Pharmacokinetics of anticonvulsants in pregnancy: Alterations in plasma protein binding

Yerby, Mark S.; Friel, Patrick N.; McCormick, Karen Booth; Koerner, Michael M.; Allen, Margot Van; Leavitt, Anne; Sells, Clifford J.; Yerby, Julie A.

doi:10.1016/0920-1211(90)90042-t

Cited by 123 publications

(91 citation statements)

References 9 publications

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“…A lower recovery of unchanged drug in the urine was observed in our pregnant women compared with data reported for nonpregnant subjects (36% versus 59%), which is entirely consistent with the hypothesis that pregnancy shifts the major route of elimination for clonidine from the kidneys to organs involved in drug metabolism (Davies et al, 1977;Arndts, 1983). The enzymes involved in clonidine metabolism are currently unknown; however, pregnancy does increase the activities of CYP3A, CYP2D6, and CYP2C9 (Yerby et al, 1990;Tracy et al, 2005;Hebert et al, 2008). Clonidine is metabolized to five metabolites including the following: p-hydroxy-clonidine; dichlorophenylguanidine; 1-(2,6-dichloro-4-hydroxyphenyl)-guanidine; 2-[(2,6-dichlorophenyl)-imino]-imidazolidine-4-one; and 2-[2,6-dichloro-4-hydroxyphenyl)-imino]-imidazolidine-4-one (Darda et al, 1978).…”

Section: Clonidine Pharmacokinetics In Pregnancysupporting

confidence: 66%

Clonidine Pharmacokinetics in Pregnancy

Buchanan¹,

Easterling²,

Carr³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The objective of this study was to determine the pharmacokinetic parameters of clonidine during pregnancy compared with previously published data in nonpregnant subjects. Serial blood and urine samples were collected in 17 women during mid to late pregnancy over one steady-state dosing interval to determine clonidine noncompartmental pharmacokinetic parameters (n ‫؍‬ 17) and creatinine clearance. In six of these pregnant subjects, maternal and umbilical cord (venous and arterial) plasma samples were collected at the time of delivery for measurement of clonidine concentrations. Clonidine apparent oral clearance was found to be 440 ؎ 168 ml/min during pregnancy compared with 245 ؎ 72 ml/min as previously reported in nonpregnant subjects (p < 0.0001) (Cunningham et al., 1994). There was a strong correlation (r ‫؍‬ 0.82, p < 0.001) between clonidine renal clearance, adjusted for variation in glomerular filtration rate, and urine pH. Umbilical cord to maternal plasma clonidine concentration ratios were 1.0 ؎ 0.1 (arterial) and 1.0 ؎ 0.1 (venous). In conclusion, clonidine is cleared more rapidly in pregnant women than in nonpregnant subjects. At the time of delivery, the fetus is exposed to similar plasma clonidine concentrations as the mother.Chronic hypertension during pregnancy is associated with complications, including fetal growth restriction, premature birth, preeclampsia, placental abruption, hypertensive crisis, and in some cases fetal demise. Very little information is available on the pharmacokinetic changes that occur for antihypertensive medications during pregnancy. Clonidine, a centrally acting, ␣-2 adrenergic agonist, has been used for the treatment of hypertension during pregnancy (Kobinger, 1978;Hartikainen-Sorri et al., 1987). In the nonpregnant population, approximately 60% of clonidine is eliminated unchanged by the kidneys (Davies et al., 1977). There are significant changes in kidney function during pregnancy, with creatinine clearance reported to increase by 50 to 60% (Davison and Noble, 1981). The pharmacokinetics of clonidine have not been studied during pregnancy. The objective of this study was to characterize the pharmacokinetics of clonidine during pregnancy. Materials and MethodsAfter receiving written informed consent from patients, we examined steady-state pharmacokinetics of orally administered clonidine in the plasma of 17 pregnant women receiving clonidine during mid pregnancy (22-26 weeks gestation) or late pregnancy (34 -38 weeks gestation). Six of these women participated in maternal and umbilical cord (arterial and venous) plasma sample collections at the time of delivery for measurement of clonidine concentrations. Gestational age was based on the last menstrual period or early ultrasound dating.Subject Selection. This study was approved by the University of Washington Investigational Review Board. Subjects were eligible to participate if they were pregnant, 18 years of age, had a hematocrit Ն28%, and were receiving oral clonidine for maternal hypertension. Dosing Regi...

