Aliskiren
Encyclopedia
Aliskiren (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 essential (primary) hypertension
.
Aliskiren was co-developed by the Swiss pharmaceutical companies Novartis
and Speedel.
It was approved by the U.S. Food and Drug Administration
in 2007 for the treatment of primary hypertension
.
(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 blood pressure. Aliskiren binds to the S3bp binding pocket of renin, essential for its activity. Binding to this pocket prevents the conversion of angiotensinogen to angiotensin I.
Aliskiren is also available as combination therapy with hydrochlorothiazide
.
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.
Aliskiren has not yet been evaluated in patients with significantly impaired renal function.
and, more important, P-glycoprotein:
Renin inhibitor
Renin inhibitor, or inhibitors of renin, are a new group of pharmaceuticals that are used primarily in treatment of hypertension.They act on the juxtaglomerular cells of kidney, which produce renin in response to decreased blood flow....
. Its current licensed indication is essential (primary) hypertension
Essential hypertension
Essential hypertension is the form of hypertension that by definition, has no identifiable cause. It is the most common type of hypertension, affecting 95% of hypertensive patients, it tends to be familial and is likely to be the consequence of an interaction between environmental and genetic...
.
Aliskiren was co-developed by the Swiss pharmaceutical companies Novartis
Novartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
and Speedel.
It was approved by the U.S. Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
in 2007 for the treatment of primary hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
.
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 angiotensin-converting enzymeAngiotensin-converting enzyme
Angiotensin I-converting enzyme , an exopeptidase, is a circulating enzyme that participates in the body's renin-angiotensin system , which mediates extracellular volume , and arterial vasoconstriction...
(ACE) to angiotensin II. Angiotensin II has both direct and indirect effects on blood pressure. It directly causes arterial smooth muscle
Smooth muscle
Smooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...
to contract, leading to vasoconstriction
Vasoconstriction
Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, particularly the large arteries, small arterioles and veins. The process is the opposite of vasodilation, the widening of blood vessels. The process is particularly important in...
and increased blood pressure. Angiotensin II also stimulates the production of aldosterone
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
from the adrenal cortex, which causes the tubules of the kidneys to increase reabsorption of sodium, with water following thereby increasing plasma volume and blood pressure. Aliskiren binds to the S3bp binding pocket of renin, essential for its activity. Binding to this pocket prevents the conversion of angiotensinogen to angiotensin I.
Aliskiren is also available as combination therapy with hydrochlorothiazide
Hydrochlorothiazide
Hydrochlorothiazide, abbreviated HCTZ, HCT, or HZT, is a first-line diuretic drug of the thiazide class that acts by inhibiting the kidneys' ability to retain water. This reduces the volume of the blood, decreasing blood return to the heart and thus cardiac output and, by other mechanisms, is...
.
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.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.
Adverse effects
- AngioedemaAngioedemaAngioedema or Quincke's edema is the rapid swelling of the dermis, subcutaneous tissue, mucosa and submucosal tissues. It is very similar to urticaria, but urticaria, commonly known as hives, occurs in the upper dermis...
- HyperkalemiaHyperkalemiaHyperkalemia refers to the condition in which the concentration of the electrolyte potassium in the blood is elevated...
(particularly when used with ACE inhibitors in diabetic patients) - HypotensionHypotensionIn physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
(particularly in volume-depleted patients) - Diarrhea and other GI symptoms
- Headache
- Dizziness
- Cough
- Rash
- Elevated uric acidUric acidUric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations of uric acid...
, goutGoutGout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...
, and renal stones - Rarely: allergic swelling of the face, lips or tongue and difficulty breathing
Contraindications
- Pregnancy: other drugs such as ACEAngiotensin-converting enzymeAngiotensin I-converting enzyme , an exopeptidase, is a circulating enzyme that participates in the body's renin-angiotensin system , which mediates extracellular volume , and arterial vasoconstriction...
inhibitors, also acting on the renin-angiotensin system have been associated with fetal malformations and neonatal death - Breast feeding: during animal studies, the drug has been found present in milk.
Aliskiren has not yet been evaluated in patients with significantly impaired renal function.
Drug interactions
Aliskiren is a minor substrate of CYP3A4CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
and, more important, P-glycoprotein:
- Reduces furosemideFurosemideFurosemide or frusemide is a loop diuretic used in the treatment of congestive heart failure and edema. It is most commonly marketed by Sanofi-Aventis under the brand name Lasix...
blood concentration. - AtorvastatinAtorvastatinAtorvastatin , sold by Pfizer under the trade name Lipitor, is a member of the drug class known as statins, used for lowering blood cholesterol. It also stabilizes plaque and prevents strokes through anti-inflammatory and other mechanisms...
may increase blood concentration, however no dose adjustment needed. - Possible interaction with ciclosporinCiclosporinCiclosporin , cyclosporine , cyclosporin , or cyclosporin A is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the immune system, and therefore the risk of organ rejection...
( 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).