[The effects of prazosin in patients with chronic refractory heart failure-acute hemodynamic effects of oral prazosin and long-term therapy (author's transl)].
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Administration, Oral↗
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Ambulatory prazosin treatment of chronic congestive heart failure: development of late tolerance reversible by higher dosage and interrupted substitution therapy.
To evaluate whether long-term administration of the oral vasodilator, prazosin, in the ambulatory therapy of chronic refractory congestive heart failure (CHF) results in gradual attentuation of its marked salutary peripheral circulatory relaxing actions, 16 coronary heart failure patients receiving chronic prazosin, 16 mg daily, were assessed for the development of vasodilator tolerance for 12 months. In six of these patients such tolerance was documented after 7 months which was readily surmountable, thereby allowing continuation of effective chronic prazosin therapy. Each of the six tolerance patients underwent four forearm plethysmography studies: prior to chronic prazosin (study I; 4.0 mg study dose), after 7 months prazosin (study II; 4.0 mg), repeated following 1 additional week on higher effective prazosin dose of 32 mg daily (study III; 8.4 mg), and following 2 weeks of prazosin withdrawal (study IV; 4.0 mg). The prazosin study dose increased forearm blood flow, decreased forearm vascular resistance and venous tone in studies I, III, and IV; these variables were unchanged by prazosin in study II. Despite vasodilator tolerance to the initial daily dosage at 7 months (study II), symptomatic effectiveness and improved cardiac performance were sustained throughout the entire 12 months of chronic prazosin therapy by increasing dosage (study III) and brief interruption of the vasodilator (study IV) (NYHA class IV pre-prazosin symptoms improved to class 2.7 at 3 months, class 2.4 at 6 months, and class 2.5 at 12 months chronic prazosin). This study showed that prazosin vasodilator tolerance occurred in approximately one third of CHF patients after several months of chronic prazosin therapy. More importantly, however, the present investigation demonstrated that chronic prazosin symptomatic efficacy can be maintained in such CHF patients by overcoming tolerance with higher effective prazosin dosage or brief prazosin discontinuation.
Administration, Oral↗
Chronic prazosin attenuates the natriuretic response to a modest saline load in anaesthetized rats.
1. The effect of chronic prazosin pretreatment (3 days) on the ability to excrete a modest saline load (i.v. saline, 0.097 ml min-1) was studied in the anaesthetized rat. Three days before the experiment, the drinking water was replaced with 0.5% dextrose (control), 0.015 mg ml-1 prazosin in 0.5% dextrose (low dose) or 0.15 mg ml-1 prazosin in 0.5% dextrose (high dose). 2. The selectivity of the prazosin for alpha 1-adrenoceptors was evaluated in pithed rats. The pressor response to phenylephrine was partially attenuated by the low dose of prazosin and completely attenuated by the high dose of prazosin. The pressor response to clonidine was slightly decreased by the 3 day prazosin pretreatment indicating a selectivity for alpha 1-adrenoceptors. 3. In rats pretreated with the low dose of prazosin, there was a significant decrease in sodium and water, but not potassium excretion as compared to the control group. Captopril failed to alter these effects of the low dose of prazosin. Blood pressure and creatinine clearance were the same in both groups. In rats pretreated with the high dose of prazosin, there was a further decrease in sodium and water but not potassium excretion. However, this dose of prazosin also significantly decreased blood pressure and increased creatinine clearance. A decrease in renal perfusion pressure with an aortic clamp to the same level as that observed with the high prazosin dose also decreased sodium and water but not potassium excretion. The decrease in sodium and water excretion was not as great as that observed with the high dose of prazosin. 4. The results indicate that chronic a,-adrenoceptor blockade with prazosin attenuates the ability to excrete a saline load in a dose-related manner. Whether this inability to excrete a saline load is analogous to the sodium and water retention observed with the clinical use of prazosin remains to be determined.
Adrenergic alpha-Antagonists↗
Clinical pharmacokinetics of prazosin.