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Section: Clonidine Pharmacokinetics In Pregnancysupporting

confidence: 66%

Clonidine Pharmacokinetics in Pregnancy

Buchanan¹,

Easterling²,

Carr³

et al. 2008

Drug Metab Dispos

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“…At least two Class II studies per AED [19][20][21][22][23][24] provided evidence that the following AEDs significantly cross the placenta: phenytoin (PHT), carbamazepine (CBZ), and levetiracetam (LVT).…”

Section: Do Maternally Ingested Aeds Cross the Placenta? Do Maternallmentioning

confidence: 99%

Practice Parameter update: Management issues for women with epilepsy—Focus on pregnancy (an evidence-based review): Vitamin K, folic acid, blood levels, and breastfeeding

et al. 2009

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Objective: To reassess the evidence for management issues related to the care of women with epilepsy (WWE) during pregnancy, including preconceptional folic acid use, prenatal vitamin K use, risk of hemorrhagic disease of the newborn, clinical implications of placental and breast milk transfer of antiepileptic drugs (AEDs), risks of breastfeeding, and change in AED levels during pregnancy. Results: Preconceptional folic acid supplementation is possibly effective in preventing major congenital malformations in the newborns of WWE taking AEDs. There is inadequate evidence to determine if the newborns of WWE taking AEDs have a substantially increased risk of hemorrhagic complications. Primidone and levetiracetam probably transfer into breast milk in amounts that may be clinically important. Valproate, phenobarbital, phenytoin, and carbamazepine probably are not transferred into breast milk in clinically important amounts. Pregnancy probably causes an increase in the clearance and a decrease in the concentration of lamotrigine, phenytoin, and to a lesser extent carbamazepine, and possibly decreases the level of levetiracetam and the active oxcarbazepine metabolite, the monohydroxy derivative. Methods:Recommendations: Supplementing women with epilepsy with at least 0.4 mg of folic acid before they become pregnant may be considered (Level C). Monitoring of lamotrigine, carbamazepine, and phenytoin levels during pregnancy should be considered (Level B) and monitoring of levetiracetam and oxcarbazepine (as monohydroxy derivative) levels may be considered (Level C). A paucity of evidence limited the strength of many recommendations. Neurology ® 2009;73:142-149 GLOSSARY AAN ϭ American Academy of Neurology; AED ϭ antiepileptic drug; CBZ ϭ carbamazepine; CI ϭ confidence interval; ESM ϭ ethosuximide; GBP ϭ gabapentin; LTG ϭ lamotrigine; LVT ϭ levetiracetam; MHD ϭ monohydroxy derivative; OR ϭ odds ratio; OXC ϭ oxcarbazepine; PB ϭ phenobarbital; PHT ϭ phenytoin; PRM ϭ primidone; TPM ϭ topiramate; VPA ϭ valproate; WWE ϭ women with epilepsy.

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“…Örneğin, epilepsili gebelerde, fenitoin ve valporik asit vb. antiepileptiklerin doz ayarlamasında bu ilaçların dağılım kinetiği göz önünde bulundurulmalı, tedavi süreci terapötik ilaç düzeyi izlemi (bağlı/serbest ilaç düzeyleri de dikkate alınarak) ile değerlendirilmelidir (2,(4)(5)(6)15). Gebeliğin üçüncü trimesterinde, valporik asidin plazma serbest ilaç konsantrasyonu sadece %29 azalmasına rağmen bu ilacın plazma toplam ilaç konsantrasyonu %50 oranında düşüş göstermiştir.…”

Section: Belirli Anda Vücuttaki Toplam Ilaç Miktarı (A)unclassified

The Impacts of the Physiological Changes Occurring During Pregnancy on Pharmacokinetic Mechanisms

