Alpha-blockers in Renal Disease - Journal of the Association of

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1 34 supplement to Journal of the association of physicians of india Published on 1st of every month 1st september, 2014 VOL. 62 Alpha-blockers in Renal Disease : Appraisal of Evidence Natarajan Gopalakrishnan*, R Sakthirajan**, T Dineshkumar** Introduction nephrectomy, in patients undergoing dialysis or transplantation, normalises I n patients of chronic kidney diseases (CKD), the significance of cardiovascular complications is well known. Progressive the sympathetic activity. 1,2 Renal ischaemia is a very important causative factor, as the accumulation of decline in renal function is associated adenosine triggers central sympathetic with increasing rates of hypertension and o u t f l o w . I n c r e a s e i n a n g i o t e n s i n II dyslipidemia. is another crucial mechanism, which Management of hypertension in CKD is may influence sy mpat het ic a c t i v i t y a critical issue, as blood pressure is often via multiple mechanisms. Angiotensin poorly controlled in early or advanced II may act on the vasomotor centre in renal disease. Many factors contribute the brainstem, and may reset the blood to the development of hypertension pressure homoeostasis to a higher level. in CKD. Sympathetic overactivity It may also act on the sympathetic nerve plays an important role, apart from terminals, to increase the release and volume overload and increased renin- prevent the reuptake of norepinephrine. angiotensin activity. This review is an Stimulation of carotid chemoreceptors is attempt to understand the significance of also a likely mechanism, observable in sympathetic activity in CKD and possible dialytic patients due to the underlying ways to address the same, with a focus mild acidaemia and nocturnal on the role of -blockers. hypoxaemia. Reduction in nitric oxide availability and oxidative stress also Causes and Consequences: result in increased sympathetic activity. Sympathetic Activity in Renal Ob esit y may influence sy mpa t h et i c Disease activity through increased leptin and insulin levels. In patients with CKD, Causes of Increased Sympathetic Activity sympathetic activity induced by high (Figure 1) s e r u m l e p t i n l e ve l s , c o n t r i b u t e s t o The signals arising from the development of hypertension. malfunctioning kidneys result in an Dyslipidaemia, observed commonly increase in the sympathetic activity. in CKD, may enhance the -1 pressor This is evident by the fact that bilateral sensitivity or impair the functioning Sympathetic Causes Consequences Activity e osin den LVH A Renal Ischaemia CCF IHD Aggravation Salt Retention Dyslipidaemia AS BP Oxidative Stress R Volume Overload O Glomerulosclerosis Obesity N Sleep apnoea Atherogenesis Smoking Vascular Compliance Professor and Head, ** Assistant * Professor, Nephrology; Madras Endothelial Factors Hypercoagulability Medical College, Chennai Fig. 1 : Causes and Consequences of Sympathetic Activity in Renal Disease

2 supplement to Journal of the association of physicians of india Published on 1st of every month 1st se ptember, 2014 VOL. 62 35 of baroreceptor reflex. Sleep apnoea is frequently Vonend et al observed that in patients with chronic observed in association with dialysis. The resultant renal failure (CRF) maintained on RAS inhibition, hypoxaemia also stimulates sympathetic activity. add-on central sympatholytic moxonidine halted CKD is associated with reduced availability of nitric the progression of renal insufficiency, relative to oxide (NO), owing to multiple factors prompting CCB nitrendipine, with minimal influence on blood a decrease in NOS activity, increase in levels of pressure.6 Moxonidine has also demonstrated natural inhibitors of NO such as asymmetric dimethyl reduction in albuminuria in early kidney disease, L-arginine (ADMA), and oxidative stress. Such a state despite no change in ambulatory blood pressure. 