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Cardiovascular Medications in Pregnancy

Alice Chan and Ali N. Zaidi

Introduction

Cardiovascular disease (CVD) is currently one of the leading causes of mortality in pregnant women [1–4], affecting 1%–2% of pregnancies [5]. Having a good understanding of the use of cardiac medications during this time is important to ensure appropriate management of these patients. However, pharmacological therapy for CVD during pregnancy can be challenging because the effects of the medications often change throughout gestation. The pharmacokinetics of the cardiovascular medications is affected by the physiological changes in pregnant women; the metabolism and the efficacy of the medications are usually altered [4]. Most cardiac conditions require use of medications. According to the Registry of Pregnancy and Cardiac Disease (ROPAC), up to one-third of women with CVD use cardiac medications during pregnancy, and this use was associated with increased fetal risk such as intrauterine fetal growth restriction (IUGR) [6]. The majority of data on the safety of medication use during pregnancy rely on observational studies and expert opinion. It should be kept in mind that drug use in pregnancy affects both the mother and the fetus, and therefore pharmacologic agents are chosen to address those concerns.

Drug Risk Categorization

The U.S. Food and Drug Administration (FDA) previously used pregnancy risk categories A, B, C, D, and X, with most cardiovascular drugs categorized as B (no animal studies have shown risk/no controlled studies in humans) or C (animal studies have shown adverse effect/no controlled studies in humans). In 2015, the FDA introduced new risk guidelines for various medications in pregnancy and lactation [7]. This new categorization provides narrative sections for pregnancy and lactation, an overall risk based on known data, and the effects on women and men of reproductive potential. However, implementation of these guidelines will occur in stages over a 5-year period. Even though most providers continue to use the U.S. FDA-approved pregnancy risk categories as outlined above [4], the new system should be followed as much as possible, as it is a more detailed description of effects of drugs on pregnancy and lactation.

Pharmacokinetics in Pregnancy

The physiological changes in pregnancy affect many body organs, including the cardiac, hepatic, and renal systems (Table 20.1). Important changes include:

1.Delayed gastric emptying and motility

2.Prolonged small bowel transit time

3.Gastroesophageal reflux

4.Increased plasma volume and fat accumulation

5.Increased volume of distribution

6.Decreased albumin and plasma binding proteins

7.Increased minute ventilation

8.Increased hepatic clearance

9.Increased renal clearance

10.Hypercoagulability

All of these changes may affect drug distribution and clearance [5]. For instance, the glomerular filtration rate (GFR) increases by 25% during pregnancy leading to an increase in the clearance rate on medications that are primarily excreted by the kidneys [5,8]. The increase in the amount of body fat and plasma volume can also affect the medication’s concentrations [4]. These factors are important to keep in mind when prescribing medications to women during their pregnancy. The hormonal influences during pregnancy on the liver increase or decrease metabolism of some drugs without clear patterns. It should also be kept in mind that pregnancy is a hypercoagulable state associated with increased risk of thromboembolism.

The dynamic physiological changes of pregnancy clearly affect the pharmacokinetic processes. Increased activity of liver enzyme systems, GFR, plasma volume, protein binding changes, and decreased serum albumin levels contribute to changes in the pharmacokinetics of many medications [9,10]. The hormonally induced alterations in receptor and transport expression may affect drug activity at receptor sites, and therefore pregnancy introduces unpredictability to the body’s handling of medications.

Absorption

Increased progesterone levels can delay intestinal motility in the small bowel while nausea and emesis can inhibit the absorption of medications. Many changes in medication absorption during pregnancy remain mostly theoretical and not proven.

Volume of Distribution (Vd)

There is an ∼50% increase in plasma volume and total body water during pregnancy, increasing the Vd of hydrophilic and lipophilic substances. As Vd rises throughout pregnancy, the concentrations of a drug may decrease, requiring an increase in drug dosage. The concentration of drugs during pregnancy depends not only on the Vd but also on the clearance of the drug by the different organ systems (i.e., lungs, kidneys, and liver). Vd is also affected by the amount of drug bound to plasma proteins (e.g., albumin). Therefore, the net exposure of a drug during pregnancy depends on the interplay between Vd, degree of binding to serum proteins, extraction ratio, and clearance [11].

Hepatic Clearance

Hepatic extraction ratio refers to the fraction of drug removed from the circulation by the liver. Some drugs like propranolol, verapamil, and nitroglycerin are rapidly taken up into hepatocytes, and their clearance depends on the rate of blood flow to the liver. In pregnancy, perfusion to the liver stays stable or increases, causing some drugs to be metabolized faster, which in turn may require an increase in drug dosing. Clearance of those drugs that are not affected by hepatic clearance, such as warfarin, depends on the intrinsic hepatic activity as well as on the unbound fraction of the drug in plasma [12].

Renal Clearance

Effective renal plasma flow increases as much as 50%–85% in pregnancy [8]. GFR increases by 45%–50% by the end of the first trimester [8] and continues to rise until term, with a possible downtrend in the last few weeks. The tubular function remains variable [13].

Medications in Pregnancy

Some cardiovascular medications may be continued in pregnancy, but others are teratogenic and will need to be changed during pregnancy. Medications such as beta blockers, digoxin, and furosemide are safe in pregnancy [4], whereas angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are contraindicated in pregnancy (Table 20.2). Patients on ACEI or ARB for treatment of heart failure and/or hypertension would need to switch these medications to a safer alternative because of their teratogenic potential once pregnancy is confirmed, or ideally, prior to anticipated pregnancy [1,4]. Table 20.3 lists commonly used cardiovascular medications.

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