Oxytocin and Other Drugs Acting on Uterus

Dr. Bipin

Oxytocin

  • Definition:

    • Oxytocin is a nonapeptide secreted by the posterior pituitary alongside argenine vasopressin (AVP or ADH).

  • Historical Context:

    • The first recorded use of pituitary extracts to induce labor occurred in 1909.

    • Initially, there was controversy regarding whether the antidiuretic and uterine stimulating activities derived from a single substance or two separate substances, resolved by du Vigneaud in 1953.

    • He succeeded in separating oxytocin and vasopressin, determining their chemical structure, and synthesizing them.

  • Structural Similarity:

    • Both oxytocin and vasopressin consist of 9 amino acids and differ only at positions 3 and 8.

Posterior Pituitary Hormones

  • Oxytocin

  • Desamino-oxytocin

Uterine Stimulants (Oxytocics)

  • Classes of Uterine Stimulants:

    • Ergot alkaloids:

    • Ergometrine (Ergonovine)

    • Methylergometrine

    • Prostaglandins (PGs):

    • PGE2 (Dinoprostone)

    • PGF₂α (Dinoprost)

    • 15-methyl PGF₂α (Carboprost)

    • Misoprostol (+ Mifepristone)

    • Miscellaneous:

    • Ethacridine

    • Quinine

Synthesis and Release

  • Synthesis:

    • Both oxytocin and AVP are synthesized within the nerve cell bodies located in the supraoptic and paraventricular nuclei of the hypothalamus.

    • They are transported down the axon and stored in nerve endings within the neurohypophysis.

  • Storage:

    • Oxytocin and AVP are contained separately in neurons, bound to their specific binding proteins (neurophysins), creating granules.

  • Release Mechanisms:

    • Both hormones are released in response to specific stimuli:

    • Oxytocin: coitus, parturition, suckling

    • ADH: hypertonic saline infusion, water deprivation, hemorrhage, pain, and apprehension.

    • The ratio of oxytocin to ADH may vary based on the stimulus.

Mechanism of Action (MOA)

  • Exam Question: What are the key aspects of Oxytocin’s MOA?

    1. Target:

    • Binds to Gq-protein coupled oxytocin receptors on myometrial (uterine smooth muscle) cells.

    1. Activation:

    • This binding activates phospholipase C, leading to the release of intracellular calcium ions (Ca²⁺).

    1. Result:

    • Increased intracellular calcium results in rhythmic contractions of the uterus (specifically in the fundus and upper segment), while the lower segment remains relaxed. This assists in pushing the fetus downward during labor.

    1. Key Exam Point:

    • The sensitivity of the uterus to oxytocin increases significantly as pregnancy progresses, attributed to estrogen upregulating the number of oxytocin receptors as term approaches. In the first two trimesters, the uterus exhibits relatively higher resistance to oxytocin.

    1. Secondary Action:

    • Stimulates myoepithelial cells in breast alveoli, leading to the milk ejection (let-down) reflex.

    1. Anti-Diuretic Effect:

    • Oxytocin has a structural similarity to ADH. At high doses, oxytocin can bind to ADH receptors, potentially causing water retention.

Pharmacokinetics (PK)

  • Administering:

    • Oxytocin can only be administered via IV or IM routes as it is destroyed by the gastrointestinal enzyme oxytocinase; thus, it is not suitable for oral administration.

  • Onset of Action:

    • IV: Approximately 1 minute

    • IM: Approximately 3-5 minutes

  • Duration of Action:

    • IV: 20-30 minutes (effect ceases quickly after infusion stops)

    • IM: 2-3 hours

  • Metabolism:

    • Rapidly metabolized by the liver and kidneys, and by plasma oxytocinase.

Clinical Indications

  • Context of Use:

    1. Induction of Labour:

    • Recommended when the advantages of delivery surpass the risks of continued pregnancy (e.g., post-term pregnancy, PROM, maternal diabetes, pre-eclampsia).

    1. Augmentation of Labour:

    • Employed to stimulate uterine contractions in cases of uterine inertia (failure to progress during labor due to inadequate contractions).

