Introduction:Hypertension in pregnancy remains a significant public healthproblem. Preeclampsia, chronic hypertension, and severe gestational hypertension,while subject to different diagnostic criteria, contribute to maternal and perinatalmorbidity and mortality. Hypertensive pregnant women are at risk for cerebrovascularaccident, cerebral edema, hepatic rupture, renal failure, heart failure, and death.Hypertension diagnosed in pregnancy identifies women at risk for subsequentcardiovascular disease when not pregnant. The fetuses of hypertensive women areat risk for complications of preterm birth after delivery for maternal indications,intra- uterine growth restriction, and stillbirth.
The risk for the severest ofoutcomes such as maternal mortality and cerebral injury is moderated through prenatalcare. Indicated early delivery protects them other and the neonate from stillbirthoften at the cost of preterm delivery and it associated complications (ThomasR. Easterling MD., 2014).Hypertensive disorders of pregnancy (HDP) are important causes ofmaternal (Duley L 1992), (Omu AE et al., 1996). and fetal (ShahDM etal1996), (Pietrantoni M et al.
, 1994) morbidity and mortality.It is believed that 10%-15% of maternal mortality in developing countries isdue to HDP (Duley L 1992), the mortality is closely associated with theseverity of hypertension, being more evident in patients with eclampsia. (DuleyL 1992), (SMG Al-Ghamdi et al., 1999).A study conducted by A. ASubande et al, in south west region of Saudi Arabia reported that 0.
92%pregnant women diagnosed with severe preeclampsia and 0.056% suffers frompreeclampsia (A. A. Sobande et al., 2007). Another study conducted innorth western region of Saudi Arabia, reported that 67.7% patients hadpreeclampsia and 15% having chronic preeclampsia ((SMG Al-Ghamdi et al., 1999).
)Labetalol and methyldopa are generally towards the top of the listof antihypertensive drugs during pregnancy recommended by most professionalassociations/societies (Magee L et al., 2008) (Chobanian AV, BakrisGL, Black HR, et al 2003) (Abalos E et al., 2007).
Treatment ofhypertension in pregnancy remains controversial in part due to assumptions thathigh blood pressure itself is not “in the pathway” of adverse outcomes. Some advocateonly treating severe hypertension (160/110 mmHg) and then treating aggressivelywith parenteral medications (Chobanian AV et al ., 2003)The use of medications in pregnancy has been progressivelyincreasing over the past3–4 decades. this is predominantly due to changing in thedemographics of pregnant women, the prevalence of preexisting medical comorbidities,and the development of obstetric conditions that require pharmacotherapy duringpregnancy. (Mitchell AA et al., 2011).
Despite this, pregnant women arestill considered therapeutic orphans, as the majority of therapeutics and biologicswere never studied in them during development. The pregnancy-induced changes inmaternal physiology affect medications’ pharmacokinetic and secondary pharmacodynamicsproperties. (Mitchell AA et al., 2011).
These numbers are not very differentfrom 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.
(LupattelliA et al .,2014). The primary goals of treatment and surveillance of HTN in pregnancyare to prevent and treat severe HTN in the mother, prolong pregnancy for as longas safely possible for a more mature fetus, and minimize fetal exposure as muchas 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 tomoderate HTN in pregnancy may reduce the risk of severe HTN, it does not decreasethe incidence of preeclampsia or affect maternal or perinatal outcomes (i.
e., placentalabruption, fetal demise, or preterm birth) (Magee LA et al., 2011), BatemanBT et al., 2012). As a result, antihypertensive treatment in pregnancy aimsto balance the benefits of controlling BP and preventing the consequences of severeHTN in the mothers.
Risks of fetal drug exposure (Fischer JH et al., 2014),(Clark SM 2015). Labetalol is a newer third-generation ?-adrenoceptor antagonistwith ?1-adrenoceptor-blocking properties responsible for vasodilatory effects (Ghanem FA etal.
, 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 eaal., 1993).
At lower doses, ?-blockadeis more prominent, whereas ?-blockade becomes prominent at higher doses (DonnellyR et al., 1991). Labetalol also has vasodilating action mediated via?2-adrenoceptor stimulation that works to decrease peripheral vascular resistancewithout a significant alteration of heart rate or cardiac output (Saotome T etal., 1993)(Daskas N et al., 2013). Overall, the hypotensive effect of labetalol resultsfrom 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 hypotensiveeffect by minimizing any reflex increase in cardiac output (Giannubilo SR etal.
