L18 - Reproductive Pharmacology

Drugs Used in Labor

• Drugs used during labor either stimulate or inhibit uterine smooth muscle contraction.

• Oxytoxics: Induce labor, reduce postpartum hemorrhage, or terminate pregnancy.

• Tocolytics: Inhibit or delay premature labor.

Oxytoxics

Oxytocin

• Indications: Induce labor, postpartum hemorrhage.

• Situations for labor induction: Maternal or fetal risk, overdue pregnancy, pre-labor rupture.

• Mechanism of Action:

  • Activates oxytocin receptors (GPCRs) on uterine smooth muscle cells.

  • Upon activation, oxytocin receptors couple to Gq proteins, activating phospholipase C (PLC).

  • PLC stimulates the generation of inositol trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol bisphosphate (PIP2).

  • PIP2 \rightarrow IP3 + DAG

  • IP3 increases calcium release from the sarcoplasmic reticulum.

  • Increased intracellular calcium leads to stronger, more frequent, and coordinated uterine contractions that propagate from the upper uterus to the lower segment.

• Contraindications: Fetal distress.

• Adverse Effects:

  • Hypotension leading to reflex tachycardia.

  • Water retention leading to maternal and neonatal hyponatremia (due to the structural similarity of oxytocin to vasopressin, it can activate vasopressin receptors in the kidney leading to increased water reabsorption).

Ergoalkaloids (e.g., Ergometrine)

• Indication: Prevent postpartum hemorrhage by causing sustained uterine contraction.

• Mechanism of Action:

  • Acts as a partial agonist at vascular alpha-1 adrenergic receptors (GPCRs).

  • Activates phospholipase C, increasing IP3 levels.

  • Promotes intracellular calcium release from the sarcoplasmic reticulum, causing vasoconstriction, and reduces postpartum bleeding.

• Action Dependence:

  • Effect depends on the contractile state of the uterus.

  • Little effect on a contracted uterus (normal post-delivery).

  • Initiates strong contraction on a relaxed uterus, reducing bleeding from the placental bed by constricting the blood vessels feeding the placental bed.

• Adverse Effects:

  • Nausea, vomiting.

  • Hypertension (due to peripheral vasoconstriction).

  • Headache.

  • Allergic reactions.

  • Pulmonary edema.

  • Gangrene (in rare cases, due to severe vasoconstriction).

Prostaglandins

• Source: Released by the uterus and endometrium in response to various stimuli.

• Mechanism of Action:

  • Interact with prostaglandin receptors (GPCRs) on the uterine muscle, causing uterine contractions and cervical ripening.

  • Activate prostaglandin receptors (EP1, EP2, or EP3), which couple to different G proteins, activating phospholipase C.

  • Increased IP3 and DAG synthesis.

  • IP3 increases intracellular calcium, promoting uterine contractions and cervical ripening.

• Indications: Induce labor and soften the cervix (cervical ripening).

• Benefits: Shortens the time to labor onset and delivery.

• Contraindications: Oxytocin administration (risk of uterine hyperstimulation).

• Adverse Effects:

  • Fetal distress.

  • Uterine hyperstimulation.

Tocolytics

• Drugs used to inhibit premature labor.

• Preterm birth is defined as occurring before the thirty seventh week of pregnancy and does occur in about ten to fifteen percent of all pregnancies.

• Purpose: Postpone threatened preterm delivery for 2-3 days to:

  • Allow maximal effect of antenatal corticosteroids (to enhance fetal lung maturation).

  • Facilitate maternal transportation to a specialized care center.

• Effects: Delay labor, but do not significantly decrease the rate of preterm delivery.

• Main Drugs:

  • Calcium channel blockers.

  • Beta-2 adrenoreceptor agonists.

  • Oxytocin antagonists.

Voltage-Gated Calcium Channel Blockers

• Indication: Threatened preterm labor (up to 34 weeks).

• Mechanism of Action:

  • Block voltage-gated calcium channels on uterine smooth muscle cells.

  • Reduce calcium availability for contraction, relaxing the uterus.

  • Block calcium entry into endothelial cells on vascular smooth muscle cells, reducing the production of vasoconstrictors.

  • Reduced intracellular calcium leads to reduced vascular smooth muscle contraction, improving blood flow.

• Adverse Reactions:

  • Hypotension.

  • Headaches.

  • Flushing.

  • Nausea.

  • Tachycardia.

Oxytocin Antagonists

• Indication: Premature labor.

• Mechanism of Action:

  • Competitive antagonists at the oxytocin receptor.

  • Prevent phospholipase C activation.

  • Reduce IP3 availability, reducing intracellular calcium.

  • Inhibit uterine contractions and delay labor onset.

Beta-2 Adrenoreceptor Agonists (e.g., Salbutamol, Ritodrine)

• Indication: Uncomplicated preterm labor (24-34 weeks gestation).

• Mechanism of Action:

  • Activate beta-2 adrenoreceptors (GPCRs) in uterine smooth muscle.

  • Increase cyclic AMP (cAMP) levels by activating adenylyl cyclase.

  • cAMP activates protein kinase A (PKA) which phosphorylates and inhibits myosin light chain kinase (MLCK), preventing smooth muscle contraction.

  • Also, increased cAMP leads to the opening of calcium-activated potassium channels, causing hyperpolarization and relaxation of smooth muscle cells in the uterus.

  • Delay labor onset by delaying uterus contractions.

