- Email: [email protected]
New Drug Available for Treating Hypertension
JNP
NEW DRUG AVAILABLE FOR TREATING HYPERTENSION On March 6, 2007, the Food and Drug Administration announced approval of the first of a new class of antihypertensive medications, aliskiren (Tekturna).1 The first new antihypertensive in 10 years, the drug is indicated for the treatment of hypertension as monotherapy and in combination with other medications. Use with maximal doses of angiotensin-converting enzyme (ACE) inhibitors has not been adequately studied.2
Mechanism of Action Aliskiren belongs to the new class of medications, renin inhibitors, that block the action of renin at the beginning of the renin-angiotensin-aldosterone system (RAAS), causing complete suppression of angiotensin II. Renin is secreted by the kidneys in
PRESCRIPTION PAD Maren Mayhew
response to decreases in blood volume and renal perfusion. It attaches to angiotensinogen to form angiotensin I (inactive). Angiotensin I is converted to angiotensin II (active) by the ACE and non-ACE pathways. An antirenin agent blocks this process at the beginning, instead of the middle, as is seen with use of ACE inhibitors. Inhibiting blockage early in the process prevents the conversion of angiotensin I to angiotensin II by non-ACE pathways, completely blocking production of angiotensin II. Angiotensin II produces vasoconstriction, releases catecholamines, and promotes aldosterone secretion and sodium reabsorption, 410
The Journal for Nurse Practitioners - JNP
thus increasing blood pressure. Angiotensin inhibits renin release, providing a negative feedback loop called the RAAS. Aliskiren blocks the effect of the increased renin levels, keeping the plasma renin activity (PRA) the same. PRA is a measurement of the elevated renin concentrations and increased capacity to generate angiotensin I. This action is unlike ACE inhibitors and angiotensin receptor blockers (ARBs), which elevate PRA.2 This is seen as a theoretical advantage of aliskiren over ACE inhibitors and ARBs.3
Pharmacokinetics Low bioavailability has been a problem in the development of renin inhibitors.4 Aliskiren is poorly absorbed from the gastrointestinal (GI) tract—only approximately 2.5%. Administration with a high-fat meal decreases the concentration of the drug. The effect is the drug is smooth over a 24-hour interval, with no decrease of efficacy before 24 hours. The blood pressure–lowering effect of aliskiren persists up to 2 weeks after treatment withdrawal, with no rebound effect.5 The half-life is 24 hours; steady state blood levels are reached in about 7 to 8 days. The drug is not extensively protein bound. Aliskiren is minimally metabolized. A small amount is metabolized by the CYP 3A4 system, but it does not inhibit or induce CYP 3A4. This is not considered clinically significant. One fourth is excreted unchanged renally. Most is excreted by the hepatobiliary route.2 Because of the lack of significant protein binding, lack of effect on the P450 enzyme system, and minimal metabolism, the potential for drug interactions is low. It has no interaction with lovastatin, digoxin, metformin, celecoxib, atenolol, atorvastatin, ramipril, or warfarin. However, it decreases the concentration of furosemide. June 2007
Lack of interaction has been shown with the following antihypertensives: amlodipine, valsartan, and hydrochlorothiazide.6
Adverse Effects Aliskiren has a side effect profile similar to placebo when given in doses less than 600 mg/day, although it does produce dose-related adverse GI effects. Diarrhea was reported in 2.3% of patients compared with placebo rate of 1.2%; this was seen more often in women and older patients. Other GI effects included abdominal pain, dyspepsia, and GI reflux. These symptoms were generally mild and rarely led to discontinuation. Although there was an increase in incidence of cough (1.1% for aliskiren compared with 0.6% for placebo), the rate of cough was about half the rate for patients taking ACE inhibitors. Headache and dizziness are also adverse reactions. Rare, serious adverse effects are head and neck angioedema, which may occur at any time during treatment. An excessive drop in blood pressure was seen rarely.
