Indomethacin

Mechanism

Mechanism of Action

Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) derived from the methylindoleacetic acid family. It acts as a reversible, potent and non-selective inhibitor of the isoenzymes cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2).

Tokinase Physiology and Prostaglandin Synthesis

Cyclooxygenase catalyzes the rate-limiting step of arachidonic acid metabolism to generate pro-inflammatory and immunological prostaglandins. By blocking the active site of COX-1 and COX-2, indomethacin stops the myometrial synthesis of PGE2 and PGF2α, two potent physiological mediators of uterine dynamics responsible for the stimulation of cellular EP and FP receptors. This decrease in prostanode tone drastically decreases the flow of cytosolic calcium from the musculocutaneous uterine cell, achieving effective tocolysis.

Pharmacokinetics

Pharmacokinetics

• Routes of administration: Oral and rectal (suppositories, excellent absorption and lower rate of direct gastric irritation).
• Bioavailability (F): > 95% after rectal or oral administration. Maximum plasma concentration reached within 1 to 2 hours.
• Distribution: Highly bound to serum albumin (99%). It quickly crosses the placental barrier by passive diffusion due to its high lipophilicity, reaching equilibrium concentrations in fetal plasma equivalent to 50-100% of maternal levels.
• Metabolism: Extensive hepatic metabolism via O-demethylation and N-deacylation catalyzed by the microsomal CYP2C9 system, followed by conjugation with glucuronic acid.
• Half-life (t_1/2): Approximately 4.5 to 9 hours in the pregnant woman; In the preterm newborn, clearance is markedly slowed (prolonged half-life of up to 15-20 hours due to the immaturity of biliary conjugation).
• Excretion: Renal (60% in the form of inactive metabolites) and fecal-biliary (33%).

Indicators and dose

Indications

• Alternative second-line tocolytic for the suppression of imminent preterm birth, with a strict gestational age restriction of less than 32 weeks of gestation.
• Non-surgical treatment of choice for severe symptomatic polyhydramnios, due to its ability to reduce fetal diuresis in utero.

Security

Contraindications and Critical Fetal Adverse Effects

Critical Safety Warning: Adverse Effects on the Feto-Placental Unit

The use of indomethacin in the third trimester of pregnancy (especially after week 32) is associated with serious fetal complications, which limits its prolonged clinical use:

• Premature Closure of the Ductus Arteriosus (Ductus): Maternal prostaglandins (PGE2) keep the ductus arteriosus patent in the fetus. By inhibiting its synthesis, indomethacin can induce ductal constriction in utero, causing severe tricuspid regurgitation, right ventricular overload, and life-threatening neonatal persistent pulmonary hypertension. The risk increases exponentially from week 31-32 of gestation.
• Severe oligohydramnios: Indomethacin reduces fetal renal plasma flow by direct vasoconstriction of the renal glomerular afferent artery. This decreases the glomerular filtration rate of the fetus, reducing fetal urine production (source of amniotic fluid volume). It occurs early after more than 48 hours of use.
• Necrotising Enterocolitis (NEC) and Intraventricular Hemorrhage (IVH): In the preterm newborn exposed shortly before birth, due to decreased mesenteric and cerebral blood flow.

Maternal Contraindications

• Gestational age greater than 32 weeks of gestation.
• Active peptic ulcer or history of gastrointestinal bleeding of any etiology.
• Moderate or severe renal failure (depression of renal perfusion mediated by prostaglandins).
• ASA-induced asthma (Samter's Triad).
• Severe platelet dysfunction or known bleeding diathesis.

Dosing and Monitoring

• Tocolytic protocol (< 32 weeks):
• Loading dose: 50 to 100 mg administered rectally (suppository) or orally.
• Maintenance dose: 25 mg orally or rectally every 4 to 6 hours for a strict maximum cumulative period of 48 hours.
• Mandatory monitoring: If administered for more than 48 hours for the treatment of polyhydramnios, specific weekly fetal echocardiographic monitoring should be performed with measurement of the amniotic fluid index (AFI) and Doppler flowmetry of the ductus arteriosus (discontinue if the ALI is < 5 cm or if elevated ductal systolic velocity is detected).

Pregnancy and Breastfeeding

FDA Category D in the third trimester (due to the risk of constriction of the fetal ductus arteriosus and oligohydramnios). Compatible with low-risk breastfeeding; Small amounts are excreted in milk, but they have no significant adverse effects in the mature infant.