Prazosin, a quinazoline derivative, is a peripheral vasodilator used in the treatment of arterial hypertension and more recently, congestive heart failure (CHF). Prazosin is extensively metabolised by the liver and has high first-pass metabolism and low oral bioavailability. In normal healthy volunteers, the time of peak concentration occurs between 1 and 3 hours after oral administration, with wide interindividual variations. The extent of oral absorption seems to be similar for different pharmaceutical forms and is not influenced by the presence of food in the digestive tract. Oral bioavailability of prazosin ranges from 43.5 to 69.3% (mean 56.9%). Prazosin is highly (92 to 97%) bound to human plasma proteins (albumin and alpha 1-acid glycoprotein) and the extent of binding is independent of the plasma concentration of the drug in the range of 20 to 150 ng/ml. Preliminary studies in humans indicate that pathways for biotransformation of prazosin are similar to those observed in the rat and dog. Only 6% of prazosin is excreted unchanged, mainly in the urine. The two main metabolites (0-demethylated) are almost completely excreted in bile. The time course of disappearance of prazosin from plasma after intravenous injecton indicates that prazosin disposition should be described by a model containing at least 2 kinetically distinct compartments. The mean elimination half-life is about 2.5 hours. After intravenous administration, the steady-state volume of distribution has been calculated to be 42.2 +/- 8.9L and the total body clearance 12.7 +/- 1.3L/h. In hypertensive patients with normal renal function, prazosin kinetics do not differ significantly from normals. However, prazosin disposition is modified in chronic renal failure and in congestive heart failure. In both cases, the plasma free fraction of prazosin is increased and plasma elimination half-life is longer. Prazosin kinetics may be expected to be altered in patients with liver diseases. Pharmacokinetic data do not suggest a mechanism to explain the disappearance of the first-dose effect during continued administration of prazosin. Although more investigation is needed to define prazosin kinetics in congestive heart failure and chronic renal failure, the available information about prolongation of elimination half-life, decreased protein binding and increased peak plasma concentrations suggest that prazosin dosage should be titrated cautiously in such patients.
Biological Availability↗
Prazosin potentiates the acute hypotensive effects of nitroglycerin but does not attenuate nitrate tolerance in normal conscious rats.
Sympathetic activation has been suggested as a mechanism of acute nitrate tolerance, but the available literature is not definitive. We investigated the effects of prazosin, an alpha1-adrenoceptor antagonist, on acute nitroglycerin (NTG) hemodynamics and tolerance development in normal conscious rats. The effect of prazosin bolus injection (300 microg/kg) on NTG hemodynamics was first determined after acute dosing. The extent of maximal mean arterial pressure (MAP) response and the duration of drug-induced hypotension to NTG bolus doses (5, 15, and 30 microg) were measured before and after prazosin. In separate studies, the effects of prazosin on NTG tolerance development were examined. Rats received either 10 microg/min NTG or vehicle infusion for 5 hours after predosing with prazosin (300 microg/kg). Maximal MAP response to the hourly 30-microg NTG i.v. bolus challenge dose (CD) was determined before and after prazosin, and during NTG or vehicle infusion. Our results showed that bolus doses of NTG (at 5, 15, and 30 microg) dose-dependently decreased maximal MAP by 20.8 +/- 5.8, 26.1 +/- 5.0, and 30.6 +/- 5.7 mm Hg, respectively. Prazosin caused an average of 16 mm Hg depression in MAP, and it only slightly potentiated the hypotensive effects of bolus doses of NTG both after acute dosing and during continuous infusion. Prazosin treatment prolonged the duration of NTG-induced MAP response by about 4-fold for all NTG doses examined (P < 0.01 versus corresponding dose before prazosin, ANOVA). In both prazosin-treated and untreated groups, NTG infusion significantly attenuated the MAP response of the NTG CD starting from 1 hour of infusion (P < 0.001 versus 0 hour response, ANOVA), confirming tolerance development. In the presence of NTG tolerance development, prazosin no longer enhanced the apparent duration of NTG action. The hypotensive effect produced by the 30-microg NTG CD lasted for 7 +/- 2 and 10 +/- 2 seconds for prazosin-treated and untreated groups, respectively (P > 0.05, ANOVA). Our results showed that, in both NTG-tolerant and control animals, prazosin only slightly potentiated the maximum hypotensive effects of a challenge NTG dose, but did not significantly alter the pharmacodynamics of NTG-induced hemodynamic tolerance. Thus, in our animal model, sympathetic blockade by prazosin neither prevented nor attenuated in vivo tolerance induced by NTG.
Adrenergic alpha-Antagonists↗
A randomized, controlled, multicenter study to compare prazosin GITS with enalapril in hypertensive patients with diabetes mellitus. Bombay Hypertension Study Group.
