04.

03-02
February 19, 2014
Nellie D. Gundao, M.D., DPBCN Endocrine IV:
Uterine Pharmacology
"Labor gives birth to ideas." – Jim Rohn

"Reformulated" from 2C 2015 transcription. Italicized – from book. o Nasal route administration as a spray (usually reserved
This is also included in the 20 items under Dra. Gundao. for postpartum uses)
 t1/2: 12-17 minutes
PHARMACOLOGIC AGENTS REGULATING UTERINE MOTILITY  Excretion mainly by kidney and liver
 Oxytocinase or cystyl-aminopeptides
DRUG CLASS MECHANISM OF ACTION o Degrades oxytocin in plasma
OXYTOCIN Specific oxytocin receptors coupled to o Increases about tenfold during pregnancy
phospholipase C, Ca2+, protein kinase C
signal transduction mechanism CLINICAL USES
PROSTAGLANDINS Several types of prostaglandin receptors
 For relief of breast engorgement during lactation
probably coupled through an adenylate
 Inadequacy of breast feeding with insufficient milk
cyclase mechanism
ejection (intranasal route)
ERGOT ALKALOIDS α-adrenergic agonists  Induction of labor
MIFEPRISTONE Progesterone receptor antagonist
β-ADRENERGIC AGONISTS Myometrial membrane receptors coupled PROSTAGLANDIN
through adenylate cyclate mechanism
 Found in:
PROSTAGLANDIN SYNTHESIS Inhibit cyclooxygenase
o Ovary
INHIBITORS
o Myometrium
MAGNESIUM SULFATE Competitive antagonist of Ca2+ (?)
o Menstrual fluid
CALCIUM CHANNEL BLOCKERS Inhibit entry of extracellular Ca2+ into  Rise in amniotic fluid during labor
myometrial cell
OXYTOCIN ANTAGONISTS Compete with oxytocin binding to its
EFFECTS
receptor
 During last two trimesters:
o PGE2 or PGF2α causes strong uterine contractions and
OXYTOCIN can induce delivery of the fetus
 Synthesized in the supraoptic and paraventricular nuclei  Much more effective than oxytocin in earlier months of
of the hypothalamus pregnancy
 Sensory stimuli arising from the cervix and vagina initiate
secretion from posterior pituitary CERVIX
 Stimulation of the breast also results in secretion
 Ripens cervix at doses that do not affect uterine motility
 Implicated in modulation of memory (amnestic effect)
 Softens cervix late in first trimester of pregnancy

EFFECTS
THERAPEUTIC USES
UTERUS
 Mid-trimester abortions
 Stimulates frequency and force of contractile activity in
 Potential use as cervical ripening agents to facilitate
uterine smooth muscle
normal or induced labor
o Action highly dependent on the presence of estrogen
 Potential use to soften cervix prior to first-trimester
 Initiation of labor and delivery
abortions by method of dilatation and evacuation
o In third trimester: spontaneous motor activity of uterus
increases progressively until sharp rise
PROSTAGLANDIN TRADE NAME
 Initiate or enhance rhythmic contractions at any time
o Slow IV infusion of a few units PGE2 Cerviprime
 Effective in initiating labor at term PGE1 Cytotec
PGF2α Prostodin
MAMMARY GLANDS 15-methyl PGF2α Carboprost
 Milk ejection
o Reflex pathways initiating release of hormone TOXICITY
o Myoepithelium  Stimulatory action on smooth muscle of alimentary tract
 Highly responsive to oxytocin  Transient pyrexia
 Catecholamines inhibit milk ejection o Actions on thermoregulatory centers in hypothalamus
o Contraction of myoepithelium  PGE2: vasodilation
 Not believed to be dependent on autonomic  PGF2α: hypertension
innervation
ERGOT ALKALOIDS
CARDIOVASCULAR SYSTEM  Produced by Claviceps purpurea
 Relaxing effect (marked but transient effect) o Fungus that infects grasses and grains (especially rye)
o Amounts given for most obstetric purposes insufficient under damp growing or storage conditions
to produce marked alterations in blood pressure
CHEMISTRY
PHARMACOKINETICS  Structurally similar to lysergic acid diethylamide (LSD)
 Effective after:
o Parenteral administration

