Hypertension in pregnancy remains a significant public health
problem. Preeclampsia, chronic hypertension, and severe gestational hypertension,
while subject to different diagnostic criteria, contribute to maternal and perinatal
morbidity and mortality. Hypertensive pregnant women are at risk for cerebrovascular
accident, cerebral edema, hepatic rupture, renal failure, heart failure, and death.
Hypertension diagnosed in pregnancy identifies women at risk for subsequent
cardiovascular disease when not pregnant. The fetuses of hypertensive women are
at risk for complications of preterm birth after delivery for maternal indications,
intra- uterine growth restriction, and stillbirth. The risk for the severest of
outcomes such as maternal mortality and cerebral injury is moderated through prenatal
care. Indicated early delivery protects them other and the neonate from stillbirth
often at the cost of preterm delivery and it associated complications (Thomas
R. Easterling MD., 2014).
Hypertensive disorders of pregnancy (HDP) are important causes of
maternal (Duley L 1992), (Omu AE et al., 1996). and fetal (Shah
DM etal1996), (Pietrantoni M et al., 1994) morbidity and mortality.
It is believed that 10%-15% of maternal mortality in developing countries is
due to HDP (Duley L 1992), the mortality is closely associated with the
severity of hypertension, being more evident in patients with eclampsia. (Duley
L 1992), (SMG Al-Ghamdi et al., 1999).A study conducted by A. A
Subande et al, in south west region of Saudi Arabia reported that 0.92%
pregnant women diagnosed with severe preeclampsia and 0.056% suffers from
preeclampsia (A. A. Sobande et al., 2007). Another study conducted in
north western region of Saudi Arabia, reported that 67.7% patients had
preeclampsia and 15% having chronic preeclampsia ((SMG Al-Ghamdi et al., 1999).)
Labetalol and methyldopa are generally towards the top of the list
of antihypertensive drugs during pregnancy recommended by most professional
associations/societies (Magee L et al., 2008) (Chobanian AV, Bakris
GL, Black HR, et al 2003) (Abalos E et al., 2007). Treatment of
hypertension in pregnancy remains controversial in part due to assumptions that
high blood pressure itself is not “in the pathway” of adverse outcomes. Some advocate
only treating severe hypertension (160/110 mmHg) and then treating aggressively
with parenteral medications (Chobanian AV et al ., 2003)
The use of medications in pregnancy has been progressively
increasing over the past3–4 decades. this is predominantly due to changing in the
demographics of pregnant women, the prevalence of preexisting medical comorbidities,
and the development of obstetric conditions that require pharmacotherapy during
pregnancy. (Mitchell AA et al., 2011). Despite this, pregnant women are
still considered therapeutic orphans, as the majority of therapeutics and biologics
were never studied in them during development. The pregnancy-induced changes in
maternal physiology affect medications’ pharmacokinetic and secondary pharmacodynamics
properties. (Mitchell AA et al., 2011). These numbers are not very different
from studies in other developed countries. Using a web-based online questionnaire,
Lupattelli et al.2 showed that more than80% of pregnant women in Europe, Australia,
and the Americans use at least one medication during pregnancy. (Lupattelli
A et al .,2014).
The primary goals of treatment and surveillance of HTN in pregnancy
are to prevent and treat severe HTN in the mother, prolong pregnancy for as long
as safely possible for a more mature fetus, and minimize fetal exposure as much
as possible to drugs that may have adverse effects (Magee LA et al.,
2011). Meta-analysis of available data has shown that while treatment of mild to
moderate HTN in pregnancy may reduce the risk of severe HTN, it does not decrease
the incidence of preeclampsia or affect maternal or perinatal outcomes (i.e., placental
abruption, fetal demise, or preterm birth) (Magee LA et al., 2011), Bateman
BT et al., 2012). As a result, antihypertensive treatment in pregnancy aims
to balance the benefits of controlling BP and preventing the consequences of severe
HTN in the mothers. Risks of fetal drug exposure (Fischer JH et al., 2014),
(Clark SM 2015).
Labetalol is a newer third-generation ?-adrenoceptor antagonist
with ?1-adrenoceptor-blocking properties responsible for vasodilatory effects (Ghanem FA et
al., 2008). It is a non-selective ?- and post- synaptic
?1-adrenoceptor-blockingdrug(a combined ?1- and ?-adrenoceptor antagonist),with
?-blockade more potent than ?-blockade by 3:1 for oral administration. (Saotome T ea
At lower doses, ?-blockade
is more prominent, whereas ?-blockade becomes prominent at higher doses (Donnelly
R et al., 1991). Labetalol also has vasodilating action mediated via
?2-adrenoceptor stimulation that works to decrease peripheral vascular resistance
without a significant alteration of heart rate or cardiac output (Saotome T et
(Daskas N et al., 2013). Overall, the hypotensive effect of labetalol results
from vasodilation through ?1-adrenoceptor blockade and activation of
?2-adrenoceptors on vascular smooth muscle (Giannubilo SR et al., 2012).
Blockade of ?1-adrenoceptors in the heart also contributes to the hypotensive
effect by minimizing any reflex increase in cardiac output (Giannubilo SR et
al., 2012). Labetalol has gained popularity for treatment of HDP and is
considered first-line therapy by many committees, especially in the treatment of
mild to moderate HTN in pregnancy. Blood pressure can be decreased it labetalol
by lowering peripheral vascular resistance with little to no decrease in
cardiac output, no significant alteration of maternal heart rate, and without compromising
utero placental blood flow (Ghanem FA et al., 2008). It is typically started at100 mg twice daily, with titration to
100–400 mg twice a day to four times daily and a maximum dosage of1200mg/d.
