A Comparison of the Relative Toxicities of ±-Sympathomimetic Tocolytic Agents

To define the relative toxicities of ritodrine sulfate, terbutaline sulfate, hexaprenaline sulfate, and ritodrine with betamethasone mongrel dogs were treated with these agents for 19 hours. The maximum dose of ritodrine was 900 ±g/min (N = 5), terbutaline 120 ±g/min (N = 4) and hexaprenaline 1.5 ±g/min (N = 4). Betamethasone was given intramuscularly (12 mg) at initiation of ritodrine and repeated in 12 hours in four animals. Arrhythmias were responsible for five deaths; 2/4 terbutaline, 2/4 ritodrine and betamethasone, 1/5 ritodrine, 0/4 hexaprenaline treated animals. Terbutaline-treated animals developed arrhythmias during more treatment cycles (50%) and at lower drug concentrations, whereas hexaprenaline-treated animals developed arrhythmias at higher drug concentrations, with an overall arrhythmia frequency of 14%. Terbutaline animals had the highest heart rate (P = 0.02) and lowest mean arterial pressure (P = 0.18); the least effect on these parameters being seen with hexaprenaline. Cardiac index was higher with terbutaline and hexaprenaline compared to ritodrine with or without betamethasone (P = 0.02). Hypoxemia was most severe with terbutaline (pO₂ = 58 mm Hg) and least severe with hexaprenaline (pO₂ = 66 mm Hg); however, this does not explain the difference in the frequency of arrhythmias since the mean pO₂ during the initial arrhythmias was 76 mm Hg in terbutaline treated animals compared to a baseline control of 85 mm Hg. Although all animals developed significant acidosis during Phases II-IV, hexaprenaline treated animals were the least acidotic (P = 0.036). Hypokalemia was most pronounced with terbutaline (P = 0.08 Phase II, P = 0.07 Phase III). Thus, terbutaline was the most toxic and hexaprenaline the least toxic of these agents, assuming an equivalent maximum recommended human dose for these drugs.