Endocrine System - Drugs used in Pregnancy

What are oxytocic drugs? (Use, Drugs, Adverse Effects, Cautions)

Use

Drugs that increase intracellular calcium levels in uterine SM, used to stimulate uterus to contract to induce labor, augment labor, and/or reduce risk and control postpartum hemorrhage

Drugs

-Synthetic Oxytocin (IV -> induce/aug labor, IM -> postpartum hemorrhage control)

-Prostaglandin Agonists (Dinoprostone and Misoprostol -> cervical ripening and labor induction)

-Ergot Alkaloids (postpartum hemorrhage control)

Adverse Effects

Can cause uterine hypertonus, which results in asphyxiation of the fetus and uterine rupture

Cautions

Patients with

-Previous history of caesarean section or uterine surgery

-Hx of uterine hypertonus

What are tocolytic drugs? (Use, Patients Used for, Drugs)

Use

Drugs that can decrease intracellular calcium levels in uterine SM, used to inhibit uterine contractions for premature labor, uterine hypertonus (ex: caused by oxytocic drug overdose), or cephalic version (turning fetus so that head is facing outwards)

In the case of premature labor, tocolytic drugs can only delay premature labor, buying time for administration of glucocorticoids, transportation to facility with NICU, or prolonging pregnancy in cases of acute self-limiting conditions

Patients Used for

Used for patients between 24wks and 33wks + 6 days of gestation, is experiencing regular contractions, and has a cervix that is dilated to more than 2 cm with efface

Drugs

-Nifedipine - first line therapy

-Indomethacin - second line therapy

-Magnesium sulphate (Poor)

-Beta2 Adrenergic Agonists (Poor)

-Oxytocin Receptor Antagonists (Poor/Not available)

What is the role of the Gi protein in inducing uterine smooth muscle contraction?

Gi protein coupled receptors decrease cAMP, resulting in less protein kinases, which results in less phosphorylation of proteins that sequester Ca2+, resulting in increased levels of Ca2+ and increased contractions

What is the role of the Gq protein in inducing uterine smooth muscle contraction?

Gq protein coupled receptors increase IP3 and DAG.

IP3 stimulates Ca2+ release from the sarcoplasmic reticulum into the cytoplasm

DAG moves extracellular calcium into the smooth muscle cell

The end result is increased contractions due to increased Ca2+ levels

What is the general role of oxytocin?

Endogenous ligands which bind to Gq protein coupled receptors (DAG and IP3 increase), resulting in increased Ca2+ levels, resulting in increased frequency and force of uterine contractions. Oxytocin also stimulates evacuation of breast milk, which is also regulated by positive feedback. Oxytocin also helps deliver the placenta and prevent postpartum hemorrhage (rationale for promoting mother-baby bonding after birth)

Release of oxytocin is regulated by positive feedback, as the uterus contractions signals increased release of oxytocin from the posterior pituitary

How is oxytocin release regulated?

Release of oxytocin is regulated by positive feedback, as the uterus contractions caused by oxytocin release signals increased release of more oxytocin from the posterior pituitary

What causes oxytocin receptors to appear in the myometrium?

Stretching of the uterus causes estrogen to create oxytocin receptors during the 2nd half of gestation

What is synthetic oxytocin? (Use, Dosage, Adverse Effects)

Use

IV administration is used to induce/augment uterus contractions - occur immediately, subsides within an hour

IM administration is used as first-line intervention to prevent post-partum hemorrhage and help deliver the placenta (first line therapy)

Dosage

IV administration - dose is increased every 15-60 minutes until a normal labor pattern (includes contraction and relaxation) is established)

Adverse Effects

-Uterine hypertonus - infusion should terminate if contractions are less than 2 minutes apart and last longer than 90 seconds

-Fetal distress and maternal complications - should also terminate infusion

-Extremely high doses can cause affinity to ADH receptors, exerting antidiuretic effects (edema, heart failure, water intoxication)

What is the use of synthetic oxytocin?

