Pulmonary hypertension, treatment

Untoward effects of both E and NE (usually to a lesser degree) are anxiety, headache, cerebral hemorrhage (from vasopressor effects), cardiac arrhythmias, especially in presence of digitaUs and certain anesthetic agents, and pulmonary edema as a result of pulmonary hypertension. The minimum subcutaneous lethal dose of E is about 4 mg, but recoveries have occurred after accidental overdosage with 16 mg subcutaneously and 30 mg intravenously, followed by immediate supportive treatment. 

As endothelins mediate potent vasoconstrictor effects, ECE inhibitors and endothelin receptor antagonists were developed for the treatment of cardiovascular diseases, such as acute and chronic heart failure, pulmonary hypertension and subarachnoid haemorrhage. As ETa recqrtors have potent mitogenic responses and may promote progression of ovarian and prostate cancer and bone metastases ETA receptors are also considered as a potential targets for anti-tumour activity. 

In low doses, inhaled NO may have a beneficial therapeutic effect, since NO in the inspired air leads to pulmonary vasodilation. In persistent pulmonary hypertension of the newborn, NO inhalation has already been used with some success. NO inhalation as the treatment for acute respiratory distress syndrome, however, has been disappointing. Only transient improvements of oxygenation were detected and the outcome of placebo-controlled trials did not show any improvement... 

Inhaled NO has been used for treatment of persistent pulmonary hypertension of newborn infants, critical respiratory failure of preterm infants, and acute hypertension of adult cardiac surgery patients. PDE-5 inhibitors such as sildenafil are also effective for treatment of pulmonary hypertension. The combination of PDE-5 and NO inhalation yields additive beneficial effects on pulmonary hemodynamics. On the other hand, measurement of exhaled NO is a noninvasive and reproducible test that is a surrogate measure of airway inflammation in patients with bronchial asthma. 

Prostacyclin (epoprostanol) is one of the few drugs effective for the treatment of Primary Pulmonary Hypertension (PPH) a rare but frequently fatal illness of young adults. Increased blood pressure in the pulmonary circulation leads to right-heart failure. Continuous infusion of epoprostanol leads to a decrease in blood pressure however, it is unclear whether this is due to direct dilator activity of the IP receptor acting on smooth muscle, or a more indirect mechanism. 

Fenfluramine has not been systematically studied in the treatment of BN, but dexfenfluramine has been evaluated with disappointingly mixed results. Due to an association with the development of heart valve abnormalities and pulmonary hypertension, particularly when coadministered with phentermine (lonamin) in the so-called Fen-Phen strategy, these medications have recently been removed from the U.S. market. 

Alternative treatments Use of iloprost with other approved treatments for pulmonary hypertension has not been studied. If patients deteriorate while on this treatment, consider alternative treatments. 

Puimonary edema If signs of pulmonary edema occur when inhaled iloprost is administered in patients with pulmonary hypertension, stop the treatment immediately. This may be a sign of pulmonary venous hypotension. 

Even though nitric oxide is the physiological mediator of a variety of responses, excess nitric oxide is toxic to many cells as a result of its role in the production of per-oxynitrite and resultant lipid oxidation. Inhibitors of the NOS enzyme are in clinical trials for the treatment of hypotension associated with septic shock. Administration of low concentrations of nitric oxide through respiratory ventilators has been implemented to treat persistent pulmonary hypertension of the newborn. 

Parke-Davis workers have performed SAR studies on endothelin receptor antagonists derived from a dimethoxy-substituted oxicam in the search of treatments for hypertension, congestive heart failure, renal failure, pulmonary hypertension, ischemia, and cerebral vasospasm <1998BMC1447>. Compound 295 displayed a 40-fold selectivity for endothelin receptor antagonist A (ETa) over endothelin receptor antagonist B (ETb) (Figure 26). 

Unlabeled Uses Treatment of atherosclerosis, gangrene, pain due to severe peripheral arterial occlusive disease, pulmonary hypertension... 

Long-term treatment of New York Heart Association Class III and IV primary pulmonary hypertension IV Infusion Procedure to determine dose range Initially, 2 ng/kg/min, increased in increments of 2 ng/kg/min q 15min until dose-limiting adverse effects occur. Chronic Infusion Start at 4 ng/kg/min less than the maximum dose rate tolerated during acute dose ranging (or one half of the maximum rate if rate was less than 5 ng/kg/min). 

Unlabeled Uses Treatment of CHF, hypertension secondary to eclampsia and pre-eclampsia, primary pulmonary hypertension. 

Higenbottam TW, Spiegelhalter D, Scott JP, Fuster V, Dinh-Xuan AT, Caine N, Wallwork J. Prostacyclin (epo-prostenol) and heart-lung transplantation as treatments for severe pulmonary hypertension. Br Heart J 1993 70(4) 366-70. 

Hoeper MM, Schwarze M, Ehlerding S, Adler-Schuermeyer A, Spiekerkoetter E, Niedermeyer J, Hamm M, Fabel H. Long-term treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analogue. N Engl J Med 2000 342(25) 1866-70. 

A 61-year-old woman developed pulmonary edema during treatment with epoprostenol for severe pulmonary hypertension associated with limited scleroderma (5). She received an infusion of epoprostenol 1 nano-gram/kg/minute, and the dosage was increased by 1-... 

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