Aliskiren

Aliskiren
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
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
ECHA InfoCard 100.127.451 Edit this at Wikidata
Chemical and physical data
Formula C30H53N3O6
Molar mass 551.758 g/mol
3D model (JSmol)
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Aliskiren (trade 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]

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, on 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 kidney impairment, low blood pressure, and high levels of potassium in the blood.
  • A warning to avoid use of aliskiren with ARBs or ACEIs was also added for patients with moderate to severe kidney 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

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]

Mechanism of action

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.[7] Binding to this pocket prevents the conversion of angiotensinogen to angiotensin I. Aliskiren is also available as combination therapy with hydrochlorothiazide.[8]

Adverse effects

Contraindications

  • Pregnancy: Other drugs such as ACE inhibitors, also acting on the renin–angiotensin system, have been associated with fetal malformations and neonatal death.[9]
  • Breastfeeding: During animal studies, the drug has been found present in milk.[9]
  • Aliskiren has been shown to increase the likelihood of adverse cardiovascular outcomes in patients with diabetes and kidney or heart disease.[10]

Drug interactions

Aliskiren is a minor inhibitor of substrate CYP3A4 and, more importantly, 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 use of ciclosporin and aliskiren at the same time is contraindicated.
  • Caution should be exercised when aliskiren is administered with ketoconazole or other moderate P-glycoprotein inhibitors (itraconazole, clarithromycin, telithromycin, erythromycin, or amiodarone).
  • Recommendations have been made to 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. Such patients should consider alternative antihypertensive treatment as necessary.[11]

Chemistry

The chemical name for aliskiren is (2 S,4S,5S,7S)-5-amino-N-(2-carbamoyl-2-methylpropyl)-4-hydroxy-2-isopropyl-7-[ 4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnonanamide.[12]

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.[13][14]

References

  1. ↑ "First Hypertension Drug to Inhibit Kidney Enzyme Approved". CBC. 2007-03-06. Retrieved 2007-03-14.
  2. 1 2 3 "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; Brenner, Barry M.; McMurray, John J.V.; de Zeeuw, Dick; Haffner, Steven M.; Solomon, Scott D.; Chaturvedi, Nish; Persson, Frederik; Desai, Akshay S.; Nicolaides, Maria; Richard, Alexia; Xiang, Zhihua; Brunel, Patrick; Pfeffer, Marc A.; 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, Richart T (2006). "Oral Renin Inhibitors". Lancet. 368 (9545): 1449–56. doi:10.1016/S0140-6736(06)69442-7. PMID 17055947.
  7. ↑ "Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin". Chemistry. 7: 493–504. doi:10.1016/S1074-5521(00)00134-4.
  8. ↑ Baldwin, CM; Plosker, GL (2009). "Aliskiren/Hydrochlorothiazide Combination". Drugs. 69 (7): 833–841. doi:10.2165/00003495-200969070-00004.
  9. 1 2 Drugs.com: Tekturna
  10. ↑ Cardiorenal end points in a trial of aliskiren for type 2 diabetes, N Engl J MED. 2012;367(23):2204-2213
  11. ↑ European Medicines Agency recommends new contraindications and warnings for aliskiren-containing medicines.
  12. ↑ "Recommended INN List 45" (PDF). WHO Drug Information. 15 (1). 2001.
  13. ↑ 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.
  14. ↑ PharmaXChange: Direct Renin Inhibitors as Antihypertensive Drugs Archived 2010-12-07 at the Wayback Machine.
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