Terbutaline

Limits on what this shows

• Null findings: By day 13 of oral dosing (5 mg three times daily) potassium no longer fell, consistent with tolerance [11]. Oral potassium 39 mEq beforehand did not prevent the fall [10]. Clinical frequency is modest in children: hypokalemia in 2 of 33 on intravenous terbutaline in a randomized trial [34], and 10 of 77 children needed potassium with no arrhythmias [35]. In tocolysis, 3 of 14 treated women had symptomatic arrhythmias at the lowest potassium versus 0 of 12 controls (P=0.14, not significant) [5].
• At-risk subgroups: Women (larger fall than men) [16]; intravenous or repeated parenteral dosing [14]; tocolysis [5]; co-prescribed non-potassium-sparing diuretics (label) [1].

Direction

Redistribution (transient low serum level). Excess-risk framing: this is a disturbance, not a dietary deficiency.

Regulatory status

Both labels: beta-adrenergic agonists "may produce significant hypokalemia in some patients", usually transient, "not requiring supplementation". Hypokalemia is named in the boxed tocolysis warning, in the overdosage section and in the non-potassium-sparing diuretic interaction. No potassium values are given [1][2].

Population evidence, tocolysis

Preterm labor on intravenous ritodrine or terbutaline (5 each, pooled): potassium 4.2 (± 0.1) to 3.3 (± 0.1) mEq/L at 30 minutes (P below 0.005) and 2.5 (± 0.1) at 4 hours; in a cohort of 83 (41 on terbutaline) the lowest value came at 6 hours [5]. Chart review of obstetric patients on intravenous terbutaline: all 18 with electrolytes measured had potassium below 3.5 mEq/L, unrelated to dose or duration [6]. Six women in preterm labor [7] and 16 third-trimester women on terbutaline or isoxsuprine (marked fall in the first 2 hours, P below 0.001) [8] agree, without concentrations in the abstracts.

Population evidence, healthy volunteers and asthma

Healthy men, intravenous bolus plus infusion: 4.17 (95% CI 4.04 to 4.30) to a nadir of 3.32 (3.06 to 3.58) mmol/L, P below 0.001, n=10 [13]. Higher rates: 4.0 to 2.5 mmol/L with QTc 358 to 456 ms, n=6 [12]. Subcutaneous 0.25 mg: 3.96 (± 0.08) to 3.3 (± 0.13) mmol/L, n=10 [10]. Asthmatics: peak fall 14% at 30 minutes, n=7 [15]; maximum fall 0.6 (single dose) versus 1.1 mEq/L (second dose at 30 minutes), QTc 377 to 441 ms, n=8 [14]. Inhaled 5 mg: lowest value 3.12 (95% CI 2.96 to 3.28) in women versus 3.65 (3.49 to 3.81) mmol/L in men, n=20 [16]. Nebulized 5 mg: maximum fall 0.70 mmol/L, significant for 4 hours, n=8 [17].

Mechanism

Named. Beta-2 receptor stimulation increases sodium-potassium pump number (1,104 to 1,273 nmol/kg dry weight, P below 0.01) [13] and raises insulin and glucose [10][5]. Somatostatin, which blocks insulin release, blunted the fall [10]; oxprenolol almost abolished it [36]. It is not renal: urinary potassium fell, muscle potassium did not change [13], and renal excretion and aldosterone did not explain the drop in tocolysis [5].

Counter-evidence held on record

Counter-evidence and confounding Healthy-volunteer and asthma studies are small (6 to 20) and short. The tocolysis values in the one quantified cohort are pooled with ritodrine, a second beta-agonist, so a drug-specific split is not available from the abstract [5]. Co-administered intravenous fluids and glucose could not be excluded in the chart review [6]. No Tier A study found a null potassium result for terbutaline. Framing caution for the consumer surface This is a transient shift into cells, not a loss from the body. It must not be read as a reason to increase dietary or supplemental potassium; the label says supplementation is usually not required, and a pre-dose potassium load did not prevent the fall. Monitoring during intravenous use is the relevant action.

Limits on what this shows

• Null findings: Tolerance on repeated oral dosing for 13 days [11]. Healthy-volunteer rises are modest (about 18 mg/dL) [10].
• At-risk subgroups: People with diabetes or ketoacidosis risk (label); pregnancy, especially with antenatal betamethasone [9]; large intravenous doses [1][2].

Direction

Excess (transient hyperglycemia). Not a deficiency; no dietary implication.

