Hyperuricemia as a risk factor for cardiovascular disease

Chronic activation of the renin–angiotensin–aldosterone system (RAAS) plays a key role in the development of hypertension, and cardiac and renal diseases. RAAS inhibitors, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), improve cardiovascular and renal outcomes. However, studies have shown that residual morbidity and mortality remains high, despite current optimal treatment. More comprehensive control of the RAAS might provide additional reductions in morbidity and mortality. Direct renin inhibitors offer the potential for enhanced RAAS control as they target the system at the point of activation, thereby reducing plasma renin activity (PRA); by contrast, ARBs and ACE inhibitors increase PRA. Elevated PRA is independently associated with cardiovascular morbidity and mortality. A single-pill combination of the direct renin inhibitor, aliskiren, and the ARB, valsartan, at once-daily doses of 150/160 mg and 300/320 mg, has recently been approved by the US FDA for the treatment of hypertension in patients not adequately controlled on aliskiren or ARB monotherapy, and as initial therapy in patients likely to need multiple drugs to achieve their blood pressure goals. This article examines the efficacy, safety and tolerability of aliskiren/valsartan combination therapy, and considers the evidence for the potential organ-protection benefits of this treatment.     

Targeting effective blood pressure control with angiotensin receptor blockers

Angiotensin receptor blockers (ARBs) have become established as a major class of antihypertensive on the basis of their powerful effects on blood pressure (BP), excellent tolerability and pleiotropic end-organ-protective effects. However, individual ARBs vary in antihypertensive efficacy, which may be important to clinical outcome. Several strategies are available to ensure that BP reductions with ARBs are at least as great as that which can be achieved with other antihypertensive classes. Firstly, several newer ARBs, including irbesartan, candesartan, telmisartan and olmesartan, have been reported to provide equivalent antihypertensive efficacy to amlodipine and greater efficacy than either losartan, valsartan or both. Secondly, increases in dose may improve the antihypertensive efficacy of agents such as valsartan, although clinical studies are necessary to provide characterisation of new, higher-dose monotherapies. Thirdly, fixed dose combinations with hydrochlorothiazide (HCTZ) increase the antihypertensive effect of all ARBs. It is likely that differences in efficacy between newer and older ARBs will in some cases be sustained in combination therapy, such that the most potent ARBs and HCTZ will provide another tier of control. The future use of ARBs is likely to involve a growing emphasis on compound-specific data, with regard to the antihypertensive efficacy and pleiotropic protective actions of agents.     

ARBs and target organ protection. Exploring benefits beyond their antihypertensive effects

Recognition of the role of the renin-angiotensin-aldosterone system (RAAS) in initiating and maintaining hypertension prompted the development of drugs that disrupt the RAAS, notably the angiotensin-converting enzyme (ACE) inhibitors and, more recently, the angiotensin II receptor blockers (ARBs). This article focuses on the use of ARBs in hypertension management and reviews evidence emerging from clinical trials that ARBs offer target organ protection over and above their antihypertensive activity.     

Metabolic syndrome: treatment of hypertensive patients

Metabolic syndrome (MetSyndr), a constellation of abnormalities [obesity, glucose intolerance, insulin resistance (IR), dyslipidemia (low HDL-cholesterol, high LDL-cholesterol and triglycerides (TG)], and elevated blood pressure (BP)], increases the risk of cardiovascular (CV) disease and premature death. From 10% to 30% of the adult population in industrialized countries has MetSyndr, which effectively predicts the development of type 2 diabetes mellitus (T2D) and CV disease. Because of the complex etiology of MetSyndr, a multi-targeted, integrated therapeutic approach is required to simultaneously treat high BP, obesity, lipid disorders and T2D (if present), to fully protect CV, cerebrovascular and renal systems. If lifestyle modification (weight control, diet, exercise, smoking cessation, moderation of alcohol intake) is ineffective, pharmaco-theraphy should be added to treat simultaneously the lipid- and non-lipid CV risk factors.Patients with HTN and MetSyndr should be started on angiotensin-converting enzyme (ACE) inhibitors, unless contraindicated. The ACE inhibitors and angiotensin receptor blockers (ARBs) reduce the odds of developing new onset T2D and also decrease albuminuria. The ACE inhibitors provide cardioprotective and renoprotective benefits beyond their effect on BP; they also improve IR. The ARBs are renoprotective in addition to being cardioprotective. Long-acting calcium channel blockers are also recommended in hypertensive patients with MetSyndr; these drugs also improve IR. Thiazides (at low doses) and selected ss-blockers can be given to patients with HTN and MetSyndr. Celiprolol in combination with diuretics has a favorable effect on glucose tolerance and IR in patients with HTN and MetSyndr, and spironolactone added to ACE inhibitor or ARB therapy provides additional reno- and CV protective benefits in patients with diabetic nephropathy. Carvedilol, a ss-blocker with vasodilating properties, added to ACE inhibitor or ARB therapy, is effective in preventing worsening of microalbuminuria in patients with HTN and MetSyndr; it also improves IR and glycemic control. Most patients eventually require two or more antihypertensive drugs to reach BP goal. It is recommended that therapy in patients whose BP is more than 20/10 mm Hg above target at diagnosis be initiated with a combination of antihypertensive drugs, administered either as individual drugs or as fixed-dose formulations. Treatment with fixed-dose combinations, such as irbesartan + hydrochlorothiazide provides good BP control in more than two-thirds of hypertensive patients with MetSyndr. Lipid and BP targets are reached in a high percent of patients with HTN and CV disease treated with a combination of amlodipine + atorvastatin.In conclusion, hypertensive patients with the MetSyndr be treated aggressively for each component of the syndrome to provide CV, cerebrovascular and renal protection.     