, 2012). Labetalol has gained popularity for treatment of HDP and isconsidered first-line therapy by many committees, especially in the treatment ofmild to moderate HTN in pregnancy. Blood pressure can be decreased it labetalolby lowering peripheral vascular resistance with little to no decrease incardiac output, no significant alteration of maternal heart rate, and without compromisingutero placental blood flow (Ghanem FA et al., 2008). It is typically started at100 mg twice daily, with titration to100–400 mg twice a day to four times daily and a maximum dosage of1200mg/d.
Labetalol is a non-selective ?-blocker and an ?1-blockerthat is widely recommended for management of hypertension in pregnancy.Disposition is mediated by glucuronidation via UDP–glucuronosyltransferase1A and2B7.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 twodiastereomeric pairs of racemates.
(RR)-labetalol is a non- selective?-blocker; (SR)-labetalol is a ?1-blocker. (SS)-labetalol and (RS)-labetalol havelittle activity (Carvalho Teresa Maria JP et al 2011).When administeredintravenously, the pharmacokinetics are not stereo selective: the ?-blocking isomer(RR)-labetaloland the ?1-blocking isomer (SR)-labetalol are cleared at the same rate (CarvalhoTeresa Maria JP et al 2011). When administered orally in pregnancy, the apparentoral 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 al2011). Stereoselective glucuronidation of orally administered drug results in morerapid clearance of the ?-active isomer compared to the ?-active isomer,limiting the impact of oral labetalol on maternal heart rate—particularly at lowerdoses.
Clinically, the pharmacokinetics of labetalol can be used to inform dosingin pregnancy. With a half-life o2.0 h, astandard12-hdosing interval(6half-lives) would not be expected to be effective.
Dosingat6-or8-hintervalswouldbemoreappropriate.The pharmacodynamics effect of oral labetalolwill be very different from that of IV labetalol. When administered orally, labetalolwill act with greater ?-effect than ?-effect.
If heart rate control is required,a substantial higher dose of labetalol may be required. In some cases, labetalolwill not control heart rate and a pure ?-blocker will be required. During pregnancy, the pregnantmother undergoes significant anatomical and physiological changes in order tonurture and accommodate the developing foetus. These changes begin afterconception and affect every organ system in the body (Locktich G). Most organ systems are affected by substantial anatomical and physiologicalchanges during pregnancy. Such pregnancy-related changes are observed indecreased gastrointestinal motility and increased gastric pH (impactingabsorption), increased total body water and plasma volume and decreasedconcentrations of drug-binding proteins (affecting the apparent volume ofdistribution and, in some cases, clearance rates), increased glomerularfiltration rate (increasing renal clearance), and altered activity of drug-metabolizing enzymes in theliver (affecting hepatic clearance). Overall, these changes in physiologicalindices take place progressively during gestation (Costantine MM (2014), (Loebstein R, Lalkin A, Koren G 1997). Plasma volume increases progressivelythroughout normal pregnancy (Rodger M2015).
Most of this 50% increase occurs by 34 weeks’ gestation and isproportional to the birthweight of the baby.Despitethe considerable challenges in conducting mechanistically drivenpharmacokinetic investigations in pregnant women, an increasing number ofstudies 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 evidencethat the activity of some but not all UGT enzymes is altered by pregnancy. Thisis of importance due to the fact that UGT enzymes often contribute not only tothe elimination of the parent drug but also to the elimination of pharmacologicallyactive metabolites or metabolites that are used as markers of P450 activity.For example, circulating concentrations of the antiepileptic drug lamotriginedecreased by about 50% during pregnancy (Francoet al., 2008), and the plasma concentration ratio of lamotrigineglucuronide to lamotrigine increased by about 2-fold in the second and thirdtrimesters of pregnancy compared with postpartum (Ohman et al.