Regulatory status

Boxed warning: "transient hyperglycemia" in the mother, and neonatal hypoglycemia. Precautions: large intravenous doses "have been reported to aggravate preexisting diabetes and ketoacidosis"; use with caution in diabetes. No glucose values are given [1][2].

Population evidence

Healthy volunteers, subcutaneous 0.25 mg: glucose 83 (± 3.6) to 101 (± 4.4) mg/dL, P below 0.01, insulin 11.7 to 19.9 microunits/mL, P below 0.001, n=10 [10]. Asthmatics: glucose and insulin rose from 15 minutes and stayed up for at least 2 hours, n=7 [15]. Healthy men: intravenous infusion and the first oral day raised glucose and insulin; by day 13 glucose rose only slightly from an already raised morning value, n=11 [11]. Intravenous tocolysis: hyperglycemia and hyperinsulinemia in 6 women [7]; glucose rose continuously (P below 0.001) with free fatty acids in 16 women [8]; terbutaline plus betamethasone (n=8) produced marked hyperglycemia at 11 hours that stayed up for 48 hours, with minimal change in a magnesium sulfate plus betamethasone comparison group [9]. Oral tocolysis: nondiabetic women (n=5 of 10 analyzed) had mean fasting glucose 111 (± 23) versus 72 (± 22) mg/dL in 41 historical controls, P below 0.001; values fell toward baseline after stopping [20]. Oral terbutaline in 6 pregnant women lowered insulin sensitivity by 28% (summary only) [37].

Mechanism

Beta-2 receptor driven. Insulin and free fatty acids rise alongside glucose [8][10], and the pregnancy study measured hepatic glucose production and insulin sensitivity as its endpoints [37]. The detailed hepatic versus muscle split is not established in the abstracts read.

Counter-evidence held on record

Counter-evidence and confounding The oral tocolysis study used historical controls, not concurrent ones, and only 5 of 10 women were nondiabetic [20]. Tocolysis cohorts are small and often receive intravenous fluids or steroids [9]. No Tier A null result for glucose was found. Framing caution for the consumer surface This is a drug-induced excess of blood glucose, not a nutrient shortfall. It does not call for any dietary or supplement change; it is a monitoring prompt for people with diabetes and for pregnancy.

Limits on what this shows

• Null findings: In 20 critically ill children all on continuous beta-agonist (albuterol), lactate was elevated in 60% and was not associated with adding intravenous terbutaline (11 children; OR 0.6); the contrast is confounded because the comparison group was also on a beta-agonist [23].
• At-risk subgroups: Intravenous infusion, tocolysis, anesthesia or surgery [5][21]; sepsis, hepatic or renal failure would be context for any lactate rise but were not studied with terbutaline in the sources read.

Direction

Excess (transient hyperlactatemia, rarely lactic acidosis). Not a deficiency.

Regulatory status

Not stated in the tablet or injection label sections returned [1][2]. A drug-information page lists lactic acidosis as rare (under 0.1%), without a source [43].

Population evidence

Preterm labor, intravenous ritodrine or terbutaline (pooled, n=10): lactate 4.7 (± 0.8) mmol/L at 4 hours and a ten-fold rise in the lactate to pyruvate ratio [5]. Six women on intravenous terbutaline had hyperlactacidemia with lower pH [7]. Maternal arterial gases before extubation in fetal surgery, terbutaline (n=9) versus atosiban (n=16): pH 7.347 versus 7.396 (P=0.006), lactate 28.33 versus 13.06 mg/dL (P=0.001) [21]. Muscle biopsies after inhaled 15 mg in 9 trained men: muscle lactate 20.3 (± 1.6) versus 13.2 (± 1.2) mmol/kg dry weight during submaximal exercise (P below 0.05) [22]. One case report of terbutaline-associated lactic acidosis that resolved after stopping [24].

Mechanism

Named. Increased glycolysis and carbohydrate oxidation: higher respiratory exchange ratio, muscle glycogen breakdown 266 versus 195 mmol/kg dry weight, and lower pyruvate dehydrogenase phosphorylation with terbutaline [22]; the authors of the case report cite increased glycolysis raising pyruvate and lactate [24].

Counter-evidence held on record

Counter-evidence and confounding The comparator in the surgical cohort was a different drug with different anesthetic conditions, and the cohort is retrospective with 9 terbutaline patients [21]. The tocolysis lactate value is pooled across two beta-agonists [5]. The only contrary finding is the confounded pediatric ICU review [23]. The label does not mention lactate. Framing caution for the consumer surface A raised lactate here is a short-lived drug effect on glucose metabolism, not a nutrient deficiency and not a reason to take thiamine or any other supplement. It matters for people on intravenous terbutaline who become breathless or unwell.

