Pheochromocytoma: a review on preoperative treatment with phenoxybenzamine or doxazosin.

BACKGROUND: During surgical treatment of pheochromocytoma,`haemodynamic instability may occur. To prevent this, patients receive preoperative treatment with an alpha-blocker. Nowadays, some centres use phenoxybenzamine, while others use doxazosin. The purpose of this review is to analyse the current evidence of the benefits and risks of phenoxybenzamine and doxazosin in the preoperative treatment of pheochromocytoma. METHODS: The literature was reviewed by searching PubMed using the following search terms: pheochromocytoma, phenoxybenzamine, doxazosin and alpha-blockade. The filter was set on English language. RESULTS: No randomised controlled trials were found. Five follow-up studies comparing phenoxybenzamine and doxazosin in the treatment of pheochromocytoma were retrieved and analysed. There was a trend that systolic arterial pressure is slightly better controlled by phenoxybenzamine. However, this resulted in more pronounced postoperative hypotension as well. The use of an alpha-blocker was often accompanied by other vasoactive agents. phenoxybenzamine was often accompanied by a beta-blocker to control reflex tachycardia, while patients on doxazosin received significantly more additional antihypertensive medicines. Most of the studies showed that the use of vasoactive drugs and fluid infusion does not differ significantly between the two drugs. Phenoxybenzamine caused significantly more orthostatic hypotension, oedema and complaints of a stuffy nose. CONCLUSION: On the basis of the current evidence, there is no evidently superior alpha-blocker for the pretreatment of patients with pheochromocytoma. Perioperative haemodynamics seem to be slightly better controlled with phenoxybenzamine, at the cost of more pronounced postoperative hypotension. Side effects occurred less often in the doxazosin group.

Heartbeat dynamics in adrenergic blocker treated conscious beagle dogs.

INTRODUCTION: Adrenergic blockade as a treatment for chronic heart failure (CHF) has proved effective, but its pharmacological mechanism on CHF remains unclear. In the past two decades, studies on heart rate variability (HRV) have reported that CHF patients generally have a reduced temporal complexity in heart rate variability. On the other hand, adrenergic blockers have been shown to restore such complexity. Fractal analysis is a novel and efficient tool to explore the adrenergic blockade effect on HRV. This paper applies the detrended fluctuation analysis (DFA) and multifractal DFA (MF-DFA) methods in an attempt to understand the effect of adrenergic blockade on cardiac dynamics in conscious beagle dogs. METHODS: DFA and MF-DFA analysis are conducted on RR interval data generated from telemetry instrumented dogs receiving a combination of 15 mg/kg nadolol and 5 mg/kg phenoxybenzamine orally administered at the 22nd and 34th hour in a parallel design (n=12). All dogs had approximately 48 h of beat-to-beat heart rate measurements recorded in the left ventricle. Complexity measures for heartbeat series are compared between the blocker and vehicle group. We also compute traditional statistics for HRV and spectral parameters and examine their correlation with fractal analysis. RESULTS: When compared to the vehicle group, the adrenergic blocker group had: 1) longer RR intervals (p=0.02) and lower beat-to-beat variability (p=0.04); 2) decreased low frequency (LF) and high frequency (HF) power (p=0.03), and higher LF-to-HF ratio; 3) larger middle-range scaling exponents (p<0.01); 4) broader multifractal spectra (p=0.03) with higher dominant singularity indices (p=0.02). DISCUSSION: Our results show that 1) adrenergic blockade alters the sympathovagal balance; 2) adrenergic blockers enhance the complexity of the cardiac dynamics; 3) the adrenergic blockade effect on cardiac dynamics is primarily the attenuation of small fluctuations in RR intervals. Fractal analysis also has the potential to be applied to early QT diagnosis.

Radial artery graft treatment with phenoxybenzamine is clinically safe and may reduce perioperative myocardial injury.

