A Comprehensive Monograph on Terbutaline (DB00871)

1. Terbutaline: An Overview and Summary of Key Properties

1.1. Introduction

Terbutaline is a synthetic sympathomimetic amine belonging to the phenylethanolamine chemical class.[1] Pharmacologically, it is classified as a selective, short-acting beta-2 (

β2​) adrenergic receptor agonist (SABA).[2] Its primary and approved therapeutic function is as a bronchodilator for the prevention and reversal of bronchospasm in patients with reversible obstructive airway diseases, including asthma, chronic bronchitis, and emphysema.[5] By selectively targeting

β2​ receptors in the bronchial smooth muscle, terbutaline provides rapid relief from symptoms such as wheezing, shortness of breath, and chest tightness, making it a cornerstone of "reliever" or "rescue" therapy in respiratory medicine.[3]

1.2. Executive Summary

This report provides an exhaustive analysis of terbutaline, synthesizing its chemical, pharmacological, clinical, and safety profiles. The clinical narrative of terbutaline is defined by a profound duality. On one hand, it is a well-established, effective, and widely used bronchodilator for a common set of respiratory conditions.[5] On the other hand, its off-label use as a tocolytic agent to manage preterm labor has been associated with significant risks, leading to severe regulatory actions.

The U.S. Food and Drug Administration (FDA) has issued its most stringent warning—a boxed warning—against the prolonged use (beyond 48–72 hours) of injectable terbutaline for tocolysis and has contraindicated the use of oral terbutaline for this purpose entirely.[9] This action was prompted by postmarketing reports of serious and sometimes fatal maternal cardiovascular adverse events, including tachycardia, myocardial ischemia, pulmonary edema, and cardiac arrhythmias.[9] This stark contrast between its accepted utility in pulmonology and its high-risk profile in obstetrics is a central theme of this monograph.

The pharmacological basis for both its therapeutic efficacy and its adverse effects lies in its mechanism of action: the preferential, but not absolute, stimulation of β2​-adrenergic receptors.[3] This agonism leads to the relaxation of smooth muscle in the bronchi and uterus. However, spillover effects on cardiac

β1​ receptors, particularly at higher doses, are responsible for its dose-limiting cardiovascular toxicities. This report will explore this dual identity in detail, providing clinicians and researchers with a nuanced understanding of terbutaline's complex risk-benefit profile across its various clinical applications.

2. Chemical Identity and Physicochemical Characteristics

2.1. Nomenclature and Identifiers

The precise identification of a pharmaceutical agent is fundamental to research and clinical practice. Terbutaline is known by several systematic names and is cataloged across numerous chemical and drug databases.

• Primary Name: Terbutaline [14]
• Systematic (IUPAC) Names: 5-(2-(tert-butylamino)-1-hydroxyethyl)benzene-1,3-diol; 5-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-1,3-benzenediol [2]
• Database Identifiers:
• DrugBank ID: DB00871 [14]
• CAS Number: 23031-25-6 (free base) [2]
• ChEMBL ID: CHEMBL1760 [15]
• Regulatory Codes (ATC): Terbutaline is classified under the Anatomical Therapeutic Chemical (ATC) classification system, reflecting its therapeutic use:
• R03AC03: Selective beta-2-adrenoreceptor agonists
• R03CC03: Terbutaline
• R03CC53: Terbutaline and other drugs for obstructive airway diseases [14]

2.2. Structural and Molecular Data

Terbutaline is classified as a small molecule drug.[15] Its structural and molecular properties are well-defined.

• Chemical Formula: C12​H19​NO3​ [7]
• Molecular Weight: 225.29 g/mol [7] (also cited as 225.3 g/mol [2] and 225.28 g/mol [16])
• Monoisotopic Mass: 225.1365 Da [7]
• Structural Representations:
• SMILES Code: OC1=CC(C(O)CNC(C)(C)C)=CC(O)=C1 [7]
• InChI Key: XWTYSIMOBUGWOL-UHFFFAOYSA-N [2]

2.3. Physicochemical Properties

The physical and chemical characteristics of terbutaline influence its formulation, stability, and pharmacokinetic behavior.