    1. Prevention of Postpartum Hemorrhage (PPH):

    • Routine administration post-delivery of the baby (after the anterior shoulder's delivery or immediately post-birth) to prevent PPH is considered standard care.

    1. Treatment of PPH:

    • Utilized to contract the uterus and manage bleeding post-delivery when uterine atony is the underlying cause.

    1. Incomplete/Missed Abortion:

    • Used to aid in expelling products of conception (though misoprostol is often preferred now).

Dosage and Administration

  • Induction/Augmentation:

    • Administered via IV infusion only:

    • Start at 1-4 mIU/min (Example: 10 IU in 1000 mL = 10 mIU/mL).

    • Increase by 1-2 mIU/min every 20-30 minutes until a contraction pattern of 3-4 contractions per 10 minutes is established.

    • Maximum typical dose: 20 mIU/min.

    • The goal is to obtain adequate contractions without inducing fetal distress.

  • Prevention of PPH:

    • 5 IU IM (single dose) or 5 IU IV (administered slowly over 5 minutes) after the placenta has been delivered.

    • Slow IV bolus must be conducted to prevent hypotension.

  • Treatment of PPH:

    • 5 IU IV (slowly over 5 minutes), followed by an IV infusion of 20 IU in 500 mL of fluid, with the rate adjusted to control uterine atony.

    • This situation is considered an emergency and can also be administered IM if IV access is not available.

Contraindications

  • Numerous contraindications exist for oxytocin administration:

    1. Hypersensitivity to the drug.

    2. Cephalopelvic Disproportion (CPD): Fetal head is too large for the maternal pelvis.

    3. Malpresentation or Malposition: E.g., transverse lie, brow presentation.

    4. Placenta Previa or Vasa Previa: Situations where the placenta is low-lying or over the cervical os.

    5. Cord Prolapse: Where the umbilical cord slips ahead of the fetus during labor.

    6. Fetal Distress: Particularly when immediate delivery isn't expected.

    7. Hypertonic Uterus: A state where the uterus is already in sustained contraction.

    8. Previous Classical C-Section or Major Uterine Surgery: Increased risk of uterine rupture.

    9. Administering less than 6 hours after applying vaginal prostaglandins (for cervical ripening) due to hyperstimulation risk.

Drug Interactions

  • Oxytocin can interact with various drugs:

    • Prostaglandins (e.g., misoprostol, dinoprostone): Synergistic effects that can potentiate uterine contractions; high risk of hyperstimulation and rupture.

    • Vasopressors (e.g., ephedrine, pseudoephedrine): Risk of severe, persistent hypertension when oxytocin is given concurrently.

    • Inhalation Anesthetics (e.g., halothane, desflurane): May reduce uterine response to oxytocin and cause hypotension.

    • Drugs that prolong QT interval (e.g., certain antiarrhythmics, antipsychotics): Oxytocin can cause QT prolongation, requiring caution and monitoring.

Side Effects & Adverse Reactions

  • Maternal Effects:

    1. Uterine Hyperstimulation (Tachysystole): Defined as more than 5 contractions in a 10-minute period — this is the most prevalent and hazardous complication, potentially leading to:

    • Uterine Rupture: Particularly in multiparous women or those with uterine scarring.

    • Abruptio Placentae: Premature separation of the placenta.

    • Fetal Hypoxia / Distress: Due to decreased placental blood flow during extended contractions.

    1. Water Intoxication (Hyponatremia): Resulting from oxytocin's ADH-like actions, high doses in large volumes of electrolyte-free fluids (such as D5W) can cause this.

    • Symptoms include headache, confusion, seizures, and coma.

    • Prevention: Always dilute oxytocin in an electrolyte solution (e.g., Normal Saline or Ringer's Lactate); avoid D5W as the sole diluent for prolonged infusions at high doses.

    1. Cardiovascular Issues:

    • Hypotension and reflex tachycardia (especially with rapid IV bolus), nausea, and vomiting are commonly noted, and prolonged QT interval can lead to arrhythmias.

