Page 348 - Basic _ Clinical Pharmacology ( PDFDrive )

334 SECTION IV Drugs with Important Actions on Smooth Muscle

at dietary manipulation—to change the polyunsaturated fatty acid group prolongs the duration of action) is used to induce second-
precursors in the cell membrane phospholipids and so change trimester abortions and to control postpartum hemorrhage that
eicosanoid synthesis—is used extensively in over-the-counter is not responding to conventional methods of management. The
products and in diets emphasizing increased consumption of success rate is approximately 80%. It is administered as a single
cold-water fish. 250-mcg intramuscular injection, repeated if necessary. Vomiting
and diarrhea occur commonly, probably because of gastrointesti-
Female Reproductive System nal smooth muscle stimulation. In some patients transient bron-
choconstriction can occur. Transient elevations in temperature are
Studies with knockout mice have confirmed a role for prosta- seen in approximately one eighth of patients.
glandins in reproduction and parturition. COX-1-derived PGF
2α
appears important for luteolysis, consistent with delayed parturition
in COX-1-deficient mice. A complex interplay between PGF and B. Facilitation of Labor
2α
oxytocin is critical to the onset of labor. EP receptor-deficient mice Numerous studies have shown that PGE , PGF , and their analogs
2α
2
2
demonstrate a preimplantation defect, which underlies some of the effectively initiate and stimulate labor, but PGF is one tenth as
2α
breeding difficulties seen in COX-2 knockouts. PGI production potent as PGE . There appears to be no difference in the efficacy
2
2
leads to maturation of uterine smooth muscle cell prior to labor. of PGE and PGF when they are administered intravenously;
2α
2
however, the most common usage is local application of PGE
2
A. Abortion analogs (dinoprostone) to promote labor through ripening of the
PGE and PGF have potent oxytocic actions. The ability of the cervix. These agents and oxytocin have similar success rates and
2
2α
E and F prostaglandins and their analogs to terminate pregnancy comparable induction-to-delivery intervals. The adverse effects of
at any stage by promoting uterine contractions has been adapted the prostaglandins are moderate, with a slightly higher incidence
to common clinical use. Many studies worldwide have established of nausea, vomiting, and diarrhea than that produced by oxytocin.
2α
2
that prostaglandin administration efficiently terminates preg- PGF has more gastrointestinal toxicity than PGE . Neither drug
nancy. The drugs are used for first- and second-trimester abortion has significant maternal cardiovascular toxicity in the recommended
2
and for priming or ripening the cervix before abortion. These doses. In fact, PGE must be infused at a rate about 20 times faster
prostaglandins appear to soften the cervix by increasing proteogly- than that used for induction of labor to decrease blood pressure
2α
can content and changing the biophysical properties of collagen. and increase heart rate. PGF is a bronchoconstrictor and should
Dinoprostone, a synthetic preparation of PGE , is admin- be used with caution in women with asthma; however, neither
2
istered vaginally for oxytocic use. In the USA, it is approved asthma attacks nor bronchoconstriction have been observed during
2α
for inducing abortion in the second trimester of pregnancy, for the induction of labor. Although both PGE and PGF pass the
2
missed abortion, for benign hydatidiform mole, and for ripening fetoplacental barrier, fetal toxicity is uncommon.
of the cervix for induction of labor in patients at or near term (see For the induction of labor or softening of the cervix, dinopros-
2
below). Dinoprostone stimulates the contraction of the uterus tone is used either as a gel (0.5 mg PGE every 6 hours; maximum
throughout pregnancy. As the pregnancy progresses, the uterus 24-hour cumulative dose of 1.5 mg) or as a controlled-release
increases its contractile response, and the contractile effect of oxy- vaginal insert (10 mg PGE ) that releases PGE over 12 hours. The
2
2
tocin is potentiated as well. Dinoprostone also directly affects the softening of the cervix for induction of labor substantially shortens
collagenase of the cervix, resulting in softening. Dinoprostone is the time to onset of labor and the delivery time. An advantage of
metabolized in local tissues and on the first pass through the lungs the controlled-release formulation is a lower incidence of gastroin-
(about 95%). The metabolites are mainly excreted in the urine. testinal effects (<1% versus 5.7%).
The plasma half-life is 2.5–5 minutes. The effects of oral PGE administration (0.5–1.5 mg/h) have
2
For abortifacient purposes, the recommended dosage is a been compared with those of intravenous oxytocin and oral
20-mg dinoprostone vaginal suppository repeated at 3- to 5-hour demoxytocin, an oxytocin derivative, in the induction of labor.
intervals depending on the response of the uterus. The mean Oral PGE 2 is superior to the oral oxytocin derivative and in most
2α
time to abortion is 17 hours, but in more than 25% of cases, the studies is as efficient as intravenous oxytocin. Oral PGF causes
abortion is incomplete and requires additional intervention. too much gastrointestinal toxicity to be useful by this route.
2α
2
Antiprogestins (eg, mifepristone) have been combined with an Theoretically, PGE and PGF should be superior to oxy-
(misoprostol) to produce tocin for inducing labor in women with preeclampsia-eclampsia
oral oxytocic synthetic analog of PGE 1 or cardiac and renal diseases because, unlike oxytocin, they have
early abortion. This regimen is available in the USA and Europe
2
(see Chapter 40). The ease of use and the effectiveness of the com- no antidiuretic effect. In addition, PGE has natriuretic effects.
bination have aroused considerable opposition in some quarters. However, the clinical benefits of these effects have not been docu-
The major toxicities are cramping pain and diarrhea. The oral mented. In cases of intrauterine fetal death, the prostaglandins
and vaginal routes of administration are equally effective, but the alone or with oxytocin seem to cause delivery effectively.
vaginal route has been associated with an increased incidence of
sepsis, so the oral route is now recommended. C. Dysmenorrhea
An analog of PGF is also used in obstetrics. This drug, Primary dysmenorrhea is attributable to increased endome-
2α
carboprost tromethamine (15-methyl-PGF ; the 15-methyl trial synthesis of PGE and PGF during menstruation, with
2α
2
2α