Calcium channel blockers
Medical > Therapy > Specific treatments
Calcium channel blockers
Since the first description of pulmonary hypertension, vasodilators have been recommendid for decreasing right ventricular afterload in these patients. Several different vasodilators such as nidefipine, diltiazem, hydralazine, prazosin, nitrates, prostacyclin and others were used for treatment of acute or chronic pulmonary hypertension (Weir et al., 1989). None of these drugs turned out to be selective for the pulmonary circulation and they all decreased systemic vascular resistance and cardiac output. Therefore, they carry the risk for systemic hypotension, which impairs coronary perfusion and causes right ventricular ischemia. Among different systemic vasodilators, nifedipine became quickly a promising drug for the treatment of pulmonary hypertension, because it decreases pulmonary artery pressure, pulmonary vascular resistance and systemic pulmonary vascular resistance, and increases cardiac output (Rich et al., 1983, Rubin et al., 1983). Calcium channel blockers such as nifedipine or diltiazem are selective inhibitors of the L-type calcium channels and decrease intracellular calcium concentration, which leads to vascular smooth muscle cells relaxation.
Rapid exposure to high altitude associated pulmonary hypertension is inhibited by the prophylactic administration of nifedipine or other vasodilators (Hackett et al., 1992, Hohenhaus et al., 1995). In high altitude pulmonary edema susceptible subjects, nifedipine attenuates excessive hypoxic pulmonary vasoconstriction and successfully prevents alveolar fluid flooding in these subjects (Bärtsch et al., 1991). Moreover, in subjects with high altitude pulmonary edema nifedipine intake caused a rapid and sustained decrease in pulmonary artery pressure, which led to a significant improvement of high altitude pulmonary edema associated clinical and radiographic signs and allowed subjects to descend by proper means (Oelz et al., 1989). Thus nifedipine is the first line option for the treatment and the prevention of high altitude pulmonary edema.
In primary pulmonary hypertension, response to treatment with calcium channel blockers was found to be associated with a more favorable outcome (Rich et al., 1983, Rubin et al., 1983). Patients with marginal response to conventional dose of a calcium channel blockers may respond to high-doses of nifedipine (up to 240 mg/day) or diltiazem (up to 900 mg/day) (Rich and Brundage, 1987). In patients, who tolerated this high-dose calcium channel blocker, the pulmonary artery pressure decreased by > 20% and pulmonary vascular resistance by ~ 50 %. In these patients, called responders, the reduction in pulmonary artery pressure is protracted and accompanied by a regression of right ventricular hypertrophy (Rich and Brundage, 1987, Rich and Kaufmann, 1991). Five-year-survival in responders was 94 % compared to 55 % in non-responders (p < 0.003) (Rich et al., 1992). Unfortunately, only a small number of patients treated with high-dose calcium channel blockers are responders (10 to 25 %) (Rich et al., 1992, Sitbon et al., 1998). A decrease in pulmonary vascular resistance by > 20 % without a decrease in pulmonary artery pressure appears not to be associated with a favorable outcome regarding a reduction in the severity of dyspnea and fatigue (Rich et al., 1992).
Adverse events with the use of calcium channel blockers occurred in 1 % of the 491 patients with pulmonary hypertension in the NIH-registry (Weir et al., 1989). Although not common, some cases of cardiac arrest with or without concomitant pulmonary edema in the course of vasodilator testing have been reported by different centers (Aromatorio et al., 1985, Batra et al., 1985, Chaouat et al., 1996, Farber et al., 1983, Packer et al., 1984, Partanen et al., 1993, Prigogine et al., 1991). Because of their long half-life and systemic effects vasodilators such as nifedipine, diltiazem or hydralazine are considered not suitable for testing of pulmonary vascular reactivity. Conversely, suitable for pulmonary vasoactivity testing are vasodilators with a short half-life, i.e. pulmonary selective vasodilators such as inhaled nitric oxide (Sitbon et al., 1998), inhaled iloprost (Olschewski et al., 1996), the short acting intravenous vasodilator adenosine (Morgan et al., 1991) or intravenous prostacyclin (Rubin et al., 1982). Acute reversibility of pulmonary vascular resistance (> 50 %) to inhaled NO not only predicted better response, but also better tolerance of nifedipine treatment with a decreased incidence of life-threatening hypotension or cardiac arrest (Sitbon et al., 1998).
