Clinical Management and Antihypertensive Treatment of Hypertensive Disorders of Pregnancy

Introduction

Preeclampsia is a pregnancy-specific, multisystemic disorder clinically characterized by new-onset hypertension accompanied by at least one other evidence of new-onset maternal or fetal organ damage or dysfunction (e.g., proteinuria, renal insufficiency, liver involvement, neurological or hematological complications, uteroplacental dysfunction, or fetal growth restriction). Preeclampsia may progress rapidly without warning to life-threatening complications including eclampsia, liver and kidney failure, and HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome.

Despite intensive research, preeclampsia remains one of the major causes of maternal, fetal, and neonatal death. The underlying cause is a lack of antenatal and obstetric care in many underprivileged areas of the world, and the only efficient treatment is delivery of the fetus and placenta. This implies a clinical challenge for balancing the needs for optimal maternal and fetal outcome, including prevention of newborn prematurity. In this chapter, we will discuss the optimal treatment for both mother and fetus, aiming to help physicians in the day-to-day management of women with preeclampsia . Accordingly, we will discuss the clinical assessment and diagnosis of hypertensive disorders in pregnancy, followed by treatment of hypertension.

In updating this chapter, we continue to emphasize the need for better study designs regarding the ideal antihypertensive drugs for pregnant women. A plethora of national guidelines offer contrasting views regarding the degree of hypertension at which drug therapy should be started during pregnancy and the authors in the initial sections of the chapter succinctly chronicle the reasons for the differing guidelines. Thereafter, we will describe the current prevention and treatment of eclampsia and optimal timing and mode of delivery. Management of preeclampsia depends upon its severity as well as the gestational age at which it becomes clinically apparent. While in most cases diagnosis is made by the appearance of new-onset gestational hypertension accompanied by evidence of target-organ injury or dysfunction—which are discussed in detail in other chapters—we have emphasized the importance of endothelial cell injury and multiorgan dysfunction as integral parts of the preeclampsia syndrome .

In the long term, women with a history of preeclampsia and their children born after a pregnancy complicated by preeclampsia are at risk of cardiovascular disease later in life. Long-term maternal cerebrovascular damage and function are discussed in Chapter 13 . Prediction and prevention of preeclampsia, as well as postpartum short- and long-term follow-up for cardiovascular disease, are discussed in Chapter 18 .

Diagnosis

Hypertensive disorders of pregnancy encompass high blood pressure diagnosed prior to and during pregnancy and are often categorized as gestational hypertension, preeclampsia, chronic hypertension, superimposed preeclampsia, eclampsia, and HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. While there is some variation in diagnostic criteria across different national and international guidelines, these categories have been largely maintained (as discussed in Chapter 1). Gestational hypertension is diagnosed by newly elevated blood pressure (≥140 mm Hg systolic and/or ≥90 mm Hg diastolic) in a previously normotensive woman generally after 20 weeks' gestation. High blood pressure should be sustained with documented elevations on at least two occasions 4 h apart. Gestational hypertension is a provisional diagnosis during pregnancy and includes women in three categories: (1) women who will progress to develop or be recognized as manifesting preeclampsia, (2) women with “transient hypertension of pregnancy” who do not develop preeclampsia and revert to normal blood pressures by 12 weeks' postdelivery, and (3) women who may have previously unrecognized chronic hypertension. Definitive diagnosis is possible only after reassessment at 6–12 weeks' postpartum. As discussed in Chapter 1, preeclampsia is defined as new onset of elevated blood pressure with target-organ damage most commonly manifested as new onset of proteinuria after 20 weeks of gestation (based on 24 h collection of greater than or equal to 300 mg urine protein, a urine protein to creatinine ratio of greater than or equal to 0.3, or urine protein dipstick of 2+ or greater); or in the absence of proteinuria, hypertension with evidence of end-organ involvement including any of the following: thrombocytopenia (platelet count of less than 100,000/μL), impaired liver function blood (elevated blood concentrations of liver transaminases to twice the normal concentration), the new development of renal insufficiency (elevated serum creatinine of greater than 1.1 mg/dL or doubling of serum creatinine in the absence of other renal disease), pulmonary edema, or new onset of cerebral or visual disturbances not attributable to other causes. Fetal growth restriction is included in most guidelines as a form of organ dysfunction contributing to the definition of preeclampsia when combined with new-onset hypertension. Fetal growth restriction is not specifically included in the American College of Obstetricians and Gynecologists (ACOG) diagnostic criteria, but remains nonetheless an important aspect of preeclampsia management. In the setting of severe hypertension (systolic blood pressure of 160 mm Hg or higher, or diastolic blood pressure of 110 mm Hg or higher), the diagnosis can be confirmed in a shorter interval to facilitate timely treatment. Chronic hypertension is defined as hypertension present prior to pregnancy or that is newly diagnosed before 20 weeks of gestation. High blood pressure that persists 6–12 weeks postpartum is also classified as chronic hypertension. Preeclampsia that is superimposed on underlying chronic hypertension may present as sudden increases in blood pressure, proteinuria, or development of end-organ involvement as outlined above. Eclampsia is the new onset of generalized seizures that occur in a preeclamptic woman (defined as prior to or during delivery or within first weeks postpartum, although later occurrence may happen if placenta tissue remains) that cannot be attributed to other causes. HELLP syndrome is generally considered a severe variant of preeclampsia.

