In 1987 the Second Task Force on Blood Pressure Control in Children recommended that nonpharmacologic therapy, including weight reduction, physical conditioning, and dietary modification, be used as first steps in the treatment of hypertension in children.1 If this approach fails and pharmacologic therapy is indicated, a stepped-care approach has been recommended. Traditionally the medications used in this setting have been thiazide diuretics, with the addition of an adrenergic blocking agent and then a vasodilator. Although these medications are effective, they have been associated with adverse effects on serum electrolytes and lipid and glucose metabolism as well as physical performance and cognitive function.
During the 1980s, several new and exciting classes of antihypertensive medications have been proven to be efficacious and well tolerated. These medications have been used extensively in adults and are now gaining acceptance among pediatric nephrologists for use in children. Several of these new drugs are particularly useful in treating hypertension associated with renovascular and renal parenchymal disease (common types of secondary hypertension in young children) because they are specific in altering the pathophysiology of these disease states. The purpose of this article is to review two new classes of antihypertensive medications - angiotensin converting enzyme inhibitors and calcium channel blockers - their mode of action and specific situations in which they may be superior to conventional therapy.
ANGIOTENSIN CONVERTING ENZYME INHIBITORS
In 1934 Goldblatt et al postulated that the reninangiotensin system played a role in hypertension.2 Renin is an enzyme synthesized in the kidney that reacts with its substrate, angiotensinogen, in the blood to form a decapeptide, angiotensin I. Angiotensin I is subsequently modified by its converting enzyme to the octapeptide, angiotensin II. The major site of converting enzyme activity is the lung. Angiotensin II raises the blood pressure through two main actions. It is a powerful vasoconstrictor and it also stimulates aldosterone secretion, which increases extracellular fluid volume through enhancement of sodium retention by the kidney. Over the years various inhibitors of components of this system have been developed to study the pathophysiology of hypertensive states and also to provide a specific treatment for hypertension associated with high renin levels.
In 1977 the first orally active angiotensin converting enzyme inhibitor, Captopril (Capoten®), was introduced. This drug blocks the generation of angiotensin II, resulting in vasodilatation and decreases of systemic vascular resistance and systemic arterial pressure. It has been used extensively in adults and more recently in infants and children.
In 1985 Mirkin et al reported the results of an International Collaborative Study that evaluated the safety and efficacy of Captopril in children with severe and refractory hypertension.3 Seventy-three hypertensive patients 15 years of age or younger were included in the study. Most had hypertension associated with renal disease or vascular anomalies. Captopril effectively lowered systolic blood pressures in 62% of the patients after 2 months of therapy and in 56% after 6 months. Adverse reactions, reported in 49% of the patients, included hypotension (7 patients), vomiting (5 patients), postural symptoms (5 patients), anemia (4 patients), rash (4 patients), and anorexia (3 patients). Other studies have reported agranulocytosis, bradycardia, neutropenia, hyperkalemia, renal damage, and loss of taste perception.4,5
In 1988 Tack and Perlman reported the results of a retrospective study of nine hypertensive premature infants (systolic blood pressure > 113 mmHg) with chronic lung disease who received Captopril therapy.6 All infants had markedly elevated peripheral renin values, 134.3 ± 128 ng/mL/hr (normal: 0.11 to 1.30 mg/mL/hr). After the initial dose of 0.3 mg/kg, systolic blood pressure decreased significantly in all infants, requiring a decrease in subsequent doses to 0. 15 to 0.2 mg/kg every 6 hours. However even during maintenance therapy on the reduced doses, unpredictable decreases in blood pressure occurred, frequently accompanied by oliguria and impaired neurological function ranging from lethargy to seizures. In a followup article, Perlman and Volpe reported that rapid decreases in blood pressure, even to normal levels for age, may have adverse neurological effects in sick infants due to an impaired adaptive cerebral blood flow response.7 Obviously, Captopril is effective, but it should be used cautiously in this population, with the objective of lowering blood pressure gradually to avoid neurological sequelae.
