrexia that could lead to hypertensive crisis {57}; extreme caution is recommended when indirect-acting sympathomimetic agents are given during or within 2 weeks after therapy with these agents {95} {84})


» Sympathomimetic agents, other    (concurrent use may result in increased effects, including unwanted cardiovascular effects, and is not recommended {01} {02} {19} {26} {28} {81}; however, one sympathomimetic may be substituted for another once the effects of the preceding medication have subsided {19} {24}; this also does not preclude use of an aerosol adrenergic bronchodilator for relief of acute bronchospasm in patients receiving chronic oral adrenergic bronchodilator therapy {01} {28})


Theophylline    (Enhanced toxicity, especially cardiotoxicity has been reported with use with sympathomimetic agents, particularly isoproterenol {57}; concurrent use with ephedrine may result in increased nausea, nervousness, and insomnia {86}; isoproterenol increases theophylline clearance resulting in decreased theophylline concentrations {86}; theophylline plasma concentrations should be monitored {90})


» Thyroid hormones    (concurrent use may increase the effects of these medications or thyroid hormone; thyroid hormones enhance the risk of coronary insufficiency when sympathomimetic agents are administered to patients with coronary artery disease {74})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/ laboratory test values
» Blood pressure and
» Heart rate    (may be increased)


Electrocardiogram (ECG) changes, including:
T-wave flattening{05}{60}
QTc-interval prolongation{05}{60}{67}
ST-segment depression{05}{60}{67}    (arrythmias may occur, usually following hypokalemia)


» Glucose    (blood glucose concentrations may be increased)


Hepatic enzymes    (serum values may be increased with high doses of terbutaline {28})


Lactic acid    (serum values may be increased {22} {32}; may result in severe metabolic acidosis after prolonged use or overdose of epinephrine {22})


» Potassium    (serum concentrations may be decreased {01} {28} {32} {67}, possibly as a result of intracellular shunting {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist

For all sympathomimetics:
» Cardiac disease, including:
Cardiac arrhythmias, especially tachyarrhythmias{01}{24}{25}{26}{28}
Ischemic heart disease{01}{15}{24}{25}{26}{28}    (beta-adrenergic receptor agonists can cause arrhythmias and ECG changes, including T-wave flattening, QTc-interval prolongation, and ST-segment depression {05} {60} {67})

    (epinephrine may precipitate or aggravate angina pectoris {15} {18} or may produce potentially fatal ventricular arrhythmias {18})

    (isoproterenol increases cardiac oxygen requirements while decreasing effective coronary artery perfusion {24})


» Diabetes mellitus{01}{03}{15}{24}{25}{26}{28}{65}{66}    (sympathomimetic agents can cause hyperglycemia, followed by increased insulin concentrations, which may aggravate pre-existing diabetes mellitus and ketoacidosis; increased insulin or hypoglycemic medication doses may be required {65} {66}; concurrent administration of sympathomimetic agents and corticosteroids may exaggerate this hyperglycemic effect {79})


» Hypertension{01}{15}{25}{26}{28} or
» Hyperthyroidism{01}{15}{24}{25}{26}{28}    (sympathomimetic agents can cause significant increases in systolic and diastolic blood pressure {01} {25} {26})

    (incidence of side/adverse effects may be increased {22})


» Seizures, history of{01}{25}{26}{28}    (may exacerbate condition)


» Sensitivity to the sympathomimetic prescribed{01}{25}{26}
For albuterol extended-release tablets (in addition to the above):
Gastrointestinal narrowing, pre-existing    (there have been rare reports of gastrointestinal obstruction from the delivery system for albuterol extended-release tablets {05})


For ephedrine or epinephrine (in addition to the above):
» Cerebral arteriosclerosis{22} or
» Brain damage, organic{17}{22}    (vasoconstriction caused by epinephrine may reduce cerebral blood flow)


Glaucoma, narrow-angle    (may be exacerbated by sympathomimetic agents with alpha 1-adrenergic activity {17})


Parkinson's disease    (rigidity and tremor may worsen temporarily after epinephrine administration {22})


Prostatic hypertrophy    (urinary retention may occur with ephedrine administration as a result of vesical sphincter spasm {13} {14})


» Psychoneurotic disorders{22}    (symptoms may worsen with epinephrine administration {22})


» Shock, nonasthmatic (i.e., cardiogenic, traumatic, or hemorrhagic)    (administration of epinephrine is not recommended {17} {18} {19})


For isoproterenol (in addition to the above):
» Cardiac disease, organic, including organic disease of the atrioventricular (AV) node and its branches    (isoproterenol may paradoxically worsen heart block or precipitate Adams-Stokes attacks during normal sinus rhythm or transient block {24})


For metaproterenol (in addition to the above):
Sensitivity to parabens    (formulations of metaproterenol sulfate oral syrup contain parabens {26})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):


For all indications
» ECG    (recommended routinely, especially with high doses {67}, although cardiac arrhythmias can occur with epinephrine even at therapeutic doses {22})


Potassium concentrations, serum    (monitoring of serum potassium concentrations may be appropriate, especially in patients taking other medications that may induce hypokalemia, such as non-potassium-sparing diuretics {83})


For use as a bronchodilator
» Arterial blood gas determinations    (arterial blood gas measurements are recommended if PEF is 150 L per minute or less {67})


» Pulmonary function studies, including:
Peak expiratory flow (PEF)
Spirometry    (recommended at regular intervals to monitor progress {67})




Side/Adverse Effects

Note: Most side/adverse effects are mild and transient {27} {28}.
Tolerance to the side/adverse effects usually develops within weeks {27} {60} or less {93}with regular use {27} {60}, although it does not occur consistently {60}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)–not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Palpitation{01}{02}{13}{18}{24}{25}{27}{28} (pounding heartbeat)
    
tachycardia{01}{02}{13}{24}{25}{27}{28}{58} (fast heartbeat)

Note: For isoproterenol, doses sufficient to cause tachycardia with greater than 130 beats per minute may increase the risk of inducing ventricular arrhythmias. Such increases may also increase cardiac workload and oxygen requirements, which may adversely affect the failing heart or the heart with a significant degree of arteriosclerosis. {24}


