HARALAMBOS GAVRAS, M.D., FOTIS CHAROCOPOS, M.D., HANS. BRUNNER, M.D., AND ..... 1:150, 1980. 26. Amann, F. W., Buhler, F. R., Cohen,. D., et al.
304
ANGIOTENSIN CONVERTING ENZYME INHIBITION: A NEW THERAPEUTIC MODALITY* HARALAMBOS GAVRAS, M.D., FOTIS CHAROCOPOS, M.D., HANS BRUNNER, M.D., AND IRENE GAVRAS, M.D. Department of Medicine Thorndike Memorial Laboratories Boston City Hospital Boston, Massachusetts
A lthough methodology for measurement of most components of the renin-angiotensin system has been available for years, interest in this system's participation in various pathologic conditions was renewed with the advent of specific pharmacologic inhibitors of those components. Two classes of inhibitors found clinical application: the chemical analogs of angiotensin II, which act as competitive antagonists at the vascular and adrenal receptor level and have variable agonistic properties as well, and the inhibitors of the peptidyl dipeptide hydrolase, the enzyme which converts the biologically inactive angiotensin I to the potent vasoconstrictor and steroidogenic angiotensin II. The former class of compounds has been used mostly for purposes of animal and clinical investigation. Only one of them, saralasin, has been proposed for use as a screening test to detect angiotensin-dependent renovascular hypertension, but its clinical use presents problems. Two of the angiotensin-converting enzyme inhibitors, teprotide (SQ20881) and captopril (SQ14225), have been used experimentally for diagnosis and treatment of a variety of clinical conditions, including various types of hypertension and congestive cardiac failure. The following is a brief account of our clinical experience with these two compounds. *Presented as part of a Symposium on Hypertension Update 1980. Practical Clinical Aspects sponsored by the Section on Medicine of the New York Academy of Medicine with the National Hypertension Association, Inc. and held at the Academy May 21, 1980. This study was supported in part by Grant HL-18318 from the National Heart and Lung Institute and Grant RR-533-10 from the Division of Research Resources, Bethesda, MD.
Bull. N.Y. Acad. Med.
305 ENZYME INHIBITION INHIBITION305
TEPROTIDE
Teprotide is a nonapeptide chemically unrelated to the angiotensins, suitable for intravenous bolus injections. At doses of 1 to 4 mg./kg. body weight it can inhibit formation of angiotensin II and eliminate its effects for 4 to 16 hours. When administered in selected hypertensive emergencies-mostly accelerated or malignant phase hypertension-it could provide both diagnostic information and immediate therapeutic effect: an antihypertensive response would signify an angiotensin-sustained hypertension, which could then be treated successfully either with an oral angiotensin-converting enzyme inhibitor or with renin-suppressing drugs. On the contrary, lack of response within 15 to 20 minutes would indicate that angiotensin does not maintain the subject's blood pressure and thus, indirectly, that probably a sodium overload exists, calling for vigorous diuretic treatment. Application of this principle to a study of 18 patients with hypertensive emergencies resulted in successful management of blood pressure with the chosen regimen in the majority of cases within the first 24 hours.' Teprotide was also tried diagnostically in patients with intractable congestive cardiac failure. The rationale was that the renin-angiotensin system is activated in heart failure, evidently in an effort to maintain effective blood pressure in the face of decreasing cardiac output. Though teleologically justified, this activation in fact increases peripheral resistance and impedes left ventricular outflow, thereby causing further deterioration in the functional capacity of the failing myocardial pump. Peripheral vasodilators decrease afterload and improve cardiac output without increasing the left ventricular work. An early pilot study using saralasin indicated that indeed inhibition of angiotensin II could reverse most hemodynamic abnormalities characteristic of decompensated heart failure.2 Subsequent trials with teprotide demonstrated that the beneficial hemodynamic effects of angiotensin inhibition in this condition were consistent and lasted for several hours after a single dose.3'4 For chronic maintenance of these effects, angiotensin blockade can be achieved with the oral converting enzyme inhibitor captopril, the only one presently available for clinical use. CAPTOPRIL This is a modified proline molecule with a side chain including a mercapto- group.5 When administered orally on an empty stomach it is Vol. 57, No. 4, May 1981
306
H. GAVRAS AND OTHERS