In 2017 and since the last edition of this textbook, the American College of Cardiology and American Heart Association (ACC/AHA) updated the criteria for diagnosing hypertension in (nonpregnant) adults with the intention to identify and modify long-term cardiovascular risk. Under these new criteria, stage I hypertension is defined as systolic blood pressure of 130–139 mmHg and/or diastolic blood pressure of 80–89 mmHg; previously referred to “prehypertension.” The 2017 ACC/AHA guidelines suggest initiating drug therapy for stage I hypertension in those nonpregnant adults who also have risk factors for cardiovascular disease. The number of reproductive-aged women in the United States classified as chronic hypertensive based on these new criteria is estimated to double. Emerging evidence indicates that stage I hypertension may increase pregnancy risks. A secondary analysis of a randomized trial of aspirin for preeclampsia prevention evaluated outcomes for women in the placebo arm who would now be classified as having stage I hypertension. These women had higher rates of preeclampsia, gestational diabetes, and medically indicated preterm birth. In a more contemporary, low-risk cohort of nulliparous pregnant women, secondary analysis also demonstrated higher rates of any hypertensive disorder (RR 2.16, 95% CI 1.31–3.57), preeclampsia, gestational hypertension, gestational diabetes, and medically indicated preterm birth in women with stage I hypertension compared to women with normal blood pressures (less than 120 mm Hg systolic and less than 80 mmHg diastolic) at the first trimester visit. There are insufficient data as to precisely how this change in classification affects pregnancy outcomes or resource utilization. Further prospective evidence is needed to guide the classification and management of pregnant women with stage I hypertension. Regardless, as these diagnosis and treatment recommendations are implemented, more women may be prescribed antihypertensive drugs prior to pregnancy, requiring additional care in drug selection to minimize risk during a subsequent planned or unplanned pregnancy. To date, there has been no change in the blood pressure criteria for diagnosing hypertensive disorders of pregnancy. However, the most recent ACOG practice bulletin suggests that a conservative approach during pregnancy with a higher degree of observation may be warranted for women with preexisting stage I hypertension.

Regardless of the precise subclassification, new onset or worsening blood pressures in pregnancy should raise concern for preeclampsia and prompt further evaluation for proteinuria and other organ involvement, progressively worsening disease, fetal status, and appropriate management depending on gestational age and clinical course.

Identifying Women with Hypertensive Disorders

Assessment for Preeclampsia

Initial evaluation of preeclampsia should generally occur in a triage or hospital setting for adequate maternal and fetal assessment.

• History and review of symptoms should include questions described above.

• Serial blood pressures should be measured to confirm sustained elevations.

• Physical examination should be performed with attention to signs of preeclampsia and associated complications; specifically, a thorough cardiopulmonary, abdominal, and neurologic examination.

