Calcium Channel Blockers in Primary Pulmonary Hypertension

extraction as a major way of increasing the oxygen supplied to the tissues. This should improve the arterial POIat any given level of work, since the PVO I will be higher. On the other hand , vasodilation may increase the degree of VAiQ inequality, worsening the efficiency of pulmonary gas exchange. Further studies will be necessary before any definitive statements can be made, although preliminary results suggest that successful vasodilation does not often lead to marked worsening of exercise hypoxemia .9,10 REFERENCES

1 Dantzker DR, Bower JS. Mechanisms of gasexchange abnormality in patients with chronic obliterative pulmonary vascular diseases . J Clin Invest 1979; 64:1050-55 2 Gazetopoulos N, Salonikides N, Davies H. Cardiopulmonary function in patients with pulmonary hypertension. Br Heart J 1974; 36:19-28 LikoffMJ, Fishman AP. Exercise testing to 3 Janicki JS, Weber evaluate patients with pulmonary vascular disease . Am Rev Respir Dis 1984; 129:593-595 4 Wagner PO , Saltzman HA, West JB. Measurement of continuous distributions of ventilation-perfusion ratios; theory. J Appl Physio11974; 36:588-99 5 Dantzker DR, Bower JS. Pulmonary vascular tone improves VAlQ matching in obliterative pulmonary hypertension. J Appl Physioll981; 51:607-13 6 D'Alonzo GE, Anderson KA, Dantzker DR. Non-invasive assessment of hemodynamic improvement during chronic vasodilator therapy in pulmonary hypertension [Abstract]. Am Rev Respir Dis 1984: 129:A62 7 Jones NL, Goodwin JF. Respiratory function in pulmonary thromboembolic disorders. Br Med J 1965; 1:1089-93 8 Dantzker DR, D'Alonzo GE, Bower JS, Popat K, Crevey BJ. Pulmonary gas exchange during exercise in patients with chronic obliterative pulmonary hypertension, Am Rev Respir Dis 1984; 130:412-16 9 Rubin LJ, Peter RH. Oral hydralazine therapy for primary pulmonary hypertension. N Eng! J Med 1980; 302:69-73 10 Lupi-Herrera E, Sandoval J, Seoane M, Bialostosky D. The role of hydralazine therapy of pulmonary arterial hypertension of unknown cause. Circulation 1982; 65:645-50

n

systemic arterial oxygen tension and the level of mixed venous oxygen. In hypoxemic patients with chronic obstructive lung disease, mixed venous oxygen tension (PVO.) can be increased by giving oxygen to raise systemic arterial saturation and PVOI. In primary pulmonary hypertension patients, systemic arterial oxygen saturation is usually near normal, but the A-V oxygen difference is wide because of the low cardiac output. In these patients the PVOI cannot be significantly increased by giving oxygen. The consequences of a low PVOI are illustrated during exercise in patients with primary pulmonary hypertension, because the cardiac output cannot increase commensurate with the metabolic requirements. V/Q'matching is not severely abnormal in these patients. The result is a fall in arterial oxygen tension during exercise. The calculated arterial oxygen tension would actually rise during exercise if the P\OI was held constant. The question of whether the increase in cardiac output associated with vasodilator therapy alters systemic oxygenation was considered. While an increase in cardiac output is associated with an increase in PVOI, it also blocks hypoxic vasoconstriction and can thus increase the shunt of desaturated blood . The final effect on systemic oxygenation is the result of a balance between these two divergent actions. The discussion turned to the consideration of the symptoms associated with pulmonary hypertension. Patients are unable to exercise because of breathlessness. However, the mechanism of the breathlessness is not certain. Airway function and alveolar ventilation are not limiting, but patients are unable to increase their cardiac output with exercise because of obstruction to blood flow through the lung. When pulmonary artery pressure is lowered by vasodilator drugs, patients claim not only to feel better and be able to do more, but also have been found to have an improved exercise tolerance. This suggests that pulmonary hypertension per se may contribute to the sensation of breathlessness. Further research should examine both the subjective assessment of dyspnea and objective measures of ventilation, in particular as related to workload.