absorbed quickly, its effects become evident within 15 to 20 minutes, and are maximal at 2 to 4 hours, with a duration of action for several hours, depending on the dose.' Because it is mostly eliminated by the kidneys,7 the dose and duration are also affected by the renal capacity of the subject. Recommended doses vary at present between 25 mg. twice daily and 150 mg. thrice daily because higher doses have been associated with increased incidence of adverse reactions. Hemodynamic effects of captopril in hypertensive patients include substantial fall of blood pressure (but not to hypotensive levels, unless the patient had been severely hypovolemic), decrease in systemic vascular resistance, increase in cardiac output, and sometimes a small increase in heart rate. In the experimental animal it has been shown that angiostensinconverting enzyme inhibition with teprotide causes a wide redistribution in fractional output: although blood flow tends to increase in most organs, regional flows to such vital organs as kidneys, adrenals, heart, and brain increase much more, at the expense of regional flows to skin and musculoskeletal tissues. This unequal redistribution of regional blood flows is apparently due to the different sensitivity of various vascular trees to the pressor effect of angiotensin II, so that "sensitive" organs receive preferentially increased flow after blockade of angiotensin I1.8 Early observations indicate that this may be true in humans treated with captopril as weI.9,10 Humoral alterations during treatment with captopril include elevation of plasma renin activity (apparently because of interruption of angiotensin 's negative feedback control on renin secretion), considerable decrease in circulating angiotensin II, aldosterone and angiotensin-converting enzyme activity and slight elevation in plasma potassium levels. Since the angiotensin-converting enzyme is identical to the kininase II that degrades the vasodilator bradykinin, its inhibition might be expected to cause elevation of kinin levels. This has been shown with teprotide," but remains controversial with captopril because animal studies did show bradykinin accumulation' but human studies did not. 13 It should be noted that enzymes other than kininase II can also degrade kinins. Therefore, most investigators believe that the antihypertensive effects of angiotensinconverting enzyme inhibitors are mainly attributable to interference with the renin-angiotensin-aldosterone axis. Captopril has been available for clinical use for the past three years. Over this period reports have shown its short-term and long-term efficacy Bull. N.Y. Acad. Med.
ENZYME INHIBITION INHIBITION
307
307
in the treatment of hypertension'4-'7 and congestive cardiac failure.'8-2' In hypertensive patients it controlled blood pressure in approximately 85%. More than one half of them, however, had a partial response to captopril alone and required addition of a diuretic before blood pressure returned to normal. This was particularly true for patients with various degrees of chronic renal failure, for whom addition of furosemide was usually necessary before a satisfactory antihypertensive effect could be achieved."2 Patients with end-stage renal failure maintained on regular hemodialysis may also require additional subtraction of sodium before their blood pressure responds to angiotensin-converting enzyme inhibition. This can be achieved by ultrafiltration, while fluid volume is being restored with parallel infusion of 5% dextrose. In general, patients with high pretreatment levels of plasma renin activity, as a group, exhibited better response on average than low-plasma renin activity patients, so that a statistically significant correlation was observed between baseline plasma renin activity and blood pressure response. However, individual values were widely scattered, so that a patient's plasma renin activity value could not predict his response to the drug.23 Not unexpectedly, low-plasma renin activity hypertensives needed addition of a diuretic more frequently than did high plasma renin activity patients to normalize their blood pressure. A tendency toward negative sodium balance was not consistent, and a significant though small elevation of plasma potassium never reached hyperkalemic levels. This is attributed to decrease but not total suppression of aldosterone after elimination of angiotensin II, probably because potassium increment by itself is a potent stimulus of aldosterone secretion. Except for rare cases of hypotension in patients who had received excessive amounts of diuretic, there were no other side-effects attributable to the drug's mechanism of action, i.e., inhibition of the angiotensin-converting enzyme. There was, however, a high incidence of allergic-type reactions. Patients with intractable congestive cardiac failure of Class III or IV, by the criteria of the New York Heart Association, with or without hypertension, were also treated successfully with captopril and in most cases their functional status improved by two steps according to the New York Heart Association classification. These patients were already being treated with digitalis and diuretics without improvement. Despite low levels of systemic blood pressure (particularly in nonhypertensive patients), treatment with captopril was very well tolerated by subjective as well as objective criteria.182' Vol. 57, No. 4, May 1981
308
308
H. GAVRAS AND AND OTHERS H. GAVRAS OTHERS~~~~~~~~~~~~~~~~~~~