Incidence rare
    
Adams-Stokes attacks{24} (fainting)—for isoproterenol
    
allergic reactions{03}{25}
including angioedema (hoarseness; large hive-like swellings on eyelids, face, genitals, hands or feet, lips, throat, tongue; sudden trouble in swallowing or breathing), bronchospasm (trouble in breathing), oropharyngeal edema (tightness in throat; trouble in breathing), skin rash
or urticaria (hives)
    
bronchospasm, paradoxical{05} (shortness of breath)—for albuterol or terbutaline
    
cardiac arrhythmias{13}{24} (fast or irregular heartbeat)
    
chest pain{01}{03}{25}
    
hypokalemia (irregular heartbeat; muscle cramps or pain; unusual tiredness or weakness)
    
severe reaction
including erythema multiforme{03}{05} (reaction starting with chills; fever; general feeling of illness; muscle aches or pains; sore throat; and/or nausea with or without vomiting; followed by sores, ulcers, or white spots in mouth or on lips; skin rash or sores; hives; and/or itching), and Stevens-Johnson syndrome{03}{05} (bleeding or crusting sores on lips; chest pain; fever with or without chills; muscle cramps or pain; painful eyes; painful sores, ulcers, or white spots in mouth; skin rash; sore throat; red or irritated eyes)—with oral albuterol in children{03}{05}
    
hypertension{03}{24}{25}{81} (increase in blood pressure)—asymptomatic; more common for epinephrine{19}
    
psychoneurotic disorders
including psychomotor agitation
disorientation
impairment of memory
assaultive behavior
panic
hallucinations
suicidal or homicidal tendencies
schizophrenic-type thought disorder
or paranoid delusions (mental problems)—for epinephrine{22}
    
seizures{28} —for terbutaline
    
urinary hesitation or retention{02}{13} (trouble in urinating)—more common for terbutaline

Note: In a few patients, presumably with organic disease of the AV node and its branches, isoproterenol injection has been reported to precipitate Adams-Stokes attacks during normal sinus rhythm or transient heart block {24}.
Cardiac arrhythmias induced by epinephrine have included fatal ventricular fibrillation {22}.
Paradoxical bronchospasm may be life-threatening {05} {88}.
For ephedrine or epinephrine, excessive doses or inadvertent intravenous administration of usual subcutaneous doses can cause acute hypertension. Rapid increases in arterial blood pressure can lead to cerebral hemorrhage, especially in elderly patients, or to angina pectoris, aortic rupture, hemiplegia, or subarachnoid hemorrhage. {14} {22}
Seizures also may occur with overdose of other sympathomimetic agents {13}.
Urinary hesitation occurs as the result of vesical sphincter spasm. Urinary retention may develop in males with prostatism. {13} {14}




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Anxiety{18} —for epinephrine
    
headache{01}{13}{18}{24}{27}{28}
    
nervousness{01}{13}{18}{24}{27}{28}
    
tremor{01}{02}{18}{25}{27}{28}{58}

Incidence less frequent
    
Dizziness{01}{02}{18}{24}{28}
    
insomnia{01}{02}{13}{25} (trouble in sleeping)
    
muscle cramps{01}{02}{13}{25}{27}{28}
    
nausea{01}{18}{25}{27}
    
sweating{01}{13}{18}{25}{27}{28}
    
vertigo{03}{13} (feeling of constant movement of self or surroundings)
    
vomiting{13}{18}{25}{27}{28}





Overdose
For specific information on the agents used in the management of bronchodilators, adrenergic overdose, see:    • Anesthetics, Barbiturate (Systemic)monograph;
   • Anesthetics, Inhalation (Systemic) monograph;
   • Anticonvulsants, Hydantoin (Systemic) monograph;
   • Barbiturates (Systemic) monograph;
   • Benzodiazepines (Systemic) monograph;
   • Beta-adrenergic Blocking Agents (Systemic) monograph;
   • Charcoal, Activated (Oral-Local) monograph;
   • Ipecac (Oral-Local) monograph;
   • Nitroprusside (Systemic) monograph;
   • Phentolamine (Systemic) monograph;
   • Sympathomimetic Agents—Cardiovascular Use (Parenteral-Systemic) monograph.


For more information on the managment of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose

Note: In general, symptoms of overdose reflect excessive beta-adrenergic stimulation or exaggeration of side/adverse effects {25} {26} {28}. In addition, ephedrine or epinephrine overdose would be expected to produce alpha-adrenergic effects.

The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)–not necessarily inclusive:
Acute
For albuterol, isoproterenol, metaproterenol, and terbutaline
    
Angina{03}{24}{25}
    
arrhythmias{03}{24}{25}{28}
    
dizziness{03}{25}
    
dry mouth{03}{25}
    
fatigue{03}{25}
    
headache{03}{25}{28}
    
hyperglycemia (followed by rebound hypoglycemia){03}{29}
    
hypertension or hypotension{03}{24}{25}{28}
    
hypokalemia{03}{25}
    
insomnia{03}{25}
    
malaise{03}{25}
    
nausea{03}{25}{28}
    
nervousness{03}{25}{28}
    
palpitation{03}{25}
    
seizures{03}{25}
    
tachycardia (with rates up to 200 beats per minute){03}{24}{28}
    
tremor{03}{25}{28}


For ephedrine
    
Blurred vision{13}
    
chills{13}
    
dilated pupils{13}
    
fever{13}
    
gasping respirations{13}
    
hypertension, followed by hypotension accompanied by anuria{13}
    
irritability{13}
    
nausea{13}
    
nervousness{13}
    
opisthotonos{13}
    
personality changes, including craving for the medication{13}
    
pulmonary edema{13}
    
respiratory failure{13}
    
seizures{13}
    
spasms{13}
    
suicidal behavior{13}
    
tachyarrhythmias{13}
    
tachycardia{13}
    
vomiting{13}

Note: Hypertension occurs initially, and may be followed by hypotension (when depletion of norepinephrine from nerves endings ends pressor effects {14}) and anuria {13}. Suddenly elevated blood pressure may lead to cerebrovascular hemorrhage {14}.
The craving for the medication is psychological {13}.
The probable lethal dose in adults is 50 mg per kg of body weight (mg/kg). The minimum lethal dose in children up to 2 years of age is approximately 200 mg. {13}



For epinephrine
    
Arterial blood pressure elevation, extreme{19}
    
bradycardia, transient, followed by tachycardia{18}
    
coldness of skin{18}
    
dyspnea{19}
    
headache{19}
    
metabolic acidosis{18}
    
myocardial infarct{80}
    
pallor, extreme{18}
    
pulmonary edema{18}
    
renal failure{18}
    
vomiting{19}

Note: Suddenly elevated arterial blood pressure may lead to cerebrovascular hemorrhage {19}, particularly in elderly patients, or to angina pectoris, aortic rupture, hemiplegia, or subarachnoid hemorrhage.
With pulmonary edema, peripheral vascular constriction together with cardiac stimulation may lead to fatalities {22}.
Tachycardia may be accompanied by potentially fatal cardiac arrhythmias, including ventricular fibrillation {22}. Ventricular premature contractions may occur within 1 minute after injection, followed by multilocal ventricular tachycardia (prefibrillation rhythm); subsidence of ventricular effects may be followed by atrial tachycardia and occasionally by atrioventricular (AV) block {18}.



