Azilsartan Medoxomil: Indications, Uses, Warnings, and Pharmacology

Overview:

Azilsartan has proven to be a secure and efficient treatment choice for all stages of hypertension, whether used independently or in combination tablets alongside Chlorthalidone or Amlodipine. Notably, AZI has demonstrated its benefits in patients with various degrees of renal impairment. Moreover, the safety profiles of AZI were found to be comparable to those of the placebo. Azilsartan medoxomil is a recent addition to the class of angiotensin receptor blockers (ARBs) used as antihypertensive agents. It obtained FDA (Food and Drug Administration) approval in February 2011.

Hypertension poses a significant risk for various conditions like ischemic heart disease, stroke, heart failure, and renal dysfunction. Therefore, managing hypertension goes beyond simply controlling blood pressure; it also aims to reduce overall cardiovascular and renal morbidity and mortality. Due to the need for improved medical outcomes, new antihypertensive agents have been developed. Angiotensin receptor blockers (ARBs), either alone or in combination, have shown promising results in reducing cardiovascular morbidity and mortality. These ARBs are considered highly effective therapeutic options for treating hypertension, even in patients with compelling indications such as heart failure, diabetes, and previous myocardial infarction. Additionally, fixed-dose combination therapies have been shown to enhance patient adherence and overall clinical effectiveness.

How Does Azilsartan Medoxomil Work?

Azilsartan medoxomil operates through a distinctive mechanism to tackle hypertension. It exerts its effects by selectively blocking the receptors for angiotensin II, a hormone known for its vasoconstrictive properties and role in sodium and water retention. By inhibiting angiotensin II's action, this medication promotes vasodilation, easing the pressure on blood vessels and effectively lowering blood pressure levels. This unique approach sets Azilsartan medoxomil apart as an effective and innovative antihypertensive agent in the management of hypertension.

Uses:

Azilsartan medoxomil is specifically intended for treating hypertension in adults aged 18 years and above. It has received approval for both solo use and combination with other antihypertensive medications.

Dosage and Strength Forms:

The dosing forms and strengths available for Azilsartan medoxomil are tablets, which come in two options: 40 milligrams (mg) and 80 mg.

Hypertension: This medication is recommended for the treatment of hypertension, and it can be used either alone or in combination with other antihypertensive drugs. The usual dose for hypertension management is 80 mg orally once daily. However, if the patient is also taking high-dose diuretics, the dose is typically reduced to 40 mg orally once daily.

Warning:

If pregnancy is detected, it is crucial to discontinue the use of this medication as soon as possible. Azilsartan medoxomil affects the renin-angiotensin system, which can lead to a condition called oligohydramnios. This condition involves a reduced amount of amniotic fluid surrounding the fetus and can result in fetal injury or death. Therefore, it is essential to stop taking the medication immediately if pregnancy is confirmed to safeguard the health and well-being of the unborn child.

For Patients:

Learn About Hypertension

Hypertension is prevalent among approximately one in three adults in the United States (U.S.) The impact of hypertension extends beyond human lives, as it incurs substantial costs to the healthcare system, with direct and indirect expenses amounting to over 93.5 billion dollars per year. Cardiovascular disease and stroke alone constitute 17 percent of the total annual health expenditures in the U.S.

To manage hypertension effectively, various classes of medications are employed, including diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), beta-adrenergic blockers, alpha-adrenergic blockers, calcium-channel blockers (CCBs), central alpha-adrenergic receptor agonists, and direct renin inhibitors (DRIs). Until recently, there were seven agents in the ARB class: Candesartan, Eprosartan, Irbesartan, Losartan, Olmesartan, Telmisartan, and Valsartan. Several of these ARBs are available in combination with other antihypertensive medications, such as Aliskiren, Amlodipine, and Hydrochlorothiazide. Apart from hypertension, four ARBs have been approved for other indications. Candesartan and Valsartan can be used in the treatment of heart failure, while Irbesartan and Losartan are indicated for managing nephropathy in patients with type-2 diabetes and hypertension.