• Proteinuria should be assessed by urine protein-to-creatinine, or albumin-to-creatinine ratios or a 24-h urine collection. Urine dipstick test is acceptable if these are not available. As there is limited evidence that higher levels of proteinuria are associated with worse outcomes, ^, proteinuria should primarily be used for the diagnosis of preeclampsia. Decision to deliver should not be based upon the degree of proteinuria. ^,

• Laboratory evaluation should include a complete blood count with platelets, liver transaminases, and serum creatinine to detect possible end-organ involvement. Although not diagnostic, uric acid may be useful in identifying a subgroup of hypertensive women who are at increased risk for premature delivery and small for gestational age infants. Peripheral blood smear, lactate dehydrogenase, haptoglobin, and/or indirect bilirubin may be ordered if there is concern for hemolysis and possible HELLP syndrome.

• Fetal well-being should be assessed with ultrasound to evaluate estimated fetal weight, growth, and amniotic fluid index. Nonstress cardiotocograph testing and/or fetal biophysical profiles should also be performed. In the setting of fetal growth restriction, umbilical artery Doppler measurement is a useful tool to assess resistance within the placental and umbilical vasculature. Use of these measurements has been shown to reduce perinatal death as well as unnecessary delivery of the preterm growth-restricted fetuses.

• Role of angiogenic factors in the clinical evaluation : Several recently published studies have assessed whether circulating levels of the angiogenic factors, such as placental growth factor (PlGF) and/or soluble fms-like tyrosine kinase-1 (sFlt-1), could improve clinical follow-up and outcome. Prior to 37 weeks, a normal angiogenic profile (low sFlt-1 and high PlGF) supports the absence of placental dysfunction, in line with the concept that an imbalance of these markers (high sFlt-1 and low PlGF) reflects placental syncytiotrophoblast stress (Please see Chapter 9 for detailed discussion of angiogenic factors). In a multicenter, prospective cohort study, Chappell and colleagues demonstrated that low PlGF (less than the fifth percentile) has high sensitivity (0.96; 95% CI, 0.89–0.99) and negative predictive value (0.98; 95% CI 0.93–0.995) for preeclampsia within 14 days in women with suspected preeclampsia prior to 35 weeks' gestation. Zeisler and colleagues identified and validated in an observational cohort that a ratio of serum sFlt-1 to PlGF of 38 or lower had a negative predictive value of 99.3% (95% CI 97.9–99.9) for no preeclampsia within a week among women with suspected preeclampsia between 24 weeks and 0 days and 36 weeks and 6 days. A follow-up study using a multicenter, stepped-wedge cluster randomized controlled study design compared a clinical algorithm incorporating PlGF to standard care without revealing PlGF to clinicians. Availability of PlGF substantially reduced time to clinical confirmation of preeclampsia (median time to diagnosis 4.1 days with concealed testing vs. 1.9 days with revealed testing, P = .027). Incidence of adverse maternal outcomes was lower where PlGF testing was implemented (odds ratio 0.32; 95% CI 0.11–0.96). There were no differences in adverse perinatal outcomes or gestational age at delivery. These data suggest the clinical utility in the setting of “rule-out” preeclampsia. Recent United Kingdom NICE guidelines recommend the Triage PlGF test and the Elecsys immunoassay sFlt-1/PlGF ratio, used with standard clinical assessment and subsequent clinical follow-up, to help rule-out preeclampsia in women presenting with suspected preeclampsia between 20 and 34 weeks plus 6 days of gestation ( https://www.nice.org.uk/guidance/dg23/chapter/1-Recommendations ). These angiogenic markers may be particularly useful among women with chronic renal disease to discriminate between worsening renal disease and new-onset preeclampsia (with placental dysfunction and therefore, low PlGF). Low PlGF and high sFlt-1 have also been shown to predict other manifestations of placental dysfunction including fetal growth restriction, spontaneous preterm labor, and stillbirth. ^, The chapter authors expect that future studies will aid in resolving cost–benefit issues of introducing these markers into general clinical practice of women with suspected placental dysfunction including preeclampsia. The use of PlGF testing in first trimester screening is also increasingly used as part of an algorithm to identify women at high risk for early-onset preeclampsia, where a low PlGF early in pregnancy would be consistent with the concept of early syncytiotrophoblast stress predicting early-onset preeclampsia.