Chronic
For ephedrine
    
Anxiety and tension, possibly leading to psychosis{13}
    
nasal congestion, chronic{13}

Note: Anxiety and tension may progress to psychosis {13}.
Nasal congestion occurs as a result of prolonged exposure of the nasal mucosa to the medication {13}.
Prolonged abuse can lead to a syndrome resembling an anxiety state (including symptoms of paranoid schizophrenia and other physical signs including tachycardia, poor nutrition and hygiene, fever, cold sweat, and dilated pupils) {13}.




Treatment of overdose


Albuterol:
Withdrawal of albuterol.

Symptomatic treatment.

For tachyarrhythmias—Judicious use of a cardioselective beta-adrenergic blocking agent, if necessary; however, caution is necessary because of the possible induction of bronchospasm by the beta-blocker {01} {03}.



Ephedrine:
Protect the patient's airway and support ventilation and perfusion {13}.

Monitor and maintain, within acceptable limits, the patient's vital signs, blood gases, and serum electrolytes. {13}

Decrease absorption from the gastrointestinal tract with activated charcoal (may be more effective than emesis or lavage); consider charcoal instead of or in addition to gastric emptying; repeated doses of charcoal may hasten elimination of absorbed drug. (It is important to safeguard the patient's airway during these procedures.) {13}

For marked hypertension, consider use of nitroprusside or phentolamine infusion {13}.

For hypotension, consider use of intravenous fluids, elevation of the legs, or inotropic vasopressors such as norepinephrine {13}.

For life-threatening supraventricular or ventricular tachycardias, treat with slow intravenous administration of propranolol, with continuous monitoring of the ECG and vital signs {13}.

For seizures, consider use of diazepam, phenytoin, or phenobarbital. For refractory seizures, general anesthesia with thiopental or halothane and paralysis with a neuromuscular blocking agent may be necessary. {13}



Epinephrine:
Because epinephrine is rapidly inactivated in the body, treatment is primarily supportive {18} {22}.

Pressor effects may be counteracted by rapidly acting vasodilators or alpha-adrenergic blocking agents {19} {22}. If prolonged hypotension follows this treatment, it may be necessary to administer another pressor (e.g., norepinephrine) {18} {21}.

If pulmonary edema interferes with respiration, treatment with a rapidly acting alpha-adrenergic blocking agent (e.g., phentolamine) and/or intermittent positive-pressure respiration is recommended {18} {22}.

For arrhythmias, consider administration of a beta-adrenergic blocking agent (e.g., propranolol) {18} {22}.

For metabolic acidosis or renal failure, use suitable corrective measures {18} {22}.



Isoproterenol:
Reduce the rate of administration or discontinue the injection until the patient's condition stabilizes {24}.

Monitor blood pressure, pulse, respiration, and ECG {24}.



Metaproterenol:
Discontinue metaproterenol {25} {26}.

Symptomatic treatment {25} {26}.



Terbutaline:
If the patient is alert, empty the stomach by inducing emesis, followed by gastric lavage {27} {28}.

If the patient is unconscious, secure the airway with a cuffed endotracheal tube before beginning lavage (and do not induce emesis) {27} {28}.

Instillation of activated charcoal slurry may help reduce absorption {27} {28}.

Maintain adequate respiratory exchange {27} {28}.

Provide cardiac and respiratory support {27} {28}.

Continue observation until the patient is symptom-free {27} {28}.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Bronchodilators, Adrenergic (Oral/Injection) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to the sympathomimetic prescribed

Pregnancy—Possible malformations including inguinal hernia and clubfoot; teratogenicity with epinephrine; risks with pre-existing hypertension or hyperglycemia



Labor and/or delivery
Beta-adrenergiic receptor agonists may decrease uterine contractions and delay labor





Breast-feeding—Epinephrine and terbutaline distributed into breast milk; consider risk-benefit for all agents





Use in the elderly—May be more sensitive to tremor, hypertension, or tachycardia, especially those patients with pre-existing ischemic heart disease
Other medications, especially tricyclic antidepressants, MAO inhibitors, ophthalmic or systemic beta-adrenergic blocking agents, cocaine, medications that sensitize the myocardium to the actions of sympathomimetic agents, other sympathomimetic agents, or thyroid hormones
Other medical problems, especially cardiac arrhythmias, ischemic heart disease, diabetes mellitus, hypertension, hyperthyroidism, history of seizures, cerebral arteriosclerosis (for epinephrine), organic brain damage (for epinephrine), psychoneurotic disorders (for epinephrine), or organic heart disease (for isoproterenol)

Proper use of this medication
» Compliance with therapy; importance of not using more medication than prescribed

Proper administration of extended-release albuterol tablets: Swallowing tablets whole without breaking, crushing, or chewing

» Proper dosing
Missed dose: If taken regularly, taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

For use as a bronchodilator
» Having a rapid-acting inhaled beta-adrenergic bronchodilator available for symptomatic relief of acute asthma attacks

For epinephrine
Knowing correct administration technique

With intramuscular use:

• Injecting into the thigh


• Not injecting into the buttock to avoid vasoconstriction


Not using if solution is discolored or cloudy

Keeping medication on hand and checking expiration date regularly

For epinephrine for emergency treatment of allergic reactions
» Using medication at first sign of allergic reaction

» Notifying physician immediately and/or going to nearest hospital emergency room

If stung by an insect, carefully removing insect's stinger to avoid additional venom from being released from the sac; applying ice packs or sodium bicarbonate soaks, if available, to area stung

For epinephrine auto-injector
» Reading patient instructions carefully before needed

Importance of not removing safety cap before ready to use

Knowing correct administration technique—

• Removing gray safety cap


• Placing black tip on the side of the thigh (mid-thigh area) at right angle to leg


• Pressing hard into thigh until auto-injector functions; holding in place several seconds; removing and discarding properly


• Massaging injection site for 10 seconds


Precautions while using this medication
» Regular visits to physician to check progress during therapy

» Not taking other medications, especially nonprescription sympathomimetic agents, unless discussed with physician