Learn More About Azilsartan Medoxomil

Before Starting Azilsartan Medoxomil:

1. Inform the doctor and pharmacist about allergies to Azilsartan, other medications, or any ingredients in Azilsartan tablets. If there is diabetes (high blood sugar) and Aliskiren (found in medications like Tekturna, Amturnide, Tekamlo, and Tekturna HCT) is being taken, the doctor should be notified. It is likely advised against taking Azilsartan if diabetes is present, and Aliskiren is also used.
2. Inform the doctor and pharmacist about all other vitamins, prescription and nonprescription medications, nutritional supplements, and herbal products currently taken or planned for use. Mention the use of angiotensin-converting enzyme (ACE) inhibitors, Aspirin, nonsteroidal anti-inflammatory medications (NSAIDs) like Ibuprofen and Naproxen, selective COX-2 inhibitors like Celecoxib, diuretics ('water pills'), lithium, and potassium supplements. The doctor may need to adjust medication dosages or closely monitor for potential side effects.
3. Additionally, disclose any history of heart failure, kidney disease, or liver disease. If breastfeeding, the doctor should be informed as well.
4. Azilsartan may cause lightheadedness, dizziness, or fainting, especially when getting up quickly from a lying position. To minimize this issue, take time to get out of bed and rest the feet on the floor for a few minutes before standing up.
5. Furthermore, exercise caution regarding factors that may cause a drop in blood pressure, such as diarrhea, vomiting, inadequate fluid intake, or excessive sweating. These situations can lead to lightheadedness and fainting. If any of these problems occur or develop during treatment, promptly inform the doctor.

How Effective Is Azilsartan Medoxomil?

Azilsartan medoxomil has been found to be an effective antihypertensive medication for the treatment of hypertension. Clinical trials and studies have demonstrated its ability to decrease blood pressure in patients with hypertension, both as a monotherapy (used alone) and in combination with other antihypertensive drugs. The effectiveness of Azilsartan medoxomil has been compared to other antihypertensive agents in clinical trials, and it has shown similar or even superior efficacy in reducing blood pressure levels. The exact effectiveness of the medication can vary depending on individual patient factors and their response to the treatment.

As with any medication, the effectiveness of Azilsartan medoxomil may also depend on factors such as adherence to the prescribed dosage, lifestyle modifications, and the presence of other medical conditions or medications that could interact with it. It is essential for patients with hypertension to maintain blood pressure regularly and make any necessary adjustments to their treatment plan for optimal effectiveness.

Starting Azilsartan Medoxomil

How to Take Azilsartan Medoxomil?

1. Azilsartan is administered orally in tablet form.

2. It is usually taken once a day, with or without food.

3. To ensure consistency, take it at approximately the same time daily.

4. Seek clarification from the doctor or pharmacist if needed.

5. Take Azilsartan precisely as directed; avoid taking more or less or taking it more frequently than prescribed.

6. Although Azilsartan effectively manages high blood pressure, it does not cure it.

7. It might take up to two weeks to observe the full benefits.

8. Continue taking the medication even if feeling well, and do not discontinue without consulting the doctor.

9. Request a copy of the patient information from the pharmacist or doctor, which is provided by the manufacturer.

Things to Do After Starting Azilsartan Medoxomil:

1. Store this medication in its original container, tightly closed and out of reach of children. Keep at room temperature, away from light, excess heat, and moisture (avoid storing in the bathroom).
2. Ensure that all medications are kept out of sight and reach of children, as many containers may not be child-resistant, and young children can open them easily. To prevent poisoning incidents, always lock safety caps and store medications in a safe location that is up and away and out of sight and reach.
3. If there are unneeded medications, dispose of them properly to prevent accidental consumption by pets, children, or others. Avoid flushing this medication down the toilet. Instead, opt for a medicine take-back program.
4. Keep all scheduled appointments with the doctor and laboratory.
5. Do not allow others to take the medication.
6. Azilsartan tablets may have a noticeable odor. If there are any concerns about the medication, inquire with a pharmacist.
7. A list of all the medications should be kept, including vitamins, over-the-counter medicines, minerals, and dietary supplements being taken. Bring this list to each doctor's visit or hospital admission. It is vital information to have on hand in case of emergencies.