In conclusion, calcium channel blockers should not be used for acute reactivity testing in chronic pulmonary arterial hypertension. Moreover, treatment of chronic pulmonary hypertension with nifedipine or diltiazem should be considered only in patients who fulfill responder's criteria during acute testing. Responders definition criteria are pulmonary artery pressure > 20 % and pulmonary vascular resistance > 20 %. This can be achieved either by inhaling nitric oxide or iloprost. Measurements regarding nitric oxide are performed during the 10 minutes inhalation, whereas for iloprost, measurements are taken 10 to 15 minutes after inhalation. In primary pulmonary hypertension iloprost inhalation-induced pulmonary vasodilation is at least equal if not more potent than inhaled nitric oxide (Hoeper et al., 2000)
References:
Aromatorio, G. J., Uretsky, B. F. and Reddy, P. S. (1985) Hypotension and sinus arrest with nifedipine in pulmonary hypertension. Chest, 87, 265-267.
Bärtsch, P., Maggiorini, M., Ritter, M., et al. (1991) Prevention of high altitude pulmonary edema by nifedipine. N Engl J Med, 325, 1284-1289.
Batra, A. K., Segall, P. H. and Ahmed, T. (1985) Pulmonary edema with nifedipine in primary pulmonary hypertension. Respiration, 47, 161-163.
Chaouat, A., Kessler, R. and Weitzenblum, E. (1996) Pulmonary oedema and pleural effusion in two patients with primary pulmonary hypertension treated with calcium channel blockers. Heart, 75, 383.
Cohen, M., Edwards, W. D. and Fuster, V. (1986) Regression in thromboembolic type of primary pulmonary hypertension during 2 1/2 years of antithrombotic therapy. J Am Coll Cardiol, 7, 172-175.
Farber, H. W., Karlinsky, J. B. and Faling, L. J. (1983) Fatal outcome following nifedipine for pulmonary hypertension. Chest, 83, 708-709.
Frank, H., Gurtner, H. P., Kneussl, M., et al. (1993) Aminorex-induced, plexogenic pulmonary arteriopathy: 25 years later! Z Kardiol, 82, 568-572.
Fuster, V., Steele, P. M., Edwards, W. D., et al. (1984) Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation, 70, 580-587.
Hackett, P. H., Roach, R. C., Hartig, G. S., et al. (1992) The effect of vasodilators on pulmonary hemodynamics in high altitude pulmonary edema: A comparison. Int J Sports Med, 13 (Suppl 1), S68-S71.
Hoeper, M. M., Olschewski, H., Ghofrani, H. A., et al. (2000) A comparison of the acute hemodynamic effects of inhaled nitric oxide and aerosolized iloprost in primary pulmonary hypertension. German PPH study group. J Am Coll Cardiol, 35, 176-182.
Hohenhaus, E., Niroomand, F., Görre, S., et al. (1995) Nifedipine dos not prevent acute mountain sickness. Am J Respir Crit Care Med, 150, 857-860.
Morgan, J. M., McCormack, D. G., Griffiths, M. J., et al. (1991) Adenosine as a vasodilator in primary pulmonary hypertension. Circulation, 84, 1145-1149.
Moser, K. M., Fedullo, P. F., Finkbeiner, W. E., et al. (1995) Do patients with primary pulmonary hypertension develop extensive central thrombi? Circulation, 91, 741-745.
Oelz, O., Maggiorini, M., Ritter, M., et al. (1989) Nifedipine for high altitude pulmonary oedema. Lancet, 2 (8674), 1241-1244.
Olschewski, H., Walmrath, D., Schermuly, R., et al. (1996) Aerosolized prostacyclin and iloprost in severe pulmonary hypertension. Ann Intern Med, 124, 820-824.
Packer, M., Medina, N. and Yushak, M. (1984) Adverse hemodynamic and clinical effects of calcium channel blockade in pulmonary hypertension secondary to obliterative pulmonary vascular disease. J Am Coll Cardiol, 4, 890-901.
Partanen, J., Nieminen, M. S. and Luomanmaki, K. (1993) Death in a patient with primary pulmonary hypertension after 20 mg of nifedipine. N Engl J Med, 329, 812; discussion 812-813.