Patients with diabetes: May increase blood glucose concentrations

For use as a bronchodilator
» Checking with physician immediately if more doses than usual are needed, or if using a rapid-acting inhaled beta-adrenergic bronchodilator to relieve symptoms more than two times per week (for mild asthma) or daily (for moderate to severe persistent asthma) {32}

For epinephrine
» Checking with physician immediately if severe pain occurs at injection site {17}

For epinephrine auto-injector
» Avoiding accidental injection into the hands or feet due to the potential for vasocontriction in these areas; getting emergency attention immediately if this occurs


Side/adverse effects
Signs of potential side effects, especially palpitation, tachycardia, Adams-Stokes attacks (for isoproterenol), allergic reactions, paradoxical bronchospasm (for albuterol or terbutaline), cardiac arrhythmias, chest pain, erythema multiforme or Stevens-Johnson syndrome (for oral albuterol in children), hypertension, psychoneurotic disorders (for epinephrine), seizures (for terbutaline), and urinary retention

Albuterol extended-release tablets: Shell may appear in stool


General Dosing Information

For use in asthma
Daily use or increasing frequency of use of supplemental short-acting inhaled beta 2-adrenergic receptor agonists may indicate a loss of asthma control and the need for an adjustment in therapy {32}.

There is some evidence of development of tolerance to the bronchodilating effects of beta-adrenergic receptor agonists (due to down regulation of beta-adrenergic receptors), although clinical significance has not been established {58} {60} {61} {67}.

For treatment of adverse effects
Recommended treatment consists of the following:    • Pressor effects, marked—Administration of rapidly acting vasodilators such as nitrites or alpha-adrenergic blocking agents. {17} {23}


ALBUTEROL

Summary of Differences
Pharmacology/pharmacokinetics: Primarily stimulates beta 2-adrenergic receptors, with some minor beta 1-adrenergic activity.

Pediatrics: Increased incidence of excitement and nervousness in children 2 to 6 years of age.

Medical considerations/contraindications: Caution in use of extended-release tablets in patients with pre-existing gastrointestinal narrowing.

Side/adverse effects:

• Paradoxical bronchospasm may occur rarely.


• Erythema multiforme and Stevens-Johnson syndrome reported rarely with oral albuterol in children.



Additional Dosing Information
Switching to albuterol sulfate extended-release tablets from maintenance therapy with albuterol sulfate tablets or syrup is acceptable. For example, a dose of one 4-mg extended-release tablet every twelve hours is comparable to a dose of one 2-mg tablet every six hours. Multiples of this regimen up to the maximum recommended daily dose also apply. {05}

Withdrawal of albuterol may be necessary if cardiovascular effects (e.g., hypertension, tachycardia) occur. {05}

It is recommended that albuterol be withdrawn immediately and alternative therapy be instituted, if paradoxical bronchospasm occurs. {05}


Oral Dosage Forms

ALBUTEROL SULFATE ORAL SOLUTION

Note: Dose and strength of albuterol sulfate oral solution are expressed in terms of the base.


Usual adult and adolescent {69} dose
Bronchodilator
Oral, 2 to 4 mg (base) three or four times a day. {79}

Note: Patients sensitive to beta-adrenergic stimulation should receive an initial dose of 2 mg (base) three or four times a day, increased gradually as needed and tolerated. {79}



Usual adult and adolescent {69} prescribing limits
32 mg (base) per day. {64}

Usual pediatric dose
Bronchodilator
Children up to 2 years of age: Safety and efficacy have not been established. {79}
Children 2 to 6 years of age: Oral, 100 mcg (0.1 mg ) (base) per kg of body weight (up to a maximum of 2 mg {01} {03}) three to four times a day. {79}

Note: Safety and efficacy for chronic therapy have not been established. {79}

Children 6 to 12 years of age—Oral, 2 mg (base) three or four times a day. {79}
Children 12 years of age and older—See Usual adult and adolescent dose. {79}


Usual pediatric prescribing limits
Children 2 to 6 years of age
400 mcg (0.4 mg) (base) per kg of body weight per day in divided doses. {79}

Children 6 to 12 years of age
8 mg (base) per day in divided doses. {79}

Children 12 years of age and over
See Usual adult and adolescent prescribing limits. {79}


Usual geriatric dose
Bronchodilator
Initial: Oral, 2 mg (base) three or four times a day. {79}


Strength(s) usually available
U.S.—
Not commercially available.

Canada—


400 mcg (0.4 mg) (base) per mL (Rx) [Ventolin{79}]

Packaging and storage:
Store at or below 25 ºC (77 ºF). {70}


ALBUTEROL SULFATE SYRUP

Note: Dose and strength of albuterol sulfate syrup are expressed in terms of the base.


Usual adult and adolescent dose {01} {03}
Bronchodilator
Oral, 2 to 4 mg (base) three or four times a day. {01} {03} Dosage may be increased gradually, as needed and tolerated, up to a maximum of 8 mg four times a day. {01} {03}

Note: Patients sensitive to beta-adrenergic stimulation should receive an initial dose of 2 mg (base) three or four times a day, increased gradually as needed and tolerated. {01} {03}



Usual adult and adolescent {01} {03} prescribing limits
32 mg (base) per day in divided doses. {01} {03} {64}

Usual pediatric dose
Bronchodilator
Children up to 2 years of age: Safety and efficacy have not been established. {01} {03}
Children 2 to 6 years of age: Oral, 100 mcg (0.1 mg) (base) per kg of body weight (up to a maximum of 2 mg) three times a day. {01} {03} Dosage may be increased gradually as needed and tolerated, to a maximum of 4 mg three times a day. {01} {03}
Children 6 to 14 years of age: Oral, 2 mg (base) three or four times a day. {01} {03} Dosage may be increased gradually as needed and tolerated, to a maximum of 24 mg per day in divided doses. {01} {03}
Children 14 years of age and older: See Usual adult and adolescent dose. {01} {03}


Usual pediatric prescribing limits
Children 2 to 6 years of age: 4 mg (base) three times a day. {01} {03} {64}
Children 6 to 14 years of age: 24 mg (base) per day in divided doses. {01} {03} {64}
Children 14 years of age and older: See Usual adult and adolescent prescribing limits. {01} {03}

Usual geriatric dose
Bronchodilator
Oral, 2 mg (base) three or four times a day, adjusted as needed and tolerated. {01} {03}


Strength(s) usually available
U.S.—


400 mcg (0.4 mg) (base) per mL (Rx) [Proventil] [Ventolin][Generic]

Canada—
Not commercially available.