• Adverse Reactions:

  • Tremor.

  • Palpitations.

  • Anxiety.

  • Restlessness.

  • Headaches.

  • Muscle cramps.

  • Hyperglycemia (due to increased glycogenolysis).

  • Tachycardia.

Treatments for Infertility

• Primarily treatments that stimulate ovulation combined with intrauterine insemination (IUI).

• Infertility is defined as the inability to get pregnant for one year or longer after regular unprotected sex.

• IUI is often a first-line treatment for unexplained fertility.

• Ovarian stimulation with IUI increases the likelihood and efficiency of ovulation and can increase the number of oocytes available for fertilization.

Ovarian Stimulation and IUI

• Ovarian stimulation helps overcome subtle ovulatory defects and luteal phase defects.

• Enhances steroid production, improving chances of fertilization and embryo implantation.

• Treatment Options:

  • Clomiphene citrate.

  • Gonadotrophins.

  • Gonadotrophin antagonists (to control ovarian stimulation and decrease premature LH surge).

Recap of Ovulation

• Beginning of Menstrual Cycle:

  • Follicles are recruited by increasing levels of follicle-stimulating hormone (FSH).

  • Granulosa cells proliferate with LH receptor expression.

  • At a follicle size of 10 millimeters, the selection of the dominant follicle takes place and this follicle then goes on to ovulate.

• Dominant Follicle Selection:

  • Occurs around day 8 (follicle size of 10 mm).

  • The dominant follicle starts to secrete estradiol. Estradiol is released from the dominant follicle leading to a fall in serum follicle stimulating hormone.

  • Other follicles break down.

• Ovulation Trigger:

  • Peak estrogen levels lead to a surge in luteinizing hormone (LH).

  • LH surge triggers ovulation around day 14.

  • Process:

  • Cohort of follicles are recruited under the influence of increasing serum levels of FSH (usually within the first two to three days of the menstrual cycle).

  • Granulosa cells of these follicles then undergo proliferation with the expression of the LH receptors.

  • At a follicle size of 10 millimeters (around day eight of the cycle), the selection of the dominant follicle takes place.

  • The growing follicles (except the dominant follicle) are unable to sustain growth and undergo atresia (death).

  • LH surge; this leads this dominant follicle to ovulate at day fourteen.

Therapeutic Interventions for Ovarian Stimulation

Gonadotrophins

• Mimic natural gonadotrophins (LH and FSH from the pituitary gland).

• Normally: LH and FSH stimulate the ovaries to produce a follicle which contains an egg and to release this egg from the ovary.

• Indications:

  • Women with hypogonadotrophic hypogonadism and polycystic ovary syndrome when other treatments fail in terms of treating infertility.

• Aim:

  • Raise serum FSH above the threshold required for follicle development for a prolonged period.

  • Enable the growth and maturation of a cohort of follicles.

• Administration:

  • Exogenous gonadotrophins (LH and FSH combinations) directly stimulate the ovaries.

  • Exogenous human chorionic gonadotropin (HCG), which contains LH and FSH activity, is then administered a bit later on to stimulate ovulation.

• Process:

  • Early days (3-7): Low-dose gonadotropin therapy to stimulate multiple follicle development.

  • Day 12-13: Injection of HCG to stimulate ovulation.

• Adverse Effects:

  • Potential for multiple gestation (maturation of multiple follicles).

  • Ovarian hyperstimulation syndrome (increased LH and FSH).

Clomiphene

• Indication: Women with infertility, intact hypothalamic-pituitary axis, and adequate estrogen production.

• Mechanism of Action:

  • Selective estrogen receptor modulator (SERM).

  • Both estrogen agonist and antagonist properties (tissue-dependent).

  • Partial estrogen agonist activity in the hypothalamus acts as an antagonist (except when estrogen levels are low).

  • Inhibits normal estrogen negative feedback on the hypothalamus, leading to increased GnRH secretion.

  • Increases LH and FSH levels due to increased GnRH.

  • Leads to the growth of multiple dominant follicles and multiple ovulations.

• Administration: Orally on days 2-5 of the cycle for five days.

• Adverse Effects:

  • Ovarian hyperstimulation syndrome.

  • Increased risk of multiple gestation.

  • Ovarian cysts.

  • Hot flashes.

  • Blurred vision.

  • Gastrointestinal distension, bloating, and discomfort.

  • Mechanism:

  • Administration of clomiphene leads to the estrogen receptor depletion at the level of the pituitary and the hypothalamus.

  • This, in turn, leads to antagonizing the estrogen negative feedback and leads to a rise in endogenous gonadotrophin secretion.

  • FSH increases from the anterior pituitary, and this leads to the maturation of multiple follicles.

  • Late follicular phase: estradiol secretion from the ovary is not registered by the hypothalamus (clomiphene remains bound to estrogen receptors).

  • Multiple ovulations.

Summary

• Drugs used to induce and delay labor.

• Induction of labor is carried out for clinical indications.

• Agents to induce labor: oxytoxics (oxytocin), ergot alkaloids, prostaglandins.

• Tocolytics are used to delay preterm labor to allow antenatal corticosteroids or transfer to appropriate facilities.

• Agents to delay labor: calcium channel blockers, beta-2 adrenoceptor agonists, and oxytocin antagonists.

• Drugs used to induce ovarian stimulation (with IUI) to treat infertility.

- Ovarian stimulation helps overcome ovulatory defects.