Antihypertensive Therapy—Its Goals

The focus of clinical management is to prevent maternal morbidity, maternal seizures, and to increase fetal surveillance. In this respect, one balances a relative short-term maternal outcome against possible long-term consequences of intrauterine drug exposure or hemodynamic insult on fetal and childhood growth and development. Maternal risks that may justify pharmacotherapy include that of superimposed preeclampsia, which, with its morbid outcomes, appears to account for most complications ascribed to chronic hypertension. Additional risks are those of placental abruption, accelerated hypertension leading to hospitalization or to target-organ damage, and cerebrovascular catastrophes. Risks to the fetus include death, growth restriction, and premature delivery, the latter occurring in many cases due to concerns regarding maternal safety.

The use of antihypertensive drugs in attempts to prolong pregnancy or modify perinatal outcomes in pregnancies complicated by various types and severities of hypertensive disorders has been of considerable interest. Treatment for women with hypertension complicating pregnancy is discussed in detail including pharmacology and use during pregnancy of specific antihypertensive drugs. There is consensus that women should receive antihypertensive drugs to lower their blood pressure, but, in the absence of clear evidence, it is unclear which antihypertensive drug is preferred. The lack of evidence on this subject is reflected by considerable practice variation. Several medications are used worldwide including the combined α/β adrenergic receptor blocker labetalol, the calcium channel blockers nicardipine and nifedipine, ketanserin (a relatively selective antagonist of 5-HT _2A serotonin receptors), the hydrazinophthalazine direct vasodilators hydralazine and dihydralazine, and some combinations of these medications. In view of the potentially relevant differences for both mother and neonate between these medications, there remains an urgent need for insight into the optimal treatment of women with severe hypertension in pregnancy. Such insight would promote uniformity in treatment, which could improve patient safety and maternal and neonatal outcome and quality of life, at lower costs. More uniform treatment of severe hypertension in pregnancy would improve maternal and neonatal outcomes and reduce admissions to maternal and neonatal intensive care. Although severe maternal complications, including eclamptic seizures, cerebral hemorrhage, HELLP syndrome, liver hematoma and rupture, pulmonary edema, and maternal death are rare, even in women with hypertension, the high prevalence of hypertension in pregnancy itself implies that many young women and their neonates/children are affected, worldwide.

In the initial edition of this text, discussion of antihypertensive therapy in pregnancy was mainly historical; the drugs noted included veratrum alkaloids, opium and its derivatives, a host of sedatives, and even spinal analgesia—the older literature was often unclear whether such treatment was prescribed for hypertension per se or for an eclamptic convulsion. More emphasis, however, was devoted to diuretics—parenthetically vehemently opposed by Chesley—and to the recurring theme that hypertension in preeclampsia might, paradoxically, be treated by volume expansion. Space prohibits republishing these historical vignettes, which bear rereading. Of interest though, veratrum alkaloids (with antihypertensive effects) were incorporated into the treatment of eclampsia even before physicians were aware that a rise of blood pressure accompanied the “puerperal convulsion.” Also, for many years, use of veratrum was called the “Brooklyn treatment,” noted here because Chesley spent most of his career on the faculty of the State University of New York in Brooklyn.

