Olmesartan+Amlodipine+Hydrochlorothiazide

Olmesartan+Amlodipine+Hydrochlorothiazide is an antihypertensive agent belonging to the Angiotensin II Receptor Blocker class, Calcium Channel Blocker class and Thiazide Diuretics.

Olmesartan+Amlodipine+Hydrochlorothiazide is approved for treating hypertension (high blood pressure) in adults. This drug combination minimizes the risk of cardiovascular events by pressure by reducing vascular resistance, relaxing blood vessels and promoting diuresis.

Olmesartan undergoes minimal metabolism and is readily absorbed from the gastrointestinal system. The liver efficiently metabolizes and absorbs amlodipine. Rapid absorption and kidney-mediated excretion are the primary mechanisms by which Hydrochlorothiazide is removed. The therapeutic benefits of the combination drug are achieved by reducing blood pressure and increasing diuresis through its activities on several physiological pathways.

The common side effects of Olmesartan+Amlodipine+Hydrochlorothiazide include oedema (swelling), hypotension (low blood pressure), headache, dizziness, tiredness, and taste change.

Olmesartan+Amlodipine+Hydrochlorothiazide is available as a tablet for convenient administration.

Olmesartan+Amlodipine+Hydrochlorothiazide is available in the United States, Canada, the United Kingdom, India and Australia.

Olmesartan+Amlodipine+Hydrochlorothiazide is an antihypertensive agent belonging to the Angiotensin II Receptor Blocker class, Calcium Channel Blocker class and Thiazide Diuretics.

Olmesartan: Olmesartan inhibits the binding of angiotensin II at type 1 angiotensin II receptors, inhibiting its ability to constrict blood vessels and release aldosterone. It also causes natriuresis and kaliuresis.

The time taken for Olmesartan to show its effect must be clinically established.

Olmesartan effect may remain in your body for approximately 24 hours.

The Tmax was found within 1-2 hours following the administration of Olmesartan, and the Cmax was about 220-2100 ng/mL.

Protein Bound: 99%

Clearance: 1.3 L/hr (plasma); 0.6 L/hr (renal)

Vd: 17 L

Half-Life: 13 hr

Amlodipine: Amlodipine primarily affects the smooth muscle of the arteries, lowering peripheral vascular resistance by preventing calcium ion inflow. According to experimental data, Amlodipine interacts with specific membrane binding sites. It mainly exerts its therapeutic effects by dilating peripheral arterioles, which lowers cardiac workload and oxygen consumption, and by promoting coronary artery dilation, which improves oxygen supply. It is beneficial in conditions like variant angina and mitigates coronary vasoconstriction. These two distinct mechanisms prove Amlodipine's effectiveness in treating angina and hypertension.

The Onset of action of Amlodipine is not clinically established.

The Duration of Action for Amlodipine in the body is approximately 24 hours.

The Tmax was found within 6-12 hours following the administration of Amlodipine.

Protein Bound: 93-98%

Clearance: 25 L/hr

Vd: 21L/kg

Half-Life: 30-50 hr

Hydrochlorothiazide: Thiazide diuretic lowers blood pressure and reduces oedema by inhibiting Na reabsorption in distal renal tubules, increasing Na and water excretion.

The Onset of action of Hydrochlorothiazide occurs within 2 hours of its administration.

The Duration of Action for Hydrochlorothiazide in the body is approximately 6-12 hours.

The Tmax was found within 1-5 hours, and Cmax 70 to 490 ng/mL following the administration of Hydrochlorothiazide.

Protein Bound: 68%

Clearance: 335 mL/min

Vd: 3.6-7.8 L/kg

Half-Life: 6-15 hr

Synergistic Benefits: Olmesartan+Amlodipine+Hydrochlorothiazide provides a synergistic approach to managing hypertension. Angiotensin II receptor blocker (ARB) olmesartan relaxes blood arteries. An effective calcium channel blocker that also relaxes blood vessels and lessens the load on the heart is amlodipine. Diuretics like Hydrochlorothiazide help the body flush out extra water and salt. They exert more overall control by lowering blood pressure through various mechanisms. An efficient and comprehensive strategy for managing hypertension is provided by this combination, which reduces the risk of cardiovascular events, including strokes and heart attacks, while also minimizing fluid retention.

When one medication fails to regulate your blood pressure, these medications are combined. Thus, they work synergistically to help lower blood pressure and manage hypertension effectively.

Data Onset of action of Olmesartan+Amlodipine is shown within a few hours, while Hydrochlorothiazide's diuretic effect may take a few hours post-administration

Data duration of action of Olmesartan+Amlodipine effects can last up to 24 hours, and Hydrochlorothiazide's diuretic effect may persist for several hours—following oral administration.

