Pbm-map drug Monograph: Aliskiren




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Introduction1-6

Aliskiren (Tekturna®, Novartis Pharmaceuticals) is a direct renin inhibitor that received FDA approval in the U.S. on March 5, 2007 for the treatment of hypertension (HTN). Aliskiren may be used as monotherapy or in combination with other antihypertensive medications.1,2


Current national clinical practice guidelines recommend a thiazide-type diuretic as first line therapy in most patients with uncomplicated HTN, as monotherapy or in combination with other antihypertensive agents.3-5 As most patients will require more than one antihypertensive agent to control their blood pressure (BP), the following drug classes may be considered in patients who are inadequately controlled on or who are unable to tolerate a thiazide-type diuretic: an angiotensin-converting enzyme inhibitor (ACEI), a long-acting calcium channel blockers (CCB), or an angiotensin II receptor antagonist (ARB) if ACEI intolerant.3,4 More recently, first or second-line antihypertensive therapy with a beta-adrenergic blocker as monotherapy has been questioned;6 although this class has been shown to be beneficial in certain concomitant conditions (refer to table below) and may also be considered as additional therapy. A number of other antihypertensive agents are available for additional BP control, although data are limited as to their beneficial effect on long term morbidity and mortality. Consideration of an alternate or additional antihypertensive class of medication should be based on positive outcome data in patients with a compelling indication as outlined below.3,4

Preferred Agents in Patients with Comorbidities4


Condition

Preferred agents

Additional/Alternative

Other agents

Diabetes Mellitus (DM)

Thiazide-type diuretic

and/or ACEI



ARB

CCB


Βeta-blocker




Systolic Heart Failure (HF)

ACEI

Beta-blocker



ARB

Hydralazine-Nitrate

Aldosterone antagonist


Diuretic (for volume overload)

LADHP


Chronic Kidney Disease (CKD)

ACEI

ARB


Diuretic (thiazide or loop, based on kidney function)

Beta-blocker

NCCB


LADHP





Post Stroke

Thiazide-type diuretic

and ACEI









Post Myocardial Infarction (MI)

Beta-blocker

ACEI


NCCB

Thiazide-type diuretic



LADHP

From the VHA/DoD Diagnosis and Management of Hypertension in the Primary Care Setting; Annotation M. Drug Treatment. Table 8. at http://www.oqp.med.va.gov/cpg/HTN04/htn_cpg/frameset.htm


ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin II receptor antagonist; CCB=calcium channel blocker; LADHP=long-acting dihydropyridine CCB; NCCB=nondihydropyridine CCB

Pharmacology1,2


Aliskiren is a direct renin inhibitor, thereby reducing plasma renin activity (PRA). The renin-angiotensin-aldosterone system (RAAS) is a key component in the regulation of blood pressure. Renin is secreted by the kidney in response to a reduction in blood volume or kidney perfusion, or to beta-adrenergic sympathetic stimulation. Renin is responsible for the formation of angiotensin I, by cleaving angiotensinogen. Angiotensin I is then converted by angiotensin-converting enzyme (ACE) to angiotensin II, a potent vasoconstrictor. There is also an increase in aldosterone secretion, resulting in sodium reabsorption. The result is an increase in blood pressure. By inhibiting renin, the administration of aliskiren results in a reduction of PRA, angiotensin I and angiotensin II, thereby reducing blood pressure. In addition, aliskiren blocks the response to the compensatory increase in renin levels that occurs by disruption of the negative feedback loop with agents that affect the RAAS.
Other agents that act at the RAAS that are frequently used for the treatment of HTN include the ACEIs that block the formation of angiotensin II by inhibition of ACE, the enzyme that converts angiotensin I to angiotensin II, and that inhibit the breakdown of bradykinin; and the ARBs that block the effects of angiotensin II at the AT1 receptor. Effects mediated by the activation of AT1 receptors are vasoconstriction (coronary, renal, cerebral), sodium retention (aldosterone production), water retention (vasopressin release), activation of sympathetic nervous system, constriction of the efferent arteriole in the kidney, growth (remodeling and restructuring of vessel walls, glomerular cells, and myocardium), inhibition of apoptosis (cell death), and increases in platelet aggregation and thrombosis. Aliskiren and the ARBs do not affect bradykinin, accumulation of which is thought to be a factor in the development of cough and angioedema associated with the ACEIs.
Pharmacokinetics1,2


Peak Plasma Concentration



Metabolism

Elimination

Food Effect

1-3hrs

24 hrs

CYP 3A4

~25% of absorbed dose

found unchanged in urine



High fat meal: AUC ↓ 71%; Cmax ↓ 85%
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