General Principles in the Choice of Antihypertensive Agents

Blood pressure, in its simplest conceptualization and ignoring pulsatility, is determined as the product of cardiac output and systemic vascular resistance. The latter is sensitive to the structure of small arterial and arteriolar resistance vessels, activity of local vasodilator and vasoconstrictor systems, humoral influences such as the renin–angiotensin system (see Chapter 15 ), and the activity of the autonomic nervous system. The former is sensitive to changes in volume status and autonomic tone, as other influences on intrinsic myocardial contractility are usually minor in healthy women. These physiologic targets, sometimes obscured in the chronic state by vascular autoregulation or our limited ability to measure relevant volumes or pressures with precision, provide the rationale for each of the available pharmacologic strategies for control of hypertension. Further, due to the homeostatic nature of blood pressure control, even when pathologically elevated, this simple physiologic construct suggests likely mechanisms of apparent resistance to antihypertensive drugs, especially when used as single agents. In nonpregnant hypertensive patients, choice of a specific antihypertensive drug is usually rationalized by the severity of hypertension and immediate risk of end-organ damage, the desired time–action characteristics of the drug, specific comorbidities, spectrum of possible adverse drug effects, cost, and known secondary causes of the hypertension. Therapy may also be based on outcomes of well-conducted, large clinical trials, on the systematic review of many smaller randomized trials, or on broad, population-based assumptions regarding the likely physiologic mechanisms leading to hypertension in a given patient.

Due to the lack of large randomized controlled trials, the choice of drugs used in hypertensive pregnant women is based on knowledge of studies with nonpregnant participants. Antihypertensive treatment of elevated blood pressure in the range from 140 to 159/90 to 109 mmHg and to target of 85 mmHg diastolic is associated with maternal benefit without increasing perinatal risk. ^, Blood pressure equal to or greater than 160/110 mmHg constitutes a medical emergency requiring antihypertensive therapy. Current data clearly support benefits of treatment of severe hypertension. Treatment of mild-to-moderate hypertension is less straightforward. Historically, concerns had been raised that tight control of blood pressure was associated with SGA, but this is not a consistent finding based on more recent Cochrane review of the data. Most of the organizations recommend antihypertensive treatment of elevated blood pressure in the range from 140 to 159/90 to 109 mmHg and to target of 85 mmHg diastolic, which is associated with maternal benefit without increasing perinatal risk. ^, ACOG recommendations limit pharmacologic treatment to ≥160 or ≥110 in the absence of clear benefit in limiting disease progression, reducing indicated preterm birth, and improving perinatal outcomes. Additional well-designed and appropriately powered studies are needed. The Chronic Hypertension and Pregnancy (CHAP) Project (targeted completion in 2022) is ongoing and should answer such questions of benefits and harms with treatment of nonsevere chronic hypertension ( ClinicalTrials.gov NCT02299414). Antihypertensive drugs show little or no effect in the risk of total fetal or neonatal death in a meta-analysis (3365 women), small for gestational age babies (2686 babies), or preterm birth less than 37 weeks' gestation (2141 women). Since the strength of recommendations is often weak and the quality of evidence low, the optimal decision about blood pressure control will depend on women's values and gestational age at decision.

Fetal Safety and Drug Use in Pregnant Women

Past government regulations and continuing ethical norms and liability concerns led the pharmaceutical industry to scrupulously avoid testing drugs in pregnant women, extended now to limit the study of vaccines in the COVID-19 pandemic. Despite regulatory changes made by the United States Food and Drug Administration (FDA) in 1993 in order to allow testing of drugs in pregnant women, adequate studies are still only rarely conducted. Therefore, clinical information remains unavailable for most currently prescribed agents in pregnancy. Indeed, rigorous evaluation of pharmacokinetics, biotransformation, maternal efficacy, fetal exposure, and long-term fetal effects of drugs used during pregnancy is generally lacking. Available information, save for assessment of teratogenicity in laboratory animals, is limited and selective. Recent recommendations of the US National Institutes of Health Task Force on Research Specific to Pregnant Women and Lactating Women called for a broad suite of policy changes to more strongly favor needed research to guide drug therapy in pregnancy. The WHO is currently working on similar policy changes to include pregnant and lactating women in trials. In the past, most regulatory agencies have used outmoded and poorly harmonized classification schemes, based mostly on animal data focused on teratogenic potential to categorize potential fetal risks on drug labels. In the United States, regulatory changes in 2015 abandoned these summary (letter; i.e., A, B, C, D, X) categories in favor of including more data and narrative, although already marketed drugs have not been reassessed adequately. This leaves clinicians in limbo, stressing the need for taking all available clinical information into account when making a prescribing decision in a particular pregnant patient.