Packaging and storage:
Store between 2 and 30 ºC (36 and 86 ºF), unless otherwise specified by manufacturer {01} {03}.


ALBUTEROL SULFATE TABLETS

Note: Dose and strength of albuterol sulfate tablets are expressed in terms of the base.


Usual adult and adolescent dose {02}
Bronchodilator
Oral, 2 to 4 mg (base) three or four times a day. {02} Dosage may be increased gradually, as needed and tolerated, up to a maximum of 8 mg four times a day. {02} {11} {12}

Note: Patients sensitive to beta-adrenergic stimulation should receive an initial dose of 2 mg (base) three or four times a day, increased gradually to a maximum of 8 mg three or four times a day if needed and tolerated. {02}



Usual adult and adolescent prescribing limits {02}
32 mg (base) per day in divided doses. {02}

Usual pediatric dose
Bronchodilator
Children up to 6 years of age: Safety and efficacy have not been established. {02}
Children 6 to 12 years of age: Oral, 2 mg (base) three or four times a day. {02}
Children 12 years of age and older: See Usual adult and adolescent dose. {02}


Usual pediatric prescribing limits
Children 6 to 12 years of age: 24 mg (base) per day in divided doses. {02}
Children 12 years of age and older: See. Usual adult and adolescent prescribing limits. {02}

Usual geriatric dose
Bronchodilator
Oral, 2 mg (base) three or four times a day. {02} Dosage may be increased gradually, as needed and tolerated, up to a maximum of 8 mg three or four times a day. {02}


Strength(s) usually available
U.S.—


2 mg (base) (Rx) [Proventil (lactose)][Generic]


4 mg (base) (Rx) [Proventil (lactose)][Generic]

Canada—
Not commercially available.

Packaging and storage:
Store between 2 and 25 ºC (36 and 77 ºF), unless otherwise specified by manufacturer. {02}


ALBUTEROL SULFATE EXTENDED-RELEASE TABLETS

Note: Dose and strength of albuterol sulfate extended-release tablets are expressed in terms of the base.


Usual adult and adolescent dose {02} {05}
Bronchodilator
Oral, 4 to 8 mg (base) every twelve hours. {02} {05} {32}

Note: In unusual circumstances, such as in adults of low body weight, an initial dose of 4 mg (base) every twelve hours is sufficient, with progression to 8 mg every twelve hours according to response. {02} {05}
If control of reversible airway obstruction is not achieved with the recommended dose, and other asthma therapy is already optimized, the initial dose may be cautiously increased stepwise under the control of the supervising physician to a maximum dose of 32 mg (base) per day in divided doses (i.e., 16 mg every twelve hours). {02} {05}



Usual adult and adolescent prescribing limits {02} {05}
32 mg (base) per day in divided doses (i.e., 16 mg [base] every twelve hours). {02} {05}

Usual pediatric dose
Bronchodilator
Children up to 6 years of age: Safety and efficacy have not been established. {02} {05}
Children 6 to 12 years of age: Oral, 4 mg (base) every twelve hours. {02} {05}

Note: If control of reversible airway obstruction is not achieved with the recommended dose, and other asthma therapy is already optimized, the initial dose may be cautiously increased stepwise under the control of the supervising physician to a maximum dose of 24 mg (base) per day in divided doses (i.e., 12 mg [base] every twelve hours). {02} {05}

Children 12 years of age and older: See Usual adult and adolescent dose. {02} {05}


Usual pediatric prescribing limits
Children 6 to 12 years of age
24 mg (base) per day in divided doses (i.e., 12 mg [base] every twelve hours). {02} {05}

Children 12 years of age and older
See Usual adult and adolescent prescribing limits. {02} {05}


Strength(s) usually available
U.S.—


4 mg (base) (Rx) [Proventil Repetabs (lactose) (sugar)] [Volmax]


8 mg (base) (Rx) [Volmax]

Canada—
Not commercially available.

Packaging and storage:
Store between 2 and 30 ºC (36 and 86 ºF), unless otherwise specified by manufacturer. {02} {05}

Auxiliary labeling:
   • Swallow whole.




Parenteral Dosage Forms

Note: Bracketed used in the Dosage Forms section refers to categories of use and/or indications that are not included in the U.S. product labeling.

ALBUTEROL SULFATE INJECTION

Note: Dose and strength of albuterol sulfate injection are expressed in terms of the base.


Usual adult dose
Severe bronchospasm and status asthmaticus
Intramuscular, 500 mcg (0.5 mg) (base) (8 mcg per kg of body weight) every four hours as required. {06}
Intravenous bolus (over two to five minutes), 250 mcg (0.25 mg) (base) (4 mcg per kg of body weight, repeated after fifteen minutes if necessary. {06}
Intravenous infusion (continuous), 5 mcg (0.005 mg) (base) per minute, increased to 10 mcg per minute and then 20 mcg per minute at fifteen- to thirty-minute intervals, if necessary. {06}


Usual adult prescribing limits
Intramuscular: 2 mg (base) per day. {06}
Intravenous bolus: 1 mg (base) per day. {06}

Usual pediatric dose
Dosage has not been established. {06}
[Hyperkalemia ]1
Continuous infusion, 0.1 mcg (base) per kg of body weight per minute.{130}{131}{132}{133}{134}{135}{136}{137}{138}{139} Or, intravenous bolus, 4.5 mcg (base) per kg body weight over fifteen to twenty minutes.{130}{131}{132}{133}{134}{135}{136}{137}{138}{139}


Strength(s) usually available
U.S.—
Not commercially available.

Canada—


50 mcg (0.05 mg) (base) per mL (Rx) [Ventolin{06} ( for bolus intravenous injection) (sulfuric acid and/or hydrochloric acid)]


500 mcg (0.5 mg) (base) per mL (Rx) [Ventolin{06} ( for intramuscular injection) (sulfuric acid and/or hydrochloric acid)]


1 mg (base) per mL (Rx) [Ventolin{06} (for intravenous infusion) (sulfuric acid and/or hydrochloric acid)]

Packaging and storage:
Store between 15 and 30 ºC (59 and 86 ºF), unless otherwise specified by manufacturer. Protect from light. {06}

Preparation of dosage form:
Albuterol injection (for intravenous infusion) is prepared for administration by diluting 5 mg (base) in 500 mL of a chosen intravenous solution to produce a solution containing 10 mcg (0.01 mg) (base) of albuterol per mL. This solution must not be injected undiluted; the concentration should be reduced by 50% before administration. Acceptable intravenous solutions include water for injection, sodium chloride injection, dextrose injection, or sodium chloride and dextrose injection. {06}

Stability:
It is recommended that all unused intravenous infusion solutions be discarded 24 hours after preparation. {06}

Incompatibilities:
It is recommended that albuterol sulfate injection not be mixed in the same syringe or infused with any other medication. {06}

Auxiliary labeling:
   • Must be diluted before administration (for solution for intravenous infusion).


