Aliskiren

Aliskiren

File:Aliskiren.svg
Systematic (IUPAC) name
(2S,4S,5S,7S)-5-amino-N-(2-carbamoyl-2,2-dimethylethyl)-4-hydroxy-7-{[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-8-methyl-2-(propan-2-yl)nonanamide
Clinical data
[[Regulation of therapeutic goods |Template:Engvar data]]	EU EMA: Rasilez US FDA: Tekturna
Pregnancy category	C in first trimester D in second and third trimesters
Routes of administration	Oral
Legal status
Legal status	UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	Low (approximately 2.5%)
Metabolism	Hepatic, CYP3A4-mediated
Biological half-life	24 hours
Excretion	Renal
Identifiers
CAS Number	173334-57-1
ATC code	C09XA02 (WHO) C09XA52
PubChem	CID 5493444
ChemSpider	21106253
Chemical data
Formula	C30H53N3O6
Molar mass	551.758 g/mol[[]]
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Aliskiren (INN) (trade names Tekturna, U.S.; Rasilez, U.K. and elsewhere) is the first in a class of drugs called direct renin inhibitor. Its current licensed indication is primary (previously essential) hypertension.

Aliskiren was co-developed by the Swiss pharmaceutical companies Novartis and Speedel. It was approved by the U.S. Food and Drug Administration in 2007 for the treatment of primary hypertension.

Mechanism of action

Renin is the first enzyme in the renin-angiotensin-aldosterone system which plays a role in blood pressure control. Renin cleaves angiotensinogen to angiotensin I, which is in turn converted by (ACE) to angiotensin II. Angiotensin II has both direct and indirect effects on blood pressure. It directly causes arterial smooth muscle to contract, leading to vasoconstriction and increased blood pressure. Angiotensin II also stimulates the production of aldosterone from the adrenal cortex, which causes the tubules of the kidneys to increase reabsorption of sodium, with water following thereby increasing plasma volume and blood pressure. Aliskiren binds to the S3^bp binding pocket of renin, essential for its activity. Binding to this pocket prevents the conversion of angiotensinogen to angiotensin I. Aliskiren is also available as combination therapy with hydrochlorothiazide.

Rationale for design

Many drugs control blood pressure by interfering with angiotensin or aldosterone. However, when these drugs are used chronically, the body increases renin production, which drives blood pressure up again. Therefore, doctors have been looking for a drug to inhibit renin directly. Aliskiren is the first drug to do so.

Aliskiren may have renoprotective effects that are independent of its blood pressure−lowering effect in patients with hypertension, type 2 diabetes, and nephropathy who are receiving the recommended renoprotective treatment. According to the AVOID study, researchers found that treatment with 300 mg of aliskiren daily, as compared with placebo, reduced the mean urinary albumin-to-creatinine ratio by 20% (95% confidence interval, 9 to 30; P<0.001), with a reduction of 50% or more in 24.7% of the patients who received aliskiren as compared with 12.5% of those who received placebo (P<0.001). Furthermore, the AVOID trial shows that treatment with 300 mg of aliskiren daily reduces albuminuria in patients with hypertension, type 2 diabetes, and proteinuria who are receiving the recommended maximal renoprotective treatment with losartan and optimal antihypertensive therapy. Therefore, direct renin inhibition will have a critical role in strategic renoprotective pharmacotherapy, in conjunction with dual blockade of the renin−angiotensin−aldosterone system with the use of ACE inhibitors and angiotensin II–receptor blockers, very high doses of angiotensin II−receptor blockers, and aldosterone blockade.

Adverse effects

• Angioedema
• Hyperkalemia (particularly when used with ACE inhibitors in diabetic patients)
• Hypotension (particularly in volume-depleted patients)
• Diarrhea and other GI symptoms
• Rash, elevated uric acid, gout, and renal stones.
• Rarely: allergic swelling of the face, lips or tongue and difficulty breathing

Contraindications

• Pregnancy: other drugs such as ACE inhibitors, also acting on the renin-angiotensin system have been associated with fetal malformations and neonatal death

• Breast feeding: during animal studies, the drug has been found present in milk.

Aliskiren has not yet been evaluated in patients with significantly impaired renal function.

Drug Interactions

Aliskiren is a minor substrate of CYP3A4 and, more important, P-glycoprotein:

• Reduces furosemide blood concentration.
• Atorvastatin may increase blood concentration, however no dose adjustment needed.
• Possible interaction with cyclosporin ( the concomitant use of cyclosporin and aliskiren is contraindicated).
• Caution should be exercised when aliskiren is administered with ketoconazole or other moderate P-gp inhibitors (itraconazole, clarithromycin, telithromycin, erythromycin, amiodarone).

See also

• Renin inhibitor

External links

• Presentation on Direct Renin Inhibitors as Antihypertensive Drugs
• Tekturna U.S. prescribing informationPDF (143 KB) at the U.S. Food and Drug Administration website
• Aliskiren at KEGG Ligand Database
• Tekamlo (aliskiren/amlodipine) Approval: August 26, 2010
• MeSH aliskiren
• Speedel

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