Eplerenone [Inspra] is a first-in-class selective aldosterone receptor blocker. The drug is used for hypertension and heart failure and has one significant side effect: hyperkalemia.
Mechanism of Action
Eplerenone produces selective blockade of aldosterone receptors, having little or no effect on receptors for other steroid hormones (e.g., glucocorticoids, progesterone, androgens). In the kidney, activation of aldosterone receptors promotes excretion of potassium and retention of sodium and water. Receptor blockade has the opposite effect: retention of potassium and increased excretion of sodium and water. Loss of sodium and water reduces blood volume, and hence blood pressure. Blockade of aldosterone receptors at nonrenal sites may prevent or reverse pathologic effects of aldosterone on cardiovascular structure and function.
Therapeutic Uses
Hypertension. For treatment of hypertension, eplerenone may be used alone or in combination with other antihypertensive agents. Maximal reductions in blood pressure take about 4 weeks to develop. In clinical trials, reductions in blood pressure were equivalent to those produced by spironolactone and superior to those produced by losartan (an ARB). In patients already using an ACE inhibitor or an ARB, adding eplerenone produced a further reduction in blood pressure.
Although it is clear that eplerenone can lower blood pressure, we have no information on what really matters: the drug’s ability to reduce morbidity and mortality in patients with isolated hypertension and lack of LV hypertrophy. Until more is known, eplerenone should be reserved for patients who have not responded to traditional antihypertensive drugs.
Heart Failure. In patients with heart failure, eplerenone can improve symptoms, reduce hospitalizations, and prolong life. Benefits appear to derive from blocking the adverse effects of aldosterone on cardiovascular structure and function. Use of eplerenone in heart failure is discussed in Chapter 48.
Pharmacokinetics
Eplerenone is administered orally, and absorption is not affected by food.
Plasma levels peak about 1.5 hours after dosing. Absolute bioavailability is
use in hypertension, aliskiren was evaluated for treating heart failure and renal failure associated with diabetes. Unfortunately, in the ATMOSPHERE and ALTITUDE trials, aliskiren was no more effective than other current treatments.
Pharmacokinetics
Aliskiren is administered orally, and bioavailability is low (only 2.5%). Dosing with a high-fat meal makes availability much lower (about 0.8%). Aliskiren undergoes some metabolism by CYP3A4 (the 3A4 isoenzyme of cytochrome P450), but the extent of metabolism is not known. About 25% of the drug is eliminated unchanged in the urine. The half-life is about 24 hours.
Adverse Effects
Aliskiren is generally well tolerated. At usual doses, the risk of angioedema, cough, or hyperkalemia is low. At high thera- peutic doses, some patients experience diarrhea. Like other drugs that affect the RAAS, aliskiren should be avoided during pregnancy.
Angioedema and Cough. With ACE inhibitors, angio- edema and cough result from inhibition of kinase II. Because aliskiren does not inhibit kinase II, the risk of these effects is low. In clinical trials, the incidence of cough was 1.1% with aliskiren versus about 10% with an ACE inhibitor. Similarly, the incidence of angioedema was 0.06% with aliskiren versus 1% with an ACE inhibitor. If angioedema does occur, aliskiren should be discontinued immediately.
Gastrointestinal Effects. Aliskiren causes dose-dependent diarrhea, seen in 2.3% of patients taking 300 mg/day. Women and older adults are most susceptible. Excessive doses (600 mg/
day) are associated with abdominal pain and dyspepsia.
Hyperkalemia. Like the ACE inhibitors, aliskiren rarely causes hyperkalemia when used alone. However, hyperkale- mia might be expected if aliskiren were combined with an ACE inhibitor, a potassium-sparing diuretic, or potassium supplements.
Fetal Injury and Death. Although aliskiren has not been studied in pregnant women, the drug is likely to pose a risk of major congenital malformations and fetal death because the risk of these events is well established with other drugs that suppress the RAAS. Therefore, like the ACE inhibitors and ARBs, aliskiren is contraindicated during the second and third trimesters, and should be discontinued as soon as possible when pregnancy occurs.
Drug Interactions
Aliskiren undergoes some metabolism by CYP3A4, but it neither induces nor inhibits the P450 system. In clinical trials, aliskiren had no significant interac- tions with atenolol, digoxin, amlodipine, or hydrochlorothiazide. However, levels of aliskiren were significantly raised by atorvastatin and ketoconazole (a P450 inhibitor), and significantly lowered by irbesartan. Levels of furosemide were lowered by aliskiren.
