Epistemis

Mifepristone and Methotrexate

  • Gynecology Oncology and Reproduction

Mifepristone / Methotrexate (e.g. *Mifegyne*, *Pfizer Methotrexate*).

Mechanism

Mechanism of Action

Mifepristone and Methotrexate are two agents that act by selectively blocking cell proliferation processes or hormonal support necessary for decidual and trophoblastic viability.

Mifepristone (Progesterone Antagonist)

It is a synthetic modulating steroid with very high competitive affinity:

  • Competitively blocks progesterone receptors in the decidua and myometrium.
  • It causes early decidual desquamation, placental abruption and a drop in local hCG levels.
  • Sensitizes the myometrium to the action of prostaglandins synergistically (multiplies the contractile effect of misoprostol).
  • Inhibits aromatase at a peripheral peripheral level.
Methotrexate (Antifolate Antimetabolite)

It is a competitive structural analogue of folic acid:

  • Irreversibly inhibits the enzyme Dihydrofolate Reductase (DHFR).
  • Blocks the synthesis of active cellular tetrahydrofolate, preventing the de novo synthesis of purine bases and thymidylate for DNA replication.
  • Selectively destroys syncytiotrophoblast cells in the phase of rapid mitotic division, stopping ectopic pregnancy.

Pharmacokinetics

Pharmacokinetics

  • Mifepristone: Oral administration with excellent absorption. Bioavailability of 70%. It binds 98% strongly to the α1acid glycoprotein. First-pass hepatic metabolism by demethylation and hydroxylation catalyzed by cytochrome CYP3A4, generating minor active metabolites. It has a very long half-life of approx. 18 to 24 hours. Biliary and fecal excretion by 90%.
  • Methotrexate (Ectopic): Administration exclusively deep intramuscular or direct local intratubal injection. Maximum serum concentration reached in 1 hour after IM route. It is 50% bound to plasma proteins. It does not undergo significant hepatic metabolism. Unaltered renal excretion almost exclusively by glomerular filtration and active tubular secretion (> 90% in 24 hours). Elimination half-life of 5 to 10 hours.

Indicators and dose

Indications

  • Mifepristone: Sequential preparative treatment for medical termination of intrauterine pregnancy in combination with a prostaglandin (misoprostol) until 9 to 22 weeks of gestation. Preparatory treatment for induction of labor due to intrauterine fetal death.
  • Methotrexate (Obstetrics): First-line non-surgical alternative medical treatment of unruptured tubal ectopic pregnancy that meets selective criteria:
    - Hemodynamically stable patient without signs of active hemoperitoneum.
    - Baseline serum β-hCG levels < 5,000 mIU/mL.
    - Diameter of the ectopic gestational sac < 4 cm measured by ultrasound.
    - Demonstrated absence of detectable embryonic cardiac activity.

Precision Dosing and Administration Scheme

  • Sequential Medical Abortion: 200 mg of Mifepristone orally in a single dose in the medical center, followed after an interval of 36 to 48 hours by the administration of 800 µg of Misoprostol vaginally or sublingually.
  • Ectopic Pregnancy (Single Dose Scheme with Methotrexate):

Single Dose Calculation of Methotrexate (IM)

It is prescribed based on the patient's calculated body surface area (SC):
Required Dose (mg) = 50 mg × Body Surface Area (m2)

It is injected via deep IM route on day 1 of the protocol. Basal plasma β-hCG levels must be measured on day 4 and day 7 post-injection. If the decrease in β-hCG between day 4 and day 7 is less than 15%, a second identical dose of methotrexate (50 mg/mm2 IM) should be administered or the need for surgical resolution by laparoscopy should be reassessed.

Pregnancy and Breastfeeding

Mifepristone is indicated for voluntary or medical termination of pregnancy. Methotrexate is a potent human teratogen and abortifacient classified in FDA Category It can induce fetal methotrexate syndrome if pregnancy continues (characterized by craniosynostosis, limb hypoplasia, severe micrognathia and profound mental retardation). Absolutely contraindicated in active breastfeeding (it is excreted in milk in concentrations with the potential to suppress the infant's immune system).

Security

Contraindications

  • Mifepristone: Chronic active adrenal insufficiency (mifepristone is also a potent glucocorticoid receptor antagonist), refractory bronchial asthma, underlying renal or hepatic insufficiency.
  • Methotrexate: Hemodynamic instability or suspicion of active tubal rupture (surgical emergency), active lactation, severe immunodeficiency, underlying blood dyscrasias (severe anemia, thrombocytopenia), peptic ulcer disease or active liver or kidney failure.

Adverse Effects (ADR)

  • Mifepristone: Self-limited prolonged heavy vaginal bleeding (associated with medical interruption, requires monitoring of hemoglobin levels), severe uterine cramping pain secondary to induced contractions.
  • Methotrexate (Systemic at low doses): Transient and reversible elevation of hepatic transaminases, stomatitis or painful ulcerative oral mucositis, transient acute rebound abdominal pain due to tubal distention due to cellular resolution ("separation" pain, occurs in 10-15% 3-7 days after treatment).

Epistemis is educational review material. It is not a medical device, does not diagnose or prescribe treatment, and does not replace formal medical training, current clinical guidelines, or professional clinical judgment.

PreviousTranexamic Acid
System
Gynecology and Obstetrics
Cluster
Gynecology Oncology and Reproduction
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