Note: Solution for intravenous infusion must be diluted appropriately before administration. {06}



EPHEDRINE

Summary of Differences
Unaccepted indications: Ephedrine has been used as a bronchodilator, a nasal decongestant, and to treat urinary incontinence; however, it has been generally replaced by safer and more effective medications.

Pharmacology/pharmacokinetics: Stimulates both alpha- and beta-adrenergic receptors. It is also indirect-acting (stimulates release of endogenous norephinephrine from sympathetic neurons, resulting in increased blood pressure and cardiac output). Stimulates CNS.

Drug interactions: Urinary acidifiers or alkalizers, guanadrel, guanethidine.

Medical considerations/contraindications: Brain damage, organic; cerebral arteriosclerosis; glaucoma, narrow-angle; prostatic hypertrophy.


Additional Dosing Information
Some tolerance to the effects of ephedrine occurs, but not addiction. Temporary withdrawal of ephedrine restores responsiveness to the medication. {13}


Oral Dosage Forms

EPHEDRINE SULFATE CAPSULES USP

Usual adult dose
Use has been generally replaced by safer and more effective agents. {53}

Usual pediatric dose
Use has been generally replaced by safer and more effective agents. {53}

Strength(s) usually available
U.S.—


25 mg (OTC)[Generic]


50 mg (OTC)[Generic]

Canada—
Not commercially available.

Packaging and storage:
Store between 15 and 30 ºC (59 and 86 ºF), unless otherwise specified by manufacturer. {13}



Parenteral Dosage Forms

EPHEDRINE SULFATE INJECTION USP

Usual adult dose
Use has been generally replaced by safer and more effective agents. {53}

Usual pediatric dose
Use has been generally replaced by safer and more effective agents. {53}

Strength(s) usually available
U.S.—


25 mg per mL (Rx)[Generic]


50 mg per mL (Rx)[Generic]

Canada—


50 mg per mL (Rx)[Generic]

Packaging and storage:
Store between 15 and 30 ºC (59 and 86 ºF), unless otherwise specified by manufacturer. Protect from light. {13} {14}


EPINEPHRINE

Summary of Differences
Indications: Allergic reactions, severe; anaphylaxis; anesthesia (local or regional) adjunct; priapism; gingival or pulpal hemorrhage.

Pharmacology/pharmacokinetics: Potent stimulant of both alpha- and beta-adrenergic receptors. Direct-acting.

Drug interactions: Insulin, oral antidiabetic agents, cocaine.

Medical considerations/contraindications: Cardiac disease; cerebral arteriosclerosis; organic brain damage; glaucoma, narrow angle; Parkinson's disease; psychoneurotic disorders; nonasthmatic shock.

Laboratory value alterations: Lactic acid serum values may be increased, which may result in severe metabolic acidosis after prolonged use or overdose of epinephrine.

Side/adverse effects:

• Hypertension and anxiety are more common.


• Psychoneurotic disorders occur rarely.


• Parenteral administration initially may produce constriction of renal blood vessels and decreased urine formation. {19}


• Repeated local injections can cause necrosis at sites of injection as a result of vascular constriction. {21}



Additional Dosing Information
The 1:1000 strength is only for subcutaneous or intramuscular use, {17} {18} further dilution to at least 1:10,000 (some clinicians prefer a dilution of 1:100,000 {99}) is required before intravenous administration. {18} {22}

The 1:1000 strength may be given by subcutaneous or intramuscular injection. {17} {18} In children, the intramuscular route is preferred due to faster absorption from this route. It is recommended that subcutaneous injection sites be rotated to avoid necrosis from vascular constriction at the injection site. {17} {22}

Injection of epinephrine into areas of the body served by end arteries or with otherwise limited blood supply (fingers, toes, nose, ears, penis) usually is not recommended because of the risk that vasoconstriction will cause sloughing of tissue. {17} {21}

When given intramuscularly, epinephrine should be injected only into the anterolateral aspect of the thigh {15} {18} or the deltoid region of the arm. {18} It should not be injected into the buttock. {15} {17}

Inadvertent vascular administration should be avoided. Accidental intravenous injection of usual subcutaneous doses may lead to cerebral hemorrhage as a result of a sudden sharp rise in blood pressure. {15} {17} Epinephrine should not be administered by intra-arterial injection because marked vasoconstriction may lead to gangrene. {18}

Accidental injection into the hands or feet should be avoided, and requires immediate emergency treatment, because it may lead to loss of blood flow to the affected area. {15} Administration of phentolamine is recommended to treat digital vasoconstriction caused by local administration of epinephrine.

Tolerance may occur with prolonged use. {22}

For additional information regarding use of epinephrine for treatment of anaphylactic shock, see the Sympathomimetic Agents—Cardiovascular Use (Parenteral-Systemic) monograph.


Parenteral Dosage Forms

EPINEPHRINE INJECTION

Usual adult and adolescent {18} dose
Allergic reactions, severe or
Anaphylaxis
Subcutaneous or intramuscular, 300 to 500 mcg (0.3 to 0.5 mg) {22}, repeated, if necessary, every ten to twenty minutes {21} for up to three doses.
Intravenous (slow and cautious), 100 to 250 mcg (0.1 to 0.25 mg). {19}

Note: Intravenous administration may be necessary if shock develops, which could reduce absorption of subcutaneous epinephrine. {22}
Only a 1:10,000 epinephrine should be used for intravenous administration.


Bronchospasm, acute
Subcutaneous, 10 mcg (0.01 mg) per kg of body weight (up to 300 to 500 mcg [0.3 to 0.5 mg]), repeated every twenty minutes as required for up to three doses {32} or
Intravenous (slow and cautious), 100 to 250 mcg (0.1 to 0.25 mg). {19}

Note: Only a 1:10,000 epinephrine solution should be used for intravenous administration.
If an intravenous route cannot be established and the patient has been intubated, the intravenous dose (of the 1:10,000 injection) can be injected via the endotracheal tube directly into the bronchial tree. {19}


Anesthetic (local or regional) adjunct
For use with local or regional anesthetics: A final concentration of 1:200,000 (5 mcg [0.005 mg] per mL) is recommended for infiltration. {22} However, concentrations may vary depending on the anesthetic agent used. {96}
For use with intraspinal anesthetics: 200 to 400 mcg (0.2 to 0.4 mg) may be mixed with spinal anesthetic agents. {17}


Usual pediatric dose
Allergic reactions, severe or
Anaphylaxis
Subcutaneous or intramuscular, 10 mcg (0.01 mg) per kg of body weight {15} {64} (up to a maximum of 300 mcg [0.3 mg] per dose {64}), repeated every fifteen minutes if needed {64} for up to three doses.

