Aliskiren

Last updated
Aliskiren
Aliskiren.svg
Clinical data
Trade names Tekturna, Rasilez
AHFS/Drugs.com Monograph
MedlinePlus a607039
License data
Pregnancy
category
  • C in first trimester
    D in second and third trimesters
Routes of
administration
By mouth (tablets)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability Low (approximately 2.5%)
Metabolism Hepatic, CYP3A4-mediated
Elimination half-life 24 hours
Excretion Renal
Identifiers
  • (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
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.127.451 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C30H53N3O6
Molar mass 551.769 g·mol−1
3D model (JSmol)
  • O=C(N)C(C)(C)CNC(=O)[C@H](C(C)C)C[C@H](O)[C@@H](N)C[C@@H](C(C)C)Cc1cc(OCCCOC)c(OC)cc1
  • InChI=1S/C30H53N3O6/c1-19(2)22(14-21-10-11-26(38-8)27(15-21)39-13-9-12-37-7)16-24(31)25(34)17-23(20(3)4)28(35)33-18-30(5,6)29(32)36/h10-11,15,19-20,22-25,34H,9,12-14,16-18,31H2,1-8H3,(H2,32,36)(H,33,35)/t22-,23-,24-,25-/m0/s1 X mark.svgN
  • Key:UXOWGYHJODZGMF-QORCZRPOSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Aliskiren (brand names Tekturna and Rasilez) is the first in a class of drugs called direct renin inhibitors. It is used for 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]

Contents

In December 2011, Novartis halted a trial of the drug after discovering increased nonfatal stroke, kidney complications, high blood potassium, and low blood pressure in people with diabetes and kidney problems. [3] [4]

As a result, in 2012:

Aliskiren was co-developed by the Swiss pharmaceutical companies Novartis and Speedel. [7] [8]

Medical uses

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

Adverse effects

Contraindications

Drug interactions

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

Mechanism of action

Aliskiren is an inhibitor of renin. [11] 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. [11] Binding to this pocket prevents the conversion of angiotensinogen to angiotensin I. Aliskiren is also available as combination therapy with hydrochlorothiazide. [12]

Chemistry

The chemical name for aliskiren is (2S,4S,5S,7S)-5-amino-N-(2-carbamoyl-2-methylpropyl)-4-hydroxy-2-isopropyl-7-[ 4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnonanamide. [13]

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, pharmacologists have been looking for a drug to inhibit renin directly. Aliskiren is the first drug to do so. [14] [15]

References

  1. "First Hypertension Drug to Inhibit Kidney Enzyme Approved". CBC. 2007-03-06. Archived from the original on 2007-03-22. Retrieved 2007-03-14.
  2. 1 2 3 "Towards better patient care: drugs to avoid in 2014". Prescrire International. 23 (150): 161–5. June 2014. PMID   25121155.
  3. Healthzone.ca: Blood-pressure drug reviewed amid dangerous side effects
  4. 1 2 Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, et al. (December 2012). "Cardiorenal end points in a trial of aliskiren for type 2 diabetes" (PDF). The New England Journal of Medicine. 367 (23): 2204–13. doi:10.1056/NEJMoa1208799. PMID   23121378.
  5. 1 2 "FDA Drug Safety Communication: New Warning and Contraindication for blood pressure medicines containing aliskiren (Tekturna)". U.S. Food and Drug Administration (FDA). 19 January 2016. Archived from the original on September 23, 2019. Retrieved 12 February 2020.
  6. "Aliskiren Information". U.S. Food and Drug Administration. 8 July 2015. Retrieved 12 February 2020.
  7. Gradman AH, Schmieder RE, Lins RL, Nussberger J, Chiang Y, Bedigian MP (March 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.
  8. Staessen JA, Li Y, Richart T (October 2006). "Oral renin inhibitors". Lancet. 368 (9545): 1449–56. doi:10.1016/S0140-6736(06)69442-7. PMID   17055947. S2CID   20729350.
  9. 1 2 Drugs.com: Tekturna
  10. EMA (2018-09-17). "European Medicines Agency recommends new contraindications and warnings for aliskiren-containing medicines". European Medicines Agency. Retrieved 2023-11-05.
  11. 1 2 Rahuel J, Rasetti V, Maibaum J, Rüeger H, Göschke R, Cohen NC, et al. (July 2000). "Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin". Chemistry & Biology. 7 (7): 493–504. doi: 10.1016/S1074-5521(00)00134-4 . PMID   10903938.
  12. Baldwin CM, Plosker GL (2009). "Aliskiren/hydrochlorothiazide combination: in mild to moderate hypertension". Drugs. 69 (7): 833–41. doi:10.2165/00003495-200969070-00004. PMID   19441870. S2CID   26512682.
  13. "Recommended INN List 45" (PDF). WHO Drug Information. 15 (1). 2001.
  14. Ingelfinger JR (June 2008). "Aliskiren and dual therapy in type 2 diabetes mellitus". The New England Journal of Medicine. 358 (23): 2503–5. doi:10.1056/NEJMe0803375. PMID   18525047.
  15. PharmaXChange: Direct Renin Inhibitors as Antihypertensive Drugs Archived 2010-12-07 at the Wayback Machine