The pharmacology of prazosin, a novel antihypertensive agent

During the past few years a large amount of pharmacological and physiological evidence has been obtained in favor of two distinct types of α-adrenoceptors. As a working hypothesis, it is feasible to assume that both α₁- and α₂-adrenoceptors are abundant on the vascular effector site, whereas the α-adrenoceptors (the blockade of which increases norepinephrine release) predominate at the level of peripheral sympathetic nerve endings. Prazosin is a novel, selective antagonist of α₁-adrenoceptors and can be considered an important advancement both pharmacologically and therapeutically since this compound in contrast to classical α-adrenoceptor blocking agents, is effective for the treatment of high blood pressure. Prazosin lacks direct myorelaxant properties and, unlike many vasodilators, in doses lowering blood pressure it does not produce undesirable increases in heart rate and plasma renin activity. Prazosin has proved to be a very useful pharmacological tool since it has permitted us the furtherance of our knowledge with respect to the subclassification of receptors mediating the effects produced by α-adrenoceptor agonists, particularly clonidine. Pharmacokinetic and metabolic studies on prazosin given orally indicate that in animals and in man this compound has a low bioavailability, short half life and undergoes extensive biotransformation. The most common clinical use of prazosin is as an antihypertensive agent and is often given in association with established blood pressure lowering drugs. Recently, it was shown to be useful in the treatment of congestive heart failure, but for this application tolerance has been described. Generally, patients treated chronically with prazosin suffer only minor unwanted effects. This is in contrast to past experience with traditional α-adrenoceptor antagonist. The most serious side effect of prazosin is known as the “first dose phenomenon” which can sometimes lead to syncope. However, it can be avoided if prazosin therapy is initiated with minimally effective doses and individually tailored to obtain the desired antihypertensive effect. Presently, the interesting clinical profile of prazosin is attributed to its novel property of being a selective antagonist of postsynaptic α₁-adrenoceptors. Howeverm this is probably an over simplification since some therapeutic observations are not entirely consistent with results which would have been expected for a selective α₁-adrenoceptor. For example, prazosin, like the classical antagonists, would be expected to produce sexual dysfunction but, in fact, does not to any significant degree. Future studies with new chemical structures sharing the pharmacological profile of prazosin will clarify the real role of the selectivity towards α₁-adrenoceptors in the therapeutic success of prazosin.     

Atenolol,methyldopa, and chlorthalidone in moderate hypertension.

Combined treatment with low doses of different drugs is widely used for moderate hypertension. The effects of atenolol and methyldopa at two dose levels and in combination at the lower doses were studied in patients with moderate hypertension on continuous treatment with moderate hypertension on continuous treatment with chlorthalidone. The mean reduction in standing blood pressures obtained with atenolol 150 and 300 mg/day was about 27/17 mm Hg and with methyldopa 750 and 1500 mg/day about 28/14 mm Hg. Combined treatment with atenolol 150 mg/day and methyldopa 750 mg/day for four weeks resulted in a reduction of 38/25 mm Hg. No difference was observed between the two doses of methyldopa. The lower dose of atenolol was better than the lower dose of methyldopa in reducing lying and standing diastolic blood pressures. These findings show that in patients on continuous treatment with chlorthalidone the addition of atenolol alone or methyldopa alone or of atenolol and methyldopa in combination is effective in the treatment of moderate hypertension.     

Nocturnal polyuria and saluresis in renal allograft recipients.

The evolution of nocturnal polyuria and saluresis in renal allograft recipients was studied by comparing the day to night (D:N) ratios of urine volume and sodium excretion in 15 patients who had undergone transplantation less than one year previously (recent-transplant group) with those in 11 patients who had undergone transplantation at least one year previously. Eleven patients with chronic renal failure and 12 normal subjects served as controls. Patients in the recent-transplant group had significantly lower D:N ratios of urine volume and sodium excretion than the patients who had undergone transplantation at least a year before, while the ratios in this last group did not differ significantly from those in the normal subjects. Nocturnal polyuria and saluresis gradually subsided in five patients studied for three months. Chronic renal failure and uraemic autonomic neuropathy were unlikely causes of the nocturia. The patients in the recent-transplant group had significantly lower D:N ratios of urine volume than the controls with chronic renal failure, and the mean Valsalva ratio in eight of them was not significantly different from that in the normal subjects. An undue sensitivity of renal allografts to postural influences was proposed.     