OBJECTIVE: To compare the long-term antihypertensive efficacy, tolerability, and metabolic effects of prazosin GITS and enalapril. DESIGN: Randomized, controlled, multicenter study of 26 weeks duration. SETTING: Office practices of 20 physicians in Mumbai, India. PATIENTS: Males and females, aged 30 to 70 yrs, with hypertension of JNC V stage 1 or 2 at the end of a 2-week placebo run-in period, and diabetes mellitus with at least acceptable glycaemic control (FBS < or = 140 mg/dl, 2-hr PMBS < or = 200 mg/dl, and glycosylated hemoglobin < or = 9.5%). Sufficient number of patients recruited so that at least 60 complete the entire study. INTERVENTIONS: Prazosin GITS (Minipress XL, 2.5-5 mg once daily) or enalapril (Enam, 5-10 mg once daily) for upto 6 weeks; continued upto 24 weeks in those showing a pre-defined response (SBP and/or DBP normalized, or DBP fall of at least 10 mm Hg with actual value of DBP < 95 mm Hg). Patients allocated to either of the two interventions by randomization. OUTCOME MEASURES: Percent patients showing pre-defined BP response at week 6; percent patients with DBP < 90 mm Hg, SBP < 140 mm Hg, and both; percent patients with DBP fall > or = 10 mm Hg; mean fall in BP among those receiving treatment for 24 weeks; mean change in serum lipids at the end of weeks 8, 16, and 24 of treatment; mean change in blood sugar and glycosylated hemoglobin at the end of weeks 8, 16, and 24 of treatment; mean change in 12-hr urinary microalbuminuria and laboratory parameters for safety at the end of week 24; frequency and intensity of adverse events judged probably or definitely related to the drug. RESULTS: Forty-Eight patients randomized to prazosin GITS group and 41 to enalapril group. Of these, 31 in prazosin GITS group (M 19, F 12; mean age-53.4 yr, SEM 1.68) and 29 in enalapril group (M17, F 12; mean age-54.7 yr, SEM 1.64) completed the entire study. Percent patients with DBP < 90 mm Hg at 24 weeks: prazosin GITS--71.0%, enalapril--72.4%; SBP < 140 mm Hg: prazosin GITS--54.8%, enalapril--55.2; both DBP < 90 mm Hg and SBP < 140 mm Hg: prazosin GITS--54.8%, enalapril--44.8%; percent patients with DBP fall of 10 mm Hg or more at 24 weeks: prazosin GITS--77.4%, enalapril--72.4%. The mean fall in the systolic and diastolic blood pressure from the end-of-placebo-phase values to all the other time points was comparable in the two groups. Treatment with prazosin GITS resulted in a favourable effect on serum triglycerides at the end of 8 weeks (p = 0.017) and 16 weeks (p = 0.011), and no detrimental effect or a marginal beneficial effect on total cholesterol, HDL cholesterol, and LDL cholesterol. Enalapril group, on the other hand, showed a significant increase in LDL cholesterol at the end of 24 weeks (p = 0.018), and a marginal increase in total cholesterol, but a beneficial effect on triglycerides at the end of 16 weeks (p = 0.015). Neither drug had any effect on glycosylated hemoglobin and 12-hr urinary microalbuminuria. Treatment with both drugs was associated with an increase in FBS and 2-hr PMBS, but this rise reached statistical significance only in prazosin GITS group. Adverse events probably or definitely related to the drug: prazosin GITS--2 of 44 patients (4.5%), enalapril--6 of 39 patients (15.4%). CONCLUSION: 1. In the doses used, prazosin GITS showed comparable antihypertensive efficacy to enalapril. 2. While enalapril had variable effect, prazosin GITS showed a consistent beneficial effect on some of the serum lipid fractions. 3. The 3-fold difference in the incidence of side effects, although not statistically significant for the available sample size, may be clinically relevant.
Adult↗
Central and peripheral prazosin binding: an in vitro autoradiographic study in the rat.
Using an in vitro autoradiographic technique the binding of [3H]prazosin to brain, spinal cord, heart and vascular tissue was studied. Histologically prepared tissue sections were incubated in 5 nM [3H]prazosin or 5 nM [3H]prazosin in the presence of 100 microM unlabelled prazosin base in order to establish sites exhibiting specific prazosin binding. Dense prazosin binding sites were found in all arterial tissue examined except mesenteric artery. Dense prazosin binding was also found in cardiac tissue. Prazosin binding to veins was present sometimes but often absent. Prazosin does not readily pass the blood brain barrier and in this in vitro study the only area, within the central nervous system, showing specific prazosin binding sites was the olfactory bulb. The selective binding of prazosin, an alpha 1-adrenoceptor antagonist, to arterial and cardiac tissue would suggest that the antihypertension induced by prazosin is mediated by a peripheral action.
Animals↗
Reassessment of the blocking activity of prazosin at low and high concentrations on sympathetic neurotransmission in the isolated mesenteric vasculature of rats.
1. The overflow of endogenous noradrenaline from the rat mesenteric arterial vasculature was determined along with the perfusion pressure response to periarterial nerve stimulation (PNS) (4-12 Hz). 2. The PNS-induced pressor responses were blocked by prazosin at 3 X 10(-8) M but not by prazosin at 10(-6) M or the combination of prazosin at 3 X 10(-8) M and yohimbine (10(-7) M). 3. The PNS-induced overflow of endogenous noradrenaline was significantly augmented by prazosin at 10(-6) M or the combination of prazosin at 3 X 10(-8) M and yohimbine (10(-7) M) but not by prazosin at 3 x 10(-8) M alone. 4. The PNS-induced pressor response and endogenous noradrenaline overflow, in the absence of prazosin, were not significantly influenced by alpha, beta-methylene-adenosine triphosphate (alpha, beta-methylene ATP) (3 X 10(-6) M). The pressor responses to PNS which remained after prazosin at 10(-6) M were abolished by pretreatment with alpha, beta-methylene ATP and therefore attributable to coreleased ATP. 5. The pressor responses to exogenous noradrenaline were abolished by prazosin at both 3 X 10(-8) M and 10(-6) M. 6. These results suggest that no functionally significant amount of ATP was coreleased with noradrenaline by PNS in the presence of prazosin at low concentrations which blocked only postjunctional alpha 1-adrenoreceptors. 7. Thus, these results indicate that the effects of prazosin at high concentrations, such as 10(-6) M, on sympathetic neurotransmission should not be ignored when considering the mechanisms of vasoconstrictor responses to PNS following high concentrations of prazosin.
Adenosine Triphosphate↗
Orthostatic hypotension occurs following alpha 2-adrenoceptor blockade in chronic prazosin-pretreated conscious spontaneously hypertensive rats.
1. Studies were performed to evaluate whether chronic prazosin treatment alters the alpha 2-adrenoceptor function for orthostatic control of arterial blood pressure in conscious spontaneously hypertensive rats (SHR). 2. Conscious SHR (male 300-350 g) were subjected to 90 degrees head-up tilts for 60 s following acute administration of prazosin (0.1 mg kg-1 i.p.) or rauwolscine (3 mg kg-1 i.v.). Orthostatic hypotension was determined by the average decrease (%) in mean arterial pressure (MAP femoral) over the 60-s tilt period. The basal MAP of conscious SHR was reduced to a similar extent by prazosin (-23%(-)-26% MAP) and rauwolscine (-16%(-)-33% MAP). However, the head-up tilt induced orthostatic hypotension in the SHR treated with prazosin (-16% MAP, n = 6), but not in the SHR treated with rauwolscine (less than +2% MAP, n = 6). 3. Conscious SHR were treated for 4 days with prazosin at 2 mg kg-1 day-1 i.p. for chronic alpha 1-adrenoceptor blockade. MAP in conscious SHR after chronic prazosin treatment was 14% lower than in the untreated SHR (n = 8). Head-up tilts in these rats did not produce orthostatic hypotension when performed either prior to or after acute dosing of prazosin (0.1 mg kg-1 i.p.). Conversely, administration of rauwolscine (3 mg kg-1 i.v.) in chronic prazosin treated SHR decreased the basal MAP by 12-31% (n = 4), and subsequent tilts induced further drops of MAP by 19-23% in these rats. 4. The pressor responses and bradycardia to the alpha 1-agonist cirazoline (0.6 and 2 micrograms kg-1 i.v.), the alpha 2-agonist Abbott-53693 (1 and 3 micrograms kg-1 i.v.), and noradrenaline (0.1 and 1.0 micrograms kg-1 i.v.) were determined in conscious SHR with and without chronic prazosin pretreatment. Both the pressor and bradycardia effects of cirazoline were abolished in chronic prazosin treated SHR (n = 4) as compared to the untreated SHR (n = 4). On the other hand, the pressor effects of Abbott-53693 were similar in both groups of SHR, but the accompanying bradycardia was greater in SHR with chronic prazosin treatment than without such treatment. Furthermore, the bradycardia that accompanied the noradrenaline-induced pressor effect in SHR was similar with and without chronic prazosin treatment despite a 47-71% reduction of the pressor effect in chronic alpha 1-receptor blocked SHR.(ABSTRACT TRUNCATED AT 400 WORDS)
Adrenergic alpha-Agonists↗
Three distinct binding sites for [3H]-prazosin in the rat cerebral cortex.
1. The putative alpha 1-adrenoceptor subtypes of rat cerebral cortex membranes were characterized in binding. 2. Specific binding of [3H]-prazosin was saturable between 20-5000 pm. Scatchard plots of the binding data were non-linear, indicating the presence of two distinct affinity sites for prazosin (pKD, high = 10.18, Rhigh = 308 fmol mg-1 protein; pKD, low = 8.96, Rlow = 221 fmol mg-1 protein). 3. In the membranes pretreated with chlorethylclonidine (CEC) two affinity sites for prazosin were also observed: the affinities were similar to those without CEC pretreatment, but the maximum numbers of binding sites were reduced by CEC pretreatment to 23 and 62% for prazosin-high (Rhigh) and low affinity sites (Rlow), respectively. 4. The prazosin-high affinity sites were further subdivided into two subclasses by WB4101(2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane) and phentolamine; the low affinity sites for WB4101 and phentolamine were more potently inactivated by CEC as compared with the high affinity sites. On the other hand, prazosin, HV723 (alpha-ethyl-3,4,5-trimethoxy-alpha-(3-((2-(2-methoxyphenoxy)ethyl)- amino )-propyl)benzeneacetonitrile fumarate) and yohimbine inhibited [3H]-prazosin binding to prazosin-high affinity sites monophasically. 5. In addition to the high affinity sites, the prazosin-low affinity sites were labelled at high concentrations of [3H]-prazosin. Thus, prazosin and WB4101 showed shallow displacement curves. On the other hand, HV723 and yohimbine did not discriminate between prazosin-high and low affinity sites. 6. Two distinct alpha 1-adrenoceptor subclassifications have been recently proposed (alpha 1A, alpha 1B subtypes and alpha 1H, alpha 1L, alpha 1N subtypes). 5. In both motoneurones and dorsal root fibres, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) effectively depressed the depolarization induced by kainoids, and neither 3-[(+/-)-2-carboxypiperazin-4-yl]propyl-1- phosphonic acid (CPP) nor picrotoxin blocked or affected the depolarization, but there were some differences in pharmacological potencies of glutamate antagonists between both preparations.6. MFPA, HFPA and acromelic acids should provide valuable pharmacological tools for analysis of physiological functions of excitatory amino acids, in particular, as specific agonists for some subtypes of kainate receptors.
Adrenergic beta-Antagonists↗
Chronic treatment with prazosin causes a subtype-specific increase in the alpha 1-adrenoceptor density of the stressed rat cerebral cortex.
The effects of chronic treatment with prazosin and of immobilization stress on the alpha 1-adrenoceptor subtypes in rat cerebral cortex have been examined. Prazosin-treated rats were allowed free access to tap water containing two different concentrations of prazosin (16 or 156 mg L-1) for 5 weeks. The mean plasma concentrations of prazosin were 5 ng mL-1 in groups treated with a low dose and 8 or 14 ng mL-1 in those treated with a high dose. Immobilization stress (2 h day-1, 2 weeks) or chronic treatment with a low dose of prazosin caused no significant change in the affinity for [3H]prazosin or in the maximum number of alpha 1-adrenoceptor sites (Bmax). However, treatment with prazosin (low dose) combined with stress increased the density of alpha 1-adrenoceptors with low affinity for prazosin. Treatment with a high dose of prazosin increased the density of alpha 1L-adrenoceptors, irrespective of stress loading. The densities of alpha 1A- and alpha 1B-adrenoceptors with high affinity for prazosin were increased only after treatment with a high dose of prazosin in combination with stress. These results indicate that three distinct alpha 1-adrenoceptor subtypes, alpha 1A, alpha 1B and alpha 1L, might be affected differently by treatment with prazosin and by stress.
Adrenergic alpha-Antagonists↗
Prazosin GITS vs atenolol in patients with hypertension and normal lipid profile: a randomized, controlled multicenter study. Hyderabad Hypertension Study Group.
OBJECTIVE: To compare the long-term antihypertensive efficacy, tolerability, and metabolic effects of prazosin GITS and atenolol. DESIGN: Randomized, controlled, multicenter study of 26 weeks duration. SETTING: Office practices of 24 physicians in Hyderabad, Andhra Pradesh, India. PATIENTS: Males and females, aged 30 to 70 yrs, with hypertension of JNC V stage 1 or 2 at the end of a 2-week placebo run-in period, and a normal lipid profile. Sufficient number of patients recruited so that at least 60 complete the entire study. INTERVENTIONS: Prazosin GITS (Minipress XL, 2.5-5 mg once daily) or atenolol (Tenormin 50-100 mg once daily) for upto 6 weeks, continued upto 24 weeks in those showing a pre-defined response (SBP and/or DBP normalized, or DBP fall of at least 10 mm Hg with actual value of DBP < 95 mm Hg). Patients allocated to either of the two interventions by randomization. OUTCOME MEASURES: Percent patients showing pre-defined BP response at week 6; percent patients with DBP < 90 mm Hg, SBP < 140 mm Hg, and both; percent patients with DBP fall > or = 10 mm Hg; mean fall in BP among those receiving treatment for 24 weeks; mean change in serum lipids at the end of weeks 8, 16, and 24 of treatment; mean change in laboratory parameters for safety at the end of week 24; frequency and intensity of adverse events judged probably or definitely related to the drug. RESULTS: 62 patients randomized to prazosin GITS group and 60 to atenolol group. Of these, 39 in prazosin GITS group (M 23, F 16; mean age-48.4 yr, SEM 1.60) and 39 in atenolol group (M 24, F 15; mean age-42.9 yr, SEM 1.48) completed the entire study. Percent patients with DBP < 90 mm Hg at 24 weeks: prazosin GITS--92.3%, atenolol--92.3%; SBP < 140 mm Hg: prazosin GITS--89.7% atenolol--94.9% both DBP < 90 mm Hg and SBP < 140 mm Hg: prazosin GITS--87.2%, atenolol--89.7%; percent patients with DBP fall of 10 mm Hg or more at 24 weeks: prazosin GITS--92.3%, atenolol--100%. The mean fall in the systolic and diastolic blood pressure from the end-of-placebo-phase values to all the other time points was comparable in the 2 groups, except at week 2, when the fall was greater for atenolol (8.8 mm Hg vs 11.4 mm Hg, p = 0.05). Treatment with prazosin GITS resulted in a favourable effect on the serum lipid profile at the end of 24 weeks (p = 0.02 for total cholesterol, p = 0.015 for the ratio of total to HDL cholesterol, p = 0.04 for LDL cholesterol). Atenolol, on the other hand, did not produce any significant change in the metabolic parameters at the end of 24 weeks. Adverse events probably or definitely related to the drug: prazosin GITS--in 10.3% patients, atenolol--in 16.7% patients. CONCLUSION: In the doses used, both prazosin GITS and atenolol had comparable efficacy and tolerability. While atenolol was neutral on serum lipids, prazosin GITS showed a beneficial effect at the end of 24 weeks.
Adult↗
Haemodynamic effects of prazosin combinations during dynamic and isometric exercise.
Haemodynamic effects of atenolol 50 mg, clonidine 0.15 mg, and prazosin 5 mg, given twice daily, and of the combinations atenolol + prazosin and clonidine + prazosin were studied in 8 hypertensive outpatients. Measurements were made at rest, during isometric sustained handgrip and submaximal ergometer work in mostly double-blind and cross-over fashion. Given individually atenolol and prazosin lowered resting supine blood pressure. The addition of prazosin increased the antihypertensive effects of atenolol but not of clonidine. At the end of the isometric exercise atenolol and prazosin given alone both lowered diastolic blood pressure as compared to respective pretreatment values. During handgrip prazosin contributed a little, but not much, to the antihypertensive effects of atenolol and clonidine. During dynamic exercise atenolol, clonidine, and prazosin given alone each lowered blood pressure, prazosin decreasing diastolic blood pressure in particular. Prazosin added to the antihypertensive effect of atenolol more than that of clonidine. Echocardiographic measurements revealed no significant differences between treatments at rest. During handgrip the mean velocity of left ventricular circumferential muscle fibre shortening was reduced by atenolol as compared to pretreatment values. We conclude that atenolol + prazosin may help the patients to maintain adequate haemodynamics during daily physical stresses whilst the combination prazosin + clonidine may not offer any particular advantages.
Adult↗
Nonadrenergic nature of prazosin-resistant, sympathetic contraction in the dog mesenteric artery.
Electrical transmural stimulation of the isolated dog mesenteric artery produced a contractile response which was abolished by guanethidine and 6-hydroxydopamine but not by prazosin. Approximately 60% of the response seen with a frequency of 3 Hz remained after the treatment with prazosin. The prazosin-resistant contraction induced by electrical transmural stimulation was potentiated by other alpha adrenoceptor antagonists (phentolamine, phenoxybenzamine, tolazoline and DG-5128). Alpha-2 adrenoceptor agonists (including norepinephrine) attenuated the prazosin-resistant contraction and this attenuation was antagonized by the alpha antagonists mentioned above. Cocaine slightly inhibited the prazosin-resistant contraction, whereas this drug markedly augmented the contractile response to electrical stimulation before treatment with prazosin. In reserpine-treated mesenteric arteries also, electrical transmural stimulation produced a contraction and this was neither suppressed nor potentiated by prazosin and other alpha antagonists but was attenuated by alpha-2 agonists. Guanethidine and 6-hydroxydopamine abolished the prazosin-resistant contraction in reserpine-treated arteries. Nicotine, but not tyramine, also produced such prazosin-resistant contraction in reserpine-treated and untreated arteries. Exogenous norepinephrine produced a concentration-dependent contraction in reserpine-treated and untreated arteries and the responses were competitively antagonized by prazosin. These results indicate that the prazosin-resistant contractions of the dog mesenteric artery induced by electrical transmural stimulation and nicotine are sympathetic in origin but not adrenergic in nature. Such prazosin- resistant contraction was observed in the dog mesenteric vein but not in carotid and femoral arteries, thereby suggesting that the nonadrenergic component may play an important role in the regulation of visceral blood flow.
Animals↗
Antihypertensive efficacy of guanfacine and prazosin in patients with mild to moderate essential hypertension.
Guanfacine, an alpha 2 adrenoceptor agonist, was compared with prazosin hydrochloride for the treatment of patients with mild to moderate essential hypertension in an 8-week, double-blind, randomized, parallel evaluation to determine efficacy and safety. The study consisted of a 2-week screening/weaning period (phase I), a 3-week treatment period with chlorthalidone 25 mg every morning (phase II), and an 8-week double-blind treatment period with diuretic plus prazosin or guanfacine (phase III). Those who had an average seated diastolic blood pressure (BP) of 95 to 114 mm Hg at the end of the phase II period were eligible to enter the phase III period and were randomly assigned to chlorthalidone plus either guanfacine, 1 mg every night, or prazosin, 1 mg three times a day. Of the 102 patients who were randomly assigned to guanfacine or prazosin, 80% completed the entire study. Guanfacine and prazosin appeared to be equally effective and reduced seated as well as standing diastolic and systolic BP. The mean seated systolic and diastolic BP were reduced 11/9 mm Hg by guanfacine and 11/10 mm Hg by prazosin. The mean reduction in seated pulse was 3 beats/minute for guanfacine and no change with prazosin. Similar changes occurred in the standing position. Very few adverse effects were reported during the study. Adverse effects with an incidence of 5% or greater for either drug group were dizziness (6% guanfacine, 8% prazosin), xerostomia (6% guanfacine, 2% prazosin), and somnolence (0% guanfacine, 6% prazosin). Three patients (6%) in the prazosin group experienced symptoms of orthostasis requiring premature discontinuation of the drug and termination from the study.
Adult↗
Studies on the mechanism of the vasodilator effects of prazosin in dogs and rabbits.
In pentobarbital (35.0 mg/kg) anaesthetised dogs, bolus injections of prazosin into the femoral artery (3.0--300.0 microgram) provoked a dose-related fall in the vascular resistance of the innervated hind limb. In contrast to papaverine, prazosin failed to produce the same effect in dogs under spinal anaesthesia even when the intrinsic femoral vascular tone was increased with vasopressin. However, vasodilator effects of prazosin were again observed when the tone of the limb was elevated by either stimulating the sympathetic lumbar chain or by infusing alpha-adrenoceptor agonists. A significant reduction of both aortic blood pressure and pressor response to bilateral carotid artery occlusion was noted in a group of normotensive dogs anaesthetised 12 h after the last dose of prazosin given twice daily at 0.5 mg/kg, p.o., for 3 day period. This short-term treatment modified neither the resting heart rate nor the positive chronotropic effect induced by either intravenous noradrenaline or electrical stimulation of pre- and post-ganglionic nerve fibres of the right stellate ganglion. However, it prevented the larger increase in heart rate in response to bilateral carotid occlusion in placebo-treated dogs after section of the vagi. A decrease in baseline sympathetic tone of the perfused hind limb as well as vasoconstrictor effects produced by i.a. injections of several alpha-adrenoceptor agonists and electrical stimulation of the lumbar sympathetic chain was observed in prazosin-treated animals. The dose--pressor response profiles to these alpha-adrenoceptor stimulants after prazosin were not parallel to those obtained in the control group. The vasoconstrictor response to angiotensin II was not changed by prazosin. In rabbit aortic strips, prazosin (0.1--3.0 micrometer) produced competitive antagonism of the contractile responses induced by cirazoline, noradrenaline and phenylephrine. In contrast to papaverine, prazosin in concentrations up to 100.0 micrometer neither relaxed the aortic strips contracted by potassium ions nor modified the concentration-response curve to calcium ions. These studies indicate that blood pressure lowering effects of prazosin given acutely or for three days can be accounted for by a clear-cut functional impairment of vascular postsynaptic alpha-adrenoceptors. No evidence for a direct myorelaxant property of prazosin could be obtained in these studies.
