DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

β 2 agonists
NO donors
1849
β 2
G s AC
cAMP
PKA
PKG
sGC
cGMP
CONTRACTION
+
L-type
Ca 2+ channel
Ca 2+
Ca 2+
Ca 2+ channel
blockers,
MgSo 4
MLCK
+
Myosin-PO 4
Calmodulin
Myosin
IP 3
Ligand-gated
Ca 2+ channel
MgSo 4
MYOMETRIAL CELL
FP
PLC
G q Gq
OXT
COX
inhibitors
PGF 2a
Arachidonic
acid
Initiation of Labor
Labor induction is indicated when the perceived risk of
continued pregnancy to the mother or fetus exceeds the
risks of delivery or pharmacological induction. Such
circumstances include premature rupture of the membranes,
isoimmunization, fetal growth restriction, uteroplacental
insufficiency (as in diabetes, pre-eclampsia,
or eclampsia), and gestation beyond 42 weeks. Before
inducing labor, it is essential to verify that the fetal
lungs are sufficiently mature and to exclude potential
contraindications (e.g., abnormal fetal position, evidence
of fetal distress, placental abnormalities, or previous
uterine surgery predisposing to uterine rupture).
Labor induction also is used increasingly in the
absence of specific criteria listed above; such elective
inductions may be predicated in part on matters of
Oxytocin
OXT
receptor
antagonists
Figure 66–2. Sites of action of tocolytic drugs in the uterine myometrium. The elevation of cellular Ca 2+ promotes contraction via
the Ca 2+ /calmodulin-dependent activation of myosin light chain kinase (MLCK). Relaxation is promoted by the elevation of cyclic
nucleotides (cAMP and cGMP) and their activation of protein kinases, which cause phosphorylation/inactivation of MLCK.
Pharmacological manipulations to reduce myometrial contraction include:
• inhibiting Ca 2+ entry (Ca 2+ channel blockers, Mg 2
SO 4
)
• reducing mobilization of intracellular Ca 2+ by antagonizing GPCR-mediated activation of the G q
-PLC-IP 3
-Ca 2+ pathway (with
antagonists of the FP and OXT receptors) or reducing production of the FP agonist, PGF 2α
(with COX inhibitors)
• enhancing relaxation by elevating cellular cyclic AMP (with β 2
adrenergic agonists that activate G s
-AC) and cyclic GMP (with NO
donors that stimulate soluble guanylyl cyclase)
sGC, soluble guanylyl cyclase; AC, adenylyl cyclase; FP, the PGF 2α
receptor; OXT, the oxytocin receptor; PLC, phospholipase C; COX,
cyclooxygenase.
convenience for the mother or medical team.
Collectively, induced or augmented labor now accounts
for ~20% of all deliveries in the U.S., two-thirds of
which are for nonmedical reasons.
Prostaglandins and Cervical Ripening. Prostaglandins
play key roles in parturition (see Chapter 33). Thus, PGE 1
,
PGE 2
, and PGF 2a
are used to facilitate labor by promoting
ripening and dilation of the cervix. They can be
administered either orally or via local administration
(either vaginally or intracervically). The ability of certain
prostaglandins to stimulate uterine contractions also
makes them valuable agents in the therapy of postpartum
hemorrhage (see “Prevention/Treatment of Postpartum
Hemorrhage”). Although prostaglandins are widely
employed for cervical ripening, their effectiveness versus
that of oxytocin alone in diminishing the need for
CHAPTER 66
CONTRACEPTION AND PHARMACOTHERAPY OF OBSTETRICAL