• Appearance: White to off-white crystalline powder.[7]
• Solubility:
• Water: 100 mM [2]
• DMSO: Slightly soluble [2]
• Methanol: Slightly soluble [2]
• Acidity/Basicity:
• CX Acidic pKa: 8.86 [15]
• CX Basic pKa: 9.76 [15]
• Storage and Stability: For short-term storage (days to weeks), it should be kept dry, dark, and at 0 - 4 °C. For long-term storage (months to years), a temperature of -20 °C is recommended. It is considered stable enough for shipping under ambient temperatures as a non-hazardous chemical.[7]

2.4. Formulations and Brand Names

Terbutaline is most commonly formulated as its sulfate salt, terbutaline sulfate (CAS# 23031-32-5), and dosages are typically expressed in terms of this salt.[4] It is marketed under various brand names, including Brethine, Bricanyl, and Brethaire.[18] The synonym KWD 2019 is also associated with the compound.[7]

The following table consolidates the key identification and physicochemical data for terbutaline.

Table 1: Physicochemical and Identification Data for Terbutaline

Property	Value	Source(s)
Identifiers
DrugBank ID	DB00871	14
CAS Number (Free Base)	23031-25-6	7
CAS Number (Sulfate)	23031-32-5	7
IUPAC Name	5-(2-(tert-butylamino)-1-hydroxyethyl)benzene-1,3-diol	7
Molecular Properties
Chemical Formula	C12​H19​NO3​	14
Molecular Weight	225.29 g/mol	7
Monoisotopic Mass	225.1365 Da	7
Physicochemical Properties
Appearance	White to off-white crystalline powder	7
AlogP	1.52	15
Polar Surface Area	72.72 A˚2	15
Rotatable Bonds	3	15
H-Bond Donors	4	15
H-Bond Acceptors	4	15
Lipinski Rule of 5 Violations	0	15

3. Comprehensive Pharmacological Profile

3.1. Pharmacodynamics: Mechanism of Action and Physiological Effects

The pharmacodynamic profile of terbutaline explains both its therapeutic utility and its potential for adverse events. Its actions are mediated through the adrenergic receptor system.

3.1.1. Primary Mechanism of Action

Terbutaline is a selective β2​-adrenergic receptor agonist.[3] Its primary therapeutic effect, bronchodilation, is achieved through a well-defined molecular pathway. Upon administration, terbutaline binds to

β2​ receptors, which are the predominant beta-receptor subtype in bronchial smooth muscle.[13] These receptors are G-protein coupled receptors that, upon agonist binding, activate the enzyme adenylyl cyclase. This activation leads to an increase in the intracellular concentration of cyclic adenosine monophosphate (cAMP).[3] The elevated levels of cAMP then activate protein kinase A (PKA), which in turn phosphorylates several intracellular proteins. This cascade results in the deactivation of myosin light-chain kinase and the activation of myosin light-chain phosphatase, leading to the relaxation of bronchial smooth muscle, a widening of the airways, and relief from bronchospasm.[1]

3.1.2. Receptor Selectivity and its Clinical Implications

A critical aspect of terbutaline's pharmacology is that its selectivity for β2​ receptors is preferential, not absolute.[3] Quantitative binding studies provide a clear picture of its receptor affinity profile, revealing Ki values of 31.3 nM for

β1​ receptors, 15.4 nM for β2​ receptors, and 79.8 nM for β3​ receptors.[2] This translates to an approximately two-fold higher affinity for

β2​ receptors compared to β1​ receptors.

This modest degree of selectivity is the central pharmacological feature that dictates terbutaline's entire clinical profile. At therapeutic concentrations required to saturate bronchial β2​ receptors to achieve effective bronchodilation, there is an inevitable and significant degree of concurrent binding to β1​ receptors, which are highly expressed in cardiac tissue. This mechanistic link directly connects the desired therapeutic effect (β2​-mediated bronchodilation) to the most common and clinically significant dose-limiting side effects (β1​-mediated tachycardia and palpitations).[3] This understanding explains why cardiovascular monitoring is essential during therapy and why the drug poses a significant risk to patients with pre-existing cardiovascular disorders.[4]

3.1.3. Physiological Effects

Terbutaline's interaction with adrenergic receptors produces a range of physiological effects, some therapeutic and others constituting adverse reactions.

• Respiratory Effects: The primary therapeutic effect is potent bronchodilation, which relieves wheezing and shortness of breath and leads to measurable improvements in pulmonary function, such as a 15% or greater increase in Forced Expiratory Volume in 1 second (FEV1​).[3] Terbutaline also exhibits some anti-inflammatory properties by inhibiting the release of immediate hypersensitivity mediators like histamine from mast cells.[2] However, this effect is subject to rapid tachyphylaxis (diminishing response with repeated use) and does not address the underlying chronic inflammatory pathways involving eosinophils, macrophages, and lymphocytes that characterize persistent asthma.[3] This distinction is clinically crucial, as it positions terbutaline firmly as a "reliever" for acute symptoms. Over-reliance on terbutaline (e.g., use more than two days per week for symptom relief) is a key indicator of inadequate underlying anti-inflammatory control and warrants a re-evaluation of the patient's maintenance therapy, which typically involves inhaled corticosteroids.[3]
• Uterine Effects (Tocolysis): β2​ receptors are also present in the smooth muscle of the uterus. Agonism at these receptors leads to uterine relaxation, which inhibits contractions. This is the mechanistic basis for its off-label use as a tocolytic agent to delay preterm labor.[7]
• Cardiovascular Effects: Stimulation of cardiac β1​ receptors can cause a clinically significant increase in heart rate (tachycardia), palpitations, and in some cases, cardiac arrhythmias.[1] Vasodilation, mediated by β2​ receptors in vascular smooth muscle, can also occur, potentially leading to changes in blood pressure.[21]
• Metabolic Effects: Terbutaline can induce significant metabolic disturbances. It is known to cause hypokalemia, likely through an intracellular shift of potassium ions, and hyperglycemia.[3] These effects are particularly concerning in patients with diabetes mellitus or those receiving concomitant therapy with non-potassium-sparing diuretics.[13]
• Musculoskeletal Effects: A very common and often distressing side effect is tremor, which results from the stimulation of β2​ receptors located in skeletal muscle.[1]

3.2. Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of terbutaline varies significantly with the route of administration, which has direct implications for its clinical use.

• Absorption: Following oral administration, absorption from the gastrointestinal tract is incomplete, with bioavailability ranging from 33% to 50%.[19] Subcutaneous and intravenous administration bypass first-pass metabolism and provide more rapid and complete drug delivery.
• Distribution: Terbutaline is distributed widely throughout the body.[19] It is known to cross the placenta, with umbilical cord concentrations reaching approximately 11% to 48% of maternal blood levels, a key consideration in its obstetric use.[10]
• Metabolism: The drug is partially metabolized in the liver, primarily through conjugation to inactive sulfate or glucuronide compounds.[1] Terbutaline is also the active metabolite of the long-acting prodrug bambuterol.[2]
• Excretion: The route of elimination is dependent on the route of administration. After parenteral administration (IV or SC), about 60% of the drug is excreted unchanged in the urine. In contrast, after an oral dose, the majority of the drug is excreted as inactive metabolites.[1] The elimination half-life is reported to be between 11 and 16 hours.[26]

Pharmacokinetic-pharmacodynamic (PK/PD) modeling studies have demonstrated a hyperbolic concentration-effect relationship for terbutaline's bronchodilatory action. These models required the inclusion of a hypothetical "effect compartment" to accurately describe the observed time course of lung function improvement, indicating a measurable delay between the peak plasma concentration of the drug and its peak physiological effect.[27]

The following table summarizes the key pharmacokinetic parameters of terbutaline, highlighting the differences between administration routes, which are critical for clinical decision-making.

Table 2: Pharmacokinetic Parameters of Terbutaline by Route of Administration

Route	Onset of Action	Peak Effect	Duration of Action	Source(s)
Oral (P.O.)	30 minutes	2–3 hours	4–8 hours	19
Subcutaneous (S.C.)	15 minutes	30 minutes	1.5–4 hours	19

4. Clinical Applications, Efficacy, and Dosing Regimens

4.1. Approved Indications in Respiratory Disease

The primary, FDA-approved clinical application for terbutaline is the prevention and treatment of bronchospasm in patients aged 12 years and older with reversible obstructive airway diseases.[8] This includes:

• Asthma (acute, maintenance, and allergic) [14]
• Chronic Bronchitis [5]
• Emphysema [5]
• Other obstructive lung diseases characterized by bronchial spasm [15]

