Hypertension occurring during childhood and adolescence is on the threshold of being recognized as a significant health problem throughout the industrialized world. Although the exact level above which blood pressure should be considered abnormally elevated for any given age has not been precisely defined, it has been known for many years that normal blood pressure in children is much lower than that in adults and increases slowly during the developmental years until it approaches adult levels at some point during late adolescence (Figure I).1 Until recently, the definition of hypertension in children regardless of age has been dependent on adult standards; consequently, hypertension was rarely recognized before the third decade of life. It is therefore not difficult to understand why the assessment of blood pressure has been a sorely neglected component of the routine physical examination of children.
The clinical impression that hypertension has little relevance to children has never been substantiated by critical epidemiologic assessments of blood pressure in this age group. Indeed, as physicians caring for children have begun to examine this aspect of health care more closely in recent years, it has become clear that greater numbers of children will be recognized during their first and second decades of life as having blood pressures significantly higher than those of their peers. Pathophysiologic alterations ascribed to adult essential hypertension probably have their onset during childhood in many cases.2 This makes it all the more important for pediatricians to develop an understanding of the dynamics of blood pressure in children, as well as of the current concepts of antihypertensive treatment. In this way, young hypertensive patients can be protected from the morbid events that result from prolonged exposure to elevated systemic blood pressure.
Figure 1. Mean blood pressures of 728 children in two-year age groups (boys and girls).1 (Reprinted by permission of the New England Journal of Medicine.)
Sufficient data regarding genetic influences on essential hypertension now exist to support the growing suspicion that hypertension will be established as a primary health concern during the preadult years. Not only have twin, sibling, and family studies among adult hypertensives shown a similarity of blood pressure dependent on the degree of familial relationship, but also recent studies in families with young children have confirmed that genetic composition has a strong contributing influence. For instance, a study of 721 children two to 14 years of age from 190 families has shown a clustering effect of blood pressure among families measurable at all levels.1 In addition, a preliminary epidemiologic study from Montreal of natural and adopted children residing in the same households demonstrated a highly significant similarity in blood pressure between natural children aged one to 21 and their parents, whereas the comparison between adopted children and these parents revealed no such similarity.3
Information from surveys such as these has obvious implications for pediatric patients. If we are to continue to fulfill our role as primary providers of preventive health-care maintenance, a concerted effort must be undertaken to detect children whose blood pressures warrant careful longitudinal evaluation or antihypertensive therapy. The number of such children with a genetic predisposition for the development of hypertension must be substantial, since it has been estimated that 15 to 20 per cent of adults in the United States are hypertensive4 and that 90 to 95 per cent of these have essential hypertension.5 The potential for recognition should be even greater in blacks, in whom hypertension develops earlier in life, is frequently more severe, and results in a higher mortality at a younger age.6
It is commonly believed among pediatricians that, in contrast to the case with adults, 80 per cent of all hypertension in children is secondary.7 Recent experience seems to indicate that this is a vastly inflated figure, resulting from analysis of patients from referral centers that see only children with the most severe elevations of blood pressure. As one might suspect, more careful examination of blood pressure in children has yielded greater numbers of hypertensives in whom complete and comprehensive evaluations have been far less rewarding.® If experience such as this continues to be confirmed, we may need to reevaluate our current philosophy of aggressive and costly evaluation of hypertensive children (except for those with extreme elevations) in favor of earlier trials of antihypertensive therapy.
The extended period between the onset of hypertension during childhood or adolescence and the appearance of overt symptoms of the type usually seen during adulthood has served to shield pediatricians from the serious consequences of this disease process. Legitimate concern has therefore arisen with regard to the advisability of early initiation of antihypertensive therapy in these patients. However, the potential merit of early intervention can be supported from experience with antihypertensive therapeutic programs for adults, which have had a significant influence in protecting against the devastating morbid events that are so commonly seen in untreated hypertensive patients.
The effects of untreated essential hypertension have been catalogued in epidemiologic studies such as that undertaken in Framingham, Massachusetts. This investigation has demonstrated that hypertension is clearly the most important contributor to the incidence of stroke.9 In addition, there is a steady increase in the risk of coronary heart disease with increasing increments of blood pressure'? and six times more congestive heart failure in hypertensive than in normotensive persons.1' In contrast, the well-publicized Veterans Administration Cooperative study has shown that these complications could be reduced to one-third if ~ patients with severe diastolic hypertension received adequate antihypertensive therapy." Attempts to modify the hypertensive state from the moment of its onset might even more profoundly affect these statistics.