Renal sympathetic nerve activity and arterial pressure responses to changes in postural position of conscious dogs

Experiments were conducted in conscious dogs to determine the relationships between postural position, arterial pressure, and renal sympathetic nerve activity. Observations of the changes in arterial pressure and renal nerve activity were made when animals spontaneously changed postural position from lying to sitting, sitting to standing, standing to sitting, and sitting to lying. Rising to sit from lying down increased arterial pressure from 109 +/- 5 to 125 +/- 3 mm Hg and increased renal nerve activity by 96 +/- 58 microV/sec (61% of control). Movement from the sitting to standing position decreased renal nerve activity by 90 +/- 39 microV/sec (48% of control) without changing mean arterial pressure. Sitting down from standing also did not change arterial pressure, whereas renal nerve activity increased by 56 +/- 17 microV/sec (33% of control). Returning to the lying position (from sitting) decreased arterial pressure, and this hypotension was associated with significant reductions in renal nerve activity. These results indicate that nonuniform changes in sympathetic outflow from the central nervous system must occur to various vascular beds during changes in postural position of conscious dogs. Thus, renal sympathetic outflow may or may not reflect changes in nerve traffic which contribute to alterations in arterial pressure.     

Serum Folate and Vitamine B12 Levels in Acute and Chronic Renal Disease. Effect of Peritoneal Dialysis

Serum folate and vitamin B₁₂ levels have been measured in 32 patients with renal failure. The initial mean serum folate level was raised above normal in seven patients with acute renal failure whereas the mean level in eight patients severely ill from chronic renal failure was significantly lower than normal. Serum folate levels fell during peritoneal dialysis and rose between dialyses in all these patients and also in one patient who was dialysed for acute pancreatitis.The mean serum B₁₂ level was raised in patients with both acute and chronic renal failure, but there was no consistent change in serum B₁₂ level during dialysis.Hypersegmented polymorphs were present in the peripheral blood film of most of the patients with acute or chronic renal failure. Their presence bore no relation to the clinical state, blood urea, serum folate, or serum B₁₂ level of the patients.     

Therapeutic experience with fludrocortisone in diabetic postural hypotension.

Fourteen patients with diabetic postural hypotension were treated with fludrocortisone for a mean 12 months (range 6-30 months). The mean daily dose of fludrocortisone was 0.2 mg (range 0.1 mg-0.4 mg). Standing systolic and diastolic blood pressures increased significantly (P less than 0.001) after treatment with fludrocortisone and the postural hypotension decreased significantly (P less than 0.001). Thirteen patients noted considerable symptomatic improvement. Fludrocortisone should be used cautiously in patients with congestive cardiac failure or the nephrotic syndrome.     

Labetalol: potent antihypertensive agent that blocks both alpha- and beta-adrenergic receptors.

Labetalol was administered as the sole antihypertensive agent to 20 ambulatory patients with mild to moderate hypertension. The mean systolic and diastolic blood pressures (+/- standard error of the mean) with the patients sitting fell significantly (P < 0.001), from 145.5 +/- 3.2 and 103.7 +/- 1.6 mm Hg respectively at the start of labetalol therapy (after a period free of antihypertensive medication) to 125.7 +/- 2.0 and 87.2 +/- 1.1 mm Hg by the end of the trial. The diastolic blood pressure was well controlled (90 mm Hg or less) with labetalol therapy in 90% of the patients. The medication was well tolerated, and no orthostatic fall in the diastolic blood pressure was observed. Pharmacologically labetalol most closely resembles a combination of a nonselective beta-adrenergic blocker like propranolol and a postsynaptic alpha-adrenergic blocker like prazosin.     

Trial of atenolol and chlorthalidone for hypertension in black South Africans.

