Pharmacy & Therapeutics - February 2008 - (Page 93)

DRUG FORECAST Angiotensinogen Volume Renin Angiotensin I (Ang I) Cardiac output Age Figure 1 Age-based contributions to blood pressure. cardiovascular and cerebrovascular events, and to protect the kidneys.4–7. This pathway begins with angiotensinogen, which renin acts upon to form inactive angiotensin I (Ang I). Ang I is converted by ACE to form angiotensin II (Ang II) (Figure 2). Ang II then acts at its own receptors to constrict blood vessels, to increase production of aldosterone and antidiuretic hormone (ADH), and to increase the thirst reflex of the hypothalamus. Ang II also inhibits renin, providing negative feedback and completing the cycle. We have gained more in-depth knowledge of this pathway in the last 10 years. For instance, we now know of at least three angiotensin receptors:8 • The AT1 receptor is responsible for many of the effects associated with Ang II. • The AT 2 receptor has an organprotective role (i.e., it protects the brain from ischemia) and antagonizes the AT1 receptor. • The AT4 receptor affects renal tubular function and may have a role in memory. In a phenomenon referred to as “ACEescape,” the body is capable of forming Ang II even when ACE is inhibited. This occurs via non-ACE enzymes in the kidney, heart, and vascular tissues. This is where the primar y benefit of directly blocking renin comes in; it appears to inhibit the entire pathway thereafter. Unlike an ACE-inhibitor, a product called aliskiren (Tekturna, Rasilez, Novartis) does not prevent the breakdown of bradykinin. 9,10 Increased levels of ACE AT1 Angiotensin II (Ang II) AT2 bradykinin cause the release of local Ang III, Ang IV AT1, AT4 vasodilators and may be part of the additional protecFigure 2 The renin–angiotensin-aldosterone system pathway. tive benefit of ACEACE = angiotensin-converting enzyme. inhibitors. In addition, ARBs block only the AT1 receptor, leaving AT2 open to meal; that is, the area-under-the-curve cause vasodilation when stimulated by (AUC) concentration is decreased by 71% circulating Ang II.11 The full effect of pre- and the peak concentration (C max) is venting the stimulation of all angiotensin decreased by 85%. The extent of metabreceptors remains to be seen. olism is unknown. Aliskiren is eliminated unchanged in the urine (25%) and in the PHARMACOLOGY feces via biliary excretion. The time to sustained antihyper tensive ef fect is Aliskiren is a highly selective competitive inhibitor of renin (Figure 3). As a approximately two weeks (Table 2). result, the conversion of angiotensinoCLINICAL STUDIES gen to angiotensin I, as well as the later production of angiotensin II, is blocked. The approval of aliskiren by the Food When Ang II levels are inhibited, the and Drug Administration (FDA) was feedback loop is suppressed, resulting based on the ef ficacy shown in six in further reductions in plasma renin con- placebo-controlled, eight-week clinical centrations. trials that included more than 2,000 patients with mild-to-moderate hyperPHARMACOKINETICS tension. Doses of aliskiren 150 mg and Aliskiren has low oral bioavailability 300 mg were more effective in reducing (about 3%), and absorption is further BP than placebo, and the effect was maindecreased when it is taken with a high-fat tained for up to one year. Safety was eval- OH H2 N O O O Figure 3 Chemical structure of aliskiren (Tekturna). H N O O NH2 Vol. 33 No. 2 • February 2008 • P&T® 93

Table of Contents Feed for the Digital Edition of Pharmacy & Therapeutics - February 2008

Pharmacy & Therapeutics - February 2008 Contents Editorial Medication Errors Prescription: Washington The Language of (Forgive Us) Change, As P&T Enters the Digital Age New Drugs/Drug News/New Medical Devices Drug Forecast Use and Outcomes of Antifibrinolytic Therapy in Patients Undergoing Cardiothoracic Surgery at 20 Academic Medical Centers in the United States Evaluation of the Management of Acute Venous Thromboembolism and Its Outcomes: One Institution's Experience American Society of Hematology, 49th Annual Meeting Pharmaceutical Approval Update

Pharmacy & Therapeutics - February 2008

For optimal viewing of this digital publication, please enable JavaScript and then refresh the page. If you would like to try to load the digital publication without using Flash Player detection, please click here.