Nephrosclerosis Medication
- Author: Fernando C Fervenza, MD, PhD; Chief Editor: Vecihi Batuman, MD, FACP, FASN more...
Medication Summary
Antihypertensives
Several antihypertensive medications, including thiazide diuretics, beta-blockers, ACE inhibitors, ARBs, and calcium channel blockers, in principle, can be used as initial monotherapy in patients with hypertension. The Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure VII (JNC VII) has recommended the following for uncomplicated hypertension:
- Therapy begins with lifestyle modification.
- If the BP goal is not achieved, thiazide-type diuretics should be used as initial therapy for most patients, either alone or in combination with one of the other classes (ie, ACE inhibitors, ARBs, beta-blockers, calcium channel blockers) that have also been shown to reduce one or more hypertensive complications in randomized controlled outcome trials.
- Selection of one of these other agents as initial therapy is recommended when a diuretic cannot be used or when a compelling indication requires the use of a specific drug.
- More than two thirds of hypertensive individuals do not achieve adequate control on one drug and require 2 or more antihypertensive agents selected from different drug classes.
- The initiation of therapy with more than one drug increases the likelihood of achieving the BP goal faster. The use of multidrug combinations often produces greater BP reduction at lower doses of the component agents, resulting in fewer adverse effects.
- Hypertension may exist in association with other conditions with compelling indications for use of a particular treatment based on clinical trial data demonstrating benefits of such therapy on the natural history of the associated condition. Compelling indications for specific therapy involve high-risk conditions that can be direct sequelae of hypertension (eg, HF, ischemic heart disease, chronic kidney disease, recurrent stroke) or commonly associated with hypertension (eg, diabetes, high coronary disease risk). Therapeutic decisions in such individuals should be directed at both the compelling indication and lowering of BP.
Low-dose thiazides
Low-dose thiazides are now recognized as achieving maximal effects on BP with minimal adverse effects. Results from multiple treatment trials show the benefits of low-dose diuretics and alpha-blockers in preventing stroke, coronary events, congestive heart failure, and all-cause mortality.
ACE inhibitors
With the exception of ACE inhibitors in patients with diabetes, no data indicate the best way to treat patients with essential hypertension while preserving renal function. However, results obtained with the use of different antihypertensive treatment in patients with chronic renal failure and/or diabetes (in both animal and human studies) may be extrapolated to guide the treatment of patients with essential hypertension.
In animal models of chronic renal failure and diabetes, control of hypertension with the use of ACE inhibitors has been clearly demonstrated, and angiotensin II receptor antagonists can decrease proteinuria, reduce the severity of glomerulosclerosis and interstitial fibrosis, and slow the progression of renal disease.
Human studies show that ACE inhibitors are capable of slowing the progression of renal failure in all forms of nephropathy, except in patients with polycystic kidneys. Based on these and other results, ACE inhibitors have become the recommended initial therapy to treat hypertension in patients with diabetes.
This recommendation is also supported by the results of the Heart Outcomes Prevention Evaluation (HOPE) trial. According to this study, an ACE inhibitor administered once daily reduces cardiovascular events in patients without heart failure but with at least one cardiovascular risk factor, not including diabetes. Similarly, the Microalbuminuria, Cardiovascular, and Renal Outcomes (MICRO-HOPE) substudy of the HOPE trial randomized 3577 subjects with diabetes who had a prior cardiovascular event or at least one other cardiovascular risk factor and no clinical proteinuria to receive either ramipril (10 mg/d) or placebo. Treatment with ramipril resulted in a 24% risk reduction of overt nephropathy development after 4.5 years of follow-up care (independent of BP reduction).
