Aliskiren

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Aliskiren
Aliskiren Structural Formulae V.1.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
AHFS/Drugs.com monograph
MedlinePlus a607039
Licence data EMA:Link, US FDA:link
Pregnancy cat.
  • C in first trimester
    D in second and third trimesters
Legal status
Routes PO (oral)
Pharmacokinetic data
Bioavailability Low (approximately 2.5%)
Metabolism Hepatic, CYP3A4-mediated
Half-life 24 hours
Excretion Renal
Identifiers
CAS number 173334-57-1 YesY
ATC code C09XA02
C09XA52 (with HCT)
PubChem CID 5493444
DrugBank DB01258
ChemSpider 4591452 N
UNII 502FWN4Q32 YesY
KEGG D03208 YesY
ChEBI CHEBI:601027 N
ChEMBL CHEMBL1639 N
Chemical data
Formula C30H53N3O6 
Mol. mass 551.758 g/mol
 N (what is this?)  (verify)

Aliskiren (INN) (trade names Tekturna, US; Rasilez, UK and elsewhere) is the first in a class of drugs called direct renin inhibitors. Its current licensed indication is essential (primary) hypertension.[1] While used for high blood pressure other better studied medications are typically recommended due to concerns of higher side effects and less evidence of benefit.[2]

In December 2011, Novartis had to halt a clinical trial of the drug after discovering increased incidence of nonfatal stroke, renal complications, hyperkalemia, and hypotension in people with diabetes and renal impairment.[3] [4]

As a result, in April 20, 2012:

  • A new contraindication was added to the product label concerning the use of aliskiren with angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs) in patients with diabetes because of the risk of renal impairment, hypotension, and hyperkalemia.
  • A warning to avoid use of aliskiren with ARBs or ACEIs was also added for patients with moderate to severe renal impairment (i.e., where glomerular filtration rate is less than 60 ml/min).

Aliskiren was co-developed by the Swiss pharmaceutical companies Novartis and Speedel.[5][6]

Medical uses[edit]

While used for high blood pressure other better studied medications are typically recommended.[2] Prescrire has stating that aliskiren is potentially more harmful than beneficial and thus list it as of 2014 as a drugs to avoid.[2]

Adverse effects[edit]

  • Angioedema
  • Hyperkalemia (particularly when used with ACE inhibitors in diabetic patients)
  • Hypotension (particularly in volume-depleted patients)
  • Diarrhea and other GI symptoms
  • Headache
  • Dizziness
  • Cough
  • Rash
  • Elevated uric acid, gout, and renal stones

Contraindications[edit]

  • 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.[7]
  • Aliskiren has been shown to increase the likelihood of adverse cardiovascular outcomes in patients with diabetes and kidney or heart disease.[8]

Drug interactions[edit]

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

  • It reduces furosemide blood concentration.
  • Atorvastatin may increase blood concentration, but no dose adjustment is needed.
  • Due to 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, or amiodarone).
  • Doctors should stop prescribing aliskiren-containing medicines to patients with diabetes (type 1 or type 2) or with moderate to severe kidney impairment who are also taking an ACE inhibitor or ARB, and should consider alternative antihypertensive treatment as necessary.[9]

Mechanism of action[edit]

Renin, the first enzyme in the renin-angiotensin-aldosterone system, plays a role in blood pressure control. It cleaves angiotensinogen to angiotensin I, which is in turn converted by angiotensin-converting enzyme (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 thus blood pressure. Aliskiren binds to the S3bp binding site of renin, essential for its activity.[10] Binding to this pocket prevents the conversion of angiotensinogen to angiotensin I. Aliskiren is also available as combination therapy with hydrochlorothiazide.[11]

Rationale for design[edit]

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.[12][13]

Aliskiren may have renoprotective effects 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%, 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. Furthermore, the AVOID trial showed 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.[14]

References[edit]

  1. ^ "First Hypertension Drug to Inhibit Kidney Enzyme Approved". CBC. 2007-03-06. Retrieved 2007-03-14. [dead link]
  2. ^ a b c "Towards better patient care: drugs to avoid in 2014". PRESCRIRE INTERNATIONAL 23 (150): 161–165. June 2014. 
  3. ^ Healthzone.ca: Blood-pressure drug reviewed amid dangerous side effects
  4. ^ Parving, Hans-Henrik; Barry M. Brenner, M.D., Ph.D., John J.V. McMurray, M.D., Dick de Zeeuw, M.D., Ph.D., Steven M. Haffner, M.D., Scott D. Solomon, M.D., Nish Chaturvedi, M.D., Frederik Persson, M.D., Akshay S. Desai, M.D., M.P.H., Maria Nicolaides, M.D., Alexia Richard, M.Sc., Zhihua Xiang, Ph.D., Patrick Brunel, M.D., and Marc A. Pfeffer, M.D., Ph.D. for the ALTITUDE Investigators (2012). "Cardiorenal End Points in a Trial of Aliskiren for Type 2 Diabetes". NEJM 367 (23): 2204–13. doi:10.1056/NEJMoa1208799. PMID 23121378. 
  5. ^ 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. 
  6. ^ 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. 
  7. ^ a b Drugs.com: Tekturna
  8. ^ Cardiorenal end points in a trial of aliskiren for type 2 diabetes, N Engl J MED. 2012;367(23):2204-2213
  9. ^ European Medicines Agency recommends new contraindications and warnings for aliskiren-containing medicines.
  10. ^ "Chemistry & Biology : Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin". ScienceDirect. Retrieved 2010-01-20. 
  11. ^ Baldwin CM, Plosker GL.[1]. doi:10.2165/00003495-200969070-00004. Drugs 2009; 69(7):833-841.
  12. ^ 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. 
  13. ^ PharmaXChange: Direct Renin Inhibitors as Antihypertensive Drugs
  14. ^ 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.

External links[edit]