AZIL 80

Indications

• Hypertension
• Essential hypertension

Dosage

Children: Refer to BNF for Children for appropriate dosing information.

Adults: Initial dose is 40 mg once daily, which may be increased to 80 mg once daily depending on blood pressure response.

Mechanism of action

Azilsartan medoxomil acts as an angiotensin II type 1 (AT1) receptor antagonist. By blocking these receptors, azilsartan prevents the actions of angiotensin II, a hormone that causes blood vessels to constrict, leading to increased blood pressure. In addition to its primary effects on blood pressure, azilsartan has been shown to enhance adipogenesis and influence the expression of genes related to metabolic processes, exhibiting potential pleiotropic effects beyond its antihypertensive properties.

Pharmacodynamics

Azilsartan demonstrates a dose-dependent reduction in blood pressure, with its antihypertensive effects being attributed to its ability to inhibit the vasoconstrictive effects of angiotensin II. The drug also exhibits antiproliferative effects on vascular cells, thereby potentially contributing to improved cardiovascular outcomes in patients with hypertension. These effects are seen at concentrations that do not typically stimulate peroxisome proliferator-activated receptor activity, indicating unique pathways of action.

Pharmacokinetics

Azilsartan is administered orally and undergoes conversion to its active form, azilsartan, in the body. It has a prolonged half-life, allowing for once-daily dosing. The drug is highly bound to plasma proteins, primarily albumin, and is metabolized in the liver via glucuronidation. The majority of the drug is excreted in the feces, with a smaller fraction eliminated through urine. Its pharmacokinetic profile supports its efficacy in maintaining blood pressure control throughout the day.

Contra-indications

• Hypersensitivity to azilsartan or any of its excipients
• Severe hepatic impairment
• Pregnancy

Adverse effects

• Dizziness
• Fatigue
• Nausea
• Diarrhea
• Headache
• Hypotension
• Elevated serum creatinine
• Hyperkalemia

Interactions

• Potassium-sparing diuretics may increase the risk of hyperkalemia
• Non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the antihypertensive effect
• Other antihypertensive agents may have additive effects leading to hypotension

Precautions

• Monitor renal function periodically
• Use with caution in patients with a history of angioedema
• Caution in patients with renal artery stenosis
• Assess the risk of hypotension in volume-depleted patients

Pregnancy

Azilsartan is contraindicated in pregnancy due to potential harm to the fetus. Discontinue as soon as pregnancy is detected.

Breast-feeding

It is not known whether azilsartan is excreted in human milk. Caution is advised when administering to breastfeeding mothers.

Storage

Store below 30°C in a dry place. Protect from light.

Formulations

• Tablets: 40 mg, 80 mg

Mechanism of action

Azilsartan medoxomil is a newly approved angiotensin receptor blocker (ARB) reported to lower 24 hr blood pressure more effectively than maximally recommended doses of older ARBs. Although azilsartan is considered to be an unusually potent angiotensin II type 1 (AT1) receptor antagonist, little is known about the potential pleiotropic effects of this molecule. /The purpose of this study was to investigate/ pleiotropic features of azilsartan in cell-based assay systems independent of its effects on blood pressure. In cultured 3T3-L1 preadipocytes, azilsartan enhanced adipogenesis and exerted greater effects than valsartan on expression of genes encoding peroxisome proliferator-activated receptor-a (PPARa), PPARd, leptin, adipsin, and adiponectin. The effects of azilsartan on adipocyte differentiation and gene expression were observed at concentrations of azilsartan that did not classically stimulate PPAR activity in cell-based transactivation assays. Azilsartan also potently inhibited vascular cell proliferation in the absence of exogenously supplemented angiotensin II. In aortic endothelial cells, azilsartan inhibited cell proliferation at concentrations as low as 1 umol/L, whereas valsartan showed little or no antiproliferative effects at concentrations below 10 umol/L. Antiproliferative effects of azilsartan were also observed in cells lacking AT1 receptors. In addition, azilsartan, but not valsartan, blocked angiotensin II-induced activation of mitogen-activated protein kinase in vascular smooth muscle cells 4-8 hr after washout of drug from the incubation media. These findings suggest that azilsartan can function as a pleiotropic ARB with potentially beneficial effects on cellular mechanisms of cardiometabolic disease through actions that could involve more than just blockade of AT1 receptors and/or reduction in blood pressure. Angiotensin receptor (type 1) blockers (ARBs) can reduce both hypertension and insulin resistance induced by local and systemic activation of the renin-angiotensin-aldosterone system. The effectiveness of azilsartan medoxomil (AZIL-M), a novel imidazole-based ARB, to facilitate metabolic improvements in conditions of angiotensin II (Ang II)-associated insulin resistance is currently unknown. The aim of this study was to determine the impact of chronic AZIL-M treatment on glucose transport activity and key insulin signaling elements in red skeletal muscle of Ang II-treated rats. Male Sprague-Dawley rats were treated for 8 weeks with or without Ang II (200 ng/kg/min) combined with either vehicle or AZIL-M (1 mg/kg/day). Ang II induced significant (p < 0.05) increases in blood pressure, which were completely prevented by AZIL-M. Furthermore, Ang II reduced insulin-mediated glucose transport activity in incubated soleus muscle, and AZIL-M co-treatment increased this parameter. Moreover, AZIL-M treatment of Ang II-infused animals increased the absolute phosphorylation of insulin signaling molecules, including Akt [both Ser473 (81%) and Thr308 (23%)] and AS160 Thr642 (42%), in red gastrocnemius muscle frozen in situ. Absolute AMPKalpha (Thr172) phosphorylation increased (98%) by AZIL-M treatment, and relative Thr389 phosphorylation of p70 S6K1, a negative regulator of insulin signaling, decreased (51%) with AZIL-M treatment. These results indicate that ARB AZIL-M improves the in vitro insulin action on glucose transport in red soleus muscle and the functionality of the Akt/AS160 axis in red gastrocnemius muscle in situ in Ang II-induced insulin-resistant rats, with the latter modification possibly associated with enhanced AMPKalpha and suppressed p70 S6K1 activation.