    1. Fetal/Neonatal Effects:

    • Bradycardia (from hypoxia due to hyperstimulation)

    • Neonatal Jaundice: Possibly due to increased RBC breakdown due to labor stress.

    • Low Apgar scores related to hypoxia.

Ergot Alkaloids

  • Drugs:

    • Ergometrine (Ergonovine)

    • Methylergometrine (Methylergonovine)

Mechanism of Action

  • Exam Question: What is the MOA?

    1. Acts as a partial agonist/antagonist at alpha-2 adrenergic, dopaminergic, and serotonergic (5-HT) receptors.

    2. Causes sustained, tetanic contractions of both the upper and lower segments of the uterus (in contrast to oxytocin's rhythmic contractions).

    3. Promotes vasoconstriction within both uterine and peripheral blood vessels.

Indications

  1. Prevention and treatment of PPH (notably effective when combined with Oxytocin).

  2. Not utilized for labor induction.

Doses

  1. IM: 0.2 mg (200 mcg) after the delivery of the anterior shoulder or placenta.

  2. IV: 0.1–0.2 mg (slowly over 60 seconds) only in emergencies (e.g., massive PPH).

Contraindications

  1. Hypertension / Pre-eclampsia / Eclampsia (considered the most critical contraindication).

  2. Severe cardiovascular disease (e.g., CAD, peripheral vascular disease).

  3. Sepsis

  4. Hepatic/Renal impairment

  5. Multiple gestation (relative contraindication).

Drug Interactions

  1. Other vasoconstrictors (e.g., dopamine, ephedrine): can lead to severe hypertension.

  2. Protease inhibitors / Macrolides / Azoles: can increase ergot levels, heightening vasospasm risk.

  3. Beta-blockers: can lead to peripheral ischemia.

Side Effects

  1. Nausea & vomiting (frequently occurring).

  2. Hypertension (may be severe).

  3. Coronary artery spasm (chest pain).

  4. Headaches and dizziness.

  5. Ergotism (rare, but can lead to gangrene with prolonged use).

PGE1 Analogue: Misoprostol (Cytotec)

Mechanism of Action

  1. Synthetic Prostaglandin E1 analogue.

  2. Binds to EP receptors, facilitating cervical ripening (by collagen breakdown) and inducing myometrial contraction (changing the cervix from a stiff closed state to a dilated, thin, and soft state prior to birth).