6 This of reduced NO availability, enhances the hypertensive highlights the importance of sympathetic activity in effect of sympathetic activity. Sympathetic overactivity human kidney disease. may be genetically determined as well, with genes Apart from kidneys, increased sympathetic like phosducin playing important roles. Some or all activity in renal disease, may significantly damage of these mechanisms may jointly play a part, in the the cardiovascular system. Adverse cardiac outcomes development of hypertension in patients with CKD. 1-3 include development of left ventricular hypertrophy, In patients on dialysis, hypertension is perceived to cardiac dysfunction, arrhythmias or failure. Vascular be largely volume dependent. However, the influence outcomes include increased arterial tone, vascular of sympathetic overactivity cannot be understated stiffness, and atherogenesis, which may result in in these patients. Sympathetic activity contributes complications. Alterations in haemostasis lead to significantly to development of hypertension in renal increased coagulability. Even younger patients with disease. renal disease may suffer from advanced coronary Consequences artery disease. 1-4 Cardiovascular deaths account for Sympathetic hyperactivity contributes to substantial mortality in CKD patients. hypertension, and leads to significant damage to the kidneys and the cardiovascular system. 1-5 In CKD, Role of -Blockers apart from the elevation in office BP, elevation in the In the Indian scenario, several drugs like clonidine ambulatory BP and lack of diurnal variation in BP are and prazosin are commonly used, which are not important clinical consequences. Ambulatory BP or represented in the international clinical guidelines of circadian rhythm of BP are better predictors of clinical hypertension. 7 Post the observations from ALLHAT, outcomes than office BP. Using these parameters, Cha regarding increased risk of cardiac failure with et al demonstrated a significantly higher prevalence of doxazosin compared to chlorthalidone, the use of masked and sustained hypertension in CKD patients. 5 -blockers as first line antihypertensive therapy Masked or sustained hypertension is increasingly has declined. 8 However, in combination with other observed in proportion to the extent of kidney disease.5 antihypertensives, -blockers have demonstrated Addressing the increased sympathetic activity a good safety and efficacy profile as third line assumes significant relevance, in the management of drugs. 9-11 The good lipid and glycaemic profile of hypertension associated with renal disease. -blockers also favour their utility in patients with Increase in blood pressure may result in these comorbidities, which are commonly observed glomerulosclerosis. This may be facilitated by podocyte with CKD. In the ASCOT trial, addition of doxazosin injury mediated through adrenoceptors, independently as the third antihypertensive drug resulted in of blood pressure. -1 adrenoceptors are also involved improvements in BP control, without any increase in vascular smooth muscle proliferation, resulting in in cardiac failure. 9 Similar results were observed progression of atherosclerosis. Catecholamines can in a study by Ohta et al, which demonstrated the also influence inflammatory activity in the tissues. beneficial effects of addition of low dose doxazosin These adrenergic effects may contribute to kidney to RAS inhibitor and CCB combination regimens. 10 damage over a period of time, independently of blood The ZAFRA study, carried out in patients of chronic pressure.1-3 In CKD, the availability of nitric oxide (NO) renal failure (CRF) with uncontrolled hypertension, is reduced, which may increase the responsiveness evaluated the utility of -blocker, as third add-on to to sympathetic activity. In such a state, even a low RAS inhibitor and CCB. 11 Over 6 months of follow-up, level of sympathetic activity may be detrimental to good antihypertensive effect was observed with the kidneys, on account of increased hypertensive and addition of -blocker to antihypertensive regimen, inflammatory actions. 1,2 without any observations of increased cardiac failure. 11 Non-clinical and clinical studies have demonstrated These observations suggest a beneficial profile of that inhibition of sympathetic activity slowed the -blockers, when used as third line antihypertensive progression of renal failure. Blockade of either of drugs, including in patients with renal failure. or adrenergic receptors, has demonstrated renal Studies on -blockers in patients with renal diseases, protection, with additive effects on combination. have consistently demonstrated beneficial effects in