There is still considerable controversy about the levels of blood pressure, either systolic or diastolic, that are sufficiently elevated to warrant the categorical diagnosis of hypertension. There appears to be a general consensus that whereas the systolic level is difficult to establish with certainty, a diastolic level of 90 mm. Hg or greater during childhood or adolescence should definitely be considered to fall into this category. However, the dearth of information on the prognosis for young people with moderate hypertension has created a dilermna for physicians who must decide whether or not to initiate antihypertensive therapy. In a study from Evans County, Georgia,13 60 per cent of 30 adolescents with initial blood pressures of 140 systolic andlor 90 diastolic were found after seven years to have either cardiovascular or cerebrovascular disease or further elevation of their blood pressure. Although 40 per cent of this group had a return of their blood pressure to normal levels after seven years, vigorous attempts should be made to maintain blood pressure below these levels.
Not every child with a diastolic blood pressure of 90 mm. Hg should be subjected to a trial of antihypertensive therapy. A significant number of children, particularly adolescents, have borderline or labile hypertension - i.e., blood pressure found to be elevated at the time of some examinations but normal at others. Some patients who are destined to develop sustained hypertension will eventually declare themselves during regular periodic examinations. Therefore, only children with persistent hypertension documented by numerous observations should be considered for initiation of therapy - and then only after it has been established that secondary forms of hypertension do not exist.
GENERAL CONSIDERATIONS IN THERAPY
In addition to appropriate selection of children for antihypertensive therapy, serious questions remain unresolved concerning the consequences of prolonged administration of these agents in the developing organism. Although serious overt adverse pharmacologic effects appear to be uncommon, adequate longitudinal evaluation during the developmental years has not been completed on sufficient numbers of children to allay concern.
Compliance has been found to be a major obstacle to therapeutic efficacy in this age group even with the most elementary of regimens. Since no ideal antihypertensive drug is currently available, it is not uncommon for therapy to consist of several antihypertensive agents used in a variety of combinations and complicated dosing schedules. Thus, at a time in their lives when freedom is paramount and order anathema, therapy becomes additionally problematic for these patients, who often find it difficult to accept either the significance or the prognostic implications of this seemingly benign illness that demands so much of them.
The recognition of essential hypertension with greater frequency at an earlier age indicates that pediatricians may soon become actively engaged in antihypertensive management as part of their role in primary health-care delivery. Proper implementation of this new responsibility will require a fundamental understanding of the pharmacology and pharmacokinetics of antihypertensive drugs, as well as the basic philosophies influencing current antihypertensive regimens. As one might expect, the large number of available antihypertensive agents reflects the inability of any single member of this group fo elicit an effective therapeutic response in all cases of hypertension. The following summary describes properties of the most useful antihypertensive agents that appear to be important in designing optimum therapeutic regimens (Figure 2, Table 1). Although each physician must select the therapeutic regimen with which he feels most comfortable, clinical experience strongly suggests that certain sequences of drug administration are more efficacious than others; in general, the discussion will emphasize these concepts.
The benzothiadiazide diuretics. more commonly referred to as thiazides, continue to be the most widely used group of antihypertensive agents and the group most frequently selected to initiate antihypertensive therapy. The most plausible explanation for their mechanism of action appears to be that they cause a decrease in salt and water content, despite evidence that demonstrates a restoration of these parameters to normal after a period of continuous thiazide therapy. In addition, thiazides may exert a direct effect on arteriolar smooth muscle. This is suggested by data demonstrating a marked vasodilatory response after the administration of diazoxide during hypertensive emergencies.
Both chlorothiazide and hydrochlorothiazide have been found to be effective in reducing the blood pressure of mild and moderate hypertensives and maintaining it at appropriate levels over extended periods of therapy. A beneficial response is usually apparent after two weeks at a dose of 10-20 mg. /kg. of chlorothiazide (maximum: 2 gm.) or 1-2 mg. /kg. of hydrochlorothiazide (maximum: 200 mg.). Although the serum half-life of the thiazides is approximately five hours, M no substantial improvement in clinical response accrues from administration of these drugs more often than every 12 hours. IS
Figure 2. Schematic diagram of sites of a acton of antihypertensive drugs.