Captopril is available only in the oral form. For patients who require a liquid preparation, a 25 mg tablet can be crushed and added to 25 or 100 mL of water, producing a solution of 1.0 and 0.25 mg/mL, respectively. The solution should be used within 30 minutes of preparation. Captopril is absorbed from the gastrointestinal tract in 30 to 90 minutes. The presence of food reduces absorption by 30% to 40%. Therefore Captopril should be given 1 hour before meals. It is rapidly metabolized, and the half-life of unchanged drug is probably fewer than 2 hours. Elimination is primarily renal and the dose should be reduced in the presence of renal failure. The drug is removed by hemodialysis.
Following the administration of Captopril to hypertensive patients, peripheral arterial resistance is reduced and cardiac output increases or remains unchanged. Reductions of blood pressure are usually maximal 60 to 90 minutes after administration. The duration of effect is dose related. In some patients, including children with bilateral renal artery stenosis, blood urea nitrogen and creatinine may increase and oliguria may occur after reduction of blood pressure with Captopril. In these patients, it may not be possible to normalize blood pressure and at the same time maintain adequate renal perfusion and function.8·9 In any patients with renal disease who are treated with angiotensin converting enzyme inhibitors, blood urea nitrogen, creatinine, and potassium should be monitored during the course of therapy.
The usual starting dose of Captopril in neonates is 0.1 to 0.4 mg/kg every 6 to 24 hours. Infants and children may be given 0. 5 to 0. 6 mg/kg per day divided every 6 to 12 hours. The initial dose for adolescents and adults is 25 mg two or three times a day, which may gradually be increased to 50 mg. A maximum daily dose of 450 mg should not be exceeded. If adequate blood pressure control is not achieved, the addition of a thiazide diuretic may prove effective, as diuretics have been shown to enhance the antihypertensive effect of angiotensin converting enzyme inhibitors.
Another new drug in this class of antihypertensive medications is enalapril maleate (Vasotec®), which is the prodrug of enalaprilat, a long-acting angiotensin converting enzyme inhibitor. It differs from Captopril in that it contains no sulfhydryl group. It is available in the oral form and recently has been released for intravenous use. The mechanism of action is the same as Captopril, although the onset of action is slower. FoIlowing oral administration, approximately 60% of enalapril is absorbed in the gastrointestinal tract. The presence of food does not affect absorption. Enalapril is then hydrolyzed to enalaprilat. The peak effect of this drug is usually seen 4 hours after oral administration. Excretion of enalapril is primarily renal and caution should be used in patients with renal insufficiency. The drug is removed by hemodialysis.
In 1987 Miller et al studied the efficacy and safety of oral enalapril in a pediatric hypertensive population. 10 Fifteen children ranging in age from 6 weeks to 18.5 years were placed on enalapril in doses ranging from 2.5 to 30 mg once a day. All of the patients had an underlying renal lesion as a cause of their hypertension. Adequate blood pressure control was achieved in all patients, although five children required the addition of diuretics. No significant adverse reactions were seen, and renal function actually improved in seven patients. In older children and adolescents, the usual dose of enalapril is 5 to 10 mg once a day. Occasionally a twice a day dose is required. Patients who are already on diuretic therapy should be started on a lower dose. Reported side effects are similar to those reported with Captopril and include hypotension, especially when used in volume depleted patients, and neutropenia.
Intravenous enalaprilat has recently become available, although experience with use in children has been limited. In one report intravenous enalaprilat was used in nine children (ages 7 months to 4 years) during routine cardiac catheterization.11 Initially, 0.01 mg/kg was given followed by 0.05 mg/kg 5 minutes later. Aortic and pulmonary arterial pressures were significantly reduced after 30 minutes compared with baseline, while heart rate remained unchanged. At this time clinical studies are underway to evaluate the efficacy and safety of intravenous enalaprilat in children for the treatment of hypertension.
In general, the angiotensin converting enzyme inhibitors appear to be useful agents in the treatment of infants and children with severe hypertension associated with high renin states such as renal parenchymal or renal vascular disease. Little has been reported on the use of these drugs for treatment of essential hypertension in the pediatric age group. In adults Captopril and enalapril have been used to treat mild to moderate essential hypertension, usually in combination with a diuretic.4,12
CALCIUM CHANNEL BLOCKERS
Calcium channel blockers have been used extensively in Europe and recently have been introduced in the United States for treatment of angina pectoris, arrhythmias, and hypertension in adults. Recent reports have described experience in the use of these agents for treatment of hypertension in children.