Indications

  1. Medical abortion (in conjunction with Mifepristone).

  2. Cervical ripening before labor induction.

  3. Prevention/Treatment of PPH (where oxytocin is unavailable or ineffective).

  4. In cases of missed abortion.

Doses

  1. PPH (Prevention): 400–600 mcg oral/sublingual single dose immediately after delivery.

  2. PPH (Treatment): 800 mcg sublingual (considered a life-saving dose).

  3. Abortion/Cervical ripening: 25–200 mcg vaginally/orally (dosage varies according to protocol).

Contraindications

  1. Previous C-section or major uterine surgery (for third-trimester usage): Risk of uterine rupture.

  2. Hypersensitivity to the drug.

  3. Glaucoma (should be approached with caution).

Drug Interactions

  1. Oxytocin: Synergistic effects resulting in increased uterine tone.

  2. Magnesium sulfate: Potentiates the effects of misoprostol.

  3. Antacids: Accelerate the breakdown of misoprostol.

Side Effects

  1. Fever & chills (very common, dose-dependent): Important to note as they can mimic sepsis!

  2. Diarrhea & abdominal pain.

  3. Nausea and vomiting.

  4. Uterine hyperstimulation.

PGE2 Analogues: Dinoprostone

Mechanism of Action

  1. Naturally occurring Prostaglandin E2.

  2. Causes cervical ripening (softening and effacement) and stimulates myometrial contractions.

Indications

  1. Cervical ripening (induction of labor in term pregnancies).

  2. Evacuation of the uterus in missed abortion.

Doses

  1. Endocervical Gel (Prepidil): 0.5 mg inserted intra-cervically; may repeat in 6-12 hours if necessary.

  2. Vaginal Insert (Cervidil): 10 mg (releases slowly over 12-24 hours).

Contraindications

  1. Same as oxytocin (CPD, placenta previa, fetal distress, etc.).

  2. Grand multiparity (>5 previous pregnancies).

  3. History of difficult or traumatic delivery.

  4. Not to be used within 6 hours after oxytocin due to hyperstimulation risk.

Drug Interactions

  1. Oxytocin: Can cause severe hyperstimulation (waiting 6-12 hours post-PGE2 administration is necessary).

  2. Beta-agonists: May reduce efficacy.

Side Effects

  1. Uterine hyperstimulation.

  2. Nausea, vomiting, diarrhea.

  3. Fever.

  4. Fetal distress.

PGF2α Analogue: Carboprost (Hemabate)

Mechanism of Action

  1. Synthetic 15-methyl PGF2α.

  2. Acts as a potent uterotonic (contracting the uterus) and induces bronchoconstriction.

Indications

  1. Refractory PPH (when oxytocin and ergometrine fail).

  2. Termination of pregnancy (second trimester).

Doses

  1. PPH: 250 mcg (0.25 mg) administered deep IM; repeat every 15-90 minutes (maximum 8 doses or 2 mg total).

Contraindications

  1. Asthma (absolute contraindication due to risk of bronchospasm).

  2. Hypersensitivity to the drug.

  3. Hepatic, renal, or cardiac disease.

  4. Hypertension.

Drug Interactions

  1. Other oxytocics can cause additive effects.

  2. Antihypertensives may oppose the effectiveness of Carboprost.

Side Effects

  1. Bronchospasm (dangerous in asthmatics).

  2. Vomiting, diarrhea, fever (often very intense).

  3. Flushing and chills.

  4. Hypertension.

Miscellaneous Drugs

Carbetocin (Long-acting Oxytocin Analogue)

Mechanism of Action

  1. Synthetic analogue that acts as an agonist at oxytocin receptors.

  2. Has a longer half-life (40-50 minutes compared to 4-5 minutes for oxytocin).

Indications

  • Prevention of PPH post-vaginal birth or C-section.

Dosing

  • Single dose of 100 mcg IV (over 1 minute) or IM immediately after delivery.

Contraindications

  1. Same as for oxytocin.

  2. Vascular diseases (especially coronary artery disease).

Drug Interactions

  • Same as for oxytocin.

Side Effects

  1. Similar to oxytocin (may have less hypotension).

  2. Flushing, nausea, abdominal pain.

Atosiban (Oxytocin Antagonist/Tocolytic)

Mechanism of Action

  1. Competitive antagonist at oxytocin receptors.

  2. Inhibits oxytocin-mediated calcium release, thus halting contractions.

Indications

  • Arrest of preterm labor (24-33 weeks gestation).

Doses

  1. IV Bolus: 6.75 mg over 1 minute.

  2. IV Infusion: 300 mcg/min for 3 hours, then 100 mcg/min for up to 45 hours.

Contraindications

  1. Gestational age < 24 weeks or > 33 weeks.

  2. Premature rupture of membranes (PROM).

  3. Intrauterine infection (chorioamnionitis).

  4. Fetal distress.

  5. Placenta previa, eclampsia.

Drug Interactions

  • Limited documentation, but avoid other tocolytics.

Side Effects

  1. Nausea and vomiting.

  2. Headache and dizziness.

  3. Hyperglycemia.

  4. Injection site reactions.

PPH Management (USMLE Question)

  1. First-line treatment: Oxytocin (IV/IM).

  2. Second-line if bleeding persists:

    1. Ergometrine (if not hypertensive).

    2. Carboprost (if not asthmatic).

    3. Misoprostol (rectal/sublingual).

  3. Third-line: Surgical interventions (Bakri balloon, B-lynch suture, hysterectomy).

Uterine Relaxants (Tocolytics)

  • Classes of Tocolytics:

    • Adrenergic agonists:

    • Ritodrine

    • Terbutaline

    • Salbutamol (Albuterol)