DISCUSSION

Discussion developed about the relationship between

Calcium Channel Blockers In Primary Pulmonary Hypertenslon* Lewis]. Rubin, M.D., EC.C.P.t

The demonstration that the calcium channel blockers reduce pulmonary vasomotor tone in experimental models of pulmonary hypertension bas served as the rationale for their use in the management of primary pulmonary hypertension . The three currently available agents, verapamil, nifedipine, and diltiazem, have varying degrees of pulmonary vasoactivity. Experience with their use is reviewed. ·From the Department of Intemal Medicine, Pulmonary Division, University of Texas Health Science Center and Dallas Veterans Administration Medical Center, Dallas. t Associate Professor of Medicine. Supported in part by the Betty Crossman Marcus Fund, Dallas,

Texas.

Reprint requests: Dr: Rubin, VA Medlcal Center, lllF, 4500 South LanctUter, Dallas 75216

Drimary pulmonary hypertension (PPH) is characterized

.£ by extreme elevations in pulmonary artery pressure and pulmonary vascular resistance and usually progresses inexorably to right ventricular fiUlure and death. The pathologic demonstration of pulmonary arteriolar muscular hypertrophy as one of the earliest and most consistent features of this disease' suggests that vasoconstriction in varying degrees may be responsible, at least in part, for the elevation in right ventricular afterload . A variety of vasodilating drugs, including hydralazine,1,3 phentolamin, ~ diazoxide, s.e nitroglycerin," and prostacycline, I have been used to treat PPH patients, with mixed results. ~u The calcium channel blockers are a relatively new class of drugs which exert varying effects on the conduction system CHEST I 88 I 4 I OCTOBER. 1986 I Supplement

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of the heart and vascular smooth muscle. Several studies have suggested that these agents may exert a pulmonary vasodilator effect in experimental animals with enhanced pulmonary vascular tone induced by hypoxic ventilation or the infusion of prostaglandin F.,. ~13 It is not surprising. therefore. that clinical studies evaluating the effects of these agents in patients with pulmonary vascular disease have been undertaken in the search fur more effective pulmonary vasodilator drugs. NIFEDIPINE

Of the three calcium channel blockers currently available. nifedipine has been the most extensively evaluated in patients with PPH. Camerini et al" reported the case of a 34year-old woman with severe pulmonary hypertension (mean pulmonary artery pressure 63 mm Hg and total pulmonary resistance 2,255 dynes-s-cm -S) who displayed a 54 percent fall in pulmonary resistance and a 14 percent decrease in pulmonary artery pressure in response to nffedipine, 20 mg. administered sublingually. Long-term treatment with nifedipine was associated with symptomatic improvement and diminished signs of right heart failure. Subsequently. McLeod and colleagues" reported similar beneficial hemodynamic effects using nifedipine in three patients with PPH. and also noted improved exercise performance using treadmill testing. WlSe18 reported that treatment with nifedipine, 10 mg orally four times daily fur four months. resulted in a marked reduction in rest and exercise pulmonary resistance and increases in cardiac output. Rubin and colleagues" reported the short- and long-term effects of nifedipine in nine patients. Nifedipine treatment increased cardiac output from 3.6±1.7 to 5.3±2.8 Umin (p
ejection fraction correlated with reductions in total pulmonary resistance (Fig 2). suggesting that the responses to nifedipine might be fullowed noninvasively. Persistent hemodynamic and symptomatic improvement were observed in fiveof the sixpatients who were given long-term oral nifedipine in doses of 40 to 120 mglday for four to 14 months. Saito et allll found a similar response in their patient with severe PPH. Olivari and colleagues" found persistent hemodynamic and symptomatic improvement and prolonged exercise tolerance with long-term nifedipine therapy in seven patients with PPH. Not unexpectedly, the effects of nifedipine have not been consistently beneficial. Berkenboom and associates" noted no response to 20 mg of nifedipine administered sublinguaUy