Adrenergic alpha-Agonists↗
Prazosin GITS vs sustained release nifedipine in patients with hypertension and abnormal lipid profile: a randomized, controlled, multicenter study. Madras Hypertension Study Group.
OBJECTIVE: To compare the long-term antihypertensive efficacy, tolerability, and metabolic effects of prazosin GITS and a sustained release (SR) preparation of nifedipine. DESIGN: Randomized, controlled, multicenter study of 26 weeks duration. SETTING: Office practices of 24 physicians in Chennai, Tamil Nadu, India. PATIENTS: Males and females, aged 30 to 70 yrs, with hypertension of JNC V stage 1 or 2 at the end of a 2-week placebo run-in period, and an abnormal lipid profile. Sufficient number of patients recruited so that at least 60 complete the entire study. INTERVENTIONS: Prazosin GITS (Minipress XL, 2.5-5 mg once daily) or sustained release nifedipine (Nicardia Retard 10-20 mg twice daily) for upto 6 weeks, continued upto 24 weeks in those showing a pre-defined response (SBP and/or DBP normalized, or DBP fall of at least 10 mm Hg with actual value of DBP < 95 mm Hg). Patients allocated to either of the two interventions by randomization. OUTCOME MEASURES: Percent patients showing pre-defined BP response at week 6; percent patients with DBP < 90 mm Hg, SBP < 140 mm Hg, and both; percent patients with DBP fall > or = 10 mm Hg; mean fall in BP among those receiving treatment for 24 weeks; mean change in blood glucose and serum lipids at the end of weeks 8, 16, and 24 of treatment; frequency and intensity of adverse events judged probably or definitely related to the drug. RESULTS: 54 patients randomized to prazosin GITS group and 52 to nifedipine SR group. Of these, 39 in prazosin GITS group (M 23, F 16; mean age-50. 6 yr, SEM 1.66) and 36 in nifedipine SR group (M 20, F 16; mean age-52.3 yr, SEM 1.71) completed the study. Percent patients with DBP < 90 mm Hg at 24 weeks: prazosin GITS--100%, nifedipine SR--100%; SBP < 140 mm Hg: prazosin GITS--94.9%, nifedipine SR--91.7%; both DBP < 90 mm Hg and SBP < 140 mm Hg: prazosin GITS--92.3%, nifedipine SR--91.7%; percent patients with DBP fall of 10 mm Hg or more at 24 weeks: prazosin GITS--76.9%, nifedipine SR--83.3%. The mean fall in the systolic and diastolic blood pressure from the end-of-placebo-phase values to all the other time points was comparable in the 2 groups. Treatment with prazosin GITS did not produce any statistically or clinically significant change in the metabolic parameters at the end of 24 weeks, while with nifedipine SR there was a significant increase in the serum LDL values at 24 weeks (p = 0.009). Adverse events probably or definitely related to the drug: prazosin GITS--1.9%, nifedipine SR--2.1%. CONCLUSION: Both drugs were equally effective and well tolerated. While prazosin GITS was neutral on serum lipids, use of nifedipine SR was associated with a significant increase in serum LDL cholesterol at the end of 24 weeks.
Adult↗
The effects of prazosin and propranolol in combination with thiazide diuretics on blood pressure and serum lipids: a multicentre study.
We have carried out randomized 12-week multicentre study to compare the effects of prazosin and propranolol on blood pressure and serum lipids in 70 patients with essential hypertension after a 4 week minimum period of treatment with thiazide diuretics. After 12 weeks treatment with prazosin (n = 40, 1.5-12.0 mg per day) or propranolol (n = 30, 30-120 mg per day) with diuretics there was a significant blood pressure reduction from 165.1/97.9 mmHg to 151.2/90.6 mmHg and from 167/96.5 mmHg to 153/91.9 mmHg, respectively. In the 12th week a significant decrease was noted in triglyceride and in low-density lipoprotein cholesterol (LDL + VLDL-C), but no significant effects were seen in high-density lipoprotein cholesterol (HDL-C) in patients receiving prazosin. On the other hand, a significant decrease in lecithin cholesterol acyltransferase (LCAT) was seen in patients receiving propranolol. Twenty-six of 40 patients receiving prazosin were given an additional 12 weeks of treatment. Twenty-two of 30 patients initially treated with propranolol were switched from propranolol to prazosin after 13 weeks and given prazosin up to the 24th week. At 24 weeks, the blood pressure was 149/93.0 mmHg in the prazosin group and 155/89.2 mmHg in the group which switched from propranolol to prazosin. Triglyceride remained reduced in the prazosin group at the 24th week. In the group which switched from propranolol to prazosin, triglyceride decreased significantly over the next 12 weeks.
Benzothiadiazines↗