    • Calcium channel blockers:

    • Nifedipine

    • Oxytocin antagonist:

    • Atosiban

    • Miscellaneous drugs:

    • Magnesium sulfate

    • Progesterone

    • Nitrates

    • Isoxsuprine

    • Halothane

Beta-2 Adrenergic Agonists

  • Drugs:

    • Ritodrine (classical), Terbutaline, Salbutamol (Albuterol)

Mechanism of Action

  1. Selective agonist at beta-2 adrenergic receptors on uterine smooth muscle.

  2. Activates Gs protein, increasing cAMP, which decreases intracellular calcium levels, leading to uterine relaxation.

Indications

  1. Acute tocolysis (stopping preterm labor for 24-48 hours).

  2. Uterine hyperstimulation caused by oxytocin.

Doses

  1. Ritodrine: IV infusion (starting at 50-100 mcg/min, titrate by 50 mcg/min every 10 minutes until contractions stop or maternal heart rate exceeds 130 bpm). Switch to IM/oral after 24 hours.

  2. Terbutaline: 0.25 mg subcutaneously every 20 minutes (maximum 3 doses).

Contraindications

  1. Maternal cardiac disease (e.g., arrhythmias, CAD, tachycardia).

  2. Hyperthyroidism.

  3. Diabetes mellitus: caution as these drugs can cause hyperglycemia.

  4. Hypertension (or pre-eclampsia).

  5. Thyrotoxicosis.

Drug Interactions

  1. Beta-blockers (e.g., Propranolol): Will antagonize the effect of beta-agonists.

  2. Corticosteroids (e.g., Betamethasone): Elevated risk of pulmonary edema.

  3. Halogenated anesthetics: Associated with increased risk of hypotension.

Side Effects

  • Maternal Side Effects (Dosage Limiting):

    1. Tachycardia and palpitations (due to beta-1 cross-reaction).

    2. Hypotension, primarily due to vasodilation.

    3. Pulmonary edema (most severe complication due to fluid overload and tachycardia).

    4. Hyperglycemia (insulin resistance).

    5. Hypokalemia (due to intracellular potassium shift).

  • Fetal Side Effects:

    1. Tachycardia.

    2. Neonatal hypoglycemia.

Calcium Channel Blockers (Nifedipine)

Mechanism of Action

  • Blocks L-type calcium channels on uterine smooth muscle, preventing calcium influx which inhibits myosin light chain kinase and promotes relaxation.

Indications

  • Used as a tocolytic agent, often preferred due to its oral route and fewer side effects; also acts as an antihypertensive.

Doses

  • Oral: Loading dose of 20-30 mg, followed by maintenance of 10-20 mg every 3-8 hours for up to 48 hours.

  • Note: Do not use sublingual nifedipine for tocolysis because it can lead to sudden hypotension.

Contraindications

  1. Hypotension.

  2. Pre-existing cardiac conditions (especially aortic stenosis).

  3. Liver disease (since nifedipine is metabolized by the liver).

  4. Concurrent use with IV magnesium sulfate (risk of neuromuscular blockade).

Drug Interactions

  1. Magnesium sulfate: increases risk of hypotension and neuromuscular blockade.

  2. Beta-agonists: can lead to increased risk of pulmonary edema.

  3. Antihypertensives: will cause additive hypotension.

Side Effects

  1. Maternal Side Effects:

    • Flushing, headache, and dizziness.

    • Hypotension (with reflex tachycardia).

    • Nausea and peripheral edema.

  2. Fetal Side Effects:

    • Minimal: Generally well-tolerated.

Oxytocin Antagonists (Atosiban)

Mechanism of Action

  1. Competitive antagonist at oxytocin receptors in the myometrium, inhibiting oxytocin-mediated calcium release which stops contractions.

Indications

  • Employed in the arrest of preterm labor (specific approval in many countries, although not universally recognized as first-line therapy).