Look Out for the Side Effects:

In general, most patients tolerate Azilsartan well in terms of adverse effects. In a clinical trial with 784 patients comparing Azilsartan medoxomil to the ACE inhibitor Ramipril, Azilsartan demonstrated a much lower frequency of overall adverse events. The trial involved starting patients on a daily dose of 20 mg of Azilsartan and 2.5 mg of Ramipril for two weeks, followed by titration up to dosages of 40 or 80 mg of Azilsartan and 10 mg of Ramipril for 22 weeks.

During the treatment period, dizziness and hypotension occurred more frequently in the Azilsartan groups, while cough, a common side effect of ACE inhibitors, occurred more often in the Ramipril group (8.2 percent of participants). Cough was reported in only one percent and 1.4 percent of the Azilsartan 40 and 80 mg groups, respectively. Additionally, the Azilsartan group showed an increase in serum potassium, sodium, and uric acid levels, but no deaths resulted from these effects or other adverse events. Adverse events leading to the discontinuation of Azilsartan in the 40 and 80 mg treatment groups were less frequent (2.4 percent and 3.1 percent, respectively) than with Ramipril (4.8 percent). The study did not record any events of hyperkalemia or angioedema.

Hypotension or orthostatic hypotension remained the most common adverse effect leading to Azilsartan discontinuation in placebo-controlled trials. Other observed adverse effects, though rare, included diarrhea (less than or equal to 2 percent in the 80 mg treatment groups), nausea, asthenia, and fatigue. Less frequent side effects included muscle spasms, dizziness, and cough. In less than or equal to 0.4 percent of patients, low hemoglobin, hematocrit, and a decreased number of red blood cells were also noted in patients taking Azilsartan.

For Doctors:

Indication:

Azilsartan, marketed as Azilsartan medoxomil, belongs to the class of angiotensin-receptor blocking (ARB) agents. It received FDA approval in 2011 as an antihypertensive agent. This medication is available both as a standalone therapy and in combination with Chlorthalidone. It is recommended for antihypertensive treatment, either alone or in combination with other blood pressure-lowering agents, for patients aged 18 years or older.

Research studies, both preclinical and clinical, have shown that Azilsartan reduces blood pressure levels more significantly than its predecessors, Valsartan, and Olmesartan. It is believed that Azilsartan may contribute to lowering mortality rates and the occurrence of cardiovascular disease. This potential benefit may be particularly relevant in patients who have had a myocardial infarction and have heart failure, opening up potential off-label uses for these patients.

In patients with diabetes mellitus and hypertension, ARBs have proven effective in reducing blood pressure when used alongside other first-line agents. ACE inhibitors and ARBs have been found to be most effective in reducing the progression of moderate-to-severe albuminuria and may be utilized off-label in this regard. Additionally, using ARBs for hypertension treatment has shown promising results in preventing the recurrence of atrial fibrillation, as these two conditions are frequently coexistent.

Pharmacology:

• Mechanism of Action: Angiotensin II, a peptide hormone, plays a significant role in the renin-angiotensin system (RAS) as the principal pressor agent. This hormone acts as a potent vasoconstrictor, directly constricting blood vessels. It also stimulates the synthesis and release of aldosterone and promotes the reabsorption of sodium in the renal tubules, leading to water retention.

Azilsartan medoxomil, as an angiotensin II receptor blocker (ARB), functions by selectively inhibiting the binding of angiotensin II to the angiotensin II type-1 receptor (AT1). Through this receptor inhibition, Azilsartan medoxomil exhibits its antihypertensive activity by counteracting the pressor effects of angiotensin II.

• Pharmacodynamics: The dosage dependence of the drug observation was made during an infusion of angiotensin II in healthy subjects. A 32-mg dose of Azilsartan medoxomil significantly reduced the maximum pressor effect of angiotensin II by about 90 percent at peak plasma concentration. After 24 hours of administration, the drug still lowered the pressure effect by approximately 60 percent. Concurrently, there was an increase in renin activity while plasma aldosterone levels decreased.