BACKGROUND: Phenoxybenzamine effectively reduces radial artery (RA) spasm in vitro, but clinical data supporting its use during coronary revascularization are lacking. Therefore, the purpose of this study was to evaluate the clinical safety and efficacy of RA treatment with phenoxybenzamine. METHODS: Data were collected prospectively on 698 patients who underwent coronary artery bypass grafting with a RA between 1997 and 2005. Of these, 311 patients received RA grafts incubated in 2 mg/mL phenoxybenzamine for 15 minutes, and 387 patients received RA grafts treated with verapamil and nitroglycerin (VG solution). Demographic, operative, and postoperative data were compared retrospectively using multivariate regression techniques. RESULTS: The incidence of perioperative myocardial events (defined as either low cardiac output syndrome or perioperative myocardial infarction) was significantly reduced in the phenoxybenzamine group (6.8% vs 11.9%, phenoxybenzamine vs VG solution; p = 0.03). Perioperative myocardial enzyme release, as measured by postoperative maximum creatine kinase, was also reduced in the phenoxybenzamine group (743.0 +/- 677.9 vs 937.2 +/- 1236.8 U/L, phenoxybenzamine vs VG solution; p = 0.014). After adjusting for patient and procedural factors, the use of phenoxybenzamine was independently associated with reductions in peak creatine kinase (by -343.0 +/- 136.7 U/L; p = 0.012) and peak troponin T level (by -0.50 +/- 0.19 ng/mL; p = 0.010). No differences in vasopressor support, length of stay, or other complications were observed. CONCLUSIONS: Treatment of RA grafts with phenoxybenzamine was associated with a reduction in perioperative myocardial injury and adverse cardiac events in this study population. Investigations to further evaluate the potential benefits of phenoxybenzamine in randomized settings are warranted.

Chronic lymphocytic leukaemia, synchronous small cell carcinoma and squamous neoplasia of the urinary bladder in a paraplegic man following long-term phenoxybenzamine therapy.

STUDY DESIGN: A case report. OBJECTIVE: To raise awareness among spinal cord clinicians of the possible carcinogenic effect of phenoxybenzamine and of the rare occurrence of small cell carcinoma in the neuropathic bladder. SETTING: Regional Spinal Injuries Centre and District General Hospital, Southport, Merseyside, United Kingdom. CASE REPORT: A 28-year-old man sustained a fracture dislocation of L-1 with consequent paraplegia (ASIA impairment scale A). Phenoxybenzamine treatment enabled his indwelling catheter to be discarded in favour of a penile sheath, but it caused unacceptable dizziness and was stopped after 7 years. After 20 years, he developed chronic lymphocytic leukaemia, which was treated with chlorambucil and fludarabine. After 2 years, investigation of bilateral hydronephrosis revealed a primary small cell carcinoma of the bladder with coexistent squamous dysplasia. Uraemia supervened and, declining active treatment, the patient died 3 weeks after diagnosis. CONCLUSION: Phenoxybenzamine, a known carcinogen in rodents, is likely also to be carcinogenic in humans, and patients with spinal cord injury who have received the drug for any significant period of time, need close follow-up to allow early detection of cancer. Phenoxybenzamine should not be prescribed on a long-term basis, and should instead be replaced with a selective alpha-blocker.

[Effects of doxazosin mosylate and phenoxybenzamine in preoperative volume expansion of pheochromocytoma: a comparative study in 38 cases].

OBJECTIVE: To compare the effects of doxazosin mosylate and phenoxybenzamine in preoperative volume expansion of pheochromocytoma. METHODS: Phenoxybenzamine 30-240 mg/d was given orally to 38 patients of pheochromcytoma for 3 weeks. After the blood pressure was restored to the primary level before taking phenoxybenzamine, doxazosin mosylate 2-8 mg/d was given orally for three weeks. If the maximum dose of doxazosin mosylate (16 mg/d) still failed to achieve efficient blood volume expansion then phenoxybenzamine was added till completely efficient blood volume expansion was achieved. The effect in volume expansion and side effects were observed with the criteria including decrease of blood pressure to less than 120/80 mm Hg and restoration of the microcirculation imaging to normal. RESULTS: All the patients got complete volume expansion after taking phenoxybenzamine with tachycardia occurring in 23 of them and postural hypotension in 13 patients. In the 25 cases mainly with increase of norepinephrine before medical treatment doxazosin mosylate was completely effective in 18 cases with their blood pressure < 180/140 mm Hg; and was partially effective in the other 7 cases with their blood pressure > 180/140 mm Hg of which 2 suffered from postural hypotension. Doxazosin mosylate was partially effective in the other 13 cases mainly with increase of both norepinephrine and epinephrine. The total efficiency rate of these two medicines was not significantly different (chi(2) = 18.05, P > 0.05). The side-effect rate of doxazosin mosylate was significantly lower than that of phenoxybenzamine (chi(2) = 324, P < 0.01). CONCLUSIONS: Doxazosin mosylate has a lower complete volume expansion rate and side-effect rate as well for patients of pheochromocytoma. Pheochromocytomas with mild or moderate level of blood pressure are indicative of the use of doxazosin mosylate.