Preparations, Dosage, and Administration
Aliskiren is available alone as Tekturna and Rasilez , in combination with hydrochlorothiazide as Tekturna HCT and Rasilez HCT , and in combination with amlodipine as Tekamlo. All formulations are indicated for hypertension.
Aliskiren alone [Tekturna, Rasilez ] is available in 150- and 300-mg tablets. The initial dosage is 150 mg once a day. If control of blood pressure is inadequate, dosage may be increased to 300 mg once a day. Daily doses above 300 mg will not increase benefits, but will increase the risk of diarrhea.
Since high-fat meals decrease absorption substantially, each daily dose should be taken at the same time with respect to meals (e.g., 1 hour before dinner), so as to achieve a consistent response.
Drugs that raise potassium levels can increase the risk of hyperkalemia. Eplerenone should not be combined with potas- sium supplements, salt substitutes, or potassium-sparing diuretics. Combining eplerenone with ACE inhibitors or ARBs should be done with caution.
Drugs similar to eplerenone (e.g., ACE inhibitors and diuretics) are known to increase levels of lithium. Although the combination of eplerenone and lithium has not been studied, caution is nonetheless advised. Lithium levels should be measured frequently.
Preparations, Dosage, and Administration
Eplerenone [Inspra] is available in 25- and 50-mg tablets. The usual starting dosage is 50 mg once a day, taken with or without food. After 4 weeks, dosage can be increased to 50 mg twice daily (if the hypotensive response has been inadequate). Raising the dosage above 100 mg/day is not recommended because doing so is unlikely to increase the therapeutic response, but will increase the risk of hyperkalemia. In patients taking weak inhibitors of CYP3A4, the initial dosage should be reduced by 50% (to 25 mg once a day).
Spironolactone
Spironolactone [Aldactone], a much older drug than eplerenone, blocks receptors for aldosterone, but also binds with receptors for other steroid hormones (e.g., glucocorticoids, progesterone, androgens). Blockade of aldosterone receptors underlies beneficial effects in hypertension and heart failure, as well as the drug’s major adverse effect: hyperkalemia. Binding with receptors for other steroid hormones underlies additional adverse effects: gynecomastia, menstrual irregularities, impotence, hirsutism, and deepening of the voice. The basic pharmacology of spironolactone and its use in heart failure are discussed in Chapters 41 and 48, respectively.
unknown. Eplerenone undergoes metabolism by CYP3A4, followed by excretion in the urine (67%) and feces (32%). The elimination half-life is 4 to 6 hours.
Adverse Effects
Eplerenone is generally well tolerated. The incidence of adverse effects is nearly identical to that of placebo. A few adverse effects—diarrhea, abdominal pain, cough, fatigue, gynecomastia, flu-like syndrome—occur slightly (1% to 2%) more often with eplerenone than with placebo.
Hyperkalemia. The greatest concern is hyperkalemia, which can occur secondary to potassium retention. Because of this risk, combined use with potassium supplements, salt substitutes, or potassium-sparing diuretics (e.g., spironolactone, triamterene) is contraindicated. Combined use with ACE inhibitors or ARBs is permissible, but should be done with caution. Eplerenone is contraindicated for patients with high serum potassium (above 5.5 mEq/L) and for patients with impaired renal function or type 2 diabetes with microalbumin- uria, both of which can promote hyperkalemia. Monitoring potassium levels is recommended for patients at risk (e.g., those taking ACE inhibitors or ARBs).
Drug Interactions
Inhibitors of CYP3A4 can increase levels of eplerenone, thereby posing a risk of toxicity. Weak inhibitors (e.g., erythromycin, saquinavir, verapamil, fluconazole) can double eplerenone levels. Strong inhibitors (e.g., ketoconazole, itraconazole) can increase levels fivefold. If eplerenone is combined with a weak inhibitor, eplerenone dosage should be reduced. Eplerenone should not be combined with a strong inhibitor.
KEY POINTS
■ The RAAS helps regulate blood pressure, blood volume, and fluid and electrolyte balance. The system can promote cardiovascular pathology.
■ The RAAS acts through production of angiotensin II and aldosterone.
■ Angiotensin II has much greater biologic activity than angiotensin I or angiotensin III.
■ Angiotensin II is formed by the actions of two enzymes:
renin and ACE.
■ Angiotensin II causes vasoconstriction (primarily in arterioles) and release of aldosterone. In addition, angio- tensin II can promote pathologic changes in the heart and blood vessels.
■ Aldosterone acts on the kidneys to promote retention of sodium and water. In addition, aldosterone can also mediate pathologic changes in cardiovascular function.
■ The RAAS raises blood pressure by causing vasoconstriction and by increasing blood volume (secondary to aldosterone- mediated retention of sodium and water).