3 36 supplement to Journal of the association of physicians of india Published on 1st of every month 1st september, 2014 VOL. 62 terms of effective BP reduction, preservation of renal various pathophysiological mechanisms lead to function and haemodynamics, and metabolic benefits. hypertension. 19 Volume overload represents a very In a study on patients with CRF, doxazosin therapy common problem in dialysis, which may also result resulted in effective BP control, along with increase in in refractory hypertension. A resultant imbalance in glomerular filtration and decrease in plasma BUN and RAS activity and ECF volume is frequently observed, creatinine levels. 12 Reduction in BP was significantly leading to an increase in plasma renin activity. correlated to reduction in proteinuria, over 6 months Increased sympathetic activity is an important feature, of doxazosin therapy. Metabolic benefits were also resulting from the fluctuating fluid volumes during evident with doxazosin therapy, in terms of reduction dialysis, apart from the several other causative factors in triglyceride levels and increase in HDL cholesterol associated with kidney disease. Apart from volume, levels. 12 A study by Yildiz et al evaluated the effects renin and sympathetic activity, other causative of doxazosin on insulin resistance, in patients with associations for hypertension in dialysis include CRF. Over 12 weeks of follow-up, insulin resistance erythropoietin replacement therapy, secondary (assessed by HOMA and fasting insulin levels) hyperparathyroidism, nocturnal hypoxaemia and significantly decreased with doxazosin therapy. 13 imbalance in endothelial vasoactive substances. 19 Another study by Erley et al evaluated the effects Management of hypertension may pose significant of various drugs (administered for 12 weeks) on clinical challenges for the dialysis patients. renal function, in hypertensive patients with non- Appropriate correction of volume overload is the insulin dependent diabetes. 14 Doxazosin therapy most essential consideration, towards addressing was associated with a significant improvement in the development of resistant hypertension. creatinine clearance, which was more pronounced Pharmacotherapeutic approach during dialysis as compared to captopril therapy. Also, doxazosin involves special considerations, as the kinetics of therapy resulted in the reduction of proteinuria by many drugs may be influenced by physiological 34%, an effect consistently observed in each diabetic changes. 20-21 1 blockers are largely bound to plasma patient studied. 14 proteins, and are relatively stable during dialysis. Chronic therapy with prazosin has demonstrated In a study by Vanholder et al, the protein binding a fall in renovascular resistance, with the afferent capacity of prazosin fell by approximately 2% in arteriole being the site of action, in principle. 15-17 This dialysis. 21 However, as prazosin is highly bound to observation implies consistent renal vasodilatation plasma proteins (> 95%), even a modest increase in during chronic prazosin therapy, which facilitates free drug concentration may have clinically relevant preservation of renal function and renal blood flow, effects. Hence, careful titration of the dose may be despite significant reduction of renal perfusion necessary and lower doses of up to 3 to 8 mg / day pressure. Prazosin has also demonstrated a marked may be effective. 21-23 Good efficacy of prazosin has decline in plasma renin activity, due to the complex been observed in all types of hypertensive patients interplay between RAS and adrenergic systems on dialysis, either as monotherapy or in combination, within the kidney. 15-17 1 adrenergic blockade may with minimal side effects. 16,22,23 In patients with complement adrenergic blockade in balancing the intradialytic hypotension, use of blockers should renal haemodynamic alterations, as is discussed in be avoided. 