Biochemical diagnosis of pheochromocytoma: how to distinguish true- from false-positive test results.

Measurements of plasma normetanephrine and metanephrine provide a highly sensitive test for diagnosis of pheochromocytoma, but false-positive results remain a problem. We therefore assessed medication-associated false-positive results and use of supplementary tests, including plasma normetanephrine responses to clonidine, to distinguish true- from false-positive results. The study included 208 patients with pheochromocytoma and 648 patients in whom pheochromocytoma was excluded. Clonidine-suppression tests were carried out in 48 patients with and 49 patients without the tumor. Tricyclic antidepressants and phenoxybenzamine accounted for 41% of false-positive elevations of plasma normetanephrine and 44-45% those of plasma and urinary norepinephrine. High plasma normetanephrine to norepinephrine or metanephrine to epinephrine ratios were strongly predictive of pheochromocytoma. Lack of decrease and elevated plasma levels of norepinephrine or normetanephrine after clonidine also confirmed pheochromocytoma with high specificity. However, 16 of 48 patients with pheochromocytoma had normal levels or decreases of norepinephrine after clonidine. In contrast, plasma normetanephrine remained elevated in all but 2 patients, indicating more reliable diagnosis using normetanephrine than norepinephrine responses to clonidine. Thus, in patients with suspected pheochromocytoma and positive biochemical results, false-positive elevations due to medications should first be eliminated. Patterns of biochemical test results and responses of plasma normetanephrine to clonidine can then help distinguish true- from false-positive results.

[Haematemesis and dysphagia in a 20-year-old woman with congenital spine malformation and situs inversus partialis]. / Hämatemesis und Dysphagie bei 20 Jahre alter Frau mit kongenitalem kaudalen Regressionssyndrom und Situs inversus partialis.

A 20-year-old woman with a four-week history of dysphagia, weight loss of four kilograms and unspecific abdominal pain was admitted because of sudden haematemesis. The physical examination showed a patient with a prominent kyphoskoliosis. The patient reported of having a situs inversus abdominalis and a tethered cord syndrome. Bladder function disorders were present since childhood. Upper endoscopy demonstrated a 4 cm large, exophytically growing necrotic tumour of the oesophagus. The CT scan showed a space occupying tumour of the oesophagus and metastases in a size of 1.5 cm in both lungs. Further imaging revealed a UICC-Stadium IVB (T2NxMIb ). Histology of the tumour biopsies showed a poor differentiated squamous cell carcinoma. Staging after the 6 th dose cisplatin (100 mg/m2/die) and 5-fluorouracil (5 x 1000 mg/m2/die) showed a mild reduction of the tumour and the metastases. The patient died ten months later of multiorgan failure after severe progress of tumour and metastatic growth. The manifestation of squamous cell carcinoma of the oesophagus is unusual in people at the age of twenty. Genetic and chromosomal analysis of the patient gave no evidence for a hereditary disorder. Drug history revealed that the patient had been treated with the alpha-receptor blocking drug phenoxybenzamine over at least 12 years for bladder dysfunction. Animal experiments of rats with exposition of phenoxybenzamine over 24 months produced gastrointestinal malignomas. By the German admission board phenoxybenzamine is only recommended for short term therapy. It seems to be likely that even in humans phenoxybenzamine acts as a mutagenic substance and should be carefully used in long-term treatment.

A modern rationale for the use of phenoxybenzamine in urinary tract disorders and other conditions.

