Aliskiren
| File: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 category |
|
| Legal status | |
| Routes of administration |
PO (oral) |
| 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 (with HCT) |
| PubChem | CID: 5493444 |
| IUPHAR/BPS | 4812 |
| DrugBank | DB01258 |
| ChemSpider | 4591452  |
| UNII | 502FWN4Q32 |
| KEGG | D03208 |
| ChEBI | CHEBI:601027 |
| ChEMBL | CHEMBL1639 |
| Chemical data | |
| Formula | C30H53N3O6 |
| Molecular mass | 551.758 g/mol |
|
|
|
|
| (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 halted a clinical trial of the drug after discovering increased incidence of nonfatal stroke, kidney complications, high blood potassium, and low blood pressure in people with diabetes and kidney 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 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]
Contents
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 of 2014 as a drug to avoid.[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
- Angioedema
- High blood potassium level (particularly when used with ACE inhibitors in diabetic patients)
- Low blood pressure (particularly in volume-depleted patients)
- Diarrhea and other GI symptoms
- Headache
- Dizziness
- Cough
- Rash
- Elevated uric acid, gout, and kidney stones
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]
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.[12][13]
See also
References
- ↑ Lua error in package.lua at line 80: module 'strict' not found.[dead link]
- ↑ 2.0 2.1 2.2 Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Healthzone.ca: Blood-pressure drug reviewed amid dangerous side effects
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ Baldwin CM, Plosker GL.[1]. doi:10.2165/00003495-200969070-00004. Drugs 2009; 69(7):833-841.
- ↑ 9.0 9.1 Drugs.com: Tekturna
- ↑ Cardiorenal end points in a trial of aliskiren for type 2 diabetes, N Engl J MED. 2012;367(23):2204-2213
- ↑ European Medicines Agency recommends new contraindications and warnings for aliskiren-containing medicines.
- ↑ Lua error in package.lua at line 80: module 'strict' not found.
- ↑ PharmaXChange: Direct Renin Inhibitors as Antihypertensive Drugs
External links
- Prescribing Information for Tekturna
- aliskiren at the US National Library of Medicine Medical Subject Headings (MeSH)
- Chemical synthesis