Additional benefit is rarely derived from increasing thiazides to amounts greater than the recommended maximum dose.16 However, even in cases of hypertension in which the response to thiazides is inadequate, continued use is recommended in conjunction with additional antihypertensive drugs, since it has been clearly demonstrated that salt and water retention is a critical limiting factor to the effectiveness of all antihypertensive agents, with the possible exception of propranolol.
The major side effect of thiazide therapy is hypokalemia, which is most likely to occur during the early weeks of thiazide administration and can be corrected with oral potassium supplements. The unpalatability of most potassium salts creates a considerable compliance problem. Under such circumstances one can use spironolactone, which, however, increases the cost of therapy and is not itself free from side effects. Fortunately, most children can eventually be maintained without potassium supplementation after equilibrium has been re-established and with the proper instruction concerning potassium-containing foods. (Foods high in potassium include cranberries, oranges, tomatoes, apples, pineapples, grapes, and bananas.) This does not, however, obviate the need for periodic assessment of serum potassium that remains essential throughout the course of thiazide therapy. Other side effects, such as hyperglycemia and hyperuricemia, that are common in adults do not appear to be of significance during childhood.
Other diurectic agents have also been found to be effective in lowering blood pressure. Chlorthalidone (Hygroton®) is similar in action to the thiazides and has the advantage of prolonged pharmacologic effect, thereby requiring only a single daily dose. This is particularly advantageous for adolescents, in whom multiple-dose schedules create serious compliance problems. Furosemide (Lasix®) is an exceptionally potent diuretic that is best reserved for patients with hypertension and reduced renal clearance. Hyponatremia and hypocalcemia can occur following initiation of furosemide therapy but pose much less of a threat than hypokalemia, which almost uniformly occurs to such a degree that potassium supplementation is required throughout the period of administration.
PEDIATRIC DOSAGE REGIMEN FOR ANTIHYPERTENSIVE AGENTS
Spironolactone (Aldactone®) has been recommended for the therapy of "low-renin" essential hypertension17 but does not seem to be extensively used in pediatrics. It can be particularly helpful as an adjunct to therapy in cases of suspected secondary hyperaldosteronism, such as those occurring in nephrosis or congestive heart failure. However, there seems no urgent reason to favor it over the thiazides as a primary antihypertensive agent.
Before the development of effective diuretic agents, salt-free diets were utilized with reasonable success in patients able to suffer the dietary restrictions of less than 1 gm. of salt per day. The severity of this restriction can be placed in its proper perspective if one realizes that the average salt intake in the American diet is far greater than 5 gm. per day.18 It is unreasonable to expect either children or adolescents to be able to significantly alter their diets other than to effect a modest reduction in salt-containing foods. However, dietary salt reduction should be encouraged as an integral facet of antihypertensive therapy, since the effectiveness of thiazide therapy is limited by excessive salt intake.
Drugs Acting on the. Adrenergic Nervous System
Methyldopa (Aldomet®). Methyldopa has been used primarily in children who do not respond to thiazide therapy alone. Its mechanism of action appears to be directly related to an interference with catecholamine production. It acts peripherally as a false transmitter at nerve endings to decrease arteriolar resistance. In addition, recent evidence strongly suggests that methyldopa is responsible for similar biochemical alterations within the central nervous system that also play an important role in decreasing systemic blood pressure.
Methyldopa therapy is initiated at 10 mg. /kg. /24 hours in two divided doses. The half- life of this drug is approximately 12 hours in normal adults, suggesting that steady-state conditions will be achieved only after two or three days of therapy. Consequently, a maximal response to any given oral dose of this drug will not be observed until a corresponding period has elapsed. A more rapid onset of action occurs if the compound is given intravenously. The dose of methyldopa can be increased in incremental fashion to 40 mg./kg. (maximum: 2 gm.) in an effort to achieve adequate blood pressure control. Administration of doses in excess of this amount rarely increases the drug's therapeutic efficacy and usually serves only to intensify side effects.
