Tocolytic agents

Definition and Clinical Importance

Tocolytic agents are medications used to suppress premature uterine contractions and delay preterm labor. The primary clinical objective of tocolysis is not to stop labor indefinitely but to delay delivery for 48 hours to 7 days. This delay allows for the administration of antenatal corticosteroids to enhance fetal lung maturity, optimize neonatal outcomes, and facilitate in-utero transfer to a tertiary care facility if necessary. Tocolytics are generally used between 24 and 34 weeks of gestation and are contraindicated in situations where prolongation of pregnancy would pose a risk to the mother or fetus.

---

Pathophysiological Basis for Use

Preterm labor is defined as the onset of labor (regular uterine contractions with cervical changes) before 37 completed weeks of gestation. The pathogenesis involves:

• Uterine overdistension

• Inflammatory cytokines

• Hormonal changes (e.g., progesterone withdrawal)

• Increased prostaglandin synthesis

• Myometrial sensitivity to oxytocin

Tocolytics work by disrupting the pathways that lead to uterine muscle contraction.

---

Mechanisms of Action by Class

1. Calcium Channel Blockers

   • Inhibit calcium influx into myometrial cells, preventing contraction.

   • Example: Nifedipine

2. Beta-2 Adrenergic Agonists

   • Activate β2 receptors in the uterus → increase cAMP → inhibit myosin light-chain kinase.

   • Example: Terbutaline, Ritodrine

3. Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

   • Inhibit cyclooxygenase (COX) → reduce prostaglandin synthesis → decrease uterine contractions.

   • Example: Indomethacin

4. Magnesium Sulfate

   • Competes with calcium at voltage-gated channels; stabilizes myometrial cell membranes.

   • Also used for fetal neuroprotection (≤32 weeks gestation)

5. Oxytocin Receptor Antagonists

   • Block oxytocin-mediated uterine contractions.

   • Example: Atosiban (not FDA-approved in the U.S., approved in Europe)

6. Nitric Oxide Donors (experimental/limited use)

   • Relax smooth muscle via cGMP pathway.

   • Example: Nitroglycerin patches

---

Commonly Used Tocolytic Agents

1. Nifedipine

   • Class: Calcium channel blocker

   • Dose: 20 mg oral loading, followed by 10–20 mg every 6–8 hours

   • Advantages: Effective, oral administration, minimal maternal side effects

   • Adverse Effects: Hypotension, flushing, headache, dizziness, tachycardia

   • Contraindications: Hypotension, cardiac disease, concurrent magnesium sulfate

2. Indomethacin

   • Class: NSAID

   • Dose: 50–100 mg loading (oral or rectal), then 25–50 mg every 6 hours (max 48 hours)

   • Advantages: Highly effective in early gestational age (<32 weeks)

   • Adverse Effects: Oligohydramnios, ductus arteriosus constriction, necrotizing enterocolitis (NEC) if prolonged

   • Contraindications: Gestational age >32 weeks, renal/hepatic disease, GI ulcers, platelet dysfunction

3. Terbutaline

   • Class: Beta-2 adrenergic agonist

   • Dose: 0.25 mg subcutaneous every 20–30 minutes (max 3 doses)

   • Advantages: Rapid onset; effective for acute use

   • Adverse Effects: Tachycardia, hyperglycemia, hypokalemia, pulmonary edema

   • Contraindications: Cardiac disease, poorly controlled hyperthyroidism or diabetes

4. Magnesium Sulfate

   • Class: Calcium antagonist; neuroprotective

   • Dose: 4–6 g IV loading, then 1–2 g/hour infusion

   • Advantages: Fetal neuroprotection (≤32 weeks)

   • Adverse Effects: Respiratory depression, flushing, hypotension, decreased reflexes

   • Contraindications: Myasthenia gravis, renal insufficiency

5. Atosiban

   • Class: Oxytocin receptor antagonist

   • Use: Approved in EU; not in U.S.

   • Dose: IV bolus followed by infusion

   • Adverse Effects: Nausea, headache, flushing

   • Benefits: Well tolerated; no major fetal side effects

6. Nitroglycerin (Glyceryl trinitrate)

   • Class: Nitric oxide donor

   • Form: Patch or IV

   • Use: Occasionally in clinical trials or refractory cases

   • Adverse Effects: Severe hypotension, headache

---

Comparative Efficacy and Clinical Guidelines

• First-line therapy: Nifedipine

• Second-line options: Indomethacin (if <32 weeks), terbutaline

• Magnesium sulfate: Primarily for fetal neuroprotection, not effective as a tocolytic beyond 48 hours

• Atosiban: Considered safe and effective in Europe but not available in the U.S.

---

Contraindications to Tocolysis (General)

• Intrauterine fetal demise

• Lethal fetal anomaly

• Non-reassuring fetal status

• Severe preeclampsia/eclampsia

• Hemorrhage (e.g., placental abruption)

• Chorioamnionitis

• Advanced cervical dilation (≥4–5 cm)

• Gestational age ≥34 weeks (no proven benefit)

---

Monitoring Parameters During Tocolysis

• Maternal: Blood pressure, pulse, glucose, respiratory status

• Fetal: Heart rate, amniotic fluid volume (especially with indomethacin)

• Serum magnesium (if using MgSO₄): Maintain therapeutic levels (4–7 mEq/L)

---

Adverse Effects by Agent

Agent	Maternal Effects	Fetal/Neonatal Effects
Nifedipine	Hypotension, tachycardia, flushing	Generally safe
Indomethacin	GI upset, renal issues	Ductus arteriosus constriction, oligohydramnios
Terbutaline	Arrhythmias, pulmonary edema	Neonatal hypoglycemia, tachycardia
Magnesium sulfate	Respiratory depression, lethargy	Neonatal hypotonia, calcium imbalance
Atosiban	Minimal; nausea	Minimal fetal effects

Special Considerations in Use

• Tocolytics are not curative—they delay labor but do not prevent preterm birth long-term.

• Single-course antenatal corticosteroids (betamethasone or dexamethasone) should be given concurrently to enhance fetal lung maturity.

• Tocolytic therapy beyond 48 hours is typically avoided due to diminishing returns and increased maternal risks.

• Avoid simultaneous use of nifedipine and magnesium sulfate due to additive hypotensive and neuromuscular blocking effects.

---

Examples of Brand Names and Formulations

Drug Name	Brand Name(s)	Route	Country Approved
Nifedipine	Adalat, Procardia	Oral	Global
Indomethacin	Indocin	Oral/Rectal	Global
Terbutaline	Brethine	SC/IV	U.S.
Magnesium sulfate	—	IV	Global
Atosiban	Tractocile	IV	Europe, Asia
Nitroglycerin	Nitro-Dur, Nitrostat	Patch/IV	Experimental