, 2008). Lamotrigine N-glucuronidation ispredominantly mediated by UGT1A4 (Greenet al., 1995), and hence, these data suggest that UGT1A4 activity isincreased during pregnancy, and has important implications for seizure controlin pregnant women taking lamotrigine. In contrast, based on zidovudine andmorphine pharmacokinetic data, UGT2B7 activity is unaltered during pregnancy (Anderson, 2005).In addition to maternal hepatic increases in UGT andP450 expression, fetal UGT and P450 activity is also of note. In this issue ofDrug Metabolism and Disposition, the mRNA expression of UGT2B7, UGT2B15, andUGT2B17 in fetal tissues including fetal liver, lungs, adrenal glands, andkidneys is shown (Ekstrom et al.
, 2013).Although the mRNA levels were overall lower than those observed in adult humantissues, it is possible that the fetal UGT enzymes do contribute todetoxification of xenobiotics within the fetus. Most studies of UGT activity toward severalendogenous and exogenous substrates report down-regulation of UGT-mediatedreactions in liver in pregnancy. Decrease in expression of UGT family isoformsas a main cause of down-regulation of UGT-mediated reactions involvingbilirubin and planar phenols during pregnancy was reported. After delivery,protein level from all isoforms gradually returned to control values or evenincreased (1A1 and 1A6) in association with increased mRNA levels (Marcelo G Luquita et al., 2001).
References: A. A. Sobande, M Eskandar, A Bahar and A Abusham (2007). Severe pre-eclampsia and eclampsia in Abha, the south westregion of Saudi Arabia. Journal of Obstetrics and Gynaecology 27(2): 150 – 154. Abalos E, Duley L, Steyn DW, Henderson-Smart DJ (2007). Antihypertensive drug therapy for mild to moderate hypertension during pregnancy. CochraneDatabase Syst Rev 1:CD002252.
Anderson GD(2005). Pregnancy-induced changes in pharmacokinetics: a mechanistic-basedapproach. Clin Pharmacokinet 44:989–1008. Bateman BT, Hernandez-Diaz S,Huybrechts K, etal (2012). Patterns of outpatientantihypertensive medication use during pregnancy in a Medic aid population.Hypertension 60(4):913–920.
Carvalho Teresa Maria JP, Cavalli Ricardode Carvalho, Cunha SérgioP, etal (2011). Influence of gestationaldiabetes mellitus on the stereoselective kinetic disposition and metabolism oflabetalol in hypertensive patients. Eur JClinPharmacol.;67(1):55–61. ChobanianAV, Bakris GL, Black HR, et al (2003).
National Heart, Lung, andBlood Institute Joint National Committee on Prevention, Detection, andTreatment of high blood pressure. The Seventh Report of the Joint Committee.JAMA 289:2560–72. Chobanian AV,Bakris GL, Black HR, etal (2003).Seventh report of the Joint National Committee on Prevention, Detection,Evaluation, andTreatment of High Blood Pressure.
Hypertension 42(6):1206–1252.ClarkSM, Dunn HE, Hankins GD (2015). A review of oral labetalol andnifedipine in mild to Moderate hypertension in pregnancy.
Semin Perinatol 39(7):548-55. Costantine MM (2014). Physiologic andpharmacokinetic changes in pregnancy. Front Pharmacol5:65. Daskas N, Crowne E, Shield JP(2013). Is labetalol really a culprit in neonatal hypoglycaemia? ArchDisChildFetalNeonatalEd 98(2):F185. Donnelly R, Macphee GJ (1991).
Clinical pharmacokinetics and kinetic-dynamic relationshipsof dilevalol and labetalol. Clin Pharmacokinet 21(2):95–109.Duley L (1992). Maternal mortality associated with hypertensive disordersof pregnancy in Africa, Asia, Latin America, and the Caribbean. Br J ObstetGynecol ;99:547-53.Ekstrom L, Johansson M, and Rane A(2013).
Tissue distribution and relative gene expression ofudp-glucuronosyltransferases (2B7, 2B15, 2B17) in the human fetus. Drug MetabDispos 41: 291–295.Fischer JH, Sarto GE, Hardman J, etal (2014). Influence of gestational age and body weight on thepharmacokinetics of labetalol in pregnancy. Clin Pharmacokinet 53(4):373–383. Franco V, Mazzucchelli I, Gatti G,Specchio LM, La Neve A, Papantonio A, Ozkaynakçi AE, and Perucca E(2008). Changes in lamotrigine pharmacokinetics during pregnancy and thepuerperium.