Preliminary experience with amlodipine in the pediatric population

The authors retrospectively examined their experience with amlodipine in the treatment of hypertension in 32 pediatric-aged patients, ranging in age from 4 to 26 years, with blood pressure (BP) readings greater than the 90th percentile for age. Amlodipine was used as the sole therapy in 9 patients and with other antihypertensive therapy in 23 patients. Additional antihypertensive drugs used in combination with amlodipine included beta-adrenergic antagonists, ACE inhibitors, and diuretics. The starting dose of amlodipine was 0.13+/-0.09 mg/kg/d. The dose was increased in 20 of 32 patients to 0.23+/-0.13 mg/kg/d. Amlodipine was administered once daily to 26 patients and twice daily to 6 patients. After therapy with amlodipine was initiated, the systolic BP decreased from 141+/-15 to 132+/-9 mm Hg (P=0.01) and the diastolic BP decreased from 84+/-16 to 77+/-8 mmHg (P=0,03). There were a total of 2145 follow-up BP readings. The follow-up systolic BP was lower than the initial BP prior to starting amlodipine 59% of the time and the diastolic BP was lower than the initial BP 61% of the time. The follow-up systolic BP was lower than the 90th percentile predicted for age 33% of the time after starting amlodipine and the diastolic BF was lower than the 90th percentile for age 52% of the time. Adverse effects were noted in 4 of the 32 patients (12.5%). These included fatigue (n=2), dizziness (n=1), and ankle edema (n=1). Amlodipine therapy was discontinued in only 1 patient (the patient with ankle edema). Given its efficacy, the low incidence of adverse effects, and availability as a suspension, amlodipine is an effective agent for the treatment of hypertension in the pediatric-aged patient.     

Calcium channel blockers in the treatment of hypertension and prevention of cardiovascular disease: results from major clinical trials

The ability of antihypertensive agents such as ss-blockers and thiazide and thiazide-like diuretics to reduce the risk of cardiovascular disease is well documented. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was undertaken to determine whether the newer classes of antihypertensive drugs-namely, calcium channel blockers (CCBs), alpha-1 blockers, and angiotensinconverting enzyme (ACE) inhibitors-were as effective as the older agents in preventing cardiovascular events. The results of ALLHAT showed that the diuretic chlorthalidone, the CCB amlodipine, and the ACE inhibitor lisinopril were equally effective in preventing the primary outcome-fatal coronary heart disease or nonfatal myocardial infarction. However, chlorthalidone and lisinopril were more effective at preventing heart failure, whereas amlodipine and chlorthalidone were more effective than lisinopril at preventing stroke. The ALLHAT findings, as well as those of other large, randomized, controlled antihypertensive trials, confirm the value of lowering blood pressure as an approach to reducing the risk, incidence, and economic burden of cardiovascular disease.     