Increases in cardiac output achieved during therapy were in the range of 30 to 40%, left ventricular pressure decreased by 25% and pulmonary wedge pressure by 35 to 45%. Decrease in systemic arterial pressure was variable, ranging between 14 and 25%. Despite this, regional flows to vital organs were not impaired, apparently because of the redistribution in blood flow preferentially to "favored" organs, as mentioned earlier. Thus, there was usually no change in coronary blood flow and increase in renal blood flow associated with unchanged myocardial oxygen extraction despite increased stroke work index, increased creatinine clearance, and improved mental status. Pretreatment plasma renin activity had limited predictive value because it did not correlate with the increase in cardiac output, although it did correlate with the fall in systemic vascular resistance. After several days to weeks of treatment, most patients had evidence of increased natriuresis, and body weight decreased by 2 to 3 kg. Because secondary hyperaldosteronism is one of the characteristics of chronic congestive cardiac failure, aldosterone suppression by angiotensinconverting enzyme is also one of the advantages of this treatment in comparison to pharmacologic vasodilators. Beneficial effects were sustained over several months of follow-up, with persisting increase in exercise tolerance and creatinine clearance. The latter is particularly important because in clinical practice attempts to alleviate a patient's edema and congestive symptoms by aggressive diuresis are usually limited by progressive azotemia. Adverse reactions to captopril ranged in severity from a minimal rash of no clinical importance to bone marrow suppression. In 12 to 23% the reaction was severe enough to require discontinuation of treatment. The incidence of severe reactions was higher in patients receiving higher doses, particularly those with some degree of renal insufficiency. The most common reaction was a maculopapular or morbilliform rash accompanied by itch and usually by eosinophilia and lymphopenia, occasionally preceded by a fever of 1 or 2 days' duration. The reaction was reversed after discontinuation of treatment and frequently was substantially improved simply by decreasing the daily dose. In one case the rash was associated with stomatitis and in another it was eventually diagnosed as pemphigus foliaceus, which, although it improved, did not disappear with discontinuation of treatment. A transient loss or alteration of taste was reported by 11% of the patients. Other serious side effects affected the hemopoietic system with a frequency of approximately 0.6%, mostly Bull. N.Y. Acad. Med.
ENZYME INHIBITION
309
leukopenia with agranulocytosis24-26 and one case each of isolated erythroid cell suppression and fatal pancytopenia. Most cases of leukopenia occurred in patients with an altered state of immunity (e.g., treated with azathioprine or suffering from lupus erythematosus) and all were reversed within a few days after interruption of treatment, except the case of pancytopenia observed in an elderly patient suspected of having an underlying plasma cell dyscrasia.27 Another potentially serious but rare adverse reaction was the development of proteinuria, sometimes accompanied by clinical signs of nephrotic syndrome and pathological characteristics of membranous glomerulopathy.28 The striking similarity between these side-effects of captopril and those of heavy metal antagonists (e.g., penicillamine27:30 has led many investigators to suspect that the molecular structure of captopril (i.e., its mercapto- group) may be responsible for these adverse reactions rather than inhibition of peptidyl dipeptide hydrolase. If so, other orally active angiotensin-converting enzyme inhibitors with different chemical formulation might be expected to be free of such reactions. It is of interest that no side effects were attributable to its mechanism of action except for the rare risk of hypotension. In particular, patients volunteered comments on the lack of drowsiness, fatigue, impotence, etc., side effects common with most antihypertensive drugs. This makes treatment of high blood pressure by angiotensin-converting enzyme inhibition particularly attractive because the major reason for patient noncompliance to presently available medications is the occurrence of intolerable side effects in otherwise asymptomatic subjects. REFERENCES 1. Tifft, C. P., Gavras, H., Kershaw, G. R., et al.: Converting enzyme inhibition in hypertensive emergencies. Ann. Int. Med. 90:43-47, 1979. 2. Gavras, H., Flessas, A., Ryan, T. J., et al.: Angiotensin II inhibition: Treatment of congestive cardiac failure in a high renin hypertension. J.A. M.A. 238:88082, 1977. 3. Gavras, H., Faxon, D. P., Berkoben, J., et al.: Angiotensin converting enzyme inhibition in patients with congestive heart failure. Circulation 58:77076, 1978. 4. Curtis, C., Cohn, J. N., Vrobel, T., and Franciosa, J. A.: Role of the renin-angiotensin system in the systemic vaso-
Vol. 57, No. 4, May 1981
5.
6.
7.
8.