Prigogine, T., Waterlot, Y., Gottignies, P., et al. (1991) Acute nonhemodynamic pulmonary edema with nifedipine in primary pulmonary hypertension. Chest, 100, 563-564.
Rich, S. and Brundage, B. H. (1987) High-dose calcium channel-blocking therapy for primary pulmonary hypertension: evidence for long-term reduction in pulmonary arterial pressure and regression of right ventricular hypertrophy. Circulation, 76, 135-141.
Rich, S., Ganz, R. and Levy, P. S. (1983) Comparative actions of hydralazine, nifedipine and amrinone in primary pulmonary hypertension. Am J Cardiol, 52, 1104-1107.
Rich, S. and Kaufmann, E. (1991) High dose titration of calcium channel blocking agents for primary pulmonary hypertension: guidelines for short-term drug testing. J Am Coll Cardiol, 18, 1323-1327.
Rich, S., Kaufmann, E. and Levy, P. S. (1992) The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med, 327, 76-81.
Rubin, L. J., Groves, B. M., Reeves, J. T., et al. (1982) Prostacyclin-induced acute pulmonary vasodilation in primary pulmonary hypertension. Circulation, 66, 334-338.
Rubin, L. J., Nicod, P., Hillis, L. D., et al. (1983) Treatment of primary pulmonary hypertension with nifedipine. A hemodynamic and scintigraphic evaluation. Ann Intern Med, 99, 433-438.
Sitbon, O., Humbert, M., Jagot, J. L., et al. (1998) Inhaled nitric oxide as a screening agent for safely identifying responders to oral calcium-channel blockers in primary pulmonary hypertension. Eur Respir J, 12, 265-270.
Weir, E. K., Rubin, L. J., Ayres, S. M., et al. (1989) The acute administration of vasodilators in primary pulmonary hypertension. Experience from the National Institutes of Health Registry on Primary Pulmonary Hypertension. Am Rev Respir Dis, 140, 1623-1630.
Back to > Medical > Therapy > Specific treatments
Calcium channel blockers
Since the first description of pulmonary hypertension, vasodilators have been recommendid for decreasing right ventricular afterload in these patients. Several different vasodilators such as nidefipine, diltiazem, hydralazine, prazosin, nitrates, prostacyclin and others were used for treatment of acute or chronic pulmonary hypertension (Weir et al., 1989). None of these drugs turned out to be selective for the pulmonary circulation and they all decreased systemic vascular resistance and cardiac output. Therefore, they carry the risk for systemic hypotension, which impairs coronary perfusion and causes right ventricular ischemia. Among different systemic vasodilators, nifedipine became quickly a promising drug for the treatment of pulmonary hypertension, because it decreases pulmonary artery pressure, pulmonary vascular resistance and systemic pulmonary vascular resistance, and increases cardiac output (Rich et al., 1983, Rubin et al., 1983). Calcium channel blockers such as nifedipine or diltiazem are selective inhibitors of the L-type calcium channels and decrease intracellular calcium concentration, which leads to vascular smooth muscle cells relaxation.
Rapid exposure to high altitude associated pulmonary hypertension is inhibited by the prophylactic administration of nifedipine or other vasodilators (Hackett et al., 1992, Hohenhaus et al., 1995). In high altitude pulmonary edema susceptible subjects, nifedipine attenuates excessive hypoxic pulmonary vasoconstriction and successfully prevents alveolar fluid flooding in these subjects (Bärtsch et al., 1991). Moreover, in subjects with high altitude pulmonary edema nifedipine intake caused a rapid and sustained decrease in pulmonary artery pressure, which led to a significant improvement of high altitude pulmonary edema associated clinical and radiographic signs and allowed subjects to descend by proper means (Oelz et al., 1989). Thus nifedipine is the first line option for the treatment and the prevention of high altitude pulmonary edema.