Twenty-four black patients (Zulus) with hypertension participated in a double-blind, placebo-controlled cross-over trial of the efficacy of a beta-blocking agent (atenolol) 100 mg once daily as compared with chlorthalidone 25 mg once daily. The two drugs were also given combined at these doses and the effects compared with those of the drugs given alone. Atenolol as sole treatment had no appreciable effect on blood pressure as compared with placebo. Chlorthalidone produced a small decrease, but this was not statistically significant. Combining the two drugs, however, produced a significant reduction in blood pressure (mean lying blood pressure p < 0.001; mean standing blood pressure p < 0.0002). These findings suggest that beta-blockers should not be regarded as baseline treatment of hypertension in blacks.     

Effect of recombinant human erythropoietin on the anemia of chronic renal failure

Phase I and Phase II studies of recombinant human erythropoietin (rhEpo) were conducted in normal volunteers and in anemic patients with chronic renal failure on maintenance hemodialysis. Three hundred U/person of rhEpo was administered intravenously to healthy normal volunteers in the Phase I study, resulting in no subjective or objective changes. In the Phase II study, 66 patients with chronic renal failure on maintenance hemodialysis with less than 20% hematocrit values were treated with rhEpo in doses of 50 U/kg to 200 U/kg two or three times a week. Hematocrit values increased significantly during the 12 weeks, and the patients' conditions improved. Patients previously requiring blood transfusions became transfusion-independent during our study. There were no obvious side effects, thus indicating the safety and efficacy of rhEpo in the anemia of chronic renal failure.     

Effect of water immersion on levels of atrial natriuretic peptide in patients with chronic renal failure

An effect of a 2-hour water immersion on the blood serum ANP was investigated in 20 haemodialysed patients with chronic renal failure and in 15 healthy individuals. Water immersion produced an increase in volume in both healthy individuals and the patients of similar degree. Baseline ANP concentration (290.0 +/- 21.9 pg/mL) was significantly higher in the dialysed patients than that in healthy individuals (66.0 +/- 5.5 pg/mL). Water immersion decreased mean arterial pressure (previously significantly higher in the patients) in both healthy individuals and examined patients, significantly increased secretory renal function (significantly higher in healthy individuals than in the examined patients), and increased ANP (previously significantly higher in healthy subjects). A significant correlation between ANP level in blood serum and changes in volume was seen only in healthy individuals. The obtained results suggest a contribution of other than changed volume factors of ANP release regulation and other than ANP factors to pathomechanism of post-immersion drop of the arteria blood pressure and increased secretory renal function in both healthy individuals and patients with renal failure.     

Approach to drug therapy for hypertension.

Prevention of complications of hypertension requires the lowering of blood pressure. The therapeutic goal is to achieve and maintain a diastolic pressure of less than 90 mm Hg with minimal adverse effects. The treatment of patients with established diastolic blood pressures between 90 and 104 mm Hg (determined from three separate readings) should be individualized; general measures such as weight loss and salt restriction should be tried first as an alternative to drug therapy. Patients with diastolic pressure in excess of 104 mm Hg should be treated with antihypertensive drugs; the first step should be the use of a thiazide diuretic in addition to general measures. Patients with diastolic pressures of 90 to 115 mm Hg may require the addition of a beta-adrenergic-receptor antagonist, methyldopa or clonidine if the therapeutic goal is not achieved; rarely they require the further addition of hydralazine or prazosin. Patients with diastolic pressures of 116 to 129 mm Hg usually require initially both a thiazide diuretic and a beta-blocker, methyldopa or clonidine; if the therapeutic goal is not achieved, hydralazine or prazosin is added, and if a further hypotensive effect is required guanethidine can be added. Patients with severe hypertension (diastolic pressures greater than 130 mm Hg) may require urgent treatment with combinations of drugs of all three levels. Emphasis should be placed on individualized therapy and patient compliance in the assessment of therapeutic failures. These "step-care" guidlines represent a framework for antihypertensive therapy devised from information available in 1977. It is not a rigid scheme and should be adjusted to the individual patient to ensure as normal a life as possible.     