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to a 36-year-old woman with PPH, and Rubin et al" reported a paradoxic increase in pulmonary artery pressure, concomitant with an increased cardiac output, in one patient. Furthermore, initial responses may not be sustained chronically, due either to the development of tolerance to the drug or to progression of the underlying disease ." VERAPAMIL

The other calcium channel blockers have not been as extensively investigated. Landmark et al" evaluated the effects of intrapulmonary injection of verapamil, 0.15 mg/kg, in 12 patients with pulmonary hypertension, nine of whom had PPH, and found small decreases in pulmonary artery pressure which were accompanied by reductions in cardiac output and systemic artery pressure. Because of this apparent negative inotropic effect, the authors advised caution in using verapamil in PPH patients.

treatment of primary pulmonary hypertension. Br Heart I 1978;

40:572-74 7 Pearl RG, Rosenthal MH. Schroeder IS, Ashton IPA. Acute hemodynamic effects of nitroglycerin in pulmonary hypertension. Ann Intern Med 1983; 99:9-13 8 Rubin LI. Groves BM, Reeves j1; Frosolono M, Handel F, Cato AE . Prostacyclin-induced acute pulmonary vasodilation in primary pulmonary hypertension. Circulation 1982; 66:334-38 9 Packer M, Greenberg B. Massie B, Dash H. Deleterious effects of hydralazine in patients with pulmonary hypertension. N Eng) I Med 1982; 306:1326-31 10 Buch J, Wennevold A. Hazards of diazoxide in pulmonary hypertension. Br Heart J 1981; 46:401-03 11 Cohen ML. Kronzon I. Adverse hemodynamic effects of phentolamine in primary pulmonary hypertension. Ann Intern Med

1981; 95:591-92 12 Kennedy T, Summer W. Inhibition of hypoxic pulmonary vasoconstriction by nifedipine. Am I Cardiol 1982; 50:864-68 13 McMurtry IF, Davidson AB, Reeves j1; Grover RF. Inhibition of

DIUlAZEM

Kambara et al22 reported a woman with PPH who had a dramatic response to diltiazem, 10 mg administered intravenously (IV). Eleven months after instituting oral diltiazem therapy, 30 mg three times daily, the patient was asymptomatic, and right ventricular strain was no longer present on ECG . Crevey et al13 evaluated the effects of diltiazem 0.25 mglkg IV on rest and exercise hemodynamics and gas exchange. They found small reductions in total pulmonary resistance during exercise and no significant change in the overall distribution of ventilation and perfusion. NEWER AGENTS

Amman and associates" recently reported that felodipine, a new and more selective" calcium channel blocker, produced improvement in two patients with PPH. U

THE FUTURE

The ideal vasodilator for use in PPH would be one with selective, or even preferential, effects on the pulmonary circulation. While it appears unlikely from experience to date that a calcium channel blocker will meet these criteria, the development of newer agents with more selective cardiac pharmacologic effects could lead to more effective and better tolerated drugs for use in patients with hypertensive pulmonary vascular disease . REFERENCES

1 Storstein O. Elfskind L. Muller C, Rokseth R. Sander S. Primary pulmonary hypertension with emphasis on its etiology and treatment. Acta Med Scand 1966; 179:197-212 2 Rubin LJ. Peter RH. Oral hydralazine therapy for primary pulmonary hypertension. N Engl J Med 1980; 302:69-73 3 Lupi-Herrera E. Sandoval I. Seoane M. Bialostozky D. The role of hydralazine therapy for pulmonary hypertension of unknown cause. Circulation 1982; 65:645-50 4 Ruskin 1M, Hutter AM. Primary pulmonary hypertension treated with oral phentolamine. Ann Intern Med 1979; 90: 772-74 5 Honey M. Cotter L, Davies N. Denison D. Clinical and haemodynamic effects of diazoxide in primary pulmonary hypertension. Thorax 1980; 35:269-76 6 Wang SWS. PoW IEF, Rowlands 01. Wade EG. Diazoxide in