The Data of Tmax and Cmax of Olmesartan+Amlodipine+Hydrochlorothiazide needs to be established.

Olmesartan+Amlodipine+Hydrochlorothiazide is available in tablets.

Tablets: To be swallowed whole with water/liquid.

As the physician recommends, take the medication by mouth once daily, generally with or without a meal.

• Olmesartan is also found to bring about regression of proteinuria in diabetic and nondiabetic, hypertensive patients with kidney diseases and those with renal failure.
• Amlodipine relaxes the blood vessels, making blood flow easily, thus lowering blood pressure. This will lower the risk of heart attack or stroke by making it easier for your heart to pump blood around your body.
• Hydrochlorothiazide may also be used to treat patients with diabetes insipidus and prevent kidney stones in patients with high calcium levels in their blood.
• Olmesartan+Amlodipine+Hydrochlorothiazide combination is used to treat hypertension or high blood pressure. Strokes, heart attacks, and renal issues can all be prevented by lowering excessive blood pressure.
• This combination may also reduce the risk of cardiovascular events such as strokes and heart attacks in patients with hypertension and other risk factors.

Olmesartan+ Amlodipine+ Hydrochlorothiazide is an antihypertensive agent belonging to the Angiotensin II Receptor Blocker class, Calcium Channel Blocker class and Thiazide Diuretics.

Olmesartan: Olmesartan is an antihypertensive medication in the angiotensin II receptor blockers class. It prevents angiotensin II's effects on aldosterone secretion and vasoconstriction by specifically preventing it from binding to the AT1 receptor. Blood arteries relax to manage high blood pressure or hypertension so blood flows more effectively.

Amlodipine: It prevents calcium ions from entering "slow channels" or particular voltage-sensitive regions of the myocardium and vascular smooth muscle during depolarization, resulting in relaxation of the latter and coronary vasodilation; it also increases myocardial oxygen delivery in people with vasospastic angina. Amlodipine directly affects vascular smooth muscle to cause peripheral arterial vasodilation, which lowers blood pressure and peripheral vascular resistance.

Hydrochlorothiazide: People with congestive heart failure, liver cirrhosis, renal problems, or oedema brought on by using steroids or oestrogen and hypertension are treated with Hydrochlorothiazide.

The Olmesartan + Amlodipine+ Hydrochlorothiazide combination benefits hypertension by effectively lowering blood pressure and related conditions through distinct mechanisms of action. Olmesartan blocks the action of angiotensin II, relaxing blood vessels. Amlodipine lowers blood pressure by relaxing blood vessel walls and reducing the heart's workload. Hydrochlorothiazide is a diuretic that reduces fluid retention. Together, they provide comprehensive blood pressure control, reduce the risk of cardiovascular events, and offer convenience with a single-pill regimen, promoting medication adherence and patient well-being.

Olmesartan+Amlodipine+Hydrochlorothiazide is approved for use in the following clinical indications:

• Patients who have already been titrated on the individual components, Hydrochlorothiazide, amlodipine, and olmesartan, are indicated for therapy of hypertension.
• This combination therapy might help to lower the risk of cardiovascular events, including heart attacks and strokes, in patients with hypertension and other cardiovascular risk factors.
• It is indicated to be used in individuals who would benefit from combination therapy or as the first line of treatment for patients likely to require many medications to achieve their blood pressure goals.

Orally: Olmesartan+Amlodipine+Hydrochlorothiazide is available as a tablet that can be taken orally. Olmesartan+Amlodipine+Hydrochlorothiazide should be taken either on an empty stomach or along with food. It is best to take this medication at least 4 hours before your bedtime, and advised to take it regularly at a fixed time each day following the physician's prescribed schedule for regular and evenly spaced intervals because the dose and duration of therapy are individualized per specific conditions to achieve the most effective and successful treatment outcome.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Olmesartan+Amlodipine+Hydrochlorothiazidehas various strengths, such as

20mg+5mg+12.5mg, 40mg+5mg+12.5mg, 40mg+5mg+25mg, 40mg+10mg+12.5mg or 40mg+10mg+25mg.

Dosage Adjustment for Adult Patients

Hypertension

Never as a first line of treatment

One dose every day.

Add-on, switch, or replacement therapy: 5-10 mg amlodipine, 20-40 mg olmesartan, 12.5-25 mg Hydrochlorothiazide daily; dose increases are permitted every two weeks; titrate by boosting one ingredient at a time; not to exceed 40 mg olmesartan/10 mg amlodipine/25 mg hydrochlorothiazide qDay

Over 75 years of age: Do not use; severe hepatic impairment requires 2.5 mg of amlodipine, which is not provided by the combination drug.

Olmesartan+Amlodipine+Hydrochlorothiazide is available in the form of Oral tablets.

Olmesartan+Amlodipine+Hydrochlorothