Terbutaline Sulfate is a synthetic beta-2 agonist, which was first introduced in the late 1960s. It is used for the management of bronchospasm associated with asthma, bronchitis, emphysema, and chronic obstructive pulmonary disease (COPD).

Clinical pharmacokinetics of terbutaline sulfate in humans

Terbutaline Sulfate acts on the beta-2 receptors located in bronchial, vascular, and uterine smooth muscle, and it stimulates the production of cyclic adenosine-3′,5′-monophosphate by activation of the enzyme adenyl cyclase, thus lowering intracellular calcium which in turn leads to inhibition of contractility of smooth muscle cells. Its off-label use includes prolonged treatment of preterm labor and uterine hyperstimulation. It is available in oral, parenteral, and inhalational formulations. The usual dose of oral Terbutaline Sulfate for adults and children (12 to 15 years) is 5 mg and 2.5 mg, respectively, whereas it is available in a dose of 250 μg via the parenteral route (subcutaneous, intramuscular, slow intravenous). The aerosol inhalation is administered in doses of 250 and 500 μg. Terbutaline Sulfate is a hydrophilic compound having a molecular weight of 225.29 g/mol. It belongs to Biopharmaceutical Classification System (BCS) class 2 having low solubility and high permeability. It can cross the placenta as well as the blood–brain barrier. After oral administration, the absorbed fraction (fa) of terbutaline is 0.26 with an interindividual variability of 0.25–0.80. The peak plasma concentration of Terbutaline Sulfate is achieved within 2–3 h.[1]

The mean bioavailability of Terbutaline Sulfate is 14–15% (Nyberg 1984). The plasma protein binding of terbutaline ranges from 14 to 25% with a volume of distribution at steady-state (Vdss) averages of 1.5 l/kg. It has a biological half-life (t1/2) of 3–4 h (Karabey et al. 2005). After oral administration, drug undergoes extensive first-pass metabolism via conjugation and the main metabolite is sulfate conjugate and 50% of the dose is excreted unchanged in the feces. The total body clearance (TBC) of terbutaline is 238 ml/min, and renal clearance (CLR) is 156.3 ml/min. Terbutaline Sulfate demonstrated a multi-exponential behavior for disposition after IV administration to healthy adults, which shows that terbutaline is markedly distributed outside the plasma compartment as the transfer between compartments takes time; hence, multiphasic Cp–time profiles are observed. Moreover, the mean residence time (MRT) of Terbutaline Sulfate was lower than t1/2 which reveals that a significant fraction of the drug is distributed into deeper compartments. Peak Cp values were reported to be higher in males as compared to females, and Tmax was reported to be 1 h after the start of infusion. The CL values were similar between groups averaging about 4 ml/min/kg of body weight. CLR contributed 60% of the TBC mostly as a non-metabolized drug after IV drug administration to healthy adults.

One of the studies in asthmatic adults provided evidence of circadian variations which shows that despite the administration of constant rate IV infusion, variations in plasma concentration of the drug were significant (Philip-Joet et al. 1992). These temporal variations affect the Tmax, AUC, and Cmax of the drug. A study reported that the Tmax value of Terbutaline Sulfate approximately got doubled in the evening, AUC decreased by 11% and Cmax also decreased at night, but in the morning, AUC and Cmax values were higher (Jonkman et al. 1988). To diminish the diurnal variations, appropriate therapeutic regimens work well in the case of terbutaline. The chrono-pharmacologic data indicates that terbutaline should be dosed higher in the evening than during the daytime when asthma is predominantly nocturnal. The PK of terbutaline has not been determined in healthy children. In the case of IV dosing to asthmatic children, Cp correlated linearly with dose and it declined in a multiexponential manner which shows that Terbutaline Sulfate distributes slowly in the body. Both children and adults have a similar volume of distribution at a steady state (Vss). Due to the rapid CL of terbutaline in children than in adults, the MRT of the drug is slightly shorter in children with a short t1/2 . A study conducted in the pediatric population showed an age-dependent difference in PK parameters of Terbutaline Sulfate. Both MRT and t1/2 of the drug were reported to increase with increasing age. The CL of the drug exhibited nonsystematic variability with age it was reported to be less in the age range of?<?2–?<?6 years, but in the age range of 6–?<?12 years, it was more and again declined in the age range of 12–?<?18 years. The Vdss did not change significantly, and the Tmax was observed to be 2 h in all cases after oral administration in asthmatic children.

Effects of Terbutaline Sulfate on Physiological and Biomechanical as Well as Perceived Exertion in Healthy Active Athletes

This study aimed to investigate the effects of beta2‐agonist terbutaline sulfate (Terbutaline Sulfate) at a supra‐therapeutic dose (8 mg) on aerobic exercise performance. Twelve (6 females and 6 males) amateur athletes familiarized with all experimental procedures had their anthropometric data obtained on day 1. On days 2 and 3 either 8 mg of Terbutaline Sulfate or a placebo (PLA) was administered orally (double‐blind manner) to participants who had rested for 3 h prior to aerobic exercise performance 20 m multistage fitness test (MSFT)]. This test was used to predict maximal oxygen uptake (VO2max) and velocity at which VO2max occurs (vVO2max). The Borg rating of perceived exertion (RPE), cardiovascular variables [heart rate (HR) and blood pressure (BP)] and blood glucose concentration [BGC] were obtained 15 min pre‐ and immediately post‐MSFT. Significant mean group differences were reported between PLA and Terbutaline Sulfate groups (p < 0.05), respectively, in the RPE (15.6 ± 1.2 vs. 17.3 ± 1.5 a.u.), maximum heart rate (HRmax: 191.2 ± 7.1 vs. 197.2 ± 8.6 bpm) and BGC (118.4 ± 18.3 vs. 141.2 ± 15.8 mg/dL) post‐MSFT. The main effect of gender (male vs. female) in Terbutaline Sulfate and PLA groups (p< 0.05) was observed, with higher estimated VO2max, vVO2max, HRmax and a lower mean HR pre‐test in male than female athletes. For these reasons, the inclusion of Terbutaline Sulfate in the Prohibited List should be re‐discussed because of the lack of ergogenic effects.[2]

All participants complained of the same adverse side effects such as tremors, tachycardia and pallor one hour following Terbutaline Sulfate administration. Based on the study by Sanchez et al. (2013), we can confirm that these marked adverse side effects may prevent possible ergogenic effects of Terbutaline Sulfate. Accordingly, Sato et al. (2010) postulated that taking these substances repeatedly could engender a decline in β2 receptor contents and side effects exhibitions. In addition, Whitsett et al. (1981) reported that Terbutaline Sulfate generated less side effects when compared with other β2‐agonists. In contrast, Van Baak et al. (2000) indicated that oral salbutamol administration had ergogenic effects in non asthmatic subjects without severe adverse side effects. A number of non‐asthmatic athletes consider inhaled β2‐agonists ergogenic although scientific evidence clearly disregards a performance enhancing effect. In conclusion, despite the presence of ergogenic effect of Terbutaline Sulfate on perceptual response, HR (HRmax) and BGC, the acute supra‐therapeutic dose of Terbutaline Sulfate seems to be without any relevant effect on aerobic performance in healthy active male and female athletes. The effect of gender in estimated VO2max and HR after the MSFT was also reported. For that reason, the inclusion of β2‐agonists in the Prohibited List should be re‐discussed because their ergogenic effects have not been confirmed. Further studies are required to examine the effects of long‐term β2‐agonist use on aerobic performance.

References

[1]Sultan, Khadeeja et al. “Clinical pharmacokinetics of terbutaline in humans: a systematic review.” Naunyn-Schmiedeberg's archives of pharmacology vol. 396,2 (2023): 213-227. doi:10.1007/s00210-022-02304-5

[2]Hafedh H, Slimani M, Miarka B, Bettayeb R, Bragazzi NL. Effects of Terbutaline Sulfate on Physiological and Biomechanical as Well as Perceived Exertion in Healthy Active Athletes: A Pilot Study. J Hum Kinet. 2019 Oct 18;69:169-178. doi: 10.2478/hukin-2018-0097. PMID: 31666899; PMCID: PMC6815083.