14 15 16 17

18

hypoxic pulmonary vasoconstriction by calcium antagonists in isolated rat lungs. Circ Res 1976;38:99-104 Camerini F, Alberti E, Klugman S, Salvi A. Primary pulmonary hypertension: effects of nifedjpine. Br Heart I 1980; 44:352-56 McLeod AA, Wise IR, Daly K, Iewitt D. Nifedipine in treatment of primary pulmonary hypertension. Br Heart I 1981; 45:619 Wise IR. Nifedipine in the treatment of primary pulmonary hypertension. Am Heart I 1983; 105:693-94 Rubin LI. Nicod P, Hillis LD, Firth BG. Treatment of primary pulmonary hypertension with nifedipine: a hemodynamic and scintigraphic evaluation. Ann Intern Med 1983;99:433-38 Saito D. Haraoka S. YoshidaH. Kusachi S, Yasuhara K, Nishihara M. et al. Primary pulmonary hypertension improved by longterm oral administration of nifedipine. Am Heart I 1983;

105:1041-42 19 Olivari MT, Levine TB. Weir EK, Cohn

IN. Hemodynamic effects of nifedipine at rest and during exercise in primary pulmonary hypertension. Chest 1984; 86:14-19 20 Berkenboom G. Sobolski J, Stoupel E. Failure of nifedipine treatment in primary pulmonary hypertension. Br Heart I 1982; 47:511 21 Landmark K, Refsum AM. Simonsen S. Storstein 0. Verapamil and pulmonary hypertension. Acta Med Scand 1978; 240: 299-302 22 Kambara H. Fujimoto K. Wakabayashi A. Kawai C. Primary pulmonary hypertension: beneficial therapy with diltiazem. Am Heart I 1981; 101:230-31 23 Crevey BI, Dantzker DR, Bower IS, Popat KD. Walker SO . Hemodynamic and gas exchange effects ofintravenous diltiazem in patients with pulmonary hypertension. Am I Cardiol 1982;

49:578-83 24 Arnman K, Ryden L, Smedgard P,Thorhallsson E . Felodipine in primary pulmonary hypertension. Acta Med Scand 1984; 215:

275-80 DISCUSSION

The subject of the validity of control measurements of pulmonary arterial pressure was raised. Pulmonary arterial pressure has been noted to fluctuate over time during catheterization in some patients. This is especially marked in young children. Consequently, to be considered significant, a vasodilator should decrease pulmonary vascular resistance by 20 to 30 percent. One discussant felt that patients who respond to one vasodiIator often respond to others as well. However, the corollary is not necessarily true. Another discussant suggested that in children a short history of CHEST I 88 I 4 I OCTOBER. 1985 I SUpplement

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symptoms tended to be associated with a greater pulmonary vascular responsiveness to vasodilators . It is not clear that this is also correct in adults. One patient was mentioned with an extremely responsive pulmonary vascuIature, who died within ten months of diagnosis despite vasodilator therapy. Patients who show no response to prostacyclin are unlikely to respond to other vasodilators . If such patients are severely compromised, both hemodynamically and symptomatically, they may be candidates for heart-lung transplantation.

Probably prostacyclin is the best agent, both in terms of

efficacy and safety, to assess the potential for pulmonary vasodilatation acutely. Prostacyclin is not widely available. Prostaglandin E I may have similar characteristics. One discussant indicated that IV diltiazem, on the other hand, may be unsafe and recommended that the effects of oral administration of diltiazem be assessed hemodynamically after a week to avoid IV use.

Use of calcium Channel Blockers In Hypoxic Lung Dlsease* John R. Mic1llJel, M.D., F.G.G.P.; Stephen Selinger, M.D.; William furhom, M.D.; Phillip Buescher, M.D.; Dean Wong, M.D.; and TIwrntu P. Kennedy, M.D., M.P.H., F.G.G.P.

COPD patients who are hypoxic develop pulmonary hype rtension primarily because alveolar hypoxia induces muscular hypertrophy of pulmonary arteries. This muscular hypertrophy wiD regress in animals if they receive continuous oxygen therapy. Since many COPD patients refuse to use oxygen continuously, calcium channel blocken, which inhibit hypoxic pulmonary vasoconstriction, may be effective adjuvant therapy. Nifedipine lowers pulmonary vascular resistance during rest and exercise in hypoxic COPD patients.