The most frequently observed adverse effects of methyldopa are sedation, which may occur shortly after therapy is started or when the dosage is increased during the course of therapy, and postural hypertension. In almost all cases these effects seem to remit, provided the dosage remains constant. Other side effects, such as lupuslike and hepatitislike reactions, have been reported but appear to be rare in children. A more common finding is a positive direct Coombs' test, which occasionally leads to hemolytic anemia. As mentioned above, diuretic therapy should be used in conjunction with methyldopa to prevent salt and water retention, which severely limits its effectiveness.
Propranolol (Inderal®). Adrenergic nervous system responses are mediated by either alpha- or betaadrenoreceptors. Propranolol acts primarily on the beta-adrenergic receptors (types 1 and 2) to block such responses as bronchiolar smoothmuscle relaxation, tachycardia, and renin release from the kidney.
Propranolol has been utilized for the treatment of cardiac dysrhythmias over the past decade, and it has recently been officially released by the FDA for use as an antihypertensive agent. Propranolol has assumed a prominent role in the therapy of adult hypertensive subjects19 and has been documented as being both effective and safe. Although similar documentation is not yet available with regard to its value in children, early reports indicate that it is likely to become an important adjunct to current therapeutic regimens.
As is the case with methyldopa, propranolol has been shown to exert its antihypertensive effect by acting upon the adrenergic nervous system in at least two distinct anatomic sites. Peripherally, it suppresses renin release from the kidney by blocking the effect of adrenergic neurotransmitter (norepinephrine) on the juxtaglomerular apparatus; centrally, it acts to suppress the intrinsic activity of the vasomotor center, leading to a decrease in vasomotor tone and a lowering of systemic blood pressure in the absence of any effect on renin levels. Therapy is usually initiated at 0.5-1 mg./kg. in four daily doses. However, the drug appears to be well tolerated in doses far in excess of those required to achieve a betablocking effect upon myocardial and arteriolar smooth muscle. As one would anticipate from its mode of action, propranolol is contraindicated in patients with a history of congestive heart failure, asthma, or diabetes mellitus. Propranolol has been reported to be particularly useful in adults when combined with vasodilator therapy to blunt the reflex tachycardia that occurs secondarily to peripheral vasodilation and limits patient tolerance to this agent. This regimen is currently under evaluation in children receiving propranolol, minoxidil, and hydrochlorothiazide.20
Guanethidine (Ismelin®). Because of its extremely long half-life, which permits administration of a single daily dose to maintain adequate blood levels, guanethidine has an obvious attraction as a primary antihypertensive agent. However, it is effective principally during those periods of the day when the patient is upright,21 effecting little alteration in blood pressure when the patient is supine. It is consequently of minimal utility in the management of neonates or infants with hypertension. Guanethidine is most appropriately used in cases of severe hypertension that are unresponsive to other forms of antihypertensive therapy.
The vasodilators act directly on arteriolar smooth muscle to reduce peripheral vascular resistance. In response to the subsequent fall in arterial blood pressure, increases in sympathetic activity and renin activity may occur that are manifested by an elevation in heart rate and cardiac output. The use of propranolol concomitantly with vasodilator agents has provided a mechanism whereby these potentially adverse effects can be blunted, permitting more aggressive and effective use of this form of therapy.22 In addition, propranolol allows newer and more potent vasodilators, which elicit even more profound compensatory cardiovascular responses, to be administered to patients without fear of disabling side effects.
Hydralazine (Apresoline®) has been used in children for a number of years but has not achieved the success noted in adult hypertensives. This is possibly related to the more severe and secondary nature of the hypertension usually recognized in children. However, now that a greater incidence of essential hypertension is being documented in this age group, hydralazine may be of value, particularly when used concurrently with propranolol. Headache, tachycardia, flushing, and nausea are minor side effects seen with this drug. The most worrisome side effect is a lupus erythematosuslike phenomenon that may be genetically determined. Recent data suggest a correlation between the rate of hepatic drug metabolism and the appearance of this phenomenon; however, the studies are not yet conclusive. Limiting the dosage of hydralazine during long-term therapy to 100-200 mg. per day, depending on age and size, will usually prevent its occurrence.
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PEDIATRIC DOSAGE REGIMEN FOR ANTIHYPERTENSIVE AGENTS