As a fast-acting bronchodilator, terbutaline is highly effective for the acute relief of symptoms. Clinical studies have demonstrated that it produces significant improvements in spirometric measurements and provides subjective relief from wheezing and dyspnea.[3]

4.2. Off-Label Use in Tocolysis: A Critical Examination

Terbutaline has a long history of off-label use as a tocolytic agent to inhibit uterine contractions and delay preterm labor.[7] The principal rationale for this short-term delay (typically up to 48–72 hours) is to create a therapeutic window for the administration of antenatal corticosteroids to the mother, a critical intervention that accelerates fetal lung maturation and reduces the complications of prematurity.[4]

4.2.1. FDA Boxed Warning and Regulatory Stance

This off-label use is fraught with significant safety concerns, which culminated in the FDA issuing a boxed warning in 2011.[9] The warning explicitly cautions against the use of injectable terbutaline for prolonged tocolysis (beyond 48–72 hours) and contraindicates the use of the oral formulation for

any tocolytic purpose.[9] This regulatory action was based on numerous postmarketing reports of serious and fatal maternal adverse events, including:

• Tachycardia and cardiac arrhythmias [9]
• Pulmonary edema [9]
• Myocardial ischemia and heart attack [9]
• Death [9]

The FDA concluded that for prolonged tocolysis, "the risk of serious adverse events outweighs any potential benefit to pregnant women".[9]

4.2.2. The Clinical Dilemma of Short-Term Tocolysis

Despite this unequivocal warning, the practice of using short-term, in-hospital injectable terbutaline for the 48–72 hour window persists in some clinical settings. This reflects a significant clinical dilemma and an unmet need in obstetrics for safe and effective tocolytic agents. The FDA itself acknowledges that in "urgent and individual obstetrical situations in a hospital setting," a clinician may judge that the benefit of a short course of injectable terbutaline outweighs the substantial risks.[11] This difficult risk-benefit calculation is often made in the absence of superior, approved alternatives, pitting the known maternal risks of terbutaline against the severe neonatal risks of extreme prematurity if delivery cannot be briefly delayed for corticosteroid administration. This situation highlights a critical gap in pharmaceutical development for obstetric care.

4.2.3. Fetal, Neonatal, and Neurodevelopmental Risks

Maternal administration of terbutaline is not without risk to the fetus and newborn. Known effects include fetal tachycardia and neonatal hypoglycemia.[10] More recently, troubling evidence has emerged from epidemiological and animal studies suggesting a potential link between prenatal terbutaline exposure and an increased risk of long-term neurodevelopmental disorders, including Autism Spectrum Disorders (ASD).[31] Preclinical studies in rats have shown that terbutaline administration during a period equivalent to the late second trimester in humans can impair the development of critical noradrenergic projections in the cerebellum and peripheral nervous system, pointing to a plausible biological mechanism for these observed associations.[31]

4.3. Formulations, Administration, and Dosing

Terbutaline is available in several formulations to suit different clinical needs:

• Oral Tablets: 2.5 mg and 5 mg strengths [18]
• Injectable Solution: 1 mg/mL for subcutaneous or intravenous administration [18]
• Inhalation Powder: 0.5 mg per inhalation [32]

Dosing regimens vary substantially by age, indication, and route of administration. The following table provides a consolidated guide to recommended dosing.

Table 3: Recommended Dosing Regimens for Terbutaline

Population	Indication	Route	Dosage Regimen	Source(s)
Adults & Adolescents >15 years	Bronchospasm	Oral	2.5–5 mg three times daily, during waking hours. Max: 15 mg/24h.	32
	Bronchospasm (Acute)	Subcutaneous (SC)	0.25 mg; may repeat once after 15–30 min if needed. Max: 0.5 mg/4h.	26
Adolescents 12–15 years	Bronchospasm	Oral	2.5 mg three times daily. Max: 7.5 mg/24h.	13
Children <12 years	Bronchospasm (Acute, Severe)	Subcutaneous (SC)	0.005–0.01 mg/kg (Max single dose: 0.4 mg); may repeat q15–20 min for up to 3 doses.	13
Adults	Preterm Labor (Off-label, In-hospital only)	Intravenous (IV)	Initiate at 2.5–20 mcg/minute infusion; titrate as tolerated. Max duration: 48–72 hours.	4
	Preterm Labor (Off-label, In-hospital only)	Subcutaneous (SC)	0.25 mg every 20–30 minutes as needed. Max duration: 48–72 hours.	4
Renal Impairment	All (Parenteral routes)	SC / IV	GFR 20–50 mL/min: Administer 50% of normal dose. GFR <10 mL/min: Avoid parenteral use.	13

