Canadian Neighbor Pharmacy: Pulmonary Vasoconstriction Play an Important Role in Patients with Primary Pulmonary Hypertension

Because vasodilator drugs have proved to be a useful approach to the management of patients with systemic hypertension and left ventricular failure, there has been great interest in their application in the treatment of patients with primary pulmonary hypertension. This therapeutic approach makes a number of assumptions that need to be critically evaluated: (1) pulmonary vasoconstriction plays an important role in a significant number of patients with primary pulmonary hypertension; (2) pulmonary vasoconstriction is pharmacologically responsive to drug therapy; (3) drugs can be developed that selectively antagonize this vasoconstrictor response; and (4) the benefits of drug therapy can be sustained for long periods with few adverse reactions.

Most of the evidence that pulmonary vasoconstriction plays an important role in the pathogenesis of pulmonary hypertensive states is derived from the study of patients with hypoxic pulmonary hypertension and reactive pulmonary hypertension associated with mitral valve disease, in whom a dramatic reduction of pulmonary artery pressures follows specific therapeutic interventions, such as oxygen therapy and mitral valve surgery. Unfortunately, there is little evidence that pulmonary vasoconstriction contributes to the clinical state of patients with primary pulmonary hypertension. Although the presence of medial hypertrophy in the pulmonary arterioles of affected patients and the association of primary pulmonary hypertension with disorders of known vasospastic origin suggest that pulmonary vasoconstriction is important in patients with primary pulmonary hypertension, the ultimate test of this hypothesis is the demonstration that hemodynamic and clinical improvement follows the administration of pulmonary vasodilator drugs to patients with this disorder. Unfortunately, our personal experience suggests that a successful therapeutic outcome following the use of currently available drugs is distinctly uncommon. It remains unclear, however; whether our unfavorable experience is due to the fact that the importance of pulmonary vasoconstriction has been overstated or that currently available drugs are seriously flawed in their ability to achieve this goal. The main aspects represented by Canadian Neighbor Pharmacy about medicine and pharmacy are collected here.

Early Experience with Vasodilator Drugs

Initial attempts to dilate the pulmonary vasculature pharmacologically in patients with primary pulmonary hypertension were cautiously conducted with drugs that were administered directly into the pulmonary artery and had a brief duration of action. These preliminary studies suggested that pulmonary vasoconstriction was important in some patients with this disorder. Isolated case reports noted short-term hemodynamic improvement following the administration of acetylcholine, tolazoline, phentolamine, and isoproterenol; unfortunately, the pulmonary vasculature in most patients in whom these drugs were tested proved unresponsive to these interventions.’ The need for parenteral administration was the primary limitation of these drugs; even if hemodynamic improvement was observed, attempts to maintain any benefit with long-term oral or sublingual drug administration generally proved to be ineffective, impractical, or associated with disabling GI reactions.

The next stage in the development of vasodilator drugs for patients with primary pulmonary hypertension was the therapeutic application of direct-acting vasodilator agents. Clinical investigators reasoned that a-adrenergic antagonists and P-adrenergic agonists foiled because the sympathetic nervous system was not involved in the pathogenesis of pulmonary vasoconstriction in most patients with this disorder; hence, a vasodilating agent that acted directly on the pulmonary circuit might exert beneficial effects not seen previously. The first direct-acting drug used successfully in patients with primary pulmonary hypertension was diazox-ide. Given directly into the pulmonary artery, Wang and colleagues first noted that the drug produced marked increases in cardiac output and decreases in pulmonary vascular resistance in three patients, followed by clinical improvement during long-term oral treatment. However, diazoxides long duration of action proved potentially dangerous. In patients in whom the magnitude of systemic vasodilation greatly exceeded that seen in the pulmonary circuit, intravenous administration of the drug resulted in prolonged and profound systemic hypotension that occasionally led to catastrophic clinical events. Furthermore, even in patients in whom the initial responses to diazoxide were favorable, long-term therapy was frequently associated with diabetes, fluid retention, hirsutism, and GI distress.

Because of the frequent occurrence of adverse reactions with diazoxide, other direct-acting vasodilator drugs were investigated in the hope that they might produce beneficial hemodynamic effects that were well tolerated. Rubin and Peter showed that oral hydralazine markedly lowered pulmonary vascular resistance and increased cardiac output in four patients with primary pulmonary hypertension, without causing important changes in systemic arterial pressure. These beneficial effects were seen at both rest and during exercise, persisted during long-term treatment with the drug, and were accompanied by symptomatic improvement. Our experience with hydralazine in 13 patients with primary and secondary pulmonary hypertension, however, contrasts dramatically with that of Rubin and Peter. Hydralazine produced only moderate pulmonary vasodilation in our patients, and the decrease in resistance in the systemic circulation exceeded that in the pulmonary circuit in all patients but one; this patient was the only one whose condition improved clinically during long-term therapy. In most of our patients, systemic arterial pressure fell and heart rate increased markedly; symptomatic hypotension was observed in four of our 13 patients, one of whom died.

Our unfavorable hemodynamic and clinical experience with hydralazine was not surprising. The drug had been used successfully for years in the treatment of systemic hypertension and left heart failure, and thus, was known to exert marked systemic vasodilator effects. Consequently, we might expect profound hypotension to follow drug administration if systemic vasodilation occurred without a proportional decrease in pulmonary vascular resistance; under such circumstances, the residual obstruction in the pulmonary circuit would attenuate any increase in cardiac output that would be needed to prevent a substantial fall in blood pressure. Most of the earlier intravenously (IV) administered vasodilator drugs had the same disadvantage, but symptomatic hypotension was infrequent, since their brief duration of action provided the opportunity for immediate reversibility of any deleterious circulatory reactions. With the advent of long-acting, orally effective drugs, we might expect serious hypotensive events to increase in frequency if these drugs are administered to patients whose pulmonary vascular responsiveness is unknown. Although some investigators have suggested that the ability of the pulmonary vasculature to respond to an oral vasodilator drug can be predicted accurately by prior testing with a short-acting IV agent (prostacyclin), the response to two vasodilator interventions in the same patients may differ markedly; thus, conclusions regarding pulmonary vascular reactivity based on a single drug challenge may be inaccurate.

Category: Pulmonary Hypertension

Tags: benefit, improvement, primary pulmonary hypertension, Pulmonary Vasoconstriction, vasodilator drugs