Bronchospasm, acute
Subcutaneous, 10 mcg (0.01 mg) per kg of body weight (up to a maximum of 300 mcg [0.3 mg] per dose). {64} The dose may be repeated every fifteen minutes for three or four doses or every four hours as necessary. {64}

Anesthetic (local or regional) adjunct
For use with local or regional anesthetics: A final concentration of 1:200,000 (5 mcg [0.005 mg] per mL) is recommended for infiltration. {64} However, concentrations may vary depending on the anesthetic agent used. {96}


Usual pediatric prescribing limits
Subcutaneous: 300 mcg (0.3 mg) per dose. {64}

Strength(s) usually available
U.S.—


100 mcg (0.1 mg) per mL (1:10,000) (Rx)[Generic](sodium chloride)

Note: The 1:10,000 strength is intended only for adult use; it is not recommended for pediatric use. {19} It is also meant for intravenous administration.



500 mcg (0.5 mg) per mL (1:2000) (0.15 mg per injector) (Rx) [EpiPen Jr. Auto-Injector (sodium chloride) (sodium metabisulfite) (hydrochloric acid)]


1 mg per mL (1:1000) (Rx) [Adrenalin (sodium bisulfite )] [Ana-Guard (sodium chloride) ( chlorobutanol) (sodium bisulfite)] [EpiPen Auto-Injector (0.3 mg per injector) ( sodium chloride) (sodium metabisulfite) (hydrochloric acid)][Generic]

Note: The 1:1000 strength is for intramuscular or subcutaneous use only; it must be diluted to a 1:10,000 strength for intravenous administration.
Although these preparations contain sulfites, this factor should not prevent the use of epinephrine in life-threatening hypersensitivity reactions or asthma attacks in patients who are sensitive to sulfites. {17}


Canada—


100 mcg (0.1 mg) per mL (1:10,000) (Rx)[Generic]

Note: The 1:10,000 strength is intended only for adult use; it is not recommended for pediatric use {19}. It is also meant for intravenous administration.



500 mcg (0.5 mg) per mL (1:2000) (Rx) [EpiPen Jr. (sodium chloride) (sodium metabisulfite) ( hydrochloric acid)]


1 mg per mL (1:1000) (Rx) [Adrenalin (sulfites)] [EpiPen (sodium chloride) (sodium metabisulfite) (hydrochloric acid)][Generic]

Note: The 1:1000 strength is for intramuscular or subcutaneous use only; it must be diluted to a 1:10,000 strength for intravenous administration.
Although these preparations contain sulfites, this factor should not prevent the use of epinephrine in life-threatening hypersensitivity reactions or asthma attacks in patients who are sensitive to sulfites. {24}


Packaging and storage:
Store between 15 and 25 ºC (59 and 77 ºF), unless otherwise specified by manufacturer. {17} Protect from light. {17} Protect from freezing. {17}

Preparation of dosage form:
Epinephrine injection 1:1000 may be prepared for intravenous or intrapleural administration by adding one part of the 1:1000 strength to ten parts of sterile water for injection, producting a 1:10,000 solution. {19}

Epinephrine injection 1:10,000 may be used undiluted for intravenous or intrapleural administration. {19}

Stability:
Epinephrine is readily oxidized, turning pink from oxidation to adrenochrome and then brown from the formation of polymers. {65} The solution should not be used if it has a pinkish or slightly darker than yellow color or contains a precipitate. {22}

Incompatibilities:
Epinephrine is readily destroyed by alkalies, as well as by oxidizing agents (oxygen, chlorine, bromine, iodine, permanganates, chromates, nitrites, and salts of easily reducible metals, especially iron). {17}

Auxiliary labeling:
   • For subcutaneous or intramuscular use only (for the 1:1000 strength).



Caution:
The 1:1000 strength should not be used for intravenous administration. Only a 1:10,000 strength may be given intravenously.

Note: For auto-injector—Include patient instructions when dispensing.



ISOPROTERENOL

Summary of Differences
Pharmacology/pharmacokinetics: Nonselective beta-adrenergic receptor agonist.

Medical considerations/contraindications: Caution also is required in patients with organic cardiac disease, including organic disease of the AV node and its branches.

Side/adverse effects: Rarely, Adams-Stokes attacks.


Additional Dosing Information
If the heart rate increases to greater than 110 beats per minute, it may be advisable to decrease the rate of infusion or temporarily discontinue the infusion. {24}


Parenteral Dosage Forms

ISOPROTERENOL HYDROCHLORIDE INJECTION USP

Usual adult dose
Bronchospasm during anesthesia
Intravenous (rapid), 10 to 20 mcg (0.01 to 0.02 mg), repeated as necessary. {24}


Usual pediatric dose
Bronchospasm
Intravenous infusion, 0.1 to 2 mcg (0.0001 to 0.002 mg) per kg of body weight per minute, starting at the minimum dose and increasing the dose every five to ten minutes until the effective dose is reached or toxicity occurs. {64}


Usual pediatric prescribing limits
2 mcg (0.002 mg) per kg of body weight per minute. {64}

Strength(s) usually available
U.S.—


200 mcg (0.2 mg) per mL (1:5000) (Rx) [Isuprel (lactic acid) (sodium chloride) ( sodium lactate) (sodium metabisulfite)][Generic]

Canada—


200 mcg (0.2 mg) per mL (1:5000) (Rx) [Isuprel (lactic acid) (sodium chloride) ( sodium lactate) (sodium metabisulfite)][Generic]

Packaging and storage:
Store between 8 and 15 ºC (46 and 59 ºF), unless otherwise specified by manufacturer. {24} Protect from light. {24} Protect from freezing. {24}

Preparation of dosage form:
For bolus intravenous administration, 200 mcg (0.2 mg) of isoproterenol hydrochloride injection is diluted to 10 mL with 5% dextrose injection or 0.9% sodium chloride injection, producing a solution containing 20 mcg (0.02 mg) of isoproterenol hydrochloride per mL. {24}

For administration by intravenous infusion to pediatric patients, the desired dose is added to 100 mL of 5% dextrose injection. {64}

Stability:
It is recommended that the injection not be used if it is pinkish or darker than slightly yellow in color or contains a precipitate. {24}


METAPROTERENOL

Summary of Differences
Pharmacology/pharmacokinetics: Somewhat selective for beta 2-adrenergic receptors; also has beta 1-adrenergic activity, including significant beta 1-adrenergic activity in the heart.