The antihypertensive effect of this class of drug occurs by vasodilatation. This is accomplished by inhibiting the movement of calcium across the cell membrane of the smooth muscle cells of resistance arterioles, diminishing vascular smooth muscle tone without changing serum calcium levels.
The three calcium channel blockers currently available in the United States are nifedipine, verapamil, and diltiazem. All three are arterial vasodilators and act on coronary as well as peripheral vessels, although to different degrees. Nifedipine is the most potent arterial vasodilator and acts primarily on peripheral vessels; whereas verapamil and diltiazem, in addition to vasodilatory effects, also exert negative chronotropic and inotropic effects on the heart. Unlike several other classes of antihypertensive medications, these drugs are not associated with bronchoconstriction or orthostatic hypotension. They seldom cause reflex tachycardia; renal blood flow and glomerular filtration rate are maintained or increased. They also increase urinary sodium excretion, which may contribute to their effectiveness, and hence diuretics may not be a necessary part of the antihypertensive regimen.
Of this group of calcium channel blockers, nifedipine (Procardia®) is the most potent vasodilator. It may be given orally or sublingualis with resulting drops in blood pressure and systemic vascular resistance seen within 10 to 15 minutes. The maximal decrease in blood pressure is seen within 60 to 90 minutes. The effect of sublingual nifedipine lasts 2 to 3 hours and the effect of oral nifedipine lasts 4 to 8 hours. Nifedipine is largely converted to inactive metabolites, 80% of which are eliminated by the kidneys. No information is available on the effects of renal or hepatic impairment on metabolism or excretion of nifedipine. Nifedipine is highly protein bound and, therefore, is not effectively eliminated by hemodialysis. Common side effects include headache, palpitations, and flushing.
Several groups have reported their experience with nifedipine in the pediatric age group. Siegler and Brewer studied 20 hypertensive children ranging in age from 14 months to 14 years.13 The average dose given was 0.33 mg/kg, with a range of 0. 15 to 0.61 mg/kg. In most of the children the dose was administered by drawing the contents of a 10 mg capsule into a 1 mL syringe, and administering the appropriate dose sublinguali^ Blood pressure began to fall within 5 to 10 minutes after sublingual administration, with a maximum decrease occurring after a mean of 24 minutes. A shortcoming of nifedipine in this study was the unpredictable duration of action. Although a majority of the patients had evidence of adequate drug effect 6 or more hours after dosing, 25% required nifedipine every 1 to 3 hours.
Evans et al have reported the use of sublingual nifedipine for acute and severe hypertension in children with renal disease. H Twelve children between 6 and 15 years of age with diastolic blood pressures greater than 110 mmHg were given sublingual nifedipine in a dose range of 0.18 to 0.32 mg/kg (mean dose 0.24 mg/kg). In the majority of patients, diastolic blood pressure fell to below 100 mmHg and remained so for 30 minutes to 6 hours. Again, a variable duration of response was seen in some children, especially those who received repetitive doses. In general, nifedipine can be used safely in children with severe hypertension. Unlike many of the conventional drugs used to treat acute hypertension in children, such as intravenous hydralazine, diazoxide, or sodium nitroprusside, nifedipine does not require parenteral administration or continuous blood pressure monitoring.
Verapamil (Isoptin®, Calan®) has been used in Europe for over 20 years for the treatment of arrhythmias, angina, and obstructive cardiomyopathy. Verapamil dilates the main coronary arteries and arterioles and slows arteriovenous conduction. It is now also used in adults for the treatment of essential hypertension, acting by decreasing systemic vascular resistance, usually without reflex tachycardia or orthostatic hypotension. Verapamil is contraindicated in heart failure and should be used cautiously in patients who are taking ß-blockers because of potentially serious cardiac depressant effects. Few data report on the use of verapamil as an antihypertensive agent in children, although it has been used for treatment of arrhythmias in the pediatric population.15
The absorption of verapamil is 90% when given orally. It is rapidly biotransformed on its first pass through the liver, with a resulting bioavailability of 20% to 30%. Peak plasma levels are reached 1 to 2 hours after administration. Side effects include flushing, headache, and palpitations. These effects usually occur less commonly than with nifedipine. The usual oral dose in adults is 80 to 120 mg three times a day. A sustained release form is also available which may be given as 120 to 240 mg once a day. No specific dose recommendations currently exist for children.