Valsartan in chronic heart failure

OBJECTIVE: To evaluate the evidence for valsartan in the treatment of heart failure and determine its need for formulary inclusion. DATA SOURCES: OVID and PubMed databases were searched (1983-June 2004) using the key words angiotensin-receptor blocker, heart failure, valsartan, Diovan, and angiotensin-converting enzyme inhibitor. Only English-language literature was selected. STUDY SELECTION AND DATA EXTRACTION: Pharmacology and pharmacokinetic evaluations for valsartan were selected. Prospective, randomized clinical trials investigating the use of valsartan and other angiotensin-receptor blockers (ARBs) in chronic heart failure were evaluated. DATA SYNTHESIS: Valsartan, a selective antagonist for angiotensin receptor subtype 1, is the first ARB to be approved for use in chronic heart failure. Clinical trial data support valsartan as an alternative to angiotensin-converting enzyme (ACE) inhibitors in ACE inhibitor-intolerant patients with chronic heart failure. Valsartan is generally well tolerated, with renal impairment, elevated serum creatinine and potassium levels, and dizziness being the most common adverse effects; consequently, patients experiencing those adverse events while taking ACE inhibitors are likely to experience them with valsartan. Although further study is needed, differences in effectiveness among races may exist with use of valsartan; however, at this time, valsartan is recommended as an alternative to ACE inhibitors regardless of race. Candesartan and losartan have been studied in similar settings. Candesartan's data support its use in heart failure; however, losartan's data have been less consistent. CONCLUSIONS: Valsartan is a safe and effective alternative for heart failure patients intolerant of ACE inhibitors. Valsartan has not been shown to be safe and effective when used in combination with ACE inhibitors.     

FIXED DOSE COMBINATIONS OF ACE INHIBITORS

SUMMARY First-line antihypertensive monotherapy is effective in reducing blood pressure to within the normal range in approximately 50% of patients. Normalisation in the remaining patients may require a combination of two or more drugs. This review considers the clinical efficacy and tolerability of combinations involving angiotensin-converting enzyme (ACE) inhibitors. The efficacy of combinations with diuretics or calcium antagonists, as initial therapy or in patients with inadequate responses to monotherapy, has been demonstrated in many trials. With combination therapy, normalisation rates approaching 80% can be achieved using submaximal doses of both components. Therapy with both combinations is well tolerated; with ACE inhibitors reducing the diuretic metabolic effects or counteracting some calcium antagonist-associated vasodilatory effects. Data on ACE inhibitors with beta-blockers are limited. When patients respond inadequately to first-line monotherapy, the increasing availability of drug combinations will allow individual selection of the most appropriate combination, taking account of additional risk factors and concomitant disease.     

Clinical role of direct renin inhibition in hypertension

Treatment strategies to improve blood pressure control, reduce end-organ damage, and improve cardiovascular outcomes are more important today than ever before. Most patients will require combination therapy to achieve target blood pressure; early initiation of combination therapy may help patients achieve blood pressure control more rapidly. Low-dose combinations may be more effective with fewer adverse effects than higher doses of single agents. Dysregulation of the renin-angiotensin-aldosterone system (RAAS) is an important contributor in the pathogenesis of hypertension and its sequelae. Treatment with a direct renin inhibitor blocks the rate-limiting step in the RAAS, resulting in decreased angiotensin I and II production and decreased urinary aldosterone excretion. Like the angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, treatment with a direct renin inhibitor increases plasma renin concentration, but unlike the other RAAS inhibitors, treatment with a direct renin inhibitor decreases plasma renin activity. This unique combination of effects on the RAAS make a direct renin inhibitor an attractive option to combine with other antihypertensive agents for the management of hypertension and its comorbidities. Clinical studies have shown that combining the direct renin inhibitor, aliskiren, with drugs representing each of the major classes of antihypertensive agents (thiazide diuretics, beta blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, and calcium-channel blockers) reduces blood pressure, improves markers for cardiovascular outcomes, or does both. Results of several ongoing randomized clinical trials should provide additional insights into the potential of therapeutic combinations that include aliskiren to improve cardiovascular morbidity and mortality in patients with hypertension and related comorbidities.     

Treating hypertension with cardioprotective therapies: the role of ACE inhibitors, ARBs, and beta-blockers

Hypertension is both a disease and risk factor for cardiovascular disease (CVD) and each 20/10 mm Hg rise in blood pressure (BP) doubles the risk for CVD. Although BP reduction through lifestyle modification and/or antihypertensive therapy has been shown to dramatically reduce the risk for CVD, recent evidence has shown that many patients with hypertension do not have adequate BP control. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) provides comprehensive guidelines on the diagnosis, classification, and management of hypertension and related CV conditions. The JNC 7 guidelines recommend that most patients receive first-line therapy with thiazide diuretics, but the majority of patients will require 2 or more antihypertensive agents to achieve adequate BP control. The selection of additional antihypertensive therapies should be based on the presence of concomitant CV and metabolic conditions as well as patient-specific factors such as race. An important role exists for angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta-blockers, particularly in patients with comorbid CV or metabolic conditions. Clinical evidence suggests that these agents may offer benefits beyond simple BP lowering. Furthermore, synergies among antihypertensive classes may improve BP control and combination therapy may also permit the use of smaller doses of each medication and reduce the risk of dose-related adverse effects.     