Limits on what this shows

• Null findings: None found for terbutaline. Adding intravenous magnesium sulfate to subcutaneous terbutaline potentiated cardiovascular and metabolic effects, which is the reverse direction of interest (the added drug, not a deficiency) [19].
• At-risk subgroups: Not studied; the authors raise short-term use in people with cardiac disease [18]. Magnesium is also given as a co-tocolytic, which would mask any fall [9].

Direction

Acute depletion (urinary loss) with possible redistribution, bounded to infusion. Not a dietary deficiency finding.

Regulatory status

Not mentioned in either label [1][2].

Population evidence

A 4-hour terbutaline infusion in 6 healthy volunteers decreased serum magnesium, ionized calcium, phosphate and potassium, and increased urinary magnesium, calcium and cyclic AMP; no concentrations in the abstract [18]. In 10 healthy men on the Tveskov regimen, serum and muscle magnesium were measured [13]; a drug-information page gives a serum magnesium decrease of 0.08 mmol/L "in these same patients" (secondhand, Tier D, attribution to Tveskov inferred from the matching design) [43]. Serum magnesium was not reported in the abstract that was read.

Mechanism

Present and named: increased urinary magnesium excretion and cyclic AMP during infusion (authors attribute the fall at least partly to renal loss) [18]. A transcellular component is not excluded.

Counter-evidence held on record

Counter-evidence and confounding One Tier A abstract without values [18] plus a second Tier A study whose magnesium value reached this review only secondhand [43]. The size (0.08 mmol/L) is small in absolute terms. No study measured magnesium after oral or inhaled use. Framing caution for the consumer surface This was an acute infusion effect in healthy volunteers. It does not show that oral or inhaled terbutaline lowers magnesium stores, and it is not a reason to supplement magnesium.

Limits on what this shows

• Null findings: None found for terbutaline.
• At-risk subgroups: Not defined. Tocolysis with fluid loading is the setting in which volume expansion occurs [7].

Direction

Acute fall in blood calcium (partly urinary loss; volume expansion also proposed). Not a dietary deficiency finding.

Regulatory status

Hypocalcemia is not mentioned in either label [1][2].

Population evidence

6 healthy volunteers, 4-hour infusion: serum calcium decreased and urinary calcium increased [18]. In 6 women in preterm labor the authors attribute lower ionized calcium and pH to hyperglycemia, insulin and lactate, with volume expansion possibly contributing [7]. In a crossover in healthy men, adding 4 g intravenous magnesium sulfate to terbutaline raised serum calcium by 0.13 mg/dL relative to terbutaline alone (summary only) [19].

Mechanism

Named but partly inferred: urinary calcium loss during infusion [18]; insulin, lactate and acid-base effects and hemodilution [7].

Counter-evidence held on record

Counter-evidence and confounding Two independent Tier A cohorts agree on direction, but neither abstract gave a numerical change, so clinical meaning cannot be judged. The preterm-labor attribution is the authors' suggestion within a six-patient study [7]. Framing caution for the consumer surface A short-lived fall in blood calcium during an infusion is not a calcium deficiency and does not call for calcium supplementation.

Limits on what this shows

• Null findings: None found.
• At-risk subgroups: Not studied.

Direction

Acute fall in serum phosphate during infusion (probable cellular shift with glucose and insulin; mechanism not stated in the abstract). Not a dietary deficiency finding.

Regulatory status

Not mentioned in either label [1][2].

Population evidence

Serum phosphate decreased in 6 healthy volunteers during a 4-hour terbutaline infusion; no concentrations in the abstract [18]. The PubMed title and abstract search for terbutaline with phosphate returned 29 records, of which only the first page of 10 was read; the only human phosphate measurement among them was this study [18].

Mechanism

Not named in the abstract. Insulin and glucose-driven cellular uptake is plausible and is documented for potassium [10], but it was not shown for phosphate.

Counter-evidence held on record

Counter-evidence and confounding One Tier A source, no concentration, 6 subjects. This is the weakest orange entry and sits close to the orange floor. Framing caution for the consumer surface A brief drop in blood phosphate during an infusion is not a phosphate deficiency and does not call for phosphate supplementation.

Limits on what this shows

• Null findings: No terbutaline study found that measured neonatal glucose against unexposed infants.
• At-risk subgroups: Infants delivered soon after maternal infusion (a time-since-infusion relation is reported for ritodrine only) [25]; maternal diabetes [20].