The beneficial effect of ACE inhibitors is attributed, at least in part, to their ability to reduce or suppress proteinuria. This is particularly important for patients with diabetes because the development of microalbuminuria is associated with an increased prevalence of cardiovascular complications. A few studies have suggested that microalbuminuria is an early marker of renal damage in patients with hypertension, and patients with microalbuminuria experience a faster decline in renal function. Ruilope et al (1994) reported a faster decline in creatinine clearance in patients who are hypertensive with microalbuminuria compared with patients who are hypertensive with normal albumin excretion (11 mL/min vs 2 mL/min).[30]
Similar findings were observed by Bianchi et al (1999).[31] In a few studies, ACE inhibitors, but not calcium channel blockers, reduced microalbuminuria in patients with essential hypertension. Other studies have also confirmed the ability of ACE inhibitors to reduce proteinuria in these patients.
Whether a reduction in microalbuminuria results in a decreased prevalence of ESRD in patients with hypertension remains to be determined. While combining an ACE inhibitor with a calcium channel blocker has been shown to reduce cardiovascular events in clinical trials of hypertension, the renoprotective effects are less uniformly demonstrated. Different studies, including the Fosinopril versus Amlodipine Cardiac Events Trial (FACET), the HOT study, and the Systolic Hypertension in Europe (Syst-Eur) trial, have reported conflicting results in terms of both cardiovascular and renal outcomes.
In the FACET, combination therapy with ACE inhibitors and calcium channel blockers resulted in significantly lower BPs compared with other groups. Moreover, combination therapy also showed the best results in reducing the mortality rate. To date, in patients with established renal failure (ie, serum creatinine >1.4 mg/dL), none of the dihydropyridine calcium channel blockers available in the United States has been shown to slow renal disease progression in the absence of an ACE inhibitor.
ACE inhibitor-ARB combination therapy
Data regarding the benefit of adding an ARB to an ACE inhibitor are mixed, and no consensus has been reached. In the Combination Treatment of Angiotensin Receptor Blocker and Angiotensin Converting Enzyme Inhibitor in Nondiabetic Renal Disease (COOPERATE) trial, combined therapy with losartan and trandolapril preserved renal function better than monotherapy with either drug. These patients had nondiabetic proteinuric chronic kidney disease.
However, since the publication of this trial, serious concerns about the quality of the data have been raised by Kunz et al. A recent meta-analysis by Kunz et al showed better reductions in proteinuria with combined therapy, although safety data were sparse.[32] Because of the lack of conclusive data regarding the benefits of combined therapy and because of the ongoing concerns for increased adverse effects, dual ACE inhibitor-ARB therapy should be prescribed cautiously.
Alpha-blocker and ACE inhibitor combination
Alpha-adrenergic receptor blockers at low doses may be used as monotherapy in the treatment of hypertension. Alpha-adrenergic receptor blockers improve insulin sensitivity, improve urine flow, reduce total cholesterol and triglyceride levels, and increase high-density lipoprotein levels.
Combinations of alpha-blockers and ACE inhibitors have additive effects for lowering BP only in patients with a baseline pulse rate that is greater than 84 beats per minute. In terms of slowing renal disease progression in patients with diabetes or impaired renal function, alpha-blockers are of no additional benefit. Some patients may require an additional arteriolar vasodilator to control BP. Finally, angiotensin II receptor blockers, alone or in combination with other antihypertensive medications, offer a therapeutic alternative. Angiotensin II receptor blockers have a favorable adverse effect profile and appear to share the same beneficial effects of ACE inhibitors; however, no conclusive human data on renal disease progression are available for these agents.
Remember that only approximately 50% of patients with hypertension reach target BP control with antihypertensive monotherapy. Approximately 80-90% of patients require a second agent. Other patients require a combination of 3 or more agents in order to reach target BP.
Diuretics
Class Summary
Induce natriuresis, reduce target organ damage and mortality rates in patients with hypertension, achieve maximal BP-lowering effects at low doses (12.5-25 mg/d), and potentiate antihypertensive effects of other BP medications. Antihypertensive effect of these agents is observed in all demographic groups. Thiazides induce vasodilation and are superior to loop diuretics as antihypertensive agents.
Hydrochlorothiazide (Esidrix, HydroDIURIL)
Inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium, water, potassium, and hydrogen ions.
