Azilsartan Medoxomil + Chlorthalidone

Uses

For the treatment of hypertension, to lower blood pressure:

• In patients not adequately controlled with ARB monotherapy
• As initial therapy in patients likely to need multiple drugs to help

Azilsartan Medoxomil + Chlorthalidone is also used to associated treatment for these conditions: Albuminuria, Atrial Fibrillation, High Blood Pressure (Hypertension)Calcium Nephrolithiasis

How Azilsartan Medoxomil + Chlorthalidone works

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.

Chlorthalidone prevents reabsorption of sodium and chloride through inhibition of the Na+/Cl- symporter in the cortical diluting segment of the ascending limb of the loop of Henle. Reduction of sodium reabsorption subsequently reduces extracellular fluid and plasma volume via an osmotic, sodium-driven diuresis. By increasing the delivery of sodium to the distal renal tubule, Chlorthalidone indirectly increases potassium excretion via the sodium-potassium exchange mechanism. The exact mechanism of chlorthalidone's anti-hypertensive effect is under debate, however, it is thought that increased diuresis results in decreased plasma and extracellular fluid volume which therefore requires decreased cardiac output and overall lowers blood pressure. Chlorthalidone has also been shown to decrease platelet aggregation and vascular permeability, as well as promote angiogenesis in vitro, which is thought to be partly the result of reductions in carbonic anhydrase–dependent pathways. These pathways may play a role in chlorthalidone's cardiovascular risk reduction effects.

Dosage

Azilsartan Medoxomil + Chlorthalidone dosage

The recommended starting dose is 40/12.5 mg taken orally once daily. Most of the antihypertensive effect is apparent within 1 to 2 weeks. This combination may be used to provide additional blood pressure lowering for patients not adequately controlled on ARB or diuretic monotherapy treatment. Patients not controlled with azilsartan medoxomil 80 mg may have an additional systolic/diastolic clinic blood pressure reduction of 13/6 mm Hg when switched to this combination 40/12.5 mg.

This combination may be used as initial therapy if a patient is likely to need multiple drugs to achieve blood pressure goals. Patients titrated to the individual components (azilsartan medoxomil and chlorthalidone) may instead receive the corresponding dose of This combination.

Side Effects

The following potential adverse reactions are-

• Fetal toxicity
• Hypotension in Volume- or Salt-Depleted Patients
• Impaired Renal Function
• Hypokalemia Hyperuricemia

Toxicity

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.

Precaution

• In patients with an activated renin-angiotensin-aldosterone system (RAAS), such as volume- and/or salt-depleted patients, this combination can cause excessive hypotension. Correct volume or salt depletion prior to administration of azilsartan and chlorthalidone.
• In patients with renal artery stenosis, This combination may cause renal failure.
• Monitor renal function in patients with renal impairment. Consider discontinuing this combination with progressive renal impairment.
• Heart rhythm problems (e.g., bradycardia, QT prolongation, ventricular tachycardia), liver problems, certain uncorrected mineral imbalances (low potassium/magnesium levels), severe kidney problems.

Interaction

Renal clearance of lithium is reduced by diuretics, such as chlorthalidone increasing the risk of lithium toxicity. NSAIDs increase risk of renal dysfunction and interfere with antihypertensive effect

Volume of Distribution

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.

Chlorthalidone has been shown to rapidly concentrate within erythrocytes and subsequently equilibrate via a slow diffusion back into the serum compartment, resulting in a large volume of distribution.

Elimination Route

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.

Half Life

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

40-50 hours

Clearance

Renal clearance of azilsartan is approximately 2.3 mL/min.

Elimination Route

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.

Approximately 50% of the administered dose is excreted unmetabolized through the kidney, and excretion is characterized by biphasic elimination with a rapid phase followed by a slow secretory phase.

Pregnancy & Breastfeeding use

Pregnancy Category D. Use of drugs that affect the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.

Contraindication

This is contraindicated in patients with anuria.

Special Warning

Pediatric Use: Safety and effectiveness of Chlorthalidone tablets in pediatric patients have not been established.

Geriatric Use: Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Acute Overdose

Symptoms of acute overdosage include nausea, weakness, dizziness, and disturbances of electrolyte balance. The oral LD50 of the drug in the mouse and the rat is more than 25,000 mg/kg body weight. The minimum lethal dose (MLD) in humans has not been established. There is no specific antidote, but gastric lavage is recommended, followed by supportive treatment. Where necessary, this may include intravenous dextrose-saline with potassium, administered with caution.

Storage Condition

Store in a cool & dry place, away from light and children.

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