MPPII 4.6 - REPRODUCTIVE PHYS. & PHARM. (LABOR & LACTATION)

Pharmacology of Inducing Labor

• Oxytocin, sold as Pitocin, is is a peptide hormone
• Pitocin promotes uterus contraction and speeds up labor
• Pitocin aids in stopping postpartum bleeding
• Pitocin is administered intravenously (IV) or intramuscularly (IM)

Pitocin Controversy

• Risks include uterus over-contraction
• Slowed maternal HR and nausea

Induction of Labor

• Between 1990 and 2018, labor induction tripled from 9.5% to 27.1%

ARRIVE Trial

• Labor induction of low-risk nulliparous women at 39 weeks reduced the frequency of c-sections

Pain Management During Labor

• Many pharmacological and non-pharmacological options exist for managing pain during labor

Systemic Analgesics

• Opioids such as Fentanyl, Morphine, and Remifentanil are options
• Sedatives like Benzodiazepines Midazolam and Diazepam are other options

Regional Analgesia

• Neuraxial Analgesia, spinal and epidural

Opioid Receptor Agonists

• Effective in acute management of moderate to severe pain by working on µ-opioid receptor
• Effects include sedation and respiratory suppression
• Can reduce cardiovascular tone and cause bradycardia by inhibiting neurotransmission

Opioid Receptor Agonists: Mechanism of Action

• GPCR signaling inhibits neurotransmission
• Decreases presynaptic calcium influx and/or increases postsynaptic K+ efflux

Fentanyl

• Fentanyl is a short-acting synthetic opioid agonist utilized for intraoperative and periprocedural analgesia.

Morphine

• Morphine is a semisynthetic derivate, commonly used outside of the context of anesthesia or procedural sedation

Remifentanil

• Remifentanil is a rapid-acting synthetic opioid, often used using continuous infusion during anesthesia

GABAA Receptor Modulators

• Benzodiazepines and barbiturates modulate GABAA receptors by acting at allosteric binding sites, enhancing GABAergic neurotransmission
• Benzodiazepines produce sedative, hypnotic, muscle relaxant, amnestic, and anxiolytic effects
• Barbiturates control epilepsy, serve as general anesthetic agents, and manage intracranial hypertension

Benzodiazepines: Mechanism of Action

• Modulate GABA effects by binding to a distinct site from the GABA-binding site, increasing the frequency of channel openings

Benzodiazepines: Therapeutic Uses

• Effective for treating anxiety disorders such as generalized anxiety disorder (GAD) and social anxiety disorder
• Can be effective for performance anxiety, posttraumatic stress disorder, obsessive-compulsive disorder, and extreme anxiety associated with phobias
• Treat anxiety related to depression and schizophrenia, but should be used for short duration because of addiction potential

Regional Analgesia

• Regional analgesia includes neuraxial analgesia and epidural options
• 70% of women giving birth make use of regional analgesia

Epidural vs Spinal

• Includes local anesthetic, opioid, or a combination of both agents
• Use of local anesthetics like Lidocaine
• and Opioids like Morphine, and Fentanyl

Antiarrhythmic Drugs: Class I

• Class I antiarrhythmic drugs block Na+ channels; subgroups include IA, IB, and IC

Antiarrhythmic Drugs: Class II

• Beta-adrenoceptor antagonists

Antiarrhythmic Drugs: Class III

• K+ channel blockers that prolong action potential (AP) and refractory period

Antiarrhythmic Drugs: Class IV

• Ca++ channel antagonists

Class IB Antiarrhythmic Drugs

• Alters ventricular action potential by blocking Na+ channels, which shortens the repolarization phase
• Class IB drugs bind to both open and inactivated Na⁺ channels
• Preferentially bind to open Na+ channels over class IA drugs
• The more time Na+ channels spend in the open or inactivated state, the more potent the effect

Lidocaine and Mexiletine

• Shorten phase 3 repolarization and decrease the duration of the action potential
• These drugs do not markedly slow conduction, having little effect on atrial or AV junction arrhythmias
• Mexiletine is used for chronic treatment of ventricular arrhythmias

Lidocaine

• Prolongs inactivation of fast voltage-gated Na+ channels in neuronal cells, responsible for action potential propagation

Mammary Glands

• Lactation occurs after birth
• Development of breast tissue and preparation for lactation occur during puberty
• Development is mediated by female gonadal hormones during puberty

Hormonal Regulation of Lactation

• Prolactin, estrogens, progestins, and hCG (fetus) at high levels prepare the breast for lactation
• Prolactin begins and sustains milk production
• Oxytocin causes the milk to be let down and ejected to allow for suckling

Prolactin Secretion

• Is a peptide hormone is produced and secreted from lactotropes in the anterior pituitary gland
• Is not associated with a hormone axis, unlike other anterior pituitary hormones
• It is produced and secreted in both males and females
• Lactotropes hypertrophy and prolactin secretion increase during pregnancy in females
• Is not associated with a hormone-binding protein, and with a half-life of 20 minutes

Prolactin Function

• Is responsible for mammary glandular tissue growth and development, ductal proliferation, breast milk synthesis, and breast preparation for lactation
• Mediated by a cytokine cell membrane receptor that stimulates the JAK/STAT signaling pathway
• The function of prolactin in men is not fully understood

Prolactin Secretion

• Secretion by lactotropes is normally suppressed by tonic dopamine secretion from the arcuate and paraventricular nuclei of the hypothalamus
• Has a negative feedback loop to the hypothalamus to adjust the release of dopamine
• Somatostatin and growth hormone decrease prolactin secretion

Conditions that increase prolactin secretion include

• Nursing and breast manipulation
• Estrogen, oxytocin, thyroid-releasing hormone, sleep, and stress

Oxytocin

• Small peptide hormone produced in hypothalamus and secreted from the posterior pituitary
• A short half-life of 3-5 minutes

Oxytocin Function

• To stimulate contraction of myoepithelial cells in breast tissue, allowing for milk ejection during lactation (milk letdown)
• Induces maternal behavior, stimulates prolactin release, and decreases nociception
• Effects are mediated by cell membrane oxytocin receptors (GPCR superfamily)
• Work primarily through the PLC-induced second messenger system

Oxytocin Secretion

• Is stimulated by cervical stretch and breast suckling through neuroendocrine reflexes
• Strong or intense emotional stimuli can decrease oxytocin levels
• Is increased by Estrogen increased synthesis of oxytocin receptors during pregnancy, potentiating effects