Dosing and Administration
with microalbuminuria may require both an ACE inhibitor or ARB and aliskiren. It is likely to be a significant addition to the treatment of hypertension. As is typical for new medications, it will be important to look at the postmarketing surveys for additional information. References 1. FDA News. FDA approves new drug treatment for high blood pressure. March 6, 2007. Available at: www.fda.gov. Accessed March 28, 2007. 2. Tekturna prescribing information. Available at: www.tekturna.com. Accessed March 28, 2007. 3. van Tassell BW. Aliskiren for renin inhibition: a new class of antihypertensives. Ann Pharmacother. 2007;41(3):456-464. 4. Staessen JA. Oral renin inhibitors. Lancet. 2006;368(9545):1449-1456. 5. Oh BH. Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and sustained 24 hour blood pressure control in patients with hypertension. J Am Coll Cardiol, 2007;49(11):1157-1163. 6. Vaidyanathan S. Lack of pharmacokinetic interactions of aliskiren, a novel direct renin inhibitor for the treatment of hypertension, with the antihypertensive amlodipine, valsartan, hydrochlorothiazide (HCTZ), and ramipril in healthy volunteers. Int J Clin Pract. 2006; 60(11):1343-1356.
Maren Mayhew, MS, ANP, GNP, is the author and editor of Pharmacology for Primary Care Providers, a textbook for NPs published by Mosby. She can be reached at marenmayhew@ comcast.net. This is a monthly column on medication news and controversies. Suggestions for topics are welcome.
1555-4155/07/$ see front matter © 2007 American College of Nurse Practitioners doi:10.1016/j.nurpra.2007.04.019
The medication is given once a day in 150 or 300 mg tablets. The usual starting dose is 150 mg. Patients should be cautioned not to take the medicine along with high-fat meals. Pricing information is not currently available, but the drug is expected to be expensive. No change in dosing is needed with renal or hepatic insufficiency. It has not been tested in patients with renal failure and does not affect the QT interval. It works equally well regardless of age or sex. It has not been studied in patients younger than 18 years. It is contraindicated in pregnancy because drugs that act directly on the reninangiotensin system can cause fetal and neonatal morbidity and death. It is not known if it is excreted in human milk.
Conclusion Aliskiren is most likely to be used in patients with suboptimal response to ACE inhibitors and ARBs or who cannot tolerate those medications because of cough or angioedema. It will be especially useful for the diabetic patient. A patient with diabetes www.npjournal.org
The Journal for Nurse Practitioners - JNP
411
NEW DRUG AVAILABLE FOR TREATING HYPERTENSION On March 6, 2007, the Food and Drug Administration announced approval of the first of a new class of antihypertensive medications, aliskiren (Tekturna).1 The first new antihypertensive in 10 years, the drug is indicated for the treatment of hypertension as monotherapy and in combination with other medications. Use with maximal doses of angiotensin-converting enzyme (ACE) inhibitors has not been adequately studied.2
Mechanism of Action Aliskiren belongs to the new class of medications, renin inhibitors, that block the action of renin at the beginning of the renin-angiotensin-aldosterone system (RAAS), causing complete suppression of angiotensin II. Renin is secreted by the kidneys in
PRESCRIPTION PAD Maren Mayhew
response to decreases in blood volume and renal perfusion. It attaches to angiotensinogen to form angiotensin I (inactive). Angiotensin I is converted to angiotensin II (active) by the ACE and non-ACE pathways. An antirenin agent blocks this process at the beginning, instead of the middle, as is seen with use of ACE inhibitors. Inhibiting blockage early in the process prevents the conversion of angiotensin I to angiotensin II by non-ACE pathways, completely blocking production of angiotensin II. Angiotensin II produces vasoconstriction, releases catecholamines, and promotes aldosterone secretion and sodium reabsorption, 410
The Journal for Nurse Practitioners - JNP
thus increasing blood pressure. Angiotensin inhibits renin release, providing a negative feedback loop called the RAAS. Aliskiren blocks the effect of the increased renin levels, keeping the plasma renin activity (PRA) the same. PRA is a measurement of the elevated renin concentrations and increased capacity to generate angiotensin I. This action is unlike ACE inhibitors and angiotensin receptor blockers (ARBs), which elevate PRA.2 This is seen as a theoretical advantage of aliskiren over ACE inhibitors and ARBs.3