For reference and convenience of experienced clinicians, we will continue to describe and note the old FDA risk letter classifications, despite their abandonment in modern prescribing. Because data from human and animal studies are so limited, most drugs are listed in the old FDA “category C,” denoting inadequate studies in humans, with the caveat that they should be used only if potential benefit justifies the potential risk to the fetus. Unfortunately, this category is so broad as to be useless; it includes those antihypertensive drugs with the greatest history of safe use in pregnant women but, for many years, also included the ACE inhibitors, which are contraindicated in later pregnancy (and were reclassified to category D). Even when drugs were placed in category B, denoting limited but reassuring human data, their presumed safety may be a function of the insensitivity of animal tests to predict subtle clinical effects, such as fetal ability to withstand hypoxic stress, changes in functional physiologic development, and altered postnatal neurocognitive development. Limited evidence of clinical safety is often extended injudiciously, such that drugs that lack significant teratogenic potential in early pregnancy may exert devastating effects on fetal organ function nearer to term; conversely, drugs that are safe in the third trimester may have irreversible effects on fetal growth or development when used earlier. By contrast, one can easily err against drug use in pregnancy, for example, when discontinuation of category D drugs might jeopardize both mother and fetus. Examples of this latter scenario would include discontinuing immunosuppressives in a pregnant renal transplant recipient or even relatively safer antiepileptic agents in a pregnant woman with a profound seizure disorder. This sort of confusion has limited important research as well, delaying recent studies of pravastatin for the potential prevention of preeclampsia due to its historical contraindication (FDA category X) during pregnancy, which was based on the lack of treatment indications for lipid-lowering during pregnancy rather than on any evidence of teratogenicity or fetal harm.

Choice of an Antihypertensive Drug for Use in Pregnancy

Following discussion of the rationale for choosing an antihypertensive drug, we turn to consideration of each class of agents available in common practice. Each of these drug classes, their apparent mechanisms of action, and, in terms of this chapter's primary goals, their suitability for use during pregnancy are described separately . Not considered are appropriate targets for blood pressure control during pregnancy, as these have not yet been established, neither for the mother or offspring, whether short or long term. ISSHP (the International Society for the Study of Hypertension in Pregnancy) argues for tight blood pressure control, with 85 mmHg as a diastolic goal, based on the CHIPS trial. The CHIPS trial enrolled however only women with chronic or gestational hypertension, where almost half developed preeclampsia. Also, there was no significant improvement with tight blood pressure control in the risk of pregnancy loss, high-level neonatal care, or overall maternal complications, although less-tight control was associated with a significantly higher frequency of severe maternal hypertension.

Whether antihypertensive therapy in pregnancy should be targeted to specific hemodynamic endpoints other than systolic and diastolic arterial pressure, such as maternal cardiac output or measures derived from maternal pulse wave analysis, ^, is also not discussed.

The costs of drugs and their use in high versus low-resource settings are also not discussed. As discussed below however, a recent RCT showed that in low-resource settings, the three oral drugs methyldopa, nifedipine, and labetalol are all viable options for pregnant women requiring antihypertensive treatment. As single drugs, sustained-release nifedipine use resulted in a higher rate of blood pressure control, while women receiving methyldopa more often had to add another drug to achieve blood pressure control.

Sympathetic Nervous System Inhibition

Introduction of agents to decrease peripheral activity of the sympathetic nervous system marked, perhaps, the beginning of the modern era of effective antihypertensive therapy. Strategies for sympathoinhibition have included ganglionic blockade (e.g., guanethidine), depletion of norepinephrine from sympathetic nerve terminals, such as reserpine, which is probably the first antihypertensive to have proven benefit in a prospective clinical trial, α ₂ -adrenergic agonists to decrease sympathetic outflow from the central nervous system (e.g., α-methyldopa and clonidine), and specific antagonists of α ₁ -or β-adrenergic receptors—including α ₁ -antagonists such as prazosin, terazosin, and doxazosin and β-blockers such as propranolol, atenolol, and metoprolol; and combined α/β antagonists including labetalol and carvedilol.