Direction

Fall in neonatal blood glucose (fetal hyperinsulinemia is the usual explanation but was not measured in the sources read). This is a clinical-outcome entry measured by glucose, not a nutrient deficiency in the mother.

Regulatory status

Boxed warning in both labels: "Increased fetal heart rate and neonatal hypoglycemia may occur as a result of maternal administration". Umbilical blood levels were 11% to 48% of maternal [1][2].

Population evidence

Oral tocolysis case series: 3 of 11 infants born to the 10 analyzed mothers were hypoglycemic in the immediate neonatal period; no comparison group and no definition in the text retrieved [20]. A historical cohort of 94 terbutaline-treated deliveries did not explore neonatal glucose [33].

Mechanism

Present: transplacental passage [1], maternal hyperglycemia and hyperinsulinemia [10][20]. Fetal insulin was not measured in the sources read.

CLASS EXTRAPOLATION

Ritodrine, a different beta-2 agonist: neonatal hypoglycemia (below 50 mg/dL) in 61.7% (58/94) after intravenous ritodrine versus 8.1% (41/509) unexposed, in 603 term-born neonates [25]. Terbutaline was NOT in that cohort, so this is context capped at yellow and was not used to grade this entry. A gestational-diabetes cohort comparing atosiban, ritodrine and nifedipine did not include terbutaline either [26].

Counter-evidence held on record

Counter-evidence and confounding The case series is small, uncontrolled and mixes diabetic and nondiabetic mothers [20]. Neonatal hypoglycemia is common for other reasons (prematurity, maternal diabetes). The grade rests on the label plus one series, which is why it is orange and bounded to the peripartum window. Framing caution for the consumer surface This is a neonatal blood glucose monitoring matter at delivery. It is not a nutrient deficiency in the mother or infant and does not call for any supplement.

Limits on what this shows

• Null findings: None found.
• At-risk subgroups: Women given prolonged or high-volume intravenous tocolysis; the boxed warning also lists myocardial ischemia [1].

Direction

Retention (excess). Supplementing or increasing sodium or fluids would be the hazard, not the remedy.

Regulatory status

Pulmonary edema is named in the boxed warning for tocolysis in both labels; sodium and fluid handling are not discussed [1][2].

Population evidence

In 10 women in preterm labor (5 on terbutaline, 5 on ritodrine), both drugs reduced glomerular filtration rate, urine flow, and urinary sodium, potassium and chloride excretion; the abstract describes sodium and fluid retention. Drug-specific values are not in the abstract [5]. Serum colloid osmotic pressure fell with intravenous terbutaline in 6 women, with volume expansion proposed [7].

Mechanism

Present, partly named: lower glomerular filtration and urine flow [5]; hemodilution [7]. Hormonal mediators were not identified (aldosterone did not explain the potassium effect) [5].

Counter-evidence held on record

Counter-evidence and confounding One cohort, pooled across two drugs, 5 women per drug in the detailed arm [5]. Intravenous fluid loading used in tocolysis is a confounder [7]. Framing caution for the consumer surface This is retention during hospital infusion, not a deficiency. It argues for fluid-balance monitoring, never for adding salt or fluid.

Limits on what this shows

• Null findings: No human folate, homocysteine or red-cell folate study with terbutaline was found in the channels tried.
• At-risk subgroups: None.

Direction

Theoretical consumption of a folate-derived one-carbon unit; unquantified and probably trivial at drug doses.

Regulatory status

Not mentioned in either label [1][2].

Evidence

Tier B. Reproterol reacted with formaldehyde released from N5,N10-methylene tetrahydrofolic acid (not from N5-methyl) to form a tetrahydroisoquinoline, in a buffer and in rat liver fractions (highest activity in the soluble fraction, some in mitochondria and microsomes); metaproterenol and terbutaline reacted with formaldehyde to give their own tetrahydroisoquinolines, and the reaction rate correlated with product formed in liver fractions and in orally dosed rats for the three drugs [32].

Mechanism

Named: Pictet-Spengler-type condensation with folate-derived formaldehyde [32]. Whether this lowers any tissue folate pool was not measured.

Counter-evidence held on record

Counter-evidence and confounding Reproterol was the lead compound; terbutaline was tested chemically and its rat product formation is stated only for the three drugs as a group [32]. The abstract was reconstructed, not read in full. Framing caution for the consumer surface Not evidence of a folate deficiency. No change in folate intake is suggested.