20 subsequent sections. Hypertension in Renal Transplantation 1 blockade is also associated with improvement Cardiovascular risk is significantly associated in endothelial functioning. A study evaluated the with renal transplantation, and accounts for a huge effect of doxazosin, carvedilol and atenolol, on mortality rate in these patients. Hypertension is endothelial fibrinolytic activity and lipoprotein widely observed post transplantation, and poses metabolism, in hypertensive patients with ischaemic risk for renal allograft dysfunction, as well as for heart disease.18 Doxazosin therapy was associated with cardiovascular complications. 19 For each 10 mmHg an improvement in endothelial fibrinolytic activity rise in systolic BP, the risk for allograft loss is (before or after anoxia), and beneficial modifications in increased by 12% to 15%. 19 BP control is of prime lipoprotein ratio. Carvedilol administration improved relevance in transplant recipients. Hypertension endothelial fibrinolytic activity only after anoxia, may develop in transplant recipients due to multiple and did not modify lipoprotein ratio. Atenolol did reasons. Apart from the causative factors observed not improve fibrinolytic activity, and unfavourably in renal disease, dysfunction of the graft, or the use modified lipoprotein ratio. 18 of immunosuppressant medications may contribute Hypertension in Dialysis to high BP. 19 Pre-glomerular vasoconstriction may Hypertension is very commonly observed in be an essential factor in hypertension, rather than ESRD patients, which results in cardiovascular glomerular hypoperfusion. 24 morbidity and mortality. In patients on dialysis, In the pharmacological considerations

4 supplement to Journal of the association of physicians of india Published on 1st of every month 1st se ptember, 2014 VOL. 62 37 for these patients, important considerations cardiac failure or dilated cardiomyopathy, the use of include renoprotection, favourable renovascular blockers has demonstrated reduction in cardiovascular haemodynamics, minimisation of metabolic risk. 31-33 In CKD patients without pre-existing cardiac complications, and efficacy in patients receiving comorbidities, the extrapolation of these cardiac calcineurin inhibitors. -blockers reduce peripheral benefits of blockers is not proven. 30-32 resistance, preserve and may improve renal Various -blockers differ in their receptor blocking, haemodynamics, and preserve renal function. 19,24-27 pharmacologic and adjunctive properties, and have Their use is associated with favourable metabolic variable effects on renal haemodynamics. The older profile and minimal risk of hyperkalaemia. -blockers nonselective agents, the cardioselective agents, have also demonstrated good efficacy in patients and newer agents with vasodilating properties, receiving cyclosporine. These characteristics make demonstrate markedly differing clinical profiles. Their -blockers preferable agents in renal transplant respective combinations with blockers may have recipients. 24-27 differing implications for clinical use. A study compared the profiles of doxazosin and Nonselective -blockers reduce the GFR and renal enalapril monotherapies in a cross-over design, in blood flow, excepting the agents with vasodilatory transplant recipients receiving cyclosporine. A similar effects. Labetolol has demonstrated conflicting BP control was observed in both the groups, but evidence on renal haemodynamic alterations. 30 doxazosin was associated with better profile in terms Nonselective -blockers like propranolol may cause of renal function, potassium level, or haemoglobin. 27 a reflex increase in sympathetic activity, owing Prazosin therapy has demonstrated good efficacy and to reduction in cardiac output and blockade of 2 tolerability profile, along with preservation of renal mediated vasodilatation. This results in unopposed function. 26 Patients may respond to relatively smaller 1 activity, and unfavourable renal haemodynamics. doses of these drugs, and initiation of therapy with Chronic administration of these agents could lower doses, with gradual titration, should be the potentially exacerbate renal dysfunction. 30 A study preferred approach. compared the effects of prazosin and propranolol, on A long term study over 3 years, evaluated the renal perfusion changes in essential hypertension. 