Use

IV administration is used to induce/augment uterus contractions - occur immediately, subsides within an hour

IM administration is used as first-line intervention to prevent post-partum hemorrhage and help deliver the placenta (first line therapy) - should be used on every patient delivering a baby

What is the dosage of synthetic oxytocin? (Including when should dosage be terminated)

IV administration - uterine response occurs almost immediately and subsides within one hours - dose should be increased every 15-60 minutes until a normal labor pattern (includes contraction and relaxation) is established)

IM administration - uterine response occurs within 3-5 minutes and persists for 2-3 hours

Dosage should be terminated if

-Uterine hypertonus occurs

-Fetal distress and maternal complications occurs

-affinity to ADH receptors occurs

What are adverse effects of synthetic oxytocin?

Adverse Effects

-Uterine hypertonus - infusion should terminate if contractions are less than 2 minutes apart and last longer than 90 seconds

-Fetal distress and maternal complications - should also terminate infusion

-Extremely high doses can cause affinity to ADH receptors, exerting antidiuretic effects (edema, heart failure, water intoxication)

What is dinoprostone? (Use, Mechanism, Dosage)

Use

Used to promote cervical ripening (thinning and effacement -> promotes uterus contractions) and initiate labor

Mechanism

Prostaglandin agonist - binds to g protein coupled EP1 (Gq) and EP3 (GI) prostaglandin receptors

Dosage

Vaginal insert or intracervical gel, patients should remain in lateral or supine position to prevent leakage of gel. The patient should also prevent bathing to avoid diluting the gel. The medication can be administered every 6 hours

What is the use of dinoprostone?

Used to promote cervical ripening (thinning and effacement -> promotes uterus contractions) and initiate labor

What is the dosage of dinoprostone?

Vaginal insert or intracervical gel, patients should remain in lateral or supine position to prevent leakage of gel. The patient should also prevent bathing to avoid diluting the gel. The medication can be administered every 6 hours

What is the mechanism of action of dinoprostone?

Prostaglandin agonist - binds to g protein coupled EP1 (Gq) and EP3 (GI) prostaglandin receptors

What are ergot alkaloids? (Use, Mechanism, Dosage, Adverse Effect)

Use

Second line treatment of postpartum hemorrhage

Mechanism

Binds to Gq protein coupled prostaglandin E1 receptors and a-1 adrenoceptors

Dosage

For Ergonovine - IM (preferred - produces contractions within 2-3 minutes that persist for 3 hours) or IV

For Methylergonovine - Orally

Adverse Effects

-Hypertension (due to binding to a1 adrenoceptors)

-Uterine hypertonus

What oxytocic drugs can be used to treat post-partum hemorrhage?

1. Synthetic Oxytocin (via IM injection) -> First-line therapy

2. Misoprostol

3. Ergot Alkaloids (ergonovine and methylergonovine)

What is the mechanism of action of ergot alkaloids?

Mechanism

Binds to Gq protein coupled prostaglandin E1 receptors and a-1 adrenoceptors

What are adverse effects of ergot alkaloids?

Adverse Effects

-Hypertension (due to binding to a1 adrenoceptors)

-Uterine hypertonus

What is uterine hypertonus?

Occurs when uterus contractions occur longer than 2 minutes and last longer than 90 seconds, can result in asphyxiation of the fetus and uterine rupture

It is a serious adverse effect of oxytocic drug therapy, and is treated via tocolytic drugs

Risk factors include

-previous caesarean section or uterine surgery

-Hx of uterine hypertonus

How can uterine hypertonus be treated?

Via tocolytic drugs

What is the use of tocolytic drugs?

Drugs that can decrease intracellular calcium levels in uterine SM, used to inhibit uterine contractions for premature labor, uterine hypertonus (ex: caused by oxytocic drug overdose), or cephalic version (turning fetus so that head is facing outwards)

In the case of premature labor, tocolytic drugs can only delay premature labor, buying time for administration of glucocorticoids, transportation to facility with NICU, or prolonging pregnancy in cases of acute self-limiting conditions

What is the rationale of administering tocolytic drugs to delay preterm delivery?

-Allows time to administer glucocorticoid therapy, which improves fetus outcomes

-Allows pt to be transported to a facility with access to a NICU

-Prolongs pregnancy in cases of acute self-limiting conditions that are unlikely to cause recurrent preterm labor

When should tocolytic drugs be administered?

Should be administered in cases of preterm labor that occurs between 24wks and 33wks + 6 days of gestation

When should glucocorticoid drugs be administered for preterm delivery?