Centrally Acting α ₂ -Adrenergic Agonists

Methyldopa is the prototypical agent of this class. It is a prodrug metabolized to α-methylnorepinephrine, which then replaces norepinephrine in the neurosecretory vesicles of adrenergic nerve terminals. Because its efficacy is equivalent to that of norepinephrine at peripheral α ₁ receptors, vasoconstriction is unimpaired. Centrally, however, it is resistant to degradation by monoamine oxidase, resulting in enhanced effect at the α ₂ sites that regulate sympathetic outflow. Decreased sympathetic tone reduces systemic vascular resistance, accompanied by only minor decrements in cardiac output, at least in young, otherwise healthy hypertensive patients. Blood pressure control is gradual, over 6–8 h, due to the indirect mechanism of action. There do not appear to be significant decreases in renin and, while the hypotensive effect is greater in the upright than supine posture, orthostatic hypotension is usually minor. Clonidine, a selective α ₂ agonist, acts similarly.

Adverse effects are mostly predictable consequences of central α ₂ -agonism or decreased peripheral sympathetic tone. These drugs act at sites in the brainstem to decrease mental alertness, impair sleep, lead to a sense of fatigue or depression in some patients, and decrease salivation to cause xerostomia. Peripheral sympathoinhibition may impair cardiac conduction in susceptible patients. Methyldopa can induce hyperprolactinemia and Parkinsonian signs in some patients. In addition, it can cause some potentially serious dose-independent adverse effects. Approximately 5% of patients receiving methyldopa will have elevated liver enzymes, with some manifesting frank hepatitis and, rarely, hepatic necrosis. Likewise, many patients will develop a positive Coombs test with chronic use, a small fraction of these progressing to hemolytic anemia.

Peripherally Acting Adrenergic-Receptor Antagonists

Cardiac β ₁ receptors mediate the chronotropic and inotropic effects of sympathetic stimulation, while receptors in the kidney modulate renin synthesis in response to renal sympathetic input. Activation of β ₂ receptors leads to relaxation of airway smooth muscle and to peripheral vasodilatation. Acutely, nonselective β-blockade decreases cardiac output, but with limited change in arterial pressure, due to increased systemic vascular resistance. Over time, vascular resistance falls to predrug levels, resulting in a persisting hypotensive response that parallels the decrease in cardiac output. Moderate decrements in renin, and thus in angiotensin II and aldosterone, may contribute to the chronic antihypertensive efficacy of β-blockers in some patients, likely accounting for their greater efficacy in patient groups not believed to have salt-sensitive hypertension. ^, Some agents, such as pindolol or oxprenolol, are partial β-receptor agonists, namely they possess some limited degree of “intrinsic sympathomimetic activity.” These drugs lead to lesser decrements in cardiac output and β ₂ stimulation may even result in significant decrements of vascular resistance. Individual drugs may also possess selective potency at β ₁ >β ₂ receptors (e.g., atenolol and metoprolol), the additional capacity to block vascular α ₁ receptors (e.g., labetalol), and may differ in their lipid solubility, such that hydrophilic agents gain less access to the central nervous system.

β-receptor antagonists are currently considered second-line agents for hypertension in nonpregnant adults (after diuretics, ACE inhibitors, angiotensin receptor blockers, and calcium channel blockers) except when specific comorbidities suggest their initial use. They are preferred agents in patients who have experienced recent myocardial infarction, ^, but appear to provide less benefit than diuretics in elderly patients with isolated systolic hypertension, in the prevention of stroke, or when compared with angiotensin receptor blockers in patients with multiple cardiovascular risk factors. Unlike other agents, long-term use of β-blockers is not associated with (beneficial) remodeling of small resistance arteries, which have been hypertrophied due to hypertension, the clinical consequences of this observation being unknown.

Adverse effects are predictable results of β-receptor blockade. They include fatigue and lethargy, exercise intolerance due mostly to (nonselective) β effects in skeletal muscle vasculature, peripheral vasoconstriction secondary to decreased cardiac output, sleep disturbance with use of more lipid-soluble drugs, and bronchoconstriction. While negative inotropy could worsen acute decompensated congestive heart failure or lead to heart block in susceptible patients, β-blockers exert paradoxical benefit in all stages of chronic heart failure with decreased systolic function.