34 antihypertensive profile of doxazosin, enalapril and Following 1 month of therapy, prazosin, but not verapamil in renal transplant recipients. 24 In long term, propranolol, was associated with preservation of 8 patients in each of the verapamil or enalapril groups, glomerular filtration rate, renal plasma flow, and compared to only 4 patients in doxazosin group, lost renal blood flow. Addition of 1 blockade may thus the graft due to chronic transplant nephropathy. Initial effectively counter the reflex vasoconstriction, and tolerance to verapamil was poor, whereas enalapril may increase blood flow to skeletal muscle, thereby use was associated with long term hyperkalaemia benefitting the glycaemic profile. 34 Nonselective and coughing. Doxazosin was very well tolerated, -blockers may also cause hyperkalaemia in ESRD and relative hypotension was observed in only 2 patients, and in patients taking mineralocorticoid patients. 24 First dose hypotension may be a concern, antagonists. 1 blockade may be protective against particularly with the older standard formulations of this adverse effect, and may also facilitate sodium -blockers. This can be minimised with the use of slow excretion. 30 and sustained release formulations. Cardioselective 1-blockers may preserve renal Combining and Blockers haemodynamics, and have been used successfully in Combination of and blockers is a rational CKD patients. However, like the nonselective agents, approach, for more effective and complete control of cardioselective agents may also result in insulin the increased sympathetic activity. Apart from the resistance and worsening lipid profile, including synergistic mechanisms of these two drug classes, increased triglyceride and decreased HDL cholesterol additional safety advantages may be expected, levels. Addition of 1-blocker can effectively negate particularly with regards to -blocker use. -blockers these adverse metabolic effects of -blockers, by are associated with good antihypertensive efficacy, improving insulin sensitivity, lowering triglyceride metabolic benefits, favourable renal haemodynamics and increasing HDL cholesterol levels. Hence, and reduction in risk of hyperkalaemia. While combination of 1 and 1 blockade may benefit -blockers offer less than adequate efficacy in diabetes as well as atherosclerotic vascular disease. 30 lowering BP and in vascular protection, most of The newer blockers with vasodilating properties these agents are associated with poor metabolic may be particularly recommended for patients profile, hyperkalaemia or unfavourable renal with pre-existing cardiac comorbidities, including haemodynamics. 28-30 In absence of cardiac disease, coronary artery disease and heart failure. A study blockers are not the preferred antihypertensive agents. evaluated the efficacy of carvedilol in patients However, in chronic kidney disease associated with undergoing haemodialysis, and with coexistent

5 38 supplement to Journal of the association of physicians of india Published on 1st of every month 1st september, 2014 VOL. 62 dilated cardiomyopathy. 32 In this study, the use of drugs in antihypertensive regimens. Combination of carvedilol was associated with significant reduction and blockers may also be a rational approach in in morbidity and mortality over 2 years, suggesting renal disease. its possible benefits in dialysis patients with chronic heart failure. 32 A meta-analysis suggested possible Acknowledgements and Disclosures benefits of carvedilol in heart failure, in patients with Dr Jignesh K Ved supported the development of early, but not advanced CKD. 33 However, in terms manuscript content. The information expressed in the of antihypertensive efficacy, vascular protection publication explicitly reflects the authors opinion on and metabolic advantages, evidence of superiority the topic. relative to blockers is lacking. A study compared add-on doxazosin or carvedilol, in hypertensive References patients with mild heart failure, receiving enalapril and furosemide. 35 Doxazosin, in combination therapy, 1. Kotanko P. Cause and consequences of sympathetic hyperactivity in rapidly improved clinical status and haemodynamics, chronic kidney disease. Blood Purif. 