Should be administered in cases of preterm labor that occurs between 24wks and 34wks + 6 days of gestation

What is glucocorticoid therapy for preterm delivery? (Use, Patients used for, Dose)

Use

Used to improve fetal outcomes in cases of preterm delivery.

-Improves fetal lung development

-Reduces risk of respiratory distress syndrome

-Reduces risk of bleeding in the brain

-Reduces risk of necrotizing enterocolitis (intestinal failure)

-Reduces risk of sepsis

Patients used for

Used for patients for preterm labor between 24wks and 34 wks + 6 days of gestation, with high probability that the client will deliver within 7 days

Dosage

-Single course of betamethasone (two doses IM, 24 hrs apart)

-Single course of dexamethasone (four doses IM, 12 hrs apart)

^Rationale for administering tocolytic drugs to delay delivery

How does glucocorticoid therapy improve fetal outcomes?

Improves fetal outcomes by:

-Improving fetal lung development

-Reducing risk of respiratory distress syndrome

-Reducing risk of bleeding in the brain

-Reducing risk of necrotizing enterocolitis (intestinal failure)

-Reducing risk of sepsis

What is the dosage for glucocorticoid therapy for preterm delivery?

Dosage

-Single course of betamethasone (two doses IM, 24 hrs apart)

-Single course of dexamethasone (four doses IM, 12 hrs apart)

^Rationale for administering tocolytic drugs to delay delivery

What are calcium channel antagonists? (Use, Mechanism of Action, Dosage, Adverse Effects)

Includes Nifedipine

Use

A type of tocolytic drug, used as first-line therapy for management of preterm labor. Can also be used for severe pregnancy-induced hypertension, although labetalol is preferred treatment strategy

Mechanism of Action

Inhibits entry of extracellular calcium into myometrial cells, resulting in slower uterine contractions

Dosage

IV for maximum of 48 hours

Adverse Effects

-Headaches

-Dizziness

-Flushing

-Hypotension -> pregnancy-induced hypertension usage

-Palpitations

What is the use of calcium channel antagonists?

A type of tocolytic drug, used as first-line therapy for management of preterm labor. Can also be used for severe pregnancy-induced hypertension, although labetalol is preferred treatment strategy

Includes Nifedipine

What is the mechanism of action of calcium channel antagonists?

Mechanism of Action

Inhibits entry of extracellular calcium into myometrial cells, resulting in slower uterine contractions

What is Indomethacin? (Use, Mechanism of Action, Dosage, Adverse Effects

Use

A type of tocolytic drug, used as second-line therapy for management of preterm labor when nifedipine is contraindicated and gestation age is lower than 32 weeks

Mechanism of Action

A prostaglandin inhibitor, inhibits prostaglandin synthesis by inhibiting COX1 and COX2 enzymes (prostaglandins are oxytocic)

Dosage

Orally for maximum of 48 hours

Adverse Effects

-Maternal Effects-

->Increased risk of post-partum hemorrhage

-Fetal Effects-

->Premature closure of ductus arteriosis -> leads to pulmonary hypertension, tricuspid regurgitation, and renal failure

->Oligohydramnios, decreased amniotic fluid production

What is the use of Indomethacin?

Use

A type of tocolytic drug, used as second-line therapy for management of preterm labor when nifedipine is contraindicated and gestation age is lower than 32 weeks

What is the mechanism of action of Indomethacin?

Mechanism of Action

A prostaglandin inhibitor, inhibits prostaglandin synthesis by inhibiting COX1 and COX2 enzymes (prostaglandins are oxytocic)

What are adverse effects of Indomethacin? (maternal and fetal)

Adverse Effects

-Maternal Effects-

->Increased risk of post-partum hemorrhage

-Fetal Effects-

->Premature closure of ductus arteriosis -> leads to pulmonary hypertension, tricuspid regurgitation, and renal failure

->Oligohydramnios, decreased amniotic fluid production

What is magnesium sulphate as a tocolytic?

A poor tocolytic drug.

However, effective at managing eclampsia and use for fetal neuroprotection in imminent preterm birth (less than 32 weeks of gestational age)

What are beta2 adrenergic agonists as tocolytics?

A poor tocolytic drug due to its rapid reduction in efficacy and various adverse effects

What are oxytocin receptor antagonists as tocolytics?

A poor tocolytic drug that are is not available or used in North America :/