Prazosin in the preoperative management of patients with phaeochromocytoma

The use of prazosin--a drug selectively blocking alpha-adrenergic receptors--was considered for the preoperative management of patients with phaeochromocytoma. Prazosin was administered to 8 patients in whom the diagnosis was established basing on the clinical symptoms and daily excretion of catecholamines and their metabolites with the urine. Preliminary diagnosis was subsequently confirmed operationally. Prazosin could be considered effective only in the part of treated patients. This was manifested by the drop in blood pressure to nearly normal values and diminished attacks. However, prazosin did not prevent blood pressure increase during anaesthesia and surgery. The use of prazosin in patients with phaeochromocytoma for preoperative management may be an alternative pharmacological therapy producing appropriate drop in blood pressure in some patients.     

Once-daily dosing with Atenolol in patients with mild or moderate hypertension.

Because of the difficulties patients have in adhering to their drug regimens a trial was performed in which patients with essential hypertension were given, in random order and for four weeks each, three different doses of atenolol to be taken once daily. Atenolol effectively decreased lying and standing blood pressures, and there was no difference between the effects of the three doses. The simplicity of the regimen, as well as atenolol''s freedom from troublesome side effects, should be valuable in helping patients adhere to long-term treatment.     

Antihypertensive efficacy of alpha-methyldopa,chlorothiazide and Supres-150 (alpha-methyldopa-chlorothiazide).

Twenty-two white men and two white women with uncomplicated essential hypertension participated in a randomized double-blind trial comparing placebo with alpha-methyldopa (750 mg/d orally) and chlorothiazide (450 mg/d orally), alone or in combination. There were no significant differences in blood pressures as measured with the patients lying down; however, with the patients standing the systolic, diastolic and mean arterial blood pressures were significantly lower (P < 0.05) after treatment with alpha-methyldopa or the combination product. The higher the blood pressure before treatment, the greater the fall with treatment. Adverse effects were infrequent.     

Treatment of Hypertension with Propranolol

When used in the treatment of hypertension propranolol is at least of similar potency to bethanidine, guanethidine, and methyldopa. Propranolol does not produce postural or exercise hypotension and it seems that it is often more acceptable to patients than conventional drugs. It usually produces the best control of the supine blood pressure.A series of 109 hypertensive patients was treated with propranolol; in nine the drug was withdrawn. In 92 of the patients a supine or standing blood pressure of 100 mm. Hg or less was achieved. Eighty of the patients had previously been treated with other potent drugs, and close comparisons and prolonged follow-up in 17 patients showed that diastolic pressures of 100 mm. Hg or less were achieved in more patients after propranolol than with guanethidine, bethanidine, or methyldopa.Sensitivity to propranolol varies widely, and dosage should be increased gradually. The hypotensive effect often takes six to eight weeks to reach its maximum. Propranolol reduces cardiac output but may also act by reducing the cardiac component of pressor stimuli; as a result the baroreceptors gradually regulate the blood pressure at a lower level. It is contraindicated in patients with obstructive airways disease or in uncompensated heart failure.     

Blood Pressure Associates with Standing Balance in Elderly Outpatients

Objectives

Assessment of the association of blood pressure measurements in supine and standing position after a postural change, as a proxy for blood pressure regulation, with standing balance in a clinically relevant cohort of elderly, is of special interest as blood pressure may be important to identify patients at risk of having impaired standing balance in routine geriatric assessment.

Materials and Methods

In a cross-sectional cohort study, 197 community-dwelling elderly referred to a geriatric outpatient clinic of a middle-sized teaching hospital were included. Blood pressure was measured intermittently (n = 197) and continuously (subsample, n = 58) before and after a controlled postural change from supine to standing position. The ability to maintain standing balance was assessed during ten seconds of side-by-side, semi-tandem and tandem stance, with both eyes open and eyes closed. Self-reported impaired standing balance and history of falls were recorded by questionnaires. Logistic regression analyses were used to examine the association between blood pressure and 1) the ability to maintain standing balance; 2) self-reported impaired standing balance; and 3) history of falls, adjusted for age and sex.

Results

Blood pressure decrease after postural change, measured continuously, was associated with reduced ability to maintain standing balance in semi-tandem stance with eyes closed and with increased self-reported impaired standing balance and falls. Presence of orthostatic hypotension was associated with reduced ability to maintain standing balance in semi-tandem stance with eyes closed for both intermittent and continuous measurements and with increased self-reported impaired standing balance for continuous measurements.

Conclusion

Continuous blood pressure measurements are of additional value to identify patients at risk of having impaired standing balance and may therefore be useful in routine geriatric care.     

Acute renal function in chronically sympathectomized deoxycorticosterone acetate-treated miniature swine

We recently validated a swine model in which chronic treatment with 6-hydroxydopamine (6-OHDA) produced an effective sympathectomy. These sympathectomized swine demonstrated a significantly attenuated hypertensive response when treated with deoxycorticosterone acetate (DOCA). Because renal nerve activity is elevated and important in controlling renal function and blood pressure in the DOCA swine model, we wanted to study the effect of chronic sympathectomy on acute renal hemodynamics and tubular function. Kidney function was assessed in 14 DOCA-treated miniature swine, 8 of which were sympathectomized by chronic treatment with 6-OHDA, while 6 served as controls. Effective renal sympathectomy in this model has been previously confirmed by a significant reduction (97%) of norepinephrine in renal cortical tissue. When anesthetized, mean arterial pressure and renal blood flow were similar between the two groups. Glomerular filtration rate was lower by 43%, urine flow rate by 71%, sodium excretion by 66%, and potassium excretion by 48% in the 6-OHDA DOCA animals. All of these parameters were significantly different from the intact DOCA controls. These results indicate that anesthetized, chronically sympathectomized swine exhibit decreased renal excretory function. The changes in renal function may have been due to the development of a tubular or glomerular supersensitivity to circulating antinatriuretic factors, since the 6-OHDA group had a 28% greater pressor response to the alpha-agonist phenylephrine and a significantly greater fall in mean arterial pressure in response to alpha-blockade with prazosin when compared with the controls. These changes in renal function may also explain why the 6-OHDA animals demonstrated a slight increase in mean arterial pressure in response to DOCA. Because acute renal denervation in DOCA-treated swine produces a diuresis and natriuresis, this study affirms that there may be important functional differences in acutely versus chronically denervated kidneys for which the implications under normal physiologic conditions are unknown.     

Influence of dosage and dietary sodium on the first-dose effects of prazosin.

The effects of the first dose of prazosin were assessed in hypertensive patients on different sodium intakes. Patients received 250, 100, or 30 mmol sodium per 24 hours for a week before taking 2 mg or 0-5 mg prazosin. The acute effects of prazosin on blood pressure and pulse rate were milder with a high sodium intake. On the 100-mmol intake symptomatic postural hypotension occurred in five out of seven patients given 2 mg prazosin and in two out of four given a 0-5-mg dose, whereas those taking 2 mg or 0-5 mg and a 250-mmol sodium intake experienced no postural symptoms. These findings indicate that particular care should be taken in starting prazosin treatment in sodium-depleted patients.     

Interaction between Clonidine and Desipramine in Man

Interaction between the tricyclic antidepressant desipramine and the antihypertensive agent clonidine has been investigated in five hypertensive patients in a double-blind placebo controlled study. Introduction of the tricyclic antidepressant led to loss of blood pressure control in four of the patients. The average blood pressure rise in the desipramine period compared with the placebo period was 22/15 mm Hg in the lying position and 12/11 mm Hg standing. Thus addition of a tricyclic antidepressant may lead to loss of blood pressure control in a hypertensive patient treated with clonidine.     

Barbiturate and anticonvulsant treatment in relation to osteomalacia with haemodialysis and renal transplantation.

Among 39 patients treated by regular haemodialysis for four years or more pathological fractures and histological evidence of osteomalacia were significantly more common in those taking barbiturates. Out of 58 transplant recipients surveyed after one year, seven had osteomalacia; four of these had been taking phenobarbitone and phenytoin and one had taken barbiturates alone. Sedatives and other drugs such as phenobarbitone and phenytoin that induce hepatic microsomal enzymes should probably be avoided when possible in patients with chronic renal failure and after transplantation.