5. Safety Profile: Adverse Effects and Toxicity

The adverse effect profile of terbutaline is characteristic of sympathomimetic amines and is largely predictable based on its pharmacology. Most adverse reactions are dose-dependent and transient.

5.1. Adverse Reactions by System Organ Class and Frequency

The following is a summary of adverse reactions associated with terbutaline, categorized by frequency where data are available.[21]

• Very Common (>10% incidence)
• Nervous System: Tremor (up to 38%), nervousness (up to 35%), drowsiness (up to 11.7%), dizziness (up to 10.2%).
• Cardiovascular: Palpitations (up to 22.9%).
• Common (1% to 10% incidence)
• Nervous System: Headache.
• Cardiovascular: Tachycardia, ventricular extrasystoles, vasodilation, decrease in diastolic blood pressure.
• Gastrointestinal: Nausea, vomiting.
• Dermatologic: Sweating.
• Psychiatric: Somnolence, insomnia.
• Respiratory: Dyspnea, chest discomfort.
• Local: Pain at injection site.
• Uncommon (0.1% to 1% incidence)
• Gastrointestinal: Dry mouth.
• Musculoskeletal: Muscle cramps.
• Respiratory: Pulmonary edema.
• Rare (<0.1% incidence)
• Cardiovascular: Myocardial ischemia, arrhythmias (e.g., atrial fibrillation, supraventricular tachycardia).
• Respiratory: Paradoxical bronchospasm (a life-threatening reaction where airways constrict immediately after using an inhaled bronchodilator).
• Hepatic: Elevation of liver enzymes.
• Hypersensitivity: Immediate hypersensitivity reactions including urticaria, angioedema, rash, bronchospasm, and hypersensitivity vasculitis.
• Metabolic Effects: Clinically significant hypokalemia (low potassium) and hyperglycemia (high blood sugar) can occur, posing risks for patients with pre-existing diabetes or those taking diuretics.[10]

5.2. Overdose and Toxicity Management

An overdose of terbutaline results in an exaggeration of its known pharmacological effects.

5.2.1. Symptoms of Overdose

The clinical presentation of terbutaline toxicity can be severe and involves multiple organ systems. Key symptoms include [6]:

• Cardiovascular: Severe tachycardia, pounding heartbeat, arrhythmias, chest pain or discomfort (angina), hypertension followed by hypotension, and shock.
• Nervous System: Severe tremor, nervousness, agitation, headache, dizziness, insomnia, and convulsions (seizures).
• Metabolic: Significant hypokalemia, hyperglycemia, and potential for ketoacidosis in diabetic patients.
• Gastrointestinal: Nausea, vomiting, dry mouth.
• General: Weakness, malaise, confusion.

5.2.2. Management of Toxicity

In any suspected overdose, immediate medical attention is critical. Management is primarily symptomatic and supportive, as there is no specific antidote.[34]

• Initial Steps: Treatment with terbutaline should be discontinued immediately.[34] Emergency medical services or a poison control center should be contacted.[6]
• Hospital-Based Management:
• Monitoring: Continuous monitoring of vital signs, cardiac rhythm via electrocardiogram (ECG), and serum electrolytes (especially potassium) and glucose is paramount.[35]
• Supportive Care: Intravenous fluids may be administered to manage hypotension. Respiratory support, including oxygen and mechanical ventilation, may be necessary in cases of severe respiratory distress.[35]
• Decontamination: For recent oral ingestions, administration of activated charcoal may be considered to limit further drug absorption.[35]
• Pharmacologic Intervention: The management of terbutaline-induced cardiotoxicity presents a significant clinical challenge, particularly in patients with asthma. The logical intervention for severe tachycardia or arrhythmias is a β1​-adrenergic blocking agent. However, non-selective beta-blockers are contraindicated in asthmatics as they can induce severe bronchospasm.[22] In this setting, a cardioselective beta-blocker (e.g., metoprolol) may be used with extreme caution to antagonize the cardiac effects while minimizing the impact on bronchial β2​ receptors. This intervention requires a careful balancing of risks and must be conducted in a setting where acute bronchospasm can be managed aggressively.[22]

6. Contraindications, Warnings, and Drug Interactions

6.1. Contraindications and Warnings

Safe use of terbutaline requires careful patient selection and awareness of its contraindications and associated risks.