BACKGROUND: Phenoxybenzamine (PBZ) is a nonselective, irreversible alpha-adrenergic receptor antagonist that is approved for the treatment of diaphoresis and hypertension associated with pheochromocytoma. It may also be useful in several chronic conditions whose pathogenesis is mediated or affected by alpha-adrenergic stimulation, such as lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH) and neurogenic bladder (eg, secondary to myelomeningocele and in sphincter dyssynergia and autonomic dysreflexia); in an adjunctive role after urogenital surgery or brachytherapy by relieving symptoms associated with increased alpha-adrenergic tone; and in the treatment of complex regional pain syndrome (CRPS) and prostatitis. However, carcinogenic concerns may have limited its potential application. OBJECTIVE: The purpose of this article is to reassess the usefulness and contemporary application of PBZ for the control of urinary tract symptoms associated with BPH and neurogenic bladder, after urogenital surgery and brachytherapy, and in certain other conditions (eg, CRPS, prostatitis). METHODS: A search of literature published from 1966 to 2002 was performed on MEDLINE using the search terms phenoxybenzamine, alpha-adrenergic blockers, benign prostatic hyperplasia, neurogenic bladder, urinary retention, and complex regional pain RESULTS: Despite concerns about possible carcinogenicity, no reports of drug-related tumors have been made since PBZ's introduction in 1953. Investigators have used PBZ in off-label trials to alleviate symptoms of a variety of conditions that cause urinary retention. In adult male patients with retention due to inguinal hernioplasty and female patients with retention caused by vaginal repair, as well as in pediatric patients with myelomeningocele, treatment with PBZ improved bladder function and, in the patients with myelomeningocele, was associated with reduced incidence of urinary tract infection. Larger tri- als of PBZ in men with BPH produced significant urinary symptom relief (P < 0.05 in 2 studies). Moreover, studies suggest that PBZ may be useful in alleviating pain due to trauma and CRPS. The most common adverse events appear to be dizziness, impotence and ejaculatory dysfunction, and nasal stuffiness. CONCLUSIONS: No drug-related tumors in humans have been reported after -50 years of clinical experience with PBZ. Clinical trials have demonstrated that it can relieve symptoms in patients with BPH and other urologic and pain-related conditions.

Complex regional pain syndrome (reflex sympathetic dystrophy and causalgia): management with the calcium channel blocker nifedipine and/or the alpha-sympathetic blocker phenoxybenzamine in 59 patients.

Complex Regional Pain Syndrome (CRPS) is the new name for entities formerly known mostly as Reflex Sympathetic Dystrophy and Causalgia. Treatment of CRPS with either the calcium channel blocker nifedipine or the alpha-sympathetic blocker phenoxybenzamine was assessed in 59 patients, 12 with early stages of CRPS, 47 with chronic stage CRPS. In the early stage CRPS patients, 3 of 5 were cured with nifedipine and 8 of 9 (2 of whom had earlier received nifedipine) with phenoxybenzamine, for a cure rate of 92% (11 out of 12). In the chronic stage CRPS patients, 10 of 30 were cured with nifedipine; phenoxybenzamine cured 7 of 17 patients when administered as a first choice and another 2 of 7 patients who received nifedipine earlier, for a total late stage success rate of 40% (19 out of 47). The most common side effects necessitating discontinuing the drug were headaches for nifedipine and orthostatic dizziness, nausea and diarrhoea for phenoxybenzamine. All male patients on phenoxybenzamine experienced impotence, but this did not lead to discontinuing this agent and immediately disappeared after stopping the drug. These results once again stress the importance of early recognition of CRPS, and treatment with either of these drugs could be considered as a first choice for early CRPS, especially because in this series this treatment was not combined with physical therapy making it very cost-effective. In the chronic stage of CRPS, treatment with these drugs was much less successful (40%), even though it was always combined with physical therapy, but it can still be considered, either as a first choice or when other types of treatment have failed.

Experience with buccal phentolamine mesylate for impotence.

Satisfactory erection with penetration can be obtained in impotent men by the oral or buccal administration of the alpha-adrenergic antagonist, phentolamine. This agent is also used in conjunction with papaverine HCl for intracavernous injection. The previous observation by Gwinup, that 50 mg of phentolamine HCl po, 1.5 hours before coitus resulted in erection in 11/16 patients, is confirmed. This study, using phenoxybenzamine as the placebo, was repeated with success in 36/85 (42.3%) patients. Because of cost and to decrease the waiting time, a buccal form of phentolamine mesylate was administered (20 mg) with erection and penetration in 21/69 (31.8%). There was no correlation between the degree of penile vascular insufficiency or age and the effectiveness of phentolamine. Buccal phentolamine is shown to increase flow velocity in the dorsal penile artery. Phentolamine produces minimal side effects, including hypertension in the subjects.

Alpha-adrenergic blockers for the treatment of benign prostatic hyperplasia.

There seems little doubt that alpha-adrenergic blockers can afford a measure of relief to many sufferers from BPH. The exact role this treatment has to play in the overall management of these patients has yet to be clearly defined. A continuing search is being made for more effective drugs, with the hope of finding one that will be more specific in its action on the prostate and produce fewer generalized effects. Whether this will prove possible may depend on whether any further subgroup of alpha receptors more specific to the prostate can be found or whether some method of targeting the drugs to the required region can be devised. If a drug treatment that reduces the size of the prostate can be found, perhaps a combination of the two forms of medical treatment will have a place. At present, it seems reasonable to conclude that there is good justification for using the alpha-blocking drugs available when employed in the manner and for the indications outlined herein.