Azilsartan Medoxomil

Azilsartan medoxomil is a prodrug that is broken down to azilsartan, which belongs in the angiotensin-receptor blocking (ARB) drug class. It is a selective AT1 subtype angiotensin II receptor antagonist. Azilsartan medoxomil is a relatively recently-developed antihypertensive drug. Many guidelines recommend the use of ARBs as first-line therapy when initiating antihypertensive therapy and indicate that the clinical efficacy of ARBs is comparable to angiotensin-converting enzyme (ACE) inhibitors that are also used as first-line treatment for hypertension.

It is used to treat hypertension as monotherapy or in combination with other antihypertensive drugs. It is also available in a combination product with chlorthalidone. As hypertension is a major risk factor for cardiovascular disease, early management of hypertension has several implications on patients' survival rate and quality of life in the future. Lowering blood pressure is associated with a reduced risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. Azilsartan medoxomil is thus speculated to lower mortality rates and the onset of cardiovascular disease. Although there is no clinical significance yet determined, azilsartan medoxomil may have potential off-label uses in patients with a history of myocardial infarction or heart failure.

Azilsartan medoxomil is an angiotensin II receptor blocker used to treat hypertension alone or in combination with other antihypertensive agents, such as chlorthalidone.

Azilsartan medoxomil is indicated for the treatment of hypertension to lower blood pressure in patients over 18 years of age. It may be used either alone or in combination with other antihypertensive agents. Some antihypertensive drugs have lesser effects on blood pressure in black patients.

Azilsartan medoxomil is available as a fixed-dose combination product with chlorthalidone, which is indicated for the treatment of hypertension in patients whose hose blood pressure is not adequately controlled on monotherapy. It may be used as initial therapy if a patient is likely to need multiple drugs to achieve blood pressure goals.

Azilsartan medoxomil belongs to the angiotensin-receptor blocking (ARB) class of drugs, which are used to decrease the progression of moderate-to-severe albuminuria and prevent the recurrence of atrial fibrillation as off-label uses in patients with diabetes mellitus and hypertension.

• Albuminuria
• Atrial Fibrillation
• High Blood Pressure (Hypertension)

Pharmacodynamic effects of azilsartan medoxomil are mediated by its active metabolite, azilsartan. Azilsartan inhibits the pressor effects of an angiotensin II infusion in a dose-related manner. At a single 32 mg dose, azilsartan inhibited the maximal pressor effect by approximately 90% at peak plasma concentrations and by 60% at 24 hours after administration. In healthy subjects receiving single and repeated doses of azilsartan medoxomil, plasma angiotensin I and II concentrations and plasma renin activity increased, while plasma aldosterone concentrations decreased. Like other ARBs, azilsartan causes dose-dependent decrease in peripheral resistance and decreases smooth muscle vascular tone. As azilsartan blocks the angiotensin II receptor, the negative regulatory feedback of angiotensin II on renin secretion is inhibited; however, the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the blood pressure-lowering effect of azilsartan. Blood pressure-lowering effects of antihypertensive agents can be reduced in patients of African descent. However, there are no recommended dosage adjustment of azilsartan on the basis of a patient’s sex, race, or degree of renal or hepatic impairment.

Azilsartan medoxomil has negligible effects on serum potassium or sodium levels. Azilsartan does not affect the biosynthesis of angiotensin II nor bradykinin levels. It also does not bind to any ion channels that are involved in cardiovascular regulation.

The renin-angiotensin-aldosterone system regulates blood pressure. Angiotensin II is a peptide hormone that is a principal pressor agent in the renin-angiotensin-aldosterone system. It is a potent, direct vasoconstrictor that binds to the angiotensin II type 1 receptor (AT1 receptor) to stimulate the synthesis and release of aldosterone and promote cardiac stimulation. Angiotensin II promotes renal tubular reabsorption of sodium, resulting in water retention. It also inhibits further secretion of renin. AT1 receptors are highly expressed in vascular smooth muscle and the adrenal gland.

Azilsartan medoxomil is a prodrug that is hydrolyzed to its active metabolite, azilsartan, in the gastrointestinal tract following oral administration. Azilsartan selectively binds to AT1 receptors as an antagonist, blocking vasoconstrictor and aldosterone-secreting effects of angiotensin II. Azilsartan has more than a 10,000-fold greater affinity for the AT1 receptor than for the AT2 receptor, which is predominantly involved in cardiovascular homeostasis. Azilsartan appears to dissociate from AT1 receptors much more slowly than other ARBs, which explains its longer duration of action when compared to other ARBs.

During absorption, azilsartan medoxomil is hydrolyzed to azilsartan. The parent drug is not detectable in plasma after oral administration. The absolute bioavailability of azilsartan is estimated to be 60%. T_max ranges from 1.5 to three hours. Steady-state levels of azilsartan are achieved within five days, and no accumulation in plasma occurs with repeated once-daily dosing.

The volume of distribution of azilsartan is approximately 16 L. In rats, a minimal amount of radiolabelled drug crossed the blood-brain barrier. Azilsartan crossed the placental barrier in pregnant rats and was distributed to the fetus.

Azilsartan is >99% bound to human plasma proteins, mainly serum albumin. Protein binding is constant at azilsartan plasma concentrations well above the range achieved with recommended doses.

Following oral administration of 14C-labeled azilsartan medoxomil, approximately 55% of radioactivity was recovered in feces and approximately 42% in urine. Of the recovered dose in urine, about 15% was excreted as azilsartan.

The elimination half-life of azilsartan is approximately 11 hours.

Renal clearance of azilsartan is approximately 2.3 mL/min.

No maximum toxic doses have been established yet for azilsartan. There is limited human data available related to azilsartan medoxomil overdosage. In clinical trials, healthy subjects tolerated once-daily doses up to 320 mg of azilsartan medoxomil well. In the event of drug overdose, supportive measures should be initiated as azilsartan is not dialyzable.

Azilsartan is a teratogenic agent with a risk of congenital abnormalities. Azilsartan and other ARB drugs are considered fetotoxic during the second and third trimesters.

• Take with or without food. Food does not affect the bioavailability.