2006;24:95-9. by reduction of afterload. Persistent superior benefits 2. Koomans HA, Blankestijn PJ, Joles JA. Sympathetic hyperactivity in were observed with doxazosin compared to carvedilol, chronic renal failure: a wake-up call. J Am Soc Nephrol. 2004;15:524-37. in terms of BP reduction, at 3 weeks and at 12 months. 3. Broeckel U, Stoll M, Hein L. The identification of phosducin as a Ejection fraction, exercise tolerance and quality of novel candidate gene for hypertension and its role in sympathetic activation. Curr Opin Nephrol Hypertens. 2011;20:118-24. life significantly improved with doxazosin compared 4. von Knel R, Dimsdale JE. Effects of sympathetic activation by to carvedilol in the initial 3 weeks; the differences in adrenergic infusions on hemostasis in vivo. Eur J Haematol. these parameters were not significant at 12 months. A 2000;65:357-69. significant improvement in lipid profile was observed 5. Cha RH, Kim S, Ae Yoon S, Ryu DR, Eun Oh J, Han SY et al. Association with doxazosin at 3 months, compared to carvedilol. 35 between blood pressure and target organ damage in patients with In a study in hypertensive patients with ischaemic chronic kidney disease and hypertension: results of the APrODiTe heart disease, doxazosin therapy demonstrated study. Hypertens Res. 2014;37:172-8. superior improvement in endothelial fibrinolytic 6. Vonend O, Marsalek P, Russ H, Wulkow R, Oberhauser V, Rump LC. activity and lipoprotein metabolism compared to Moxonidine treatment of hypertensive patients with advanced renal carvedilol and atenolol. 18 failure. J Hypertens. 2003;21:1709-17. These observations collectively suggest that 7. Indian Society of Nephrology. Clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease -blockers are important components in combination (CKD). Indian J Nephrol 2005;15, Supplement 1:S14-S22. antihypertensive therapy, owing to their superior 8. Chapman N, Chen CY, Fujita T, Hobbs FD, Kim SJ, Staessen JA et al. benefits in terms of BP control and metabolic Time to re-appraise the role of alpha-1 adrenoceptor antagonists in advantages. Combination of and blockers may the management of hypertension? J Hypertens. 2010;28:1796-803. result in synergistic antihypertensive benefits, possible 9. Chapman N, Chang CL, Dahlf B, Sever PS, Wedel H, Poulter NR et al. reduction in cardiovascular risk, and limitation of Effect of doxazosin gastrointestinal therapeutic system as third-line adverse effects. In the ASCOT trial, 11,768 patients antihypertensive therapy on blood pressure and lipids in the Anglo- were administered doxazosin as a third line therapy.9,36 Scandinavian Cardiac Outcomes Trial. Circulation. 2008;118:42-8. In patients who were concomitantly receiving atenolol, 10. Ohta Y, Tsuchihashi T, Onaka U, Eto K, Ueno M. Usefulness of the reductions in systolic and diastolic BP were more alpha1-blocker doxazosin as a third-line antihypertensive drug. pronounced on addition of doxazosin, as compared Hypertens Res. 2007;30:301-6. to patients not receiving blocker based regimen. 9.36 11. Robles NR, Campder FG, Ocn J, Manjn M, Pastor L, Herrera J et Combination of these two antihypertensive drug al. Doxazosin associated to the combination renin-angiotensin axis blocker and calcium-channel blocker in patients with chronic renal classes, may thus be a rational approach in patients failure. Nefrologia. 2005;25:515-20. with renal disease. 12. Mori Y, Matsubara H, Nose A, Shibasaki Y, Masaki H, Kosaki A et al. Conclusion Safety and availability of doxazosin in treating hypertensive patients with chronic renal failure. Hypertens Res. 2001;24:359-63. Increased sympathetic activity is an important 13. Yildiz A, Hursit M, Celik AV, Kayacan SM, Yazici H, Akkaya V et al. feature in renal disease, which significantly contributes Doxazosin, but not amlodipine decreases insulin resistance in patients with chronic renal failure: a prospective, randomized- to development of hypertension and to target organ controlled study. Clin Nephrol. 