In primary pulmonary hypertension, response to treatment with calcium channel blockers was found to be associated with a more favorable outcome (Rich et al., 1983, Rubin et al., 1983). Patients with marginal response to conventional dose of a calcium channel blockers may respond to high-doses of nifedipine (up to 240 mg/day) or diltiazem (up to 900 mg/day) (Rich and Brundage, 1987). In patients, who tolerated this high-dose calcium channel blocker, the pulmonary artery pressure decreased by > 20% and pulmonary vascular resistance by ~ 50 %. In these patients, called responders, the reduction in pulmonary artery pressure is protracted and accompanied by a regression of right ventricular hypertrophy (Rich and Brundage, 1987, Rich and Kaufmann, 1991). Five-year-survival in responders was 94 % compared to 55 % in non-responders (p < 0.003) (Rich et al., 1992). Unfortunately, only a small number of patients treated with high-dose calcium channel blockers are responders (10 to 25 %) (Rich et al., 1992, Sitbon et al., 1998). A decrease in pulmonary vascular resistance by > 20 % without a decrease in pulmonary artery pressure appears not to be associated with a favorable outcome regarding a reduction in the severity of dyspnea and fatigue (Rich et al., 1992).
Adverse events with the use of calcium channel blockers occurred in 1 % of the 491 patients with pulmonary hypertension in the NIH-registry (Weir et al., 1989). Although not common, some cases of cardiac arrest with or without concomitant pulmonary edema in the course of vasodilator testing have been reported by different centers (Aromatorio et al., 1985, Batra et al., 1985, Chaouat et al., 1996, Farber et al., 1983, Packer et al., 1984, Partanen et al., 1993, Prigogine et al., 1991). Because of their long half-life and systemic effects vasodilators such as nifedipine, diltiazem or hydralazine are considered not suitable for testing of pulmonary vascular reactivity. Conversely, suitable for pulmonary vasoactivity testing are vasodilators with a short half-life, i.e. pulmonary selective vasodilators such as inhaled nitric oxide (Sitbon et al., 1998), inhaled iloprost (Olschewski et al., 1996), the short acting intravenous vasodilator adenosine (Morgan et al., 1991) or intravenous prostacyclin (Rubin et al., 1982). Acute reversibility of pulmonary vascular resistance (> 50 %) to inhaled NO not only predicted better response, but also better tolerance of nifedipine treatment with a decreased incidence of life-threatening hypotension or cardiac arrest (Sitbon et al., 1998).
In conclusion, calcium channel blockers should not be used for acute reactivity testing in chronic pulmonary arterial hypertension. Moreover, treatment of chronic pulmonary hypertension with nifedipine or diltiazem should be considered only in patients who fulfill responder's criteria during acute testing. Responders definition criteria are pulmonary artery pressure > 20 % and pulmonary vascular resistance > 20 %. This can be achieved either by inhaling nitric oxide or iloprost. Measurements regarding nitric oxide are performed during the 10 minutes inhalation, whereas for iloprost, measurements are taken 10 to 15 minutes after inhalation. In primary pulmonary hypertension iloprost inhalation-induced pulmonary vasodilation is at least equal if not more potent than inhaled nitric oxide (Hoeper et al., 2000)
References:
Aromatorio, G. J., Uretsky, B. F. and Reddy, P. S. (1985) Hypotension and sinus arrest with nifedipine in pulmonary hypertension. Chest, 87, 265-267.
Bärtsch, P., Maggiorini, M., Ritter, M., et al. (1991) Prevention of high altitude pulmonary edema by nifedipine. N Engl J Med, 325, 1284-1289.
Batra, A. K., Segall, P. H. and Ahmed, T. (1985) Pulmonary edema with nifedipine in primary pulmonary hypertension. Respiration, 47, 161-163.
Chaouat, A., Kessler, R. and Weitzenblum, E. (1996) Pulmonary oedema and pleural effusion in two patients with primary pulmonary hypertension treated with calcium channel blockers. Heart, 75, 383.
Cohen, M., Edwards, W. D. and Fuster, V. (1986) Regression in thromboembolic type of primary pulmonary hypertension during 2 1/2 years of antithrombotic therapy. J Am Coll Cardiol, 7, 172-175.
Farber, H. W., Karlinsky, J. B. and Faling, L. J. (1983) Fatal outcome following nifedipine for pulmonary hypertension. Chest, 83, 708-709.
Frank, H., Gurtner, H. P., Kneussl, M., et al. (1993) Aminorex-induced, plexogenic pulmonary arteriopathy: 25 years later! Z Kardiol, 82, 568-572.
Fuster, V., Steele, P. M., Edwards, W. D., et al. (1984) Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation, 70, 580-587.