Doses

  1. IV Bolus: 6.75 mg over 1 minute.

  2. IV Infusion (High): 300 mcg/min for 3 hours.

  3. IV Infusion (Low): 100 mcg/min for up to 45 hours.

Contraindications

  1. Gestational age < 24 weeks or > 33 weeks.

  2. Premature rupturing of membranes (PROM).

  3. Intrauterine infection (chorioamnionitis).

  4. Fetal distress or intrauterine growth restriction (IUGR).

  5. Placenta previa or eclampsia.

Drug Interactions

  • Not extensively documented; other tocolytics should be avoided.

Side Effects

  1. Nausea and vomiting.

  2. Headaches and dizziness.

  3. Hyperglycemia.

  4. Injection site reactions.

NSAIDs (Prostaglandin Synthesis Inhibitors)

Indomethacin

Mechanism of Action

  • Inhibits cyclooxygenase (COX) enzymes, thus reducing synthesis of prostaglandins (specifically PGE2 and PGF2α) which are necessary for uterine contractions and cervical ripening.

Indications

  1. Tocolytic (especially effective in early preterm labor < 28-32 weeks).

  2. Polyhydramnios (as it reduces fetal urine production).

Doses

  • Oral/PR: Loading dose of 50-100 mg (orally or rectally), followed by 25 mg every 4-6 hours for up to 48 hours (maximum duration: 48-72 hours).

Contraindications

  1. Advanced gestation (> 32 weeks): risk of premature closure of the ductus arteriosus.

  2. Oligohydramnios: further reduces fetal urine output.

  3. Platelet dysfunction / bleeding disorders.

  4. Renal impairment.

  5. Asthma (aspirin-sensitive).

  6. Peptic ulcer disease.

Drug Interactions

  1. Anticoagulants (Warfarin, Heparin): Increased bleeding risks.

  2. Lithium, Digoxin: Increased toxicity risks.

  3. Other NSAIDs: Additive toxicity.

Side Effects

  1. Maternal Side Effects:

    • Nausea and heartburn (GI upset).

    • Increased bleeding risk due to antiplatelet effect.

  2. Fetal/Neonatal (Major Concerns):

    • Premature closure of ductus arteriosus (if used past 32 weeks or >72 hours).

    • Oligohydramnios: reduces fetal renal blood flow.

    • Risk for necrotizing enterocolitis (NEC) and intraventricular hemorrhage (IVH) in neonates.

Magnesium Sulfate

Mechanism of Action

  1. Acts as a calcium antagonist by competing with calcium at voltage-gated channels and intracellular sites, decreasing calcium availability and inhibiting muscle contraction.

  2. Increases prostacyclin levels (a vasodilator).

Indications

  1. Tocolysis (less effective than alternatives, but used in specific cases).

  2. Neuroprotection of the fetus (primarily used in preterm labor < 32 weeks to prevent cerebral palsy).

  3. Seizure prophylaxis in pre-eclampsia/eclampsia.

Doses

  1. IV Loading: 4-6 grams over 20-30 minutes.

  2. IV Maintenance: 1-2 grams/hour for 24-48 hours.

Contraindications

  1. Myasthenia Gravis (absolute contraindication).

  2. Renal failure (creatinine > 1.5 mg/dL) — risk of drug accumulation.

  3. Hypocalcemia.

  4. Heart block or myocardial damage.

Drug Interactions

  1. Nifedipine: May potentiate hypotension and neuromuscular blockade.

  2. Neuromuscular blockers (e.g., Suxamethonium): Risk of prolonged paralysis.

  3. Aminoglycosides (Gentamicin): Increased risk of neuromuscular blockade.

Side Effects

  1. Loss of deep tendon reflexes (DTRs): First indication of toxicity at 8-12 mg/dL.

  2. Respiratory depression at 15-17 mg/dL.

  3. Cardiac arrest at levels > 25 mg/dL.

  4. Flushing, sweating, warmth.

  5. Hypotension.

  6. Antidote: Calcium Gluconate (1 gram IV over 10 minutes).

Conclusion

  • This comprehensive document details the roles, mechanisms, and side effects of oxytocin and other drugs affecting uterine activity, vital information for effective management of labor and postpartum scenarios.

Thank you!