Akıcı¹,

Tamirci²,

Gören³

2017

Clin Exp Health Sci

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GİRİŞFarmakokinetik, kısaca vücudun ilaca ne yaptığı olarak bilinir. İlacın vücuda uygulanmasını takiben sırasıyla absorpsiyon, dağılım, metabolizma ve atılım olaylarını inceler ve bunlara bağlı olarak ilacın vücutta ilgili yerdeki konsantrasyonunu değerlendirir (1, 2). Farmakokinetik, her bir ilaç için bu olayların ayrı ayrı belirlenmesini, bu sayede ilacın hangi yolla, hangi dozda, nasıl, ne sürede ve ne zaman kullanılması gerektiği gibi sorulara yanıt elde edilmesini sağlar (2). İlacın kullanım koşullarını belirleyen farmakokinetik bilgilere ruhsatlandırma öncesi yapılması zorunlu preklinik ve klinik araştırmalarla erişilir. İlaç geliştirmeye ait bu rutin işlemler sırasında ne yazık ki gebe kadınlara ait, yok denecek kadar az veri üretilir. İlacın pazara erişimi sonrası yapılan klinik araştırmalarda ise öncesine kıyasla kısmen daha fazla bilgi üret-mek mümkündür. Ancak bu son aşamada elde edilen bilgiler de çoğu kez yetersiz kalır. Bu aşamada genel olarak gözlemsel çalışmalardan veri elde edilir (3-5). Süreç, pazarda mevcut ilaçlar için bu eksikliğini uzun yıllar korur. Bu nedenle pek çok ilacın gebelikte kullanımına dair ayrıntılı bilgi ihtiyacı, yeni ilaçlarda daha belirgin olmak üzere kendini hissettirmeyi sürdürür. İlaç özelinde yaşanan bu eksikliklerin yol açabileceği sorunlar oldukça çeşitlidir. Teratojeniteye neden olma, etkisiz kalma, hasta ve sağlık çalışanlarına bazen abartıya kaçabilen dü-zeyde endişe yaşatma, bunlara bağlı tedavi hatalarıyla karşılaşma bu sorunlardan bazılarıdır. Gebeliğin yol açtığı fizyolojik değişikliklerin farmakokinetik mekanizmaları nasıl ve ne yönde etkilediğinin konunun muhataplarınca iyi bilinmesi gerekir. Bunun sağlanması, yaşanan sıkıntıları azaltmanın yollarından birisidir (1, 3, 6). ÖzTaşıdığı risklerden dolayı kaçınılmaya çalışılsa da gebeler çeşitli gerekçelerle ilaç kullanmak zorunda kalmaktadır. Tarafların eldeki sınırlı bilgiyi bile yeterince etkin kullanamaması, yaşanan endişeyi artırmakta, eksik ya da yanlış tedavi sorunlarına kapı aralamaktadır. Başta hekimler olmak üzere sağlık çalışanları, ilaç kullanımın-da sıradan erişkin bireylere göre gebelerin önemli bazı farklılıkları olduğunu iyi bilmeli ve bunun gerekliliklerine uygun hareket etmelidir. Annenin vücudunda, plasentada, embriyoda ve fötusta gebelik süresince oluşan zamansal değişimle-rin ilacın farmakokinetiğine yansımaları, bu farklılıkların başında gelmektedir. Absorpsiyon, dağılım, metabolizma ve atılım olaylarının her birini ilgilendiren önemli değişiklikler, oldukça çeşitlilik gösterir. Bu değişiklikler, gebenin kullanacağı ilacın seçiminden, yarar sağlanabilecek optimal dozun belirlenmesine, tedavi ve takip süresinin ayarlanmasından, etki/advers etki yorumlanmasına kadar klinik süreçte bir dizi işlemin hayata geçirilmesinde belirleyicidir. Gestasyonel yaş, annenin yaşı ve altta yatan hastalıklar, bu hastalıkların farmakokinetik mekanizmaları etkileme durumları vb. bireysel etkenlerin de işin içerisine karıştığı tedavi sürecinin gebelikte başarılı şekilde yönetimi, çeşitli güçlükleri barındırır ve ...

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Pharmacokinetics of anticonvulsants in pregnancy: Alterations in plasma protein binding

Cited by 123 publications

References 9 publications

Clonidine Pharmacokinetics in Pregnancy

Clonidine Pharmacokinetics in Pregnancy

Practice Parameter update: Management issues for women with epilepsy—Focus on pregnancy (an evidence-based review): Vitamin K, folic acid, blood levels, and breastfeeding

The Impacts of the Physiological Changes Occurring During Pregnancy on Pharmacokinetic Mechanisms

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