■ In addition to the traditional RAAS, in which angiotensin II is produced in the blood and then carried to target tissues, angiotensin II can be produced locally by individual tissues.
■ Beneficial effects of ACE inhibitors result largely from inhibition of ACE and partly from inhibition of kinase II (the name for ACE when the substrate is bradykinin).
■ By inhibiting ACE, ACE inhibitors decrease production of angiotensin II. The result is vasodilation, decreased blood volume, and prevention or reversal of pathologic changes in the heart and blood vessels mediated by angiotensin II and aldosterone.
■ ACE inhibitors (and ARBs) are used to treat patients with hypertension, heart failure, MI, and established diabetic nephropathy. In addition, they are used to prevent MI, stroke, and death from cardiovascular causes in patients at high risk for a cardiovascular event. Of note, ACE inhibitors (and ARBs) are not effective for primary preven- tion of diabetic nephropathy.
■ Preliminary data indicate that ACE inhibitors (and ARBs) can reduce the risk of developing diabetic retinopathy, although they can’t slow the progression of established retinopathy.
■ ACE inhibitors can produce significant first-dose hypoten- sion by causing a sharp drop in circulating angiotensin II.
■ Cough, secondary to accumulation of bradykinin, is the most common reason for discontinuing ACE inhibitors.
■ By suppressing aldosterone release, ACE inhibitors can cause hyperkalemia. Exercise caution in patients taking potassium supplements, salt substitutes, or potassium- sparing diuretics.
■ ACE inhibitors can cause major fetal malformations and should be avoided during pregnancy. Until recently,
Continued
we thought that risk was limited to exposure during the second and third trimesters. However, new data indicate that exposure during the first trimester may be dangerous as well.
■ ACE inhibitors can cause a precipitous drop in blood pressure in patients with bilateral renal artery stenosis (or stenosis in the artery to a single remaining kidney).
■ ARBs block the actions of angiotensin II in blood vessels, the adrenals, and all other tissues.
■ ARBs are similar to ACE inhibitors in that they cause vasodilation, suppress aldosterone release, promote excre- tion of sodium and water, reduce blood pressure, and cause birth defects and angioedema.
■ ARBs differ from ACE inhibitors in that they have a much lower incidence of hyperkalemia or cough.
■ Aliskiren, a DRI, binds tightly with renin and thereby inhibits cleavage of angiotensinogen into angiotensin I.
As a result, the drug suppresses the entire RAAS.
■ Like the ACE inhibitors and ARBs, aliskiren causes vasodilation, suppresses aldosterone release, promotes excretion of sodium and water, reduces blood pressure, and causes birth defects and angioedema.
■ Despite their similarities, aliskiren, ARBs, and ACE inhibi- tors are not clinically interchangeable.
■ Aldosterone antagonists (spironolactone, eplerenone) block receptors for aldosterone.
■ By blocking aldosterone receptors, aldosterone antagonists can (1) promote renal excretion of sodium and water (and can thereby reduce blood volume and blood pressure) and (2) prevent or reverse pathologic effects of aldosterone on cardiovascular structure and function.
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Summary of Major Nursing Implications
aANGIOTENSIN-CONVERTING ENZYME INHIBITORS
Benazepril Captopril Enalapril Enalaprilat Fosinopril Lisinopril Moexipril Perindopril Quinapril Ramipril Trandolapril
Unless indicated otherwise, the implications summarized in the sections that follow pertain to all of the ACE inhibitors.
Preadministration Assessment Therapeutic Goals
ACE inhibitors are used to:
• Reduce blood pressure in patients with hypertension (all ACE inhibitors).
• Improve hemodynamics in patients with heart failure (captopril, enalapril, fosinopril, lisinopril, quinapril).
• Slow progression of established diabetic nephropathy (captopril).
• Reduce mortality following acute MI (lisinopril).
• Treat heart failure after MI (ramipril, trandolapril).
• Reduce the risk of MI, stroke, or death from cardiovascular causes in patients at high risk (ramipril).
• Reduce cardiovascular mortality or nonfatal MI in patients with stable coronary artery disease (perindopril).
Baseline Data
Determine blood pressure, and obtain a white blood cell count and differential.
Identifying High-Risk Patients
ACE inhibitors are contraindicated during the second and third trimesters of pregnancy and for patients with (1) bilateral renal artery stenosis (or stenosis in the artery to a single remaining kidney) or (2) a history of hypersensitivity reactions (especially angioedema) to ACE inhibitors.