6.1.1. Absolute Contraindications

• Hypersensitivity: Known hypersensitivity to terbutaline or any other sympathomimetic amine.[13]
• Tocolysis:
• Oral Terbutaline: Contraindicated for both acute and maintenance tocolysis.[10]
• Injectable Terbutaline: Contraindicated for prolonged tocolysis (beyond 48–72 hours) or for maintenance tocolysis in an outpatient or home setting.[10]

6.1.2. Warnings and Precautions

Use with caution is warranted in patients with the following conditions:

• Cardiovascular Disease: Including coronary insufficiency, cardiac arrhythmias, and hypertension, due to the drug's stimulatory effects on the heart.[10]
• Diabetes Mellitus: Terbutaline can increase serum glucose and may aggravate pre-existing diabetes and ketoacidosis. Blood glucose monitoring is essential.[10]
• Hyperthyroidism: The drug may stimulate thyroid activity.[10]
• Seizure Disorders: May cause CNS stimulation and lower the seizure threshold.[10]
• Hypokalemia: May cause or worsen low potassium levels, increasing the risk of cardiac events.[10]

6.2. Clinically Significant Drug and Food Interactions

Terbutaline is subject to numerous drug interactions, some of which can be life-threatening. There are over 400 known drug interactions, with a significant number classified as major or moderate.[38]

6.2.1. Drug-Drug Interactions

The most critical interactions are summarized in the table below.

Table 4: Major Drug Interactions with Terbutaline

Interacting Drug Class	Mechanism of Interaction	Potential Outcome	Clinical Management	Source(s)
Monoamine Oxidase Inhibitors (MAOIs) & Tricyclic Antidepressants (TCAs)	Potentiation of sympathomimetic effects on the vascular system.	Hypertensive crisis, severe cardiovascular stimulation.	Co-administration should be done with extreme caution or avoided. A 2-week washout period after discontinuing MAOIs/TCAs is recommended.	13
Beta-Adrenergic Blockers (e.g., propranolol, metoprolol)	Pharmacodynamic antagonism at beta-receptors.	Mutual inhibition of effects; beta-blockers can cause severe bronchospasm in asthmatic patients.	Concomitant use is generally contraindicated in patients with asthma. In select situations (e.g., post-MI), a cardioselective beta-blocker may be used with extreme caution.	13
Other Sympathomimetic Agents (e.g., albuterol, epinephrine)	Additive adrenergic effects.	Increased risk of adverse cardiovascular events (tachycardia, palpitations, hypertension).	Concomitant systemic use is not recommended.	25
Non-Potassium-Sparing Diuretics (Loop, Thiazide)	Additive hypokalemic effects.	Worsening of hypokalemia, increasing the risk of cardiac arrhythmias.	Use with caution. Monitor serum potassium levels closely.	4
QTc-Prolonging Drugs (e.g., certain antiarrhythmics, antibiotics)	Additive effect on cardiac repolarization.	Increased risk of life-threatening arrhythmias (e.g., Torsades de Pointes).	Avoid co-administration where possible. Monitor ECG if use is unavoidable.	18

6.2.2. Drug-Food Interactions

A moderate interaction exists between terbutaline and caffeine. Caffeine can enhance the cardiac inotropic and general stimulatory effects of β2​-agonists, potentially increasing the incidence and severity of side effects such as nervousness, palpitations, and tachycardia. Patients sensitive to caffeine may need to limit or avoid intake of coffee, tea, colas, chocolate, and other caffeine-containing products while on terbutaline therapy.[39]

7. Use in Special Populations

7.1. Pregnancy and Lactation

The use of terbutaline in pregnancy is complex and indication-dependent.

