Clinical pharmacology and therapeutic applications of the new oral converting enzyme inhibitor, enalapril

Improved non-invasive and invasive methods of blood pressure measurements in the newborn infant led to an increasing recognition of neonatal hypertension as a not uncommon occurrence in the neonatal period. Arterial blood pressure in the newborn is a function of gestational and postnatal ages. Systolic and diastolic blood pressures in term newborns greater than 90 mmHg and 60 mmHg, respectively, and values greater than 80 mmHg and 50 mmHg in premature newborns have been arbitrarily set as hypertension in this population. Renovascular causes may be responsible for up to 80% of neonatal hypertension followed by coarctation of the aorta and drugs (e.g. steroids). The pharmacological management of neonatal hypertension is empirical and remains a matter of debate. Drugs used in the management include the acetylcholine esterase (ACE) inhibitors (Enalapril, captopril), beta blockers (Labetolol, Atenolol), vasodilators (Hydralazine, Diazoxide), calcium channel blockers (Nifedipine) and diuretics (Furosemide, ethacrynic acid, thiazides). Definitive management should be directed to the aetiology of the hypertension. Systematic studies on the safe and effective drug management of neonatal hypertension should be a part of future research.

Antihypertensive drug therapy is used in children primarily to treat secondary forms of hypertension, because the prevalence of essential hypertension in the first decade of life is considerably less than 1% of the childhood population. This prevalence increases during the second decade of life, but the percentage of teenagers with essential hypertension continues to be low. Pharmaceutical companies have been able to target drug development to specific physiologic and biochemical systems. The converting enzyme inhibitors and calcium-channel blockers have greatly improved the success of therapy concomitant with a reduction in the incidence of adverse effects. The result has been a major change during the past decade in the recommendations for antihypertensive drug therapy.

In the neonate, there are a number of age-related differences in drug disposition (bioavailability, distribution, metabolism, and excretion), and these are directly related to the degree of prematurity. This article discusses the use of drugs that are commonly administered to the neonatal patient, with special emphasis given to renal considerations. These drugs include diuretics, theophylline, converting enzyme inhibitors, calcium channel blockers, indomethacin, and dopamine.

Sensory and behavioral performance of three normotensive and one renovascular hypertensive baboon was tested before, during and following chronic oral dosing with the angiotensin converting enzyme (ACE) inhibitor enalapril. Performance measurements during a five-color simultaneous matching to sample task were obtained during enalapril dosing of 0.18 and 0.61 mg/kg/day, and vehicle. Each dose was administered for 21 consecutive days preceded and followed by 14 baseline and recovery periods, respectively. BP from awake animals as well as serum ACE activity were measured. Systolic BPs decreased by a maximum of 6–8% (8 mmHg). ACE activity was decreased in a dose-dependent fashion by 54.01% and 81.63% for 0.18 mg/kg and 0.61 mg/kg doses, respectively. At 0.61 mg/kg, the duration of simple key-press motor behavior increased by 15% in the first week and then progressively returned to baseline levels. Systematic changes in choice reaction times or color discrimination accuracy were not observed. Although the renovascular hypertensive baboon displayed greater hypotension and ACE inhibition, behavioral effects were not significantly different from normotensive baboons. The present study extends to sensory functions the lack of adverse behavioral side-effects of enalapril.

The pharmacologic therapy of mild primary hypertension (diastolic blood pressure less than 105 mm Hg) has effectively reduced hypertensive arteriolar end organ disease such as cerebrovascular accidents, congestive heart failure, and nephropathy, but there has been no convincing evidence that coronary heart disease (CHD) or its complications, acute myocardial infarction or angina, have been reduced. The risks of therapy with certain antihypertensive drugs may outweigh their treatment benefits as it relates to CHD. The optimal treatment strategy should be to reduce all CHD risk factors, reverse the hemodynamic abnormalities present by lowering the systemic vascular resistance (SVR), preserving cardiac output (CO) and perfusion, and to select the best antihypertensive drug for concomitant medical diseases or problems while maintaining a good quality of life. Antihypertensive drugs that have favorable or neutral effects on CHD risk factors include alpha blockers, calcium channel blockers, central alpha agonists, and angiotensin-converting enzyme inhibitors. On the other hand, diuretics and beta blockers without intrinsic sympathomimetic activity have unfavorable effects on many CHD risk factors. Baseline and serial evaluation of the effects of these drugs on serum lipids, lipid subfractions, glucose, uric acid, electrolytes, exercise tolerance, left ventricular hypertrophy, blood pressure, SVR, CO, perfusion, concomitant diseases, and side effects is necessary to evaluate overall cardiovascular risk.