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Aliskiren
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
Identifiers
CAS number 173334-57-1
ATC code C09XA02 C09XA52
PubChem 5493444
ChemSpider 21106253
Chemical data
Formula C 30H53N3O6  
Mol. mass 551.758 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability Low (approximately 2.5%)
Metabolism Hepatic, CYP3A4-mediated
Half life 24 hours
Excretion Renal
Therapeutic considerations
Licence data

EU EMEA:linkUS FDA:link

Pregnancy cat. C in first trimester
D in second and third trimesters
Legal status POM (UK) -only (US)
Routes Oral
 Yes check.svgY(what is this?)  (verify)

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.[1][2] It was approved by the U.S. Food and Drug Administration in 2007 for the treatment of primary hypertension.[3]

Contents

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 has both direct and indirect effects on blood pressure. It directly causes arterial smooth muscle to contract, leading to vasoconstriction and with it an increase in blood pressure. Angiotensin also stimulates the production of aldosterone, which causes the tubules of the kidneys to increase re-uptake of sodium and water, increasing plasma volume and blood pressure. Aliskiren binds to the S3bp binding pocket of renin, essential for its activity [4]. Binding to this pocket prevents the conversion of angiotensinogen to angiotensin I.

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.[5]

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.[6]

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[7]
  • Breast feeding: during animal studies, the drug has been found present in milk [8].

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 ciclosporin ( the concomitant use of ciclosporin 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).

References

  1. ^ Gradman A, Schmieder R, Lins R, Nussberger J, Chiang Y, Bedigian M (2005). "Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients". Circulation 111 (8): 1012–8. doi:10.1161/01.CIR.0000156466.02908.ED. PMID 15723979.  
  2. ^ Straessen JA, Li Y, and Richart T (2006). "Oral Renin Inhibitors". Lancet 368 (9545): 1449–56. doi:10.1016/S0140-6736(06)69442-7. PMID 17055947. http://linkinghub.elsevier.com/retrieve/pii/S0140673606694427.  
  3. ^ "First Hypertension Drug to Inhibit Kidney Enzyme Approved". CBC. 2007-03-06. http://www.cbc.ca/cp/HealthScout/070306/6030611AU.html. Retrieved 2007-03-14.  
  4. ^ http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6VRP-40S0BHP-9&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_version=1&_urlVersion=0&_userid=10&md5=cd88f72d4f6d5568c07664397a92b584
  5. ^ Ingelfinger JR (June 2008). "Aliskiren and dual therapy in type 2 diabetes mellitus". N. Engl. J. Med. 358 (23): 2503–5. doi:10.1056/NEJMe0803375. PMID 18525047. http://content.nejm.org/cgi/pmidlookup?view=short&pmid=18525047&promo=ONFLNS19.  
  6. ^ Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK. "Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy," N Engl J Med 2008;358:2433-46.
  7. ^ http://www.medicinescomplete.com/mc/bnf/56/200228.htm
  8. ^ http://www.medicinescomplete.com/mc/bnf/56/200205.htm

External links

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