Pharmacokinetics Low bioavailability has been a problem in the development of renin inhibitors.4 Aliskiren is poorly absorbed from the gastrointestinal (GI) tract—only approximately 2.5%. Administration with a high-fat meal decreases the concentration of the drug. The effect is the drug is smooth over a 24-hour interval, with no decrease of efficacy before 24 hours. The blood pressure–lowering effect of aliskiren persists up to 2 weeks after treatment withdrawal, with no rebound effect.5 The half-life is 24 hours; steady state blood levels are reached in about 7 to 8 days. The drug is not extensively protein bound. Aliskiren is minimally metabolized. A small amount is metabolized by the CYP 3A4 system, but it does not inhibit or induce CYP 3A4. This is not considered clinically significant. One fourth is excreted unchanged renally. Most is excreted by the hepatobiliary route.2 Because of the lack of significant protein binding, lack of effect on the P450 enzyme system, and minimal metabolism, the potential for drug interactions is low. It has no interaction with lovastatin, digoxin, metformin, celecoxib, atenolol, atorvastatin, ramipril, or warfarin. However, it decreases the concentration of furosemide. June 2007
Lack of interaction has been shown with the following antihypertensives: amlodipine, valsartan, and hydrochlorothiazide.6
Adverse Effects Aliskiren has a side effect profile similar to placebo when given in doses less than 600 mg/day, although it does produce dose-related adverse GI effects. Diarrhea was reported in 2.3% of patients compared with placebo rate of 1.2%; this was seen more often in women and older patients. Other GI effects included abdominal pain, dyspepsia, and GI reflux. These symptoms were generally mild and rarely led to discontinuation. Although there was an increase in incidence of cough (1.1% for aliskiren compared with 0.6% for placebo), the rate of cough was about half the rate for patients taking ACE inhibitors. Headache and dizziness are also adverse reactions. Rare, serious adverse effects are head and neck angioedema, which may occur at any time during treatment. An excessive drop in blood pressure was seen rarely.
Dosing and Administration
with microalbuminuria may require both an ACE inhibitor or ARB and aliskiren. It is likely to be a significant addition to the treatment of hypertension. As is typical for new medications, it will be important to look at the postmarketing surveys for additional information. References 1. FDA News. FDA approves new drug treatment for high blood pressure. March 6, 2007. Available at: www.fda.gov. Accessed March 28, 2007. 2. Tekturna prescribing information. Available at: www.tekturna.com. Accessed March 28, 2007. 3. van Tassell BW. Aliskiren for renin inhibition: a new class of antihypertensives. Ann Pharmacother. 2007;41(3):456-464. 4. Staessen JA. Oral renin inhibitors. Lancet. 2006;368(9545):1449-1456. 5. Oh BH. Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and sustained 24 hour blood pressure control in patients with hypertension. J Am Coll Cardiol, 2007;49(11):1157-1163. 6. Vaidyanathan S. Lack of pharmacokinetic interactions of aliskiren, a novel direct renin inhibitor for the treatment of hypertension, with the antihypertensive amlodipine, valsartan, hydrochlorothiazide (HCTZ), and ramipril in healthy volunteers. Int J Clin Pract. 2006; 60(11):1343-1356.
Maren Mayhew, MS, ANP, GNP, is the author and editor of Pharmacology for Primary Care Providers, a textbook for NPs published by Mosby. She can be reached at marenmayhew@ comcast.net. This is a monthly column on medication news and controversies. Suggestions for topics are welcome.
1555-4155/07/$ see front matter © 2007 American College of Nurse Practitioners doi:10.1016/j.nurpra.2007.04.019
The medication is given once a day in 150 or 300 mg tablets. The usual starting dose is 150 mg. Patients should be cautioned not to take the medicine along with high-fat meals. Pricing information is not currently available, but the drug is expected to be expensive. No change in dosing is needed with renal or hepatic insufficiency. It has not been tested in patients with renal failure and does not affect the QT interval. It works equally well regardless of age or sex. It has not been studied in patients younger than 18 years. It is contraindicated in pregnancy because drugs that act directly on the reninangiotensin system can cause fetal and neonatal morbidity and death. It is not known if it is excreted in human milk.
Conclusion Aliskiren is most likely to be used in patients with suboptimal response to ACE inhibitors and ARBs or who cannot tolerate those medications because of cough or angioedema. It will be especially useful for the diabetic patient. A patient with diabetes www.npjournal.org
The Journal for Nurse Practitioners - JNP
411