Angiotensin-converting enzyme inhibitors
Class Summary
Reduce proteinuria, have specific renal protective effects in both diabetic and nondiabetic renal impairment, and reduce morbidity and mortality rates in congestive heart failure. Less effective as monotherapy if patient >50 y. Black patients require increased doses. Inhibit or blunt all adverse metabolic effects of thiazides, and reduce left ventricular hypertrophy.
Fosinopril (Monopril)
Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.
Ramipril (Altace)
Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.
Angiotensin II receptor antagonists
Class Summary
Indicated in patients intolerant of ACE inhibitors because they do not interfere with the breakdown of bradykinin or cause cough. Reduce left ventricular hypertrophy and thirst similarly to ACE inhibitors and reduce proteinuria.
Losartan (Cozaar)
Blocks vasoconstrictor and aldosterone-secreting effects of angiotensin II. May induce a more complete inhibition of renin-angiotensin system than ACE inhibitors, does not affect response to bradykinin, and is less likely to be associated with cough and angioedema. For patients unable to tolerate ACE inhibitors.
Angiotensin II receptor blockers reduce BP and proteinuria, protecting renal function and delaying onset of ESRD.
Valsartan (Diovan)
Prodrug that produces direct antagonism of angiotensin II receptors. Displaces angiotensin II from AT1 receptor and may lower BP by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses. May induce more complete inhibition of renin-angiotensin system than ACE inhibitors, does not affect response to bradykinin, and is less likely to be associated with cough and angioedema. For patients unable to tolerate ACE inhibitors.
Calcium channel blockers
Class Summary
Effective as monotherapy in black patients and elderly patients. Potentiate ACE inhibitor effects. Renal protection is not proven, but reduce morbidity and mortality rates in congestive heart failure. Indicated in patients with diastolic dysfunction.
Verapamil (Calan, Covera, Verelan)
During depolarization, inhibits calcium ion from entering slow channels or voltage-sensitive areas of vascular smooth muscle and myocardium.
Amlodipine (Norvasc)
Relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery. Benefits nonpregnant patients with systolic dysfunction, hypertension, or arrhythmias. Can be used during pregnancy if clinically indicated.
Felodipine (Plendil)
Relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery.
Beta-adrenergic blocking agents
Class Summary
Suppress renin secretion. Monotherapy less effective in black patients. Reduce morbidity and mortality rates after myocardial infarction. Not considered a first-line therapy in the absence of a compelling indication (eg, coronary artery disease).[29]
Labetalol (Normodyne, Trandate)
Blocks beta1-, alpha-, and beta2-adrenergic receptor sites, decreasing BP.
Direct vasodilators
Class Summary
Cause arteriolar dilation by blocking arterial wall calcium uptake. Effective in severe hypertension (minoxidil more effective than hydralazine). Best if used in combination with a diuretic plus a beta-blocker.
Minoxidil (Loniten)
Most potent vasodilator available for oral use.
Relaxes arteriolar smooth muscle, causing vasodilation, which, in turn, may reduce BP.
Hydralazine (Apresoline)
Decreases systemic resistance through direct vasodilation of arterioles.
Alpha-adrenergic agonists
Class Summary
Improve hemodynamic status by increasing myocardial contractility and heart rate, resulting in increased cardiac output. Also increase peripheral resistance by causing vasoconstriction. Increased cardiac output and increased peripheral resistance lead to increased BP.
Methyldopa (Aldomet)
DOC in pregnancy. Mechanism of action is likely due to drug's metabolism to alpha-methyl norepinephrine, which lowers arterial pressure by stimulating central inhibitory alpha-adrenergic receptors, false neurotransmission, or reducing plasma renin activity.
Clonidine (Catapres)
Stimulates alpha-2 adrenoreceptors in brain stem, activating an inhibitory neuron, which results in reduced sympathetic outflow. Decreases vasomotor tone and heart rates. Used in hypertensive emergency. Useful when patient has a migraine in association with hypertension.
Doxazosin (Cardura)
Inhibits postsynaptic alpha-adrenergic receptors, resulting in vasodilation of veins and arterioles and decrease in total peripheral resistance and BP.
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