Use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in clinical practice

This survey was performed to determine the clinical characteristics of patients treated with renin-angiotensin-aldosterone system (RAAS) inhibitors in clinical practice. A total of 386 investigators were asked to consecutively include outpatients under treatment with RAAS inhibitors (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers [ARBs] or both) for at least 6 months. In total, 2895 patients were included. The most frequent reason for prescribing RAAS inhibitors (particularly ARBs) was hypertension (p < 0.0001). When compared with ARBs, angiotensin-converting enzyme inhibitors were more frequently prescribed in patients with ischemic heart disease or heart failure, but lesser prescribed in those with left ventricular hypertrophy, diabetic nephropathy or microalbuminuria. Patients with left ventricular hypertrophy, diabetic nephropathy or microalbuminuria were more commonly treated with the combination of treatments.     

RAS blockade with ARB and ACE inhibitors: current perspective on rationale and patient selection

Cardiovascular disease represents a continuum that starts with risk factors such as hypertension and progresses to atherosclerosis, target organ damage, and ultimately to myocardial infarction, heart failure, stroke or death. Renin-angiotensin system (RAS) blockade with angiotensin converting enzyme (ACE) inhibitors or angiotensin AT(1)-receptor blockers (ARBs) has turned out to be beneficial at all stages of this continuum. Both classes of agent can prevent or reverse endothelial dysfunction and atherosclerosis, thereby reducing the risk of cardiovascular events. Such a reduction has been shown mainly for ACE inhibitors in patients with coronary artery disease, but recent studies revealed that ARBs are not inferior in this respect. However, no such data are currently available on the combination of these drugs. Both ACE inhibitors and ARBs have been shown to reduce target organ damage in organs such as the kidney, brain and heart, and to decrease cardiovascular mortality and morbidity in patients with congestive heart failure. Experimental data point to an influence of ACE inhibitors and ARBs on the number and function of endothelial progenitor cells revealing additional mechanisms of action of these drugs. The VALIANT trial has shown equivalent effects of ARB valsartan and the ACE-inhibitor captopril in patients post myocardial infarction, but the dual RAS-blockade, compared to monotherapy, did not further reduce events. In secondary prevention, the most-recently published ONTARGET study provides evidence that on top of a better tolerability AT(1)-receptors antagonists are equal to ACE inhibitors in the prevention of clinical endpoints like cardiovascular mortality and morbidity, myocardial infarction and stroke. The combined RAS blockade, however, achieved no further benefits in vascular high-risk patients and was associated with more adverse events. In chronic heart failure, ValHeFT and CHARM-ADDED have shown that combined RAS inhibition with ACE inhibitor and valsartan or candesartan reduced morbidity and mortality in certain patient subgroups. Accumulating evidence also points to benefits of the combination therapy in individuals with proteinuric nephropathies. In conclusion, while combined RAS-inhibition is not generally indicated in patients along the cardio-reno-vascular continuum, it has already proven to be effective in heart failure patients with incomplete neuroendocrine blockade. In secondary prevention, monotherapy with either RAS inhibitor is equally efficacious. Furthermore, novel pharmacologic agents such as renin inhibitors may prove useful in preventing common side effects of RAS blockade such as angiotensin escape and AT(1)-receptor upregulation, giving clinicians additional therapeutic tools to optimally treat the individual patient.     

Pharmaco‐nutrient interactions – a systematic review of zinc and antihypertensive therapy