Martin Page 1 of 4
 Endocrine IV: Uterine Pharmacology

DERIVATIVES DRUG INDICATION

GENERIC NAME TRADE NAME NOTES ERGONOVINE, Uterine smooth muscle stimulation (for treatment
ERGOTOXINE  Mixture of 3 alkaloids METHYLERGONOVINE of postpartum atony or hemorrhage)
 First α-adrenoceptor ERGONOVINE, Diagnosis of coronary spasm (variant angina
agonist METHYLERGOMETRINE during coronary angiography)
ERGOTAMINE Gynergen METHYSERGIDE Migraine prophylaxis
METHYSERGIDE Sansert  Withdrawn ERGOTAMINE Treatment of acute migraine

ERGONOVINE ADVERSE EFFECTS

 Retroperitoneal fibrosis (methysergide)
EFFECTS  Gangrene (ergotamine)
 Affect: o Postoperative deep vein thrombosis (heparin +
o α-adrenoceptors dihydroergotamine)
o Dopamine receptors
o 5-HT receptors CONTRAINDICATIONS
o Other receptor types  Vasospastic disorders
 Major effects
o Serotonin (5-HT2) receptor agonist-partial agonist POTENTIAL SIDE EFFECTS OF UTERINE STIMULATORS
(uterus)
o Direct stimulation of vascular and nonvascular smooth DRUG MATERNAL SIDE EFFECTS FETAL SIDE EFFECTS
muscle OXYTOCIN Uterine hypertonus Hypoxia
Uterine rupture
ERGOT POISONING Hypotension
Water intoxication (in
 Most dramatic effects
extremely high doses)
o Dementia with florid hallucination
o Prolonged vasospasm which may result in gangrene PROSTAGLANDINS Uterine hypertonus Hypoxia
o Stimulation of uterine smooth muscle which may Uterine rupture
result in abortion Vomiting
 In medieval times: called "St. Anthony's fire" after the Diarrhea
saint whose help was sought in relieving the burning pain of Fever
vasospastic ischemia Bronchospasm
ERGOT ALKALOIDS Hypertension Not for use during
Headache pregnancy
THERAPEUTIC USES
Vomiting
 Treatment of postpartum uterine atony or hemorrhage
Bradycardia
 Diagnosis of coronary spasm
o Variant angina during coronary angiography
 Treatment of migraine

EFFECTS OF ERGOT ALKALOIDS AT SEVERAL RECEPTORS

ERGOT ALKALOID α-ADRENOCEPTOR DOPAMINE RECEPTOR SEROTONIN RECEPTOR UTERINE SMOOTH MUSCLE CELL STIMULATION
BROMOCRIPTINE - +++ - 0
ERGONOVINE ++ - (PA) +++
ERGOTAMINE -- (PA) 0 + (PA) +++
LYSERGIC ACID DIETHYLAMIDE 0 +++ -- +
++ in CNS
METHYSERGIDE +/0 +/0 ---- (PA) +/0
Agonist effects are indicated by +, antagonist by -, no effect by 0.
Relative affinity for the receptor is indicated by the number of + or - signs. PA means partial agonist

LABOR
INDUCTION OF LABOR
 Indications:
o Diabetes
o Hypertensive states
o Placental insufficiency
o Continuation of pregnancy considered to be a greater
risk to the mother or the fetus than the risks of
delivery or pharmacological induction

OXYTOCIN
 Drug of choice for induction of labor
 IV infusion (10 milliunits/mL)
 Trained personnel must be present during entire procedure
 Uterine activity carefully monitored
o Too much activity  immediately discontinue infusion

Martin Page 2 of 4
 Endocrine IV: Uterine Pharmacology

AUGMENTATION OF LABOR
 In most circumstances, oxytocin should not be used for the
augmentation of labor if labor is progressing normally

DYSFUNCTIONAL LABOR
 Very prolonged latent phase of cervical dilatation
 Significant arrest of dilatation or descent
 Managed by experienced obstetrician

THIRD STAGE OF LABOR AND PUERPERIUM

 Uterine-stimulating agents
o Usually given after delivery of placenta
o Aid in maintaining uterine tone after delivery
 Alternatives to oxytocin if ineffective:
o Ergonovine or methylergonovine may be used in
non-hypertensive patient
 IM or IV (0.2 mg)
o 15-methyl PGF2α (carboprost)
 IM (0.25 mg)