• Metabolism: Azilsartan undergoes metabolism to produce two main metabolites, M-I and M-II, through processes of decarboxylation and O-dealkylation, respectively. However, these metabolites exhibit low affinity for the AT1 receptor, and as a result, they do not affect the pharmacological activity of Azilsartan medoxomil.

• Elimination: The estimated renal clearance of this medication is approximately 2.3 milliliters per minute (mL per minute). The steady-state concentrations are achieved within five days, and it has an elimination half-life of 11 hours. Around 55 percent of the product is eliminated in the feces, while 42 percent is excreted in the urine, with 15 percent of the drug being unchanged.

Considerations for Administration:

Dosing Considerations:

The drug can be used as a single entity or in combination with other antihypertensive agents.

Hepatic Impairment:

No dose adjustment is required for patients with mild-to-moderate hepatic impairment. However, in cases of severe impairment, monitoring is recommended (data not available).

Renal Impairment:

No dose adjustment is needed for patients with mild-to-severe renal impairment or end-stage renal disease. Patients with moderate-to-severe renal impairment may have higher serum creatinine values.

What Are the Contraindications of Azilsartan Medoxomil?

• As mentioned earlier, Azilsartan belongs to the same drug class as some older antihypertensives like Losartan and Valsartan. Pregnancy is an absolute contraindication for all ARBs and other drugs affecting the RAAS system, such as ACE inhibitors and direct renin inhibitors.

• Azilsartan is considered a teratogenic antihypertensive drug, and if taken during early pregnancy, the risk of congenital abnormalities significantly increases. As a result, the FDA issued a US-boxed warning regarding the fetal risk associated with Azilsartan's use. These precautions also apply to women planning to become pregnant. Although research in human lactating mothers is lacking, small amounts of Azilsartan have been detected in the milk of lactating rats.

• Randomized controlled trial data suggest that combining ARB therapy with ACE inhibitors or Aliskiren can increase the risk of cardiovascular and renal problems, especially in individuals with diabetes mellitus.

• A patient with a history of angioedema caused by ACE inhibitors may begin treatment with an ARB six weeks after discontinuing the ACE inhibitor. In combination therapy with Chlorthalidone, Azilsartan is contraindicated in cases of anuria, along with pregnancy.

What Are the Drug Interactions of Azilsartan Medoxomil?

• Caution should be exercised when coadministering NSAIDs with angiotensin II receptor antagonists in elderly patients, those with volume depletion (including those on diuretic therapy), or those with compromised renal function. This combination may lead to a decline in renal function, potentially causing acute renal failure, although these effects are usually reversible.

• In most patients receiving a combination of two RAS inhibitors, no additional benefits are observed compared to monotherapy. Hence, it is generally advised to avoid the combined use of RAS inhibitors. In patients receiving such therapy along with other agents that affect the RAS, close monitoring of blood pressure, renal function, and electrolytes is essential.

• Furthermore, Aliskiren should not be coadministered with Azilsartan in patients with diabetes, and its use should be avoided in patients with renal impairment (GFR less than 60 mL/min).

Other Specifications:

Azilsartan Medoxomil During Pregnancy:

When pregnancy is detected, the medication should be promptly discontinued. Its impact on the renin-angiotensin system can lead to oligohydramnios, a condition characterized by reduced amniotic fluid, which may pose a risk of fetal injury and/or death. Hence, immediate discontinuation is crucial upon pregnancy detection.

Breastfeeding and Azilsartan Medoxomil:

The presence of this medication in breast milk is uncertain. In such cases, it is advisable to consider alternative antihypertensive therapies or opt not to breastfeed.

Azilsartan Medoxomilin Geriatric Patients:

Azilsartan medoxomil is an antihypertensive medication used in geriatric patients (aged 65 or older) to treat high blood pressure. Dosage adjustments may be needed, and regular monitoring is essential to ensure effectiveness and safety. Adherence, potential interactions, and comprehensive care are important considerations for optimal outcomes in older patients.