constriction of chronic congestive heart failure. Circulation 58:763-70, 1978. Ondetti, M. A., Rubin, B., and Cushman, D. W.: Design of specific inhibitors of angiotensin converting enzyme: New class of orally active antihypertensive agents. Science /96:441-44, 1977. Ferguson, R. K., Brunner, H. R., Turini, G. A., et al.: A specific orally active inhibitor of angiotensin-converting enzyme in man. Lancet /:775-78, 1977. Kripalani, K. J., McKinstry, D. N., Singhvi, S. M., et al.: Disposition of captopril in normal subjects. Clin. Pharmacol. Ther. 27:636-41, 1980. Gavras, H., Liang, C. S., and Brunner, H. R.: Redistribution of regional blood
310
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
H. GAVRAS AND OTHERS
flow after inhibition of the angioteninconverting enzyme. Circ. Res. (Suppl.) 43:I-19-1-63, 1978. Mimran, A., Brunner, H. R., Turini, G. A., et al.: Effect of captopril on renal vascular tone in patients with essential hypertension. Clin. Sci. 57:421-23, 1979. Hollenberg, N. K., Swartz, S. L., Passan, D. R., and Williams, G. H.: Increased glomerular filtration rate after converting enzyme inhibition in essential hypertension. N. Engl. J. Med. 301: 9-12, 1979. Williams, G. H. and Hollenberg, H. K.: Accentuated vascular and endocrine response to SQ 20,881 in hypertension. N. Engl. J. Med. 297:184, 1977. McCaa, R. E., Hall, J. E., and McCaa, C. S.: The effects of angiotensin I converting enzyme inhibitor in arterial blood pressure and urinary sodium excretion: role of the renin angiotensin and kallikrein-kinin systems. Circulation Res. (Suppl.) 43:32, 1978. Johnston, C. I., Millar, J. A., McGrath, B. P., and Matthews, P. G.: Long-term effects of captopril (SQ14225) on blood pressure and hormone levels in essential hypertension. Lancet 2:493-95, 1979. Gavras, H., Brunner, H. R., Turini, G. A., et al.: Antihypertensive effect of the oral angiotensin converting-enzyme inhibitor SQ14225 in man. N. Engl. J. Med. 298:991-95, 1978. Case, D. B., Atlas, S. A., Laragh, J. H., et al.: Clinical experience with blockade of the renin-angiotensin-aldosterone system by an oral converting-enzyme inhibitor (SQ 14,225, captopril) in hypertensive patients. Progr. Card. Dis. 2/:195-206, 1978. Bravo, E. L. and Tarazi, R. C.: Converting enzyme inhibition with an orally active compound in hypertensive man. Hypertension 1:39-46, 1979. Brunner, H. R., Gavras, H., Waeber, B., et al.: Oral angiotensin-converting enzyme inhibitor in long-term treatment of hypertensive patients. Ann. Int. Med. 90:19-23, 1979. Turini, G. A., Gribic, M., Brunner, H. R., et al.: Improvement of chronic congestive heart failure by oral captopril.
Lancet /:1213-15, 1979. 19. Davis, R., Ribner, H. S., Keung, E., et al.: Treatment of chronic congestive heart failure with captopril, an oral inhibitor of angiotensin-converting enzyme. N. Engl. J. Med. 301:117-21, 1979. 20. Ader, R., Chatterjee, K., Ports, T., et al.: Immediate and sustained hemodynamic and clinical improvement in chronic heart failure by an oral angiotensin converting enzyme inhibitor. Circulation 6/:931-37, 1980. 21. Dzau, V. J., Colucci, W. S., Williams, G. H., et al.: Sustained effectiveness of converting enzyme inhibitor in patients with severe congestive heart failure. N. Engl. J. Med. 302:1373-79, 1980. 22. Brunner, H. R., Waeber, B., Wauters, J. P., et al.: Inappropriate renin secretion unmasked by captopril (SQ14,225) in hypertension of chronic renal failure. Lancet 2:704-07, 1978. 23. Waeber, B., Gavras, I., Brunner, H. R., and Gavras, H.: Safety and efficacy of chronic therapy with captopril in hypertensive patients: An update. Submitted for publication. 24. Staessen, J., Fagard, R., Lijnen, P., and Amery, A.: Captopril and agranulocytosis. Lancet 1:926-27, 1980. 25. Van Brummelen, P., Willemze, R., Tan, W. D., and Thompson, J.: Captopril-associated agranulocytosis. Lancet 1:150, 1980. 26. Amann, F. W., Buhler, F. R., Cohen, D., et al.: Captopril associated agranulocytosis. Lancet /:150, 1980. 27. Gavras, I., Graff, L. G., Rose, B., et al.: Fatal pancytopenia attributable to captopril. Submitted for publication. 28. Hoorntje, S. J., Kallenberg, C. G. M., Weening, J. J., et al.: Immune complex glomerulopathy in patients treated with captopril. Lancet 1:1212-15, 1980. 29. Stein, H. B., Patterson, A. C., Offer, R. C., et al.: Adverse effects of d-penicillamine in rheumatoid arthritis. Ann. Int. Med. 92:24-29, 1980. 30. Marsden, R. A., Ryan, T. J., Vanhegan, R. I., et al.: Pemphigus foliaceus induced by penicillamine. Br. Med. J. 2:123-24, 1976.
Bull. N.Y. Acad. Med.