• Use in Pregnancy for Tocolysis: As detailed extensively, the use of terbutaline for preterm labor is highly restricted. The FDA boxed warning strongly advises against its use for prolonged tocolysis (>48–72 hours) due to the risk of severe and fatal maternal cardiotoxicity.[9] Oral terbutaline is strictly contraindicated for this purpose.[25] Potential risks to the fetus include tachycardia, neonatal hypoglycemia, and possible long-term neurodevelopmental effects.[10]
• Use in Pregnancy for Bronchospasm: The management of asthma during pregnancy requires a careful risk-benefit analysis. Uncontrolled asthma poses significant risks to both the mother (e.g., preeclampsia) and the fetus (e.g., preterm birth, low birth weight).[10] Terbutaline (Pregnancy Category C) crosses the placenta.[10] Its use for its approved indication should be reserved for situations where the benefits of treating an acute bronchospasm are deemed to outweigh the potential risks to the fetus.
• Use in Lactation: It is not definitively known if terbutaline is excreted in human milk.[25] The American Academy of Pediatrics (AAP) has previously stated that the drug is likely compatible with breastfeeding, as amounts distributed into breast milk are generally considered insufficient to affect a nursing infant.[37] However, caution is advised.

7.2. Pediatric and Geriatric Considerations

• Pediatric Use: Terbutaline is approved for the treatment of bronchospasm in adolescents aged 12 and older.[8] Specific dosing recommendations exist for the 12–15 year age group.[13] Oral administration is not recommended for children under 12 years of age due to insufficient data on safety and efficacy.[33] Subcutaneous terbutaline is sometimes used off-label in younger children for the management of severe, acute asthma exacerbations in a hospital setting.[13]
• Geriatric Use: While there are no specific dosage adjustments recommended for geriatric patients, caution is strongly advised. Elderly individuals are more likely to have pre-existing cardiovascular conditions, hypertension, and age-related decline in renal function, making them more susceptible to the adverse effects of sympathomimetic drugs.[25] Dose selection should be conservative, typically starting at the lower end of the adult dosing range, with careful monitoring.[25]

8. Conclusion and Expert Recommendations

Terbutaline is a potent, rapid-acting β2​-adrenergic agonist with a well-established and valuable role in the management of reversible obstructive airway diseases. Its efficacy as a "reliever" medication for acute bronchospasm in asthma, bronchitis, and emphysema is undisputed. However, the clinical profile of terbutaline is defined by a critical duality: its utility in respiratory medicine is starkly contrasted by the severe, life-threatening risks associated with its off-label use as a prolonged tocolytic agent in obstetrics. This has rightfully led to stringent FDA warnings and contraindications that must be strictly adhered to.

Based on a comprehensive review of its pharmacology, clinical efficacy, and safety data, the following expert recommendations are provided for clinicians:

1. For Respiratory Indications: Clinicians should emphasize to patients that terbutaline is a symptom reliever, not a long-term controller of underlying airway inflammation. The frequency of SABA use is a critical marker of asthma control. Patients requiring terbutaline for symptom relief more than two days per week should undergo a thorough re-evaluation of their anti-inflammatory (controller) therapy, as this indicates inadequate disease management.[3] Patients must be educated on the risks of overuse, which can lead to diminished efficacy and an increased risk of adverse events.[10]
2. For Obstetric Indications: There must be strict adherence to the FDA boxed warning. The use of oral terbutaline for tocolysis is contraindicated and must not be done. The use of injectable terbutaline for tocolysis should be an exceptional event, restricted to urgent, in-hospital situations where the goal is a short-term delay (not exceeding 48–72 hours) to allow for the administration of antenatal corticosteroids. This decision requires a comprehensive risk-benefit discussion with the patient, continuous maternal cardiovascular monitoring, and fetal surveillance. The emerging data on potential long-term neurodevelopmental risks in exposed offspring further heightens the need for extreme caution.
3. General Patient Monitoring and Safety: Given its predictable, dose-dependent sympathomimetic effects, careful patient monitoring is essential. This includes assessment of heart rate and blood pressure, especially in patients with cardiovascular comorbidities. In patients receiving higher doses, parenteral therapy, or concomitant diuretics, baseline and periodic monitoring of serum potassium and blood glucose is warranted. All patients should be counseled on recognizing the symptoms of toxicity, such as severe palpitations, chest pain, or excessive tremor, and instructed to seek immediate medical attention if they occur.

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