Background: Antihypertensive medicines are to known to cause diverse disturbances to electrolyte homeostasis; however, their potential to affect zinc is less well known. The primary aim was to explore whether antihypertensive medicines have the potential to affect zinc status. Methods: A review of electronic databases was undertaken. Full‐length English language articles describing clinical trials involving antihypertensive medicines and reporting on zinc measurements were reviewed. Results: Eight eligible studies were identified which involved the use of ACE inhibitors, thiazide diuretics, beta blockers, or ARB drugs of which five included a control group Studies used urinary zinc excretion, plasma zinc levels or erythrocyte zinc as key measures of zinc status. Studies reported increased urinary zinc losses for captopril (from 50 mg/day), enalapril (20 mg/day), losartan (50 mg/day), losartan (50 mg/day) together with hydrochlorothiazide (12.5 mg/day), captopril (75 mg/day) together with frusemide (40 mg/day) and stand‐alone hydrochlorothiazide (25 mg/day). Serum levels of zinc decreased with captopril (50–150 mg/day), verapamil (240 mg/day), atenolol (50–150 mg/day) and the combination of losartan (50 mg/day) and hydrochlorothiazide (12.5 mg/day), eryrthrocyte levels decreased with use of valsartan (80 mg/day) and in some studies for captopril, but not for metoprolol (100 mg/day), atenolol (50–150 mg/day), verapamil (240 mg/day), doxazosin (4 mg/day) or amlodipine 10 mg/day). Major limitations were that most studies were small and did not report on dietary zinc intake. Conclusion: The available evidence suggests that use of ACE inhibitors and angiotensin 2 receptor antagonists or thiazide diuretics have the potential to reduce zinc levels in hypertensive patients. Additional research using larger participant numbers and accounting for dietary zinc intakes are required.     

Current possibilities of ACE inhibitor and ARB combination in arterial hypertension and its complications

The renin–angiotensin–aldosterone system (RAAS) plays a crucial role in blood pressure regulation and hypertension-related complications. Angiotensin-converting enzyme inhibitors (ACEIs) were the first to be used to block the RAAS and now have many compelling indications in the treatment of hypertension and its cardiovascular and renal complications. Angiotensin II receptor blockers (ARBs), introduced 20 years later, have been shown to be equally as effective as antihypertensive treatment and are also associated with a lower number of side effects. Furthermore, in clinical trials ARBs and ACEIs were associated with comparable benefits for their most typical indications. This was confirmed in the 2007 New European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines for the management of hypertension by comparable specific recommendations for ARB and ACEI treatment. There is sufficient theoretical background and, in some cases, also clinical evidence that combination therapy with ACEIs and ARBs may be more beneficial than monotherapy with either of the groups alone, both in uncomplicated hypertension and with concomitant heart failure or renal dysfunction. However, the combination of ACEI and ARB was not recommended in the ESH/ESC 2007 Guidelines. This may change after the publication of the Ongoing Telmisartan Alone and in Combination with Ramipril Global End point Trial (ONTARGET) study, the preliminary results of which have just been presented. In heart failure, recent studies have shown that the combination of ACEI and ARB decreases cardiovascular mortality and the number of hospitalizations due to aggravation of heart failure. These results have been reflected in the newest ESC guidelines of the heart failure treatment. Nephroprotective properties of the combination of ACEs and ARBs have been proved both in studies on nondiabetic and diabetic nephropathy. The potential benefits, indications in prespecified groups of patients, the most recent data from clinical trials and latest research regarding dual blockade of RAAS will be reviewed in this article.     

Current possibilities of ACE inhibitor and ARB combination in arterial hypertension and its complications

The renin-angiotensin-aldosterone system (RAAS) plays a crucial role in blood pressure regulation and hypertension-related complications. Angiotensin-converting enzyme inhibitors (ACEIs) were the first to be used to block the RAAS and now have many compelling indications in the treatment of hypertension and its cardiovascular and renal complications. Angiotensin II receptor blockers (ARBs), introduced 20 years later, have been shown to be equally as effective as antihypertensive treatment and are also associated with a lower number of side effects. Furthermore, in clinical trials ARBs and ACEIs were associated with comparable benefits for their most typical indications. This was confirmed in the 2007 New European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines for the management of hypertension by comparable specific recommendations for ARB and ACEI treatment. There is sufficient theoretical background and, in some cases, also clinical evidence that combination therapy with ACEIs and ARBs may be more beneficial than monotherapy with either of the groups alone, both in uncomplicated hypertension and with concomitant heart failure or renal dysfunction. However, the combination of ACEI and ARB was not recommended in the ESH/ESC 2007 Guidelines. This may change after the publication of the Ongoing Telmisartan Alone and in Combination with Ramipril Global End point Trial (ONTARGET) study, the preliminary results of which have just been presented. In heart failure, recent studies have shown that the combination of ACEI and ARB decreases cardiovascular mortality and the number of hospitalizations due to aggravation of heart failure. These results have been reflected in the newest ESC guidelines of the heart failure treatment. Nephroprotective properties of the combination of ACEs and ARBs have been proved both in studies on nondiabetic and diabetic nephropathy. The potential benefits, indications in prespecified groups of patients, the most recent data from clinical trials and latest research regarding dual blockade of RAAS will be reviewed in this article.     