Diltiazem (Cardizem®) has been successfully used for the management of angina and is now being evaluated in adults for the treatment of hypertension. It is probably a less potent vasodilator than nifedipine and has less negative inotropic and chronotropic action than verapamil. To date, no experience with the use of this drug for treatment of hypertension in children has been reported.
In summary, calcium channel blockers may play a useful role in the management of pediatric hypertension. Nifedipine can be very useful for the treatment of episodic or short-term hypertension. It can also be used safely for the treatment of acute severe hypertension and does not require parenteral administration or continuous blood pressure monitoring. Verapamil may also prove to be a useful agent in the management of hypertension in children. Like nifedipine, verapamil does not cause the derangements of electrolytes or carbohydrate metabolism that can occur with other classes of drugs. In addition it may require a less frequent dose schedule than nifedipine. Unlike other vasodilators such as hydralazine, verapamil seldom causes reflex tachycardia and may prove useful as a single agent to treat mild to moderate hypertension.
Two new classes of antihypertensive medications-the angiotensin converting enzyme inhibitors and calcium channel blockers - are particularly useful in treating hypertension secondary to renal parenchymal and renovascular disease. In many cases they may be used as single agents, thus avoiding the need for a multiple drug regimen. The side effects commonly reported with other classes of antihypertensive medications, such as electrolyte, glucose, and lipid abnormalities, do not generally occur with these medications. They have been used successfully in children, although further studies to determine their long-term safety and efficacy are needed.
1. Report of the Second Task Force on Blood Pressure Control in Children. Pediatrics 1987; 79:1-25.
2. Goldblatt H, Lynch J, Hanzal RF, et al: Studies on experimental hypertension. The production of persistent elevation of systolic blood pressure by means of renal ischemia. ; Exp Med 1934; 59:347.
3. Mirkin BL, Newman TJ: Efficacy and safety of Captopril in the treatment of severe childhood hypertension: Report of the International Collaborative Study Group, ftdiamcs 1985; 75:1091-1100.
4. Davies RO, Irvin JD, Kramsch DK, et al: Enalapril worldwide experience. AmJ Med 1984; 77(Suppl 2A):23-35.
5. Fröhlich ED, Cooper RA, Lewis EJ: Review of the overall experience of Captopril in hypertension. Arch lnr Med 1984; 144:1441-14444.
6. Pcrlman J, Tack E: Renal failure in sick hypertensive premature infants receiving Captopril therapy. J Pediotr 1988; 112:805-810.
7. Petlman J, Volpe JJ: Neurological complications of Captopril in sick hypertensive premature infants receiving Captopril therapy, rVdiorrics 1989; 83:47-52.
8. Green TP, Nevins TE, Houser MT, et al: Renal failure as a complication of acute antihypertensive therapy. Pediatrics 1981; 67:850-854.
9. Schreiber MJ, Fang LS: Renal failure associated with Captopril. JAMA 1983; 250:31.
10. Millet K, Atkin B, Rodel PV, et al: Enalapril: A well tolerated and efficacious agent for the pediatric hypertensive patient. ) Cardiovasc Pharmacol 1987; 10:SI54-S156.
11. Webster M, Neutzc JM, Calder AL: The acute hemodynamic effects of intravenous enalaprilat in children with ventricular septal defect. Australian und New Zealand Journal of Mediane 1987; 17:567.
12. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Captopril. Evaluation of low doses, twice daily doses and the addition of diuretic for the treatment of mild to moderate hypertension. Clin Sci 1982; 63:443s.
13. Siegler R, Brewer E: Effect of sublingual ot oral nifedipine in the treatment of hypertension. J Pediotr 1988; 112:811-813.
14. Evans J, Shaw N, Brocklebank J: Sublingual nifedipine in acute seven hypertension. Arch Dis Chad 1988; 63:975-977.
15. Porter CJ, Garson A, Gilette P: Verapamil: An effective calcium channel blocking agent for pediatric patients. Pediatrics 1983; 71:748-755.