Labetalol is a non-selective ?-blocker and an ?1-blocker
that is widely recommended for management of hypertension in pregnancy.
Disposition is mediated by glucuronidation via UDP–glucuronosyltransferase1A and
2B7.Earlyreportssug- gest atotalterminaleliminationhalf-lifeof1.7 7 0.27 h,
substantially shorter than that reported outside pregnancy, approximately 6–8
(8-4) h (Rogers RC et al., 1990). Labetalol is a chiral drug with two
diastereomeric pairs of racemates. (RR)-labetalol is a non- selective
?-blocker; (SR)-labetalol is a ?1-blocker. (SS)-labetalol and (RS)-labetalol have
little activity (Carvalho Teresa Maria JP et al 2011).When administered
intravenously, the pharmacokinetics are not stereo selective: the ?-blocking isomer(RR)-labetalol
and the ?1-blocking isomer (SR)-labetalol are cleared at the same rate (Carvalho
Teresa Maria JP et al 2011). When administered orally in pregnancy, the apparent
oral clearance of (RR)-labetalol (4.4;CI:36–7.4 L/h/kg)is higher than for(SR)-
labetalol (2.9;CI:2.0–4.9 L/h/kg) (Carvalho Teresa Maria JP et al 2011).
The AUCfor (RR)-labetalol (45.6; CI:40.3–74.4 ngh/mL)is roughly half that for(SR)-
labetalol (84.2;CI:63.8–119 ngh/mL) (Carvalho Teresa Maria JP et al
2011). Stereoselective glucuronidation of orally administered drug results in more
rapid clearance of the ?-active isomer compared to the ?-active isomer,
limiting the impact of oral labetalol on maternal heart rate—particularly at lower
doses. Clinically, the pharmacokinetics of labetalol can be used to inform dosing
in pregnancy. With a half-life o2.0 h, astandard12-hdosing interval
(6half-lives) would not be expected to be effective. Dosing
at6-or8-hintervalswouldbemoreappropriate.The pharmacodynamics effect of oral labetalol
will be very different from that of IV labetalol. When administered orally, labetalol
will act with greater ?-effect than ?-effect. If heart rate control is required,
a substantial higher dose of labetalol may be required. In some cases, labetalol
will not control heart rate and a pure ?-blocker will be required.
During pregnancy, the pregnant
mother undergoes significant anatomical and physiological changes in order to
nurture and accommodate the developing foetus. These changes begin after
conception and affect every organ system in the body (Locktich G). Most organ systems are affected by substantial anatomical and physiological
changes during pregnancy. Such pregnancy-related changes are observed in
decreased gastrointestinal motility and increased gastric pH (impacting
absorption), increased total body water and plasma volume and decreased
concentrations of drug-binding proteins (affecting the apparent volume of
distribution and, in some cases, clearance rates), increased glomerular
filtration rate (increasing renal clearance), and altered activity of drug-metabolizing enzymes in the
liver (affecting hepatic clearance). Overall, these changes in physiological
indices take place progressively during gestation (Costantine MM (2014), (Loebstein R, Lalkin A, Koren G 1997). Plasma volume increases progressively
throughout normal pregnancy (Rodger M
2015). Most of this 50% increase occurs by 34 weeks’ gestation and is
proportional to the birthweight of the baby.
the considerable challenges in conducting mechanistically driven
pharmacokinetic investigations in pregnant women, an increasing number of
studies have been conducted to characterize cytochrome P450 (P450),
transporter, and UDP glucuronosyltransferase (UGT) activity during pregnancy.
The changes in P450 enzyme activity during pregnancy, there is clear evidence
that the activity of some but not all UGT enzymes is altered by pregnancy. This
is of importance due to the fact that UGT enzymes often contribute not only to
the elimination of the parent drug but also to the elimination of pharmacologically
active metabolites or metabolites that are used as markers of P450 activity.
For example, circulating concentrations of the antiepileptic drug lamotrigine
decreased by about 50% during pregnancy (Franco
et al., 2008), and the plasma concentration ratio of lamotrigine
glucuronide to lamotrigine increased by about 2-fold in the second and third
trimesters of pregnancy compared with postpartum (Ohman et al., 2008). Lamotrigine N-glucuronidation is
predominantly mediated by UGT1A4 (Green
et al., 1995), and hence, these data suggest that UGT1A4 activity is
increased during pregnancy, and has important implications for seizure control
in pregnant women taking lamotrigine. In contrast, based on zidovudine and
morphine pharmacokinetic data, UGT2B7 activity is unaltered during pregnancy (Anderson, 2005).
In addition to maternal hepatic increases in UGT and
P450 expression, fetal UGT and P450 activity is also of note. In this issue of
Drug Metabolism and Disposition, the mRNA expression of UGT2B7, UGT2B15, and
UGT2B17 in fetal tissues including fetal liver, lungs, adrenal glands, and
kidneys is shown (Ekstrom et al., 2013).
Although the mRNA levels were overall lower than those observed in adult human
tissues, it is possible that the fetal UGT enzymes do contribute to
detoxification of xenobiotics within the fetus.
Most studies of UGT activity toward several
endogenous and exogenous substrates report down-regulation of UGT-mediated
reactions in liver in pregnancy. Decrease in expression of UGT family isoforms
as a main cause of down-regulation of UGT-mediated reactions involving
bilirubin and planar phenols during pregnancy was reported. After delivery,
protein level from all isoforms gradually returned to control values or even
increased (1A1 and 1A6) in association with increased mRNA levels (Marcelo G Luquita et al., 2001).
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