THERAPEUTIC ABORTION
FIRST TRIMESTER
 Most commonly by suction curettage BETA ADRENERGIC RECEPTOR AGONISTS
 Used for treatment of premature labor
MIFEPRISTONE (RU486)  Contraindication: cardiac disease
 Synthetic 19-norsteroid
 Progesterone antagonist TERBUTALINE Oral
 Inhibits effect of progesterone on the uterus RITODRINE HYDROCHLORIDE Oral or IV
ISOXSUPRINE (Duvadilan, Isoxsilan) Vasodilator
PROSTAGLANDIN SUCCESS RATE
PROSTAGLANDIN + MIFEPRISTONE 99% MAGNESIUM SULFATE
METHOTREXATE + MISOPROSTOL 96%  Often used to control eclamptic seizure
 Attractive alternative if β2-adrenergic receptor agonists are
SECOND TRIMESTER contraindicated
 Intraamniotic injection of hypertonic (20%) solution of NaCl
 Vaginal suppositories of PGE2 (dinoprostone, prostin E2) CALCIUM CHANNEL BLOCKERS
 IM (0.25 mg) 15-methyl PGF2 (Hemabate)  Relax myometrium in vitro
 Markedly inhibit amplitude of oxytocin-induced contractions
TOCOLYSIS
 Greek tokos (childbirth) and lytic (capable of dissolving) NIFEDIPINE (Procardia, Adalat)
 Loading dose: 10 mg SL
TOCOLYTICS  Repeated every 20 minutes for 2-3 more doses
 Inhibitors of uterine motility
PROSTAGLANDIN SYNTHASE INHIBITORS
INDOMETHACIN (Indocin)
CLINICAL USES
 Used to halt preterm labor
 To delay or prevent premature labor in selected individuals
 Fetal and neonatal side effects:
 To slow or arrest delivery for brief periods in order to
o Premature closure of ductus arteriosus
undertake other therapeutic measures
o Production of pulmonary hypertension
 Premature labor
o Premature births account for a large fraction of
perinatal morbidity and mortality OXYTOCIN ANTAGONISTS
o Often difficult to determine whether premature birth is  Currently being studied as possible tocolytic agents
imminent
 50% or more with regular uterine contractions will ATOSIBAN
respond to bed rest and hydration  In studies: as effective as beta agonists
 Pregnancies where AOG:  Few side effects
o >20 weeks
o <34-36 weeks

Martin Page 3 of 4
 Endocrine IV: Uterine Pharmacology

POTENTIAL SIDE EFFECTS OF TOCOLYTICS

DRUG GROUP MATERNAL SIDE EFFECTS FETAL SIDE EFFECTS

β-ADRENERGIC RECEPTOR AGONISTS Hypotension Tachycardia
Tachycardia Hyperglycemia
Palpitations
Dysrhythmias
Pulmonary edema
Hyperglycemia
Hypokalemia
PROSTAGLANDIN SYNTHASE INHIBITORS Gastrointestinal bleeding Constriction of the ductus arteriosus
Nausea Oligohydramnios
Headaches Associated with increased incidence of neonatal
Myelosuppression intraventricular hemorrhage, necrotizing enterocolitis,
and patent ductus arteriosus
MAGNESIUM SULFATE Skin flushing Muscle relaxation
Palpitations CNS depression (rare)
Headaches
Depressed reflexes
Respiratory depression
Impaired cardiac conduction
OXYTOCIN ANTAGONISTS Nausea None known
Vomiting
Headaches

PHARMACOKINETIC PARAMETERS OF AGENTS USED TO REGULATE UTERINE MOTILITY

DRUG ROUTE METABOLIC HALF-LIFE DISPOSITION

OXYTOCIN IV for labor 1-6 minutes Metabolized in plasma, liver and kidney
IV or IM postpartum
PROSTAGLANDIN E2 Intracervical, intravaginal, IV Variable Metabolized locally
Some systemic absorption
<1 minute Metabolized ubiquitously, but particularly in lung
CARBOPROST IM - -
ERGOMETRINE Oral or IM - -
IV only in emergency
RITODRINE IV or oral ~2 hours -
INDOMETHACIN Oral or rectal suppository ~4-5 hours Renal and biliary excretion
MAGNESIUM SULFATE IV or IM - Renal excretion
ATOSIBAN IV ~20 minutes Probably metabolized in liver, kidney and plasma

This is the last lecture transcription for Basic Pharmacology.

Finals reviewer to follow ASAP.

To the last four SGD groups, kindly upload your .ppt files to:
PLM-CM 2016-2D/4th Shifting/Pharmacology/Seminar Reports

Aral mabuti, 2-D! 

mjac

Martin Page 4 of 4