Ther Drug Monit 30:544–547. Ghanem FA, Movahed A. (2008). Use of anti-hypertensive drugs duringpregnancy and lactation. Cardiovascular Drug Reviews 26(1), 38-49.
Giannubilo SR, Bezzeccheri V, CecchiS, etal (2012). Nifedipine versus labetalol in thetreatment ofhypertensive disorders of pregnancy. Arch GynecolObstet 286(3):637–642. Green MD, Bishop WP, and Tephly TR(1995). Expressed human UGT1.4 protein catalyzes the formation of quaternaryammonium-linked glucuronides.
Drug Metab Dispos 23:299–302. LocktichG (1997). Clinical biochemistry ofpregnancy. Crit Rev Clin Lab Sci ; 34: 6. Loebstein R, Lalkin A, Koren G (1997). Pharmacokinetic changes during pregnancy and their clinicalrelevance. Clin Pharmacokinet 33(5):328–43.
Lupattelli A,Spigset O, Twigg MJ, etal (2014).Medication use in pregnancy: across-sectional, multinational web-based study.Br Med J 4(2):e004365.MageeL, Helewa M, Moutquin JM, von Dadelszen P, Hypertension Guidelines Committee (2008),.
Diagnosis, evaluation, and management of the hypertensive disorders ofpregnancy. JOGC;30(Suppl. 1):S1–48. Magee LA, Abalos E, von Dadelszen P, CHIPS Study Group, et al (2011). How to manage hypertension in pregnancy effectively. Br JClin Pharmacol 72(3):394–401. Marcelo G Luquita, Viviana ACatania, Enrique J Sánchez Pozzi, Luis M Veggi, TimHoffman, José M Pellegrino, Shin-ichi Ikushiro, YoshikazuEmi, Takashi Iyanagi, Mary Voreand Aldo D. Mottino (2001).
Molecular Basis ofPerinatal Changes in UDP-Glucuronosyltransferase Activity in Maternal RatLiver. Journal of Pharmacology and ExperimentalTherapeutics 298 (1) 49-56. Mitchell AA,Gilboa SM, Werler MM, etal (2011).Medication use during pregnancy, with Ohman I, Luef G, and Tomson T(2008). Effects of pregnancy and contraception on lamotrigine disposition: newinsights through analysis of lamotrigine metabolites.
Seizure 17: 199–202. Omu AE,Al-Othman S, Al-Qattan F, Al-Falah FZ, Sharma P (1996). A comparative study of obstetric outcome of patients withpregnancy-induced hypertension: economic considerations. Acta Obstet GynecolScand;75:443-8.Pietrantoni M, O’Brien WF (1994). The current impact ofhypertensive disorders of pregnancy. Clin Exp Hypertens 16:479-92. RodgerM, Sheppard D, Gandara E, Tinmouth A (2015).
Haematological problems in obstetrics. BestPrac Res Clin Obstet Gynaecol; 29(5): 671–684. Rogers RC, Sibai BM, Whybrew WD(1990). Labetalol pharmacokinetics in pregnancy-induced hypertension. Am JObstet Gynecol 162(2):362–366.
Saotome T,Minoura S, Terashi K, Sato T, Echizen H, & Ishizaki T (1993). Labetalol in Hypertension During theThird Trimester of Pregnancy: Its Antihypertensive Effect and Pharmacokinetic?Dynamic Analysis. The Journal of ClinicalPharmacology, 33(10), 97. Shah DM, Reed G (1996). Parameters associatedwith adverse perinatal outcome in hypertensive pregnancies. J Hum Hypertens10:511-5. SMG Al-Ghamdi, AS Al-Harbi, A Khalil, AEl-Yahyia (1999), Hypertensive Disorders of Pregnancy: Prevalence,Classification and Adverse Outcomes in Northwestern Saudi Arabia. Annals ofSaudi Medicine 19(6): 557-560.
Thomas R.Easterling, MD (2014).Pharmacologicalmanagementofhypertensionin pregnancy. Seminars in Perinatology38 : 487 – 4 9 5.