Medical considerations/contraindications: Sensitivity to parabens; formulations of metaproterenol sulfate syrup contain parabens.


Oral Dosage Forms

METAPROTERENOL SULFATE SYRUP USP

Usual adult dose
Bronchodilator
Oral, 20 mg three or four times a day, adjusted as needed. {26}


Usual pediatric dose
Bronchodilator
Children up to 6 years of age: Safety and efficacy have been demonstrated in a limited number of patients. Daily doses of 1.3 to 2.6 mg per kg of body weight (mg/kg) have been well tolerated. {26}
Children 6 to 9 years of age or

Children weighing less than 27 kilograms: Oral, 10 mg three or four times a day. {26}
Children 9 years of age or older or

Children weighing more than 27 kilograms: Oral, 20 mg three or four times a day. {26}


Strength(s) usually available
U.S.—


200 mcg (0.2 mg) per mL (Rx) [Alupent][Generic]

Canada—


200 mcg (0.2 mg) per mL (Rx) [Alupent]

Packaging and storage:
Store between 15 and 30 ºC (59 and 86 ºF), unless otherwise specified by manufacturer. {26} Protect from light. {26}


METAPROTERENOL SULFATE TABLETS USP

Usual adult dose
Bronchodilator
Oral, 20 mg three or four times a day, adjusted as needed. {25}


Usual pediatric dose
Bronchodilator
Children up to 6 years of age: Safety and efficacy have not been established. {25}
Children 6 to 9 years of age or

Children weighing less than 27 kilograms: Oral, 10 mg three or four times a day. {25}
Children 9 years of age or older or

Children weighing more than 27 kilograms: Oral, 20 mg three or four times a day. {25}


Strength(s) usually available
U.S.—


10 mg (Rx) [Alupent (lactose)][Generic]


20 mg (Rx) [Alupent (lactose)][Generic]

Canada—


20 mg (Rx) [Alupent (lactose)]

Packaging and storage:
Store between 15 and 30 ºC (59 and 86 ºF), unless otherwise specified by manufacturer. {25} Protect from light. {25}


TERBUTALINE

Summary of Differences
Indications: Premature labor.

Pharmacology/pharmacokinetics: Primarily stimulates beta 2-adrenergic receptors, with some minor beta 1-adrenergic activity.

Laboratory value alterations: Hepatic enzymes may be increased with high doses of terbutaline.

Side/adverse effects: Paradoxical bronchospasm may occur rarely; difficulty in urinating is more common.


Oral Dosage Forms

TERBUTALINE SULFATE TABLETS USP

Usual adult and adolescent dose
Bronchodilator
Oral, 5 mg three times a day, at approximately six-hour intervals (while the patient is awake). {27} {28} If unacceptable side effects occur, the dose may be decreased to 2.5 mg three times a day. {27}


Usual adult prescribing limits
15 mg per day. {27} {28}

Usual pediatric dose
Bronchodilator
Children up to 6 years of age: Safety and efficacy have not been established. {64}
Children 6 to 12 years of age: Oral, 50 to 75 mcg (0.05 to 0.075 mg) per kg of body weight three times a day, {30} {64} at approximately six-hour intervals (while the patient is awake).
Children 12 to 15 years of age: Oral, 2.5 mg three times a day, at approximately six-hour intervals (while the patient is awake). {27} {28}
Children 15 years of age and older: See Usual adult and adolescent dose.


Usual pediatric prescribing limits
Children 6 to 11 years of age: 150 mcg (0.15 mg) per kg of body weight per dose or up to a total of 5 mg per day. {64}

Children 12 to 15 years of age: 7.5 mg per day. {27} {64}

Strength(s) usually available
U.S.—


2.5 mg (Rx) [Brethine (lactose)] [Bricanyl (lactose)]


5 mg (Rx) [Brethine (lactose)] [Bricanyl (lactose)]

Canada—


2.5 mg (Rx) [Bricanyl (scored) (lactose )]


5 mg (Rx) [Bricanyl (scored) (lactose )]

Packaging and storage:
Store between 15 and 30 ºC (59 and 86 ºF), {27} {28} unless otherwise specified by manufacturer. Protect from light. {27}



Parenteral Dosage Forms

TERBUTALINE SULFATE INJECTION USP

Usual adult dose
Bronchodilator
Subcutaneous (injected into the lateral deltoid area), 250 mcg (0.25 mg), repeated in fifteen to thirty minutes if significant clinical improvement has not occurred. {29}

Note: If the patient does not respond after a second dose, other therapeutic measures should be considered. {29}


[Tocolytic ]1
Subcutaneous, 250 mcg (0.25 mg) every one to six hours {46} {52} {56} or
Intravenous infusion, 10 mcg (0.01 mg) per minute, the dose being increased by 5 mcg (0.005 mg) per minute every ten minutes until contractions stop or a maximum dose of 25 mcg (0.025 mg) per minute is reached. {46} {56}


Usual adult prescribing limits
Bronchodilator
500 mcg (0.5 mg) in a four-hour period. {29}


Usual pediatric dose
Bronchodilator
Children up to 6 years of age—Safety and efficacy have not been established. {30}
Children 6 to 12 years of age—Subcutaneous, 5 to 10 mcg (0.005 to 0.01 mg) per kg of body weight, repeated every fifteen to twenty minutes for up to three doses. {32} {64}
Children 12 years of age or older—Subcutaneous, 250 mcg (0.25 mg), repeated in fifteen to thirty minutes if significant clinical improvement has not occurred. {64}

Note: If the patient does not respond after a second dose, other therapeutic measures should be considered. {64}



Usual pediatric prescribing limits
Children 6 to 12 years of age: 400 mcg (0.4 mg) per dose. {64}
Children 12 years of age or older: 500 mcg (0.5 mg) in a four-hour period. {64}

Strength(s) usually available
U.S.—


1 mg per mL (Rx) [Bricanyl (sodium chloride) (hydrochloric acid)]

Canada—
Not commercially available.

Packaging and storage:
Store between 15 and 30 ºC (59 and 86 ºF), unless otherwise specified by manufacturer. {29} Protect from light. {29} Protect from freezing. {29}



Revised: 06/17/2002



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