Exercise caution in patients with salt or volume depletion, renal impairment, or collagen vascular disease, and in those taking potassium supplements, salt substitutes, potassium- sparing diuretics, ARBs, aliskiren, or lithium.
Implementation: Administration Routes
Oral. All ACE inhibitors (except enalaprilat).
Intravenous. Enalaprilat.
Dosage and Administration
Dosage is low initially and then gradually increased.
Instruct patients to administer captopril and moexipril at least 1 hour before meals. All other oral ACE inhibitors can be administered with food.
Ongoing Evaluation and Interventions Monitoring Summary
Monitor blood pressure closely for 2 hours after the first dose and periodically thereafter. Obtain a white blood cell count and differential every 2 weeks for the first 3 months of therapy and periodically thereafter.
Evaluating Therapeutic Effects
Hypertension. Monitor for reduced blood pressure. The usual target pressure is systolic/diastolic of 140/90 mm Hg or 130/80 in patients with diabetes.
Heart Failure. Monitor for a lessening of signs and symptoms (e.g., dyspnea, cyanosis, jugular vein distention, edema).
Continued Diabetic Nephropathy. Monitor for proteinuria and
altered glomerular filtration rate.
Minimizing Adverse Effects
First-Dose Hypotension. Severe hypotension can occur with the first dose. Minimize hypotension by (1) withdrawing diuretics 2 to 3 days before initiating ACE inhibitors and (2) using low initial doses. Monitor blood pressure for 2 hours following the first dose. Instruct patients to lie down if hypotension develops. If necessary, infuse normal saline to restore pressure.
Cough. Warn patients about the possibility of persistent dry, irritating, nonproductive cough. Instruct them to consult the prescriber if cough is bothersome. Stopping the ACE inhibitor may be indicated.
Hyperkalemia. ACE inhibitors may increase potassium levels. Instruct patients to avoid potassium supplements and potassium-containing salt substitutes unless they are pre- scribed by the provider. Potassium-sparing diuretics must also be avoided.
Fetal Injury. Warn women of childbearing age that taking ACE inhibitors during the second and third trimesters of pregnancy can cause major fetal injury (hypotension, hyper- kalemia, skull hypoplasia, anuria, reversible and irreversible renal failure, death) and that taking these drugs earlier in pregnancy may pose a risk as well. If the patient becomes pregnant, withdraw ACE inhibitors as soon as possible. Closely monitor infants who have been exposed to ACE inhibitors during the second or third trimester for hypotension, oliguria, and hyperkalemia.
Angioedema. This rare and potentially fatal reaction is characterized by giant wheals and edema of the tongue, glottis, and pharynx. Instruct patients to seek immediate medical attention if these symptoms develop. If angioedema is diagnosed, ACE inhibitors should be discontinued and never used again. Treat severe reactions with subcutaneous epinephrine.
Renal Failure. Renal failure is a risk for patients with bilateral renal artery stenosis or stenosis in the artery to a single remaining kidney. ACE inhibitors must be used with extreme caution in these people.
Neutropenia (Mainly With Captopril). Neutropenia poses a high risk of infection. Inform patients about early signs of infection (fever, sore throat, mouth sores), and instruct them to notify the prescriber if these occur. If neutropenia develops, withdraw the drug immediately; neutrophil counts should normalize in approximately 2 weeks. Neutropenia is most likely in patients with renal impairment and collagen vascular diseases (e.g., systemic lupus erythematosus, scleroderma); monitor these patients closely.
Minimizing Adverse Interactions
Diuretics. Diuretics may intensify first-dose hypotension.
Withdraw diuretics 2 to 3 days before beginning an ACE inhibitor. Diuretics may be resumed later if needed.
Antihypertensive Agents. The antihypertensive effects of ACE inhibitors are additive with those of other antihyperten- sive drugs (e.g., ARBs, diuretics, sympatholytics, vasodilators,
calcium channel blockers). When an ACE inhibitor is added to an antihypertensive regimen, dosages of the other drugs may require reduction.
Drugs That Elevate Potassium Levels. ACE inhibitors increase the risk of hyperkalemia associated with potassium supplements, potassium-sparing diuretics, and possibly aliskiren. Risk can be minimized by avoiding potassium supplements and potassium-sparing diuretics except when they are clearly indicated.
Lithium. ACE inhibitors can increase serum levels of lithium, causing toxicity. Monitor lithium levels frequently.
Nonsteroidal Anti-Inflammatory Drugs. NSAIDs (e.g., aspirin, ibuprofen) can interfere with the antihypertensive effects of ACE inhibitors. Advise patients to minimize NSAID use.
ANGIOTENSIN II RECEPTOR BLOCKERS