Page 695 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 37 Hypothalamic & Pituitary Hormones 681

S S Toxicity & Contraindications
Cys - Tyr - IIe - Gln - Asn - Cys - Pro - Leu - Gly - NH 2 When oxytocin is used judiciously, serious toxicity is rare. The
1 2 3 4 5 6 7 8 9 toxicity that does occur is due either to excessive stimulation of
Oxytocin uterine contractions or to inadvertent activation of vasopressin
receptors. Excessive stimulation of uterine contractions before
S S
delivery can cause fetal distress, placental abruption, or uterine
Cys - Tyr - Phe - Gln - Asn - Cys - Pro - Arg - Gly - NH 2 rupture. These complications can be detected early by means
1 2 3 4 5 6 7 8 9 of standard fetal monitoring. High concentrations of oxytocin
Arginine vasopressin with activation of vasopressin receptors can cause excessive fluid
retention, or water intoxication, leading to hyponatremia, heart
S S failure, seizures, and death. Bolus injections of oxytocin can cause
O
hypotension. To avoid hypotension, oxytocin is administered
CH CH C - Tyr - Phe - Gln - Asn - Cys - Pro - D-Arg - Gly - NH 2 intravenously as dilute solutions at a controlled rate.
2
2
1 2 3 4 5 6 7 8 9
Contraindications to oxytocin include fetal distress, fetal mal-
Desmopressin presentation, placental abruption, and other predispositions for
FIGURE 37–5 Posterior pituitary hormones and desmopressin. uterine rupture, including previous extensive uterine surgery.
(Adapted, with permission, from Ganong WF: Review of Medical Physiology, 21st ed.
McGraw-Hill, 2003. Copyright © The McGraw-Hill Companies, Inc.)
OXYTOCIN ANTAGONIST
Atosiban is an antagonist of the oxytocin receptor that has been
prostaglandins and leukotrienes that augment uterine contraction. approved outside the United States as a treatment (tocolysis) for
In small doses oxytocin increases both the frequency and the force preterm labor. Atosiban is a modified form of oxytocin that is
of uterine contractions. At higher doses, it produces sustained administered by intravenous infusion for 2–48 hours. In a small
contraction. number of published clinical trials, atosiban appears to be as effec-
Oxytocin also causes contraction of myoepithelial cells sur- tive as β-adrenoceptor-agonist tocolytics and to produce fewer
rounding mammary alveoli, which leads to milk letdown. Without adverse effects. In 1998, however, the FDA decided not to approve
oxytocin-induced contraction, normal lactation cannot occur. At atosiban based on concerns about efficacy and safety.
high concentrations, oxytocin has weak antidiuretic and pressor
activity due to activation of vasopressin receptors.
VASOPRESSIN (ANTIDIURETIC
Clinical Pharmacology HORMONE, ADH)
Oxytocin is used to induce labor for conditions requiring Vasopressin is a peptide hormone released by the posterior pituitary
expedited vaginal delivery such as uncontrolled maternal diabe- in response to rising plasma tonicity or falling blood pressure. It pos-
tes, worsening preeclampsia, intrauterine infection, or ruptured sesses antidiuretic and vasopressor properties. A deficiency of this
membranes after 34 gestational weeks. It is also used to augment hormone results in diabetes insipidus (see also Chapters 15 and 17).
protracted labor. Oxytocin can also be used in the immediate
postpartum period to stop vaginal bleeding due to uterine atony. Chemistry & Pharmacokinetics
Before delivery, oxytocin is usually administered intrave-
nously via an infusion pump with appropriate fetal and maternal A. Structure
monitoring. For induction of labor, an initial infusion rate of Vasopressin is a nonapeptide with a 6-amino-acid ring and a
0.5–2 mU/min is increased every 30–60 minutes until a physi- 3-amino-acid side chain. The residue at position 8 is arginine in
ologic contraction pattern is established. The maximum infusion humans and in most other mammals except pigs and related spe-
rate is 20 mU/min. For postpartum uterine bleeding, 10–40 units cies, whose vasopressin contains lysine at position 8 (Figure 37–5).
are added to 1 L of 5% dextrose, and the infusion rate is titrated Desmopressin acetate (DDAVP, 1-desamino-8-d-arginine vaso-
to control uterine atony. Alternatively, 10 units of oxytocin can be pressin) is a long-acting synthetic analog of vasopressin with mini-
administered by intramuscular injection. mal pressor activity and an antidiuretic-to-pressor ratio 4000 times
During the antepartum period, oxytocin induces uterine con- that of vasopressin. Desmopressin is modified at position 1 and
tractions that transiently reduce placental blood flow to the fetus. contains a d-amino acid at position 8. Like vasopressin and oxytocin,
The oxytocin challenge test measures the fetal heart rate response desmopressin has a disulfide linkage between positions 1 and 6.
to a standardized oxytocin infusion and provides information
about placental circulatory reserve. An abnormal response, seen as B. Absorption, Metabolism, and Excretion
late decelerations in the fetal heart rate, indicates fetal hypoxia and Vasopressin is administered by intravenous or intramuscular
may warrant immediate cesarean delivery. injection. The half-life of circulating vasopressin is approximately