Profiling Antihypertensive Therapy

The objectives of treating hypertension are to achieve adequate control of blood pressure (BP) and maintain it under tight control. Maintenance of tight control of BP will most likely prevent stroke, heart attack, and heart failure, cause regression of left ventricular hypertrophy, and quite possibly preserve or improve renal function. The last two salutary effects combined will further reduce the morbidity and mortality in the treated hypertensive subjects. Choice of antihypertensive drugs is of significant importance so that our efforts to control hypertension do not grossly alter the quality of life. The cost of therapy is also an important consideration. Thus, thiazide diuretics, beta-blockers, and central inhibitors that are relatively inexpensive and adequately lower BP should be a common choice. However, if drowsiness interferes with work, or impotence becomes a threat for the marital partner or significant other, adjustment has to be made. The metabolic abnormalities consisting mainly of impaired glucose tolerance, hypercholesterolemia, and insulin resistance often induced by these relatively inexpensive drugs have put calcium channel blocker and ACE inhibitor group of drugs on the top of the list for antihypertensive therapy. They are far more expensive, yet offer no greater antihypertensive advantage than a diuretic or central inhibitor, except in special circumstances.     

Amlodipine versus Angiotensin-receptor blockers for nonhypertension indications

OBJECTIVE: To review the efficacy and safety data of amlodipine and the angiotensin-receptor blockers (ARBs), focusing on heart failure, angina, percutaneous coronary intervention (PCI), and renal protection. DATA SOURCE: A MEDLINE search (1966-December 2001) was completed using amlodipine, angiotensin-receptor antagonist, losartan, valsartan, candesartan, and telmisartan as key words. English-language articles were identified and included. STUDY SELECTION AND DATA EXTRACTION: All identified articles were evaluated. Articles representative of the subject matter of our review were included. DATA SYNTHESIS: Amlodipine and the ARBs lower blood pressure to a similar extent. Amlodipine is an effective antianginal agent, whereas ARBs are not. However, amlodipine is not effective in the treatment of heart failure; ARBs may be useful in this setting. ARBs are also effective in preserving renal function and may provide some protection from restenosis in patients who have had a PCI. The ARBs may also be useful in preventing both diabetic and nondiabetic nephropathy. CONCLUSIONS: Concomitant disease states should be considered when choosing between an ARB and amlodipine for the management of hypertension.     

University of Miami Division of Clinical Pharmacology Therapeutic Rounds: managing hypertension in patients with kidney disease-implications for preservation of renal function

Renal parenchymal hypertension is defined as hypertension caused by disease of the kidneys. Impaired renal sodium excretion leading to extracellular fluid volume (ECFV) expansion is the most clinically important mechanism leading to hypertension in patients with kidney disease. Most patients with renal parenchymal hypertension have sodium-sensitive hypertension, and, consequently, sodium restriction and loop diuretics constitute the initial steps in effective antihypertensive therapy in patients with renal disease. The loop diuretics (furosemide, ethacrynic acid, bumetanide, torasemide) are used for the management of ECFV and hypertension in patients with renal disease because thiazide diuretics are generally not effective in patients with serum creatinine values above 2.0 mg/dL or creatinine clearances below 30 mL/min. The Joint National Committee VI recommends the use of angiotensin-converting enzyme (ACE) inhibitors in patients with hypertension and chronic renal disease to control hypertension and to slow progressive renal failure. Antihypertensive treatment with ACE inhibitors may favorably alter renal hemodynamics, thereby slowing the progression of renal dysfunction. ACE inhibitors have been found to be useful agents in preventing the progression of renal disease in the settings of established insulin-dependent diabetes mellitus (IDDM) nephropathy, non-insulin-dependent diabetes mellitus (NIDDM) nephropathy, IDDM patients with normal blood pressures and microalbuminuria, NIDDM patients with microalbuminuria and normal renal function, and a variety of non-diabetic renal diseases, especially in the setting of significant proteinuria. Calcium antagonists are effective for treating hypertensive patients with chronic renal impairment, and the initial results for calcium antagonists and for combination calcium antagonist-ACE inhibitor therapy have been encouraging. Although promising, the calcium antagonists and the new angiotensin II antagonists have not been studied as intensively as ACE inhibitors in regard to their ability to slow the progression of renal insufficiency.