indication

For the treatment of mild to moderate hypertension. It may be used alone or in combination with other antihypertensive agents.

pharmacology

Aliskiren is a nonpeptide renin inhibitor marketed under the trade name Tekturna by Novartis.

mechanism of action

Renin is secreted by the kidney in response to decreases in blood volume and renal perfusion. Renin cleaves angiotensinogen to form the inactive decapeptide angiotensin I (Ang I). Ang I is converted to the active octapeptide angiotensin II (Ang II) by angiotensin-converting enzyme (ACE) and non-ACE pathways. Ang II is a powerful vasoconstrictor and leads to the release of catecholamines from the adrenal medulla and prejunctional nerve endings. It also promotes aldosterone secretion and sodium reabsorption. Together, these effects increase blood pressure. Ang II also inhibits renin release, thus providing a negative feedback to the system. This cycle, from renin through angiotensin to aldosterone and its associated negative feedback loop, is known as the renin-angiotensin-aldosterone system (RAAS). Aliskiren is a direct renin inhibitor, decreasing plasma renin activity (PRA) and inhibiting the conversion of angiotensinogen to Ang I. Whether aliskiren affects other RAAS components, e.g., ACE or non-ACE pathways, is not known. All agents that inhibit the RAAS, including renin inhibitors, suppress the negative feedback loop, leading to a compensatory rise in plasma renin concentration. When this rise occurs during treatment with ACE inhibitors and ARBs, the result is increased levels of PRA. During treatment with aliskiren, however, the effect of increased renin levels is blocked, so that PRA, Ang I and Ang II are all reduced, whether aliskiren is used as monotherapy or in combination with other antihypertensive agents. PRA reductions in clinical trials ranged from approximately 50%-80%, were not dose-related and did not correlate with blood pressure reductions. The clinical implications of the differences in effect on PRA are not known.

toxicity

The most likely manifestation of overdosage would be hypotension.

biotransformation

Approximately 80% of the drug in plasma following oral administration is unchanged. Cytochrome P450 (CYP) 3A4 oxidation produces two major metabolites that account for approximately 5% of the drug in plasma. Aliskiren is eliminated primarily through the biliary/fecal route as unchanged drug and, to a lesser extent, via oxidative metabolism via CYP3A4. Only 0.6% of the oral dose is recovered in urine.

absorption

Rapidly absorbed following oral administration. Absolute bioavailability = 2.6%

half life

24-41 hours

route of elimination

About one fourth of the absorbed dose appears in the urine as parent drug.