2002;58:405-10. damage. blockers have an essential place in the 14. Erley CM, Haefele U, Heyne N, Braun N, Risler T. Microalbuminuria management of hypertension in renal disease, owing in essential hypertension. Reduction by different antihypertensive to their good antihypertensive efficacy, favourable drugs. Hypertension. 1993;21:810-5. metabolic profile, excellent tolerability particularly 15. 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6 supplement to Journal of the association of physicians of india Published on 1st of every month 1st se ptember, 2014 VOL. 62 39 patients undergoing chronic hemodialysis. Am J Cardiol. 1984;53:40A- 27. Martnez-Castelao A, Hueso M, Sanz V, Rejas J, Sarrias J, Alsina J 45A. et al. Double-blind, crossover, comparative study of doxazosin 17. OConnor DT, Preston RA, Sasso EH. Renal perfusion changes during and enalapril in the treatment of hypertension in renal transplant treatment of essential hypertension: prazosin versus propranolol. J patients under cyclosporine immunosuppression. Transplant Proc. Cardiovasc Pharmacol. 1979;1(6 Suppl):S38-42. 2002;34:403-6. 18. Gonzlez Maqueda I. Adrenoreceptors, endothelial function, and lipid 28. Che Q, Schreiber MJ Jr, Rafey MA. Beta-blockers for hypertension: are profile: effects of atenolol, doxazosin, and carvedilol. Coron Artery Dis. they going out of style? Cleve Clin J Med. 2009;76:533-42. 1994;5:909-18. 29. Tomiyama H, Yamashina A. Beta-Blockers in the Management 19. Prasad GV, Ruzicka M, Burns KD, Tobe SW, Lebel M. Hypertension in of Hypertension and/or Chronic Kidney Disease. Int J Hypertens. dialysis and kidney transplant patients. Can J Cardiol. 2009;25:309-14. 2014;2014:919256. 20. Inrig JK. Antihypertensive agents in hemodialysis patients: a current 30. Bakris GL, Hart P, Ritz E. Beta blockers in the management of chronic perspective. Semin Dial. 2010;23:290-7. kidney disease. Kidney Int. 2006;70:1905-13. 21. Vanholder R, Van Landschoot N, De Smet R, Schoots A, Ringoir S. Drug 31. Badve SV, Roberts MA, Hawley CM, Cass A, Garg AX, Krum H et al. protein binding in chronic renal failure: evaluation of nine drugs. Effects of beta-adrenergic antagonists in patients with chronic kidney Kidney Int. 1988;33:996-1004. disease: a systematic review and meta-analysis. J Am Coll Cardiol. 2011;58:1152-61. 22. Harter HR, Delmez JA. Effects of prazosin in the control of blood pressure in hypertensive dialysis patients. J Cardiovasc Pharmacol. 32. Cice G, Ferrara L, DAndrea A, DIsa S, Di Benedetto A, Cittadini A et al. 1979;1(6 Suppl):S43-55. Carvedilol increases two-year survival in dialysis patients with dilated cardiomyopathy: a prospective, placebo-controlled trial. J Am Coll 23. Lowenthal DT, Hobbs D, Affrime MB, Twomey TM, Martinez EW, Onesti Cardiol. 2003;41:1438-44. G. Prazosin kinetics and effectiveness in renal failure. Clin Pharmacol Ther. 1980;27:779-83. 33. Wali RK, Iyengar M, Beck GJ, Chartyan DM, Chonchol M, Lukas MA et al. Efficacy and safety of carvedilol in treatment of heart failure with 24. Martnez-Castelao A,Hueso M,Sanz V,Rejas J,Alsina J,Griny JM. chronic kidney disease: a meta-analysis of randomized trials. Circ Treatment of hypertension after renal transplantation: long-term Heart Fail. 2011;4:18-26. efficacy of verapamil, enalapril, and doxazosin. Kidney Int Suppl. 1998;68:S130-4. 34. OConnor DT, Preston RA, Sasso EH. Renal perfusion changes during treatment of essential hypertension: prazosin versus propranolol. J 25. Oliveras A, Hurtado S, Vzquez S, Puig JM, Lloveras J. Efficacy and Cardiovasc Pharmacol. 1979;1(6 Suppl):S38-42. safety of doxazosin GITS in hypertensive renal transplant patients: comparison of 8 and 4 mg. Transplant Proc. 2003;35:1732-5. 35. Zaca F, Benassi A, Bolzani R, Ghidoni I, Santese G, Schipani A et al. Comparative effects of doxazosin and carvedilol on clinical status 26. Curtis JR, Bateman FJ. Use of prazosin in management of hypertension and left ventricular function in hypertensive patients with mild heart in patients with chronic renal failure and in renal transplant recipients. failure. High Blood Press Cardiovasc Prev. 2005;12:37-44. Br Med J. 1975;4:432-4. 36. Richards TR, Tobe SW. Combining other antihypertensive drugs with -blockers in hypertension: a focus on safety and tolerability. Can J Cardiol. 2014;30(5 Suppl):S42-6.

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