Hackett, P. H., Roach, R. C., Hartig, G. S., et al. (1992) The effect of vasodilators on pulmonary hemodynamics in high altitude pulmonary edema: A comparison. Int J Sports Med, 13 (Suppl 1), S68-S71.
Hoeper, M. M., Olschewski, H., Ghofrani, H. A., et al. (2000) A comparison of the acute hemodynamic effects of inhaled nitric oxide and aerosolized iloprost in primary pulmonary hypertension. German PPH study group. J Am Coll Cardiol, 35, 176-182.
Hohenhaus, E., Niroomand, F., Görre, S., et al. (1995) Nifedipine dos not prevent acute mountain sickness. Am J Respir Crit Care Med, 150, 857-860.
Morgan, J. M., McCormack, D. G., Griffiths, M. J., et al. (1991) Adenosine as a vasodilator in primary pulmonary hypertension. Circulation, 84, 1145-1149.
Moser, K. M., Fedullo, P. F., Finkbeiner, W. E., et al. (1995) Do patients with primary pulmonary hypertension develop extensive central thrombi? Circulation, 91, 741-745.
Oelz, O., Maggiorini, M., Ritter, M., et al. (1989) Nifedipine for high altitude pulmonary oedema. Lancet, 2 (8674), 1241-1244.
Olschewski, H., Walmrath, D., Schermuly, R., et al. (1996) Aerosolized prostacyclin and iloprost in severe pulmonary hypertension. Ann Intern Med, 124, 820-824.
Packer, M., Medina, N. and Yushak, M. (1984) Adverse hemodynamic and clinical effects of calcium channel blockade in pulmonary hypertension secondary to obliterative pulmonary vascular disease. J Am Coll Cardiol, 4, 890-901.
Partanen, J., Nieminen, M. S. and Luomanmaki, K. (1993) Death in a patient with primary pulmonary hypertension after 20 mg of nifedipine. N Engl J Med, 329, 812; discussion 812-813.
Prigogine, T., Waterlot, Y., Gottignies, P., et al. (1991) Acute nonhemodynamic pulmonary edema with nifedipine in primary pulmonary hypertension. Chest, 100, 563-564.
Rich, S. and Brundage, B. H. (1987) High-dose calcium channel-blocking therapy for primary pulmonary hypertension: evidence for long-term reduction in pulmonary arterial pressure and regression of right ventricular hypertrophy. Circulation, 76, 135-141.
Rich, S., Ganz, R. and Levy, P. S. (1983) Comparative actions of hydralazine, nifedipine and amrinone in primary pulmonary hypertension. Am J Cardiol, 52, 1104-1107.
Rich, S. and Kaufmann, E. (1991) High dose titration of calcium channel blocking agents for primary pulmonary hypertension: guidelines for short-term drug testing. J Am Coll Cardiol, 18, 1323-1327.
Rich, S., Kaufmann, E. and Levy, P. S. (1992) The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med, 327, 76-81.
Rubin, L. J., Groves, B. M., Reeves, J. T., et al. (1982) Prostacyclin-induced acute pulmonary vasodilation in primary pulmonary hypertension. Circulation, 66, 334-338.
Rubin, L. J., Nicod, P., Hillis, L. D., et al. (1983) Treatment of primary pulmonary hypertension with nifedipine. A hemodynamic and scintigraphic evaluation. Ann Intern Med, 99, 433-438.
Sitbon, O., Humbert, M., Jagot, J. L., et al. (1998) Inhaled nitric oxide as a screening agent for safely identifying responders to oral calcium-channel blockers in primary pulmonary hypertension. Eur Respir J, 12, 265-270.
Weir, E. K., Rubin, L. J., Ayres, S. M., et al. (1989) The acute administration of vasodilators in primary pulmonary hypertension. Experience from the National Institutes of Health Registry on Primary Pulmonary Hypertension. Am Rev Respir Dis, 140, 1623-1630.
Back to > Medical > Therapy > Specific treatments
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SSPH Research Prize 2012
Deadline for submission: April 30, 2012
Further information
Symposium "pulmonal-arterielle Hypertension im Kindesalter"
Donnerstag, 10. Mai 2012, 16.00-18.00, Bern
Further information:
5th International Congress of the Swiss Society of Pulmonary Hypertension (SSPH)
28.-29. September 2012, Thun, Congress Hotel Seepark Thun
Informationen: www.imk.ch/sgph2012
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