T

he rationale for considering the combined use of vasodilators and low-flowoxygen in patients with COPO and hypoxemia is based on five hypotheses. The extent to which these hypotheses are correct will likely determine the long-term usefulness of vasodilators in these patients. 1. Hypoxic pulmonary vasoconstriction and hypoxia-induced vascular smooth muscle hypertrophy play key roles in the pathogenesis of pulmonary hypertension in patients with COPO. 2. The changes caused by alveolar hypoxia-hypertrophy of vascular smooth muscle, pulmonary hypertension, and right ventricular hypertrophy-are potentially reversible. 3. Even short periods of hypoxia on a chronic basis will cause arterial smooth muscle hypertrophy, pulmonary hypertension, and right ventricular hypertrophy. 4. Low-flow oxygen therapy may not, in portions of the lung, eliminate alveolar hypoxia, especially during exercise . Consequently, low-8ow oxygen may be insufficient therapy to cause regression of the hypoxia-induced pathologic changes. 5. Long-term therapy with vasodilator drugs may augment the beneficial hemodynamic effects oflow-f1ow oxygen therapy. Although polycythemia and destruction of the pulmonary vascuIar bed by emphysema may contribute to the development ofpulmonary hypertension in patients with COPO, the clinical and pathologic evidence available indicates that *From the Departments of Medicine, Anesthesiology, and Critical Care Medicine, and Environmental Health Sciences, The Johns Hopkins Medical Institutions, Baltimore. Supported in part by the Clinical Research Center grant RR35from the U.S. Public Health Service. ~=: Dr: M/c1llJe1, Brady 417, 6000 North Broadway,

alveolar hypoxia is probably the major mechanism.'? Ample evidence exists in laboratory animals that the pathologic changes caused by hypoxia will reverse. U Although little clinical data exist, the study of Sime et ale clearly demonstrates the potential for reversibility in man . They found that high-altitude natives with hypoxic pulmonary hypertension had remarkable regression of their pulmonary hypertension after living at sea level for two years. Intermittent exposure to hypoxia is a potent stimulus for the development of the physiologic and pathologic changes caused by hypoxia.7•e In filet, a recent report suggests that two hours per day of hypoxia may be sufficient to produce these pathologic changes ." Intermittent periods of hypoxia willalso maintain the pathologic changes caused by hypoxia, whereas continuous relief of hypoxia will promote regression of these changes . to LoW-FLOW OxYGEN

Low-flow oxygen therapy improves mortality in patients with COPD and hypoxemia. 11,11 Although long-term low80w oxygen therapy slows the rate at which pulmonary vascular resistance increases in these patients, it does not lead to a dramatic reduction in pulmonary vascular resistance.11,1I If continuous inhibition of hypoxia is required for regression of the pathologic changes, part of the lack of dramatic improvement in pulmonary vascular resistance may be the intermittent use of oxygen by patients. Most patients, because of social, psychologic, or financial reasons, refuse to use oxygen continuously. Additionally, low-flowoxygen therapy may not completely eliminate focal areas of alveolar hypoxia in these patients, especially during exercise. The further reduction in pulmonary vascular resistance produced when nifedipine is added to low-flow oxygen therapy supports the concept that focal areas of hypoxic pulmonary vasoconstriction persist despite low-flow oxygen therapy.13 CALCIUM CHANNEL BLOCKERS

The effects of a variety of vasodilators have been assessed in patients with CO PO and hypoxemia. U-III We have been most interested in the possible role of calcium channel blockers because these compounds inhibit hypoxic pulmonary vasoconstrictiou.":" In 1976 McMurtry et al" reported that verapamil inhibited hypoxic pulmonary vasoconstriction in rats. Subsequent studies have shown that nifedipinelB,W will inhibit acute hypoxic pulmonary vasoconstriction in