As many as 10% to 13% of children will have elevated blood pressure (BP) on a single measurement (13,14), but persistent hypertension is observed in only 1% to 2.5% of the pediatric population (15,16,17,18). More recent data estimates that the prevalence of pre-hypertension is nearly 10% and established hypertension 4%, with greater burden on minority children (19). Despite the availability of widely accepted normative BP data (20), the accurate diagnosis of persistent hypertension can be difficult. Errors in cuff selection and technique are still common despite publication of accepted methods for performing casual BP measurement in children (18). Labile BP and the “white coat” effect complicate the diagnosis in children with high normal BP or borderline to moderate hypertension (21,22). The use of ambulatory blood pressure monitoring (ABPM) in these children has helped to separate those who require evaluation and treatment from those who need only longitudinal observation (20,23,24). Accurate diagnosis is extremely important because failure to diagnose and adequately control clinically significant hypertension may result in the development of target organ damage (25,26,27,28,29,30). Conversely, improper diagnosis and subsequent treatment of normotensive children may risk unnecessary exposure to adverse events.

Selection of appropriate therapy often depends on the suspected cause of hypertension. Secondary causes of hypertension, particularly renal and renovascular diseases, are commonly observed among preadolescent children (Table 49.2) (20,31,32). During adolescence, secondary causes of hypertension continue to occur, but the prevalence of primary hypertension increases dramatically (20,33). It is likely that obesity, insulin resistance, and genetically determined factors contribute to the development of hypertension in some adolescents (34,35,36,37). Both primary and secondary hypertension in children and adolescents may result in significant target organ damage (25,26,27,28,29,30). It is particularly important that these children receive adequate antihypertensive therapy. The working group has recommended that pharmacologic treatment be initiated in individuals with symptomatic hypertension,
secondary hypertension, evidence of target organ damage (left ventricular hypertrophy), diabetes (type 1 and 2), and persistent hypertension after attempted life-style change (20). Unfortunately, these recommendations lack the support of clinical trials.

Dietary modifications, weight reduction, and aerobic exercise are useful interventions in almost all children with hypertension (20). These nonpharmacologic therapies are often employed initially as the sole treatment in children with prehypertension (90th to 95th percentile) and stage I (95th to 99th percentile) primary hypertension who do not exhibit target organ damage and have few, if any, additional cardiovascular risk factors (38). It is important to note that nonpharmacologic therapies often augment the effectiveness of selected antihypertensive agents in both primary and secondary hypertension in children [e.g., sodium chloride restriction and angiotensin-converting enzyme (ACE) inhibitor therapy].

In children, as in adults, many physicians have abandoned the traditional stepped-care approach to therapy. Individualized selection of therapeutic agents in children depends on many factors (Table 49.3).

A scheme for classifying antihypertensive agents is presented in Table 49.4. Diuretics, although quite useful in the treatment of hypertension in children, are considered elsewhere (Chapter 43). Angiotensin-II-receptor antagonists (ARBs),
ACE inhibitors, calcium channel blockers (CCBs), adrenergic inhibitors, and direct vasodilators represent the main focus of this chapter.

Although initial data concerning the pharmacokinetics, effectiveness, and safety of antihypertensives in children are becoming available, the large-scale comparative trials conducted in adults that show superiority of one drug or one therapeutic approach over another have not been conducted in children. For a variety of reasons, it is unlikely that studies similar to the widely publicized Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (39), which compared representative drugs from four different therapeutic classes in a population of 33,357 subjects, will be conducted in children in the foreseeable future. Many similar studies are ongoing in the adult population (40). Hence, in treating children with hypertension, choices among available drug classes rely less on specific comparative data collected from pediatric patients and more on the suspected cause of the elevated BP, previous clinical experience, extrapolation from studies conducted in adults, and availability of pediatric formulations. Recommended dosing for antihypertensive agents for children and adolescents (Table 49.5) and neonates (Table 49.6) is based on currently available information and may be subject to change depending on the outcome of ongoing studies. Antihypertensive agents used in the treatment of hypertensive emergencies and urgencies are presented in Table 49.7.

The sympathetic division of the autonomic nervous system plays a key role in the regulation of BP. At the postganglionic synapse, norepinephrine is released from vesicles in the presynaptic membrane in response to sympathetic stimulation and binds to receptors on postganglionic effector organs. Stimulation of sympathetic nerves terminating in the adrenal medulla results in release of epinephrine and, to a lesser extent, other catecholamines into circulating blood.

The effects of the adrenergic nervous system are mediated through α and β receptors, each of which has subtypes. The α₁ adrenoceptors are located in the heart and smooth muscle in blood vessels, the intestinal tract, and the genitourinary tract. The cardiovascular effects of α₁ stimulation include vasoconstriction, increased systemic vascular resistance, and increased BP. Stimulation of α₂ receptors, which are located primarily at the postganglionic presynaptic membrane, inhibits further release of norepinephrine. Distinct subtypes of both α₁ and α₂ receptors have been identified. β₁ – and β₂ -adrenergic receptors are segregated based on their response to norepinephrine and epinephrine. The β₁ receptors, located primarily in the heart, adipose tissue, and juxtaglomerular cells, respond equivalently to epinephrine and norepinephrine. Stimulation of β₁ receptors results in tachycardia, increased myocardial contractility, increased conduction velocity in the atrioventricular node, and lipolysis. At β₂ receptors, response to norepinephrine is much less than that seen after stimulation with epinephrine. The β₂ receptors are found in many organs including the liver, skeletal muscle, and smooth muscle located in the vasculature and the gastrointestinal, respiratory, and genitourinary tracts. Stimulation of β₂ receptors results in smooth muscle relaxation and bronchodilation, vasodilation, and increased glucose release. As with α receptors, distinct subtypes of both β₁ and β₂ receptors have been identified.

β-Adrenergic-receptor antagonists are distinguished by selectivity for the β₁ -adrenergic receptor (Table 49.8), the presence of intrinsic sympathomimetic activity, unique pharmacologic properties (Table 49.9), and α-adrenergic blocking activity. Cardioselective drugs have greater affinity for β₁ -adrenergic receptors, and nonselective agents have approximately equal affinity for both β₁ – and β₂ -adrenergic receptors. At higher doses, cardioselective agents may demonstrate not only β₁ -antagonist activity but also some degree of β₂ antagonism. Some β-adrenergic antagonists, including acebutolol and pindolol, have small but significant β-agonist effect, known as intrinsic sympathomimetic activity. Because the agonist effect is significantly less than the antagonist effect, the antihypertensive properties of these agents are not compromised. Intrinsic sympathomimetic activity of β-adrenergic blockers helps to reduce selected adverse effects resulting from β₁ antagonism (e.g., bradycardia).

Adrenergic antagonists reversibly or irreversibly bind to α and β receptors. Receptor blockade antagonizes the effects of norepinephrine at the postganglionic synaptic membrane as well as circulating catecholamines. The resultant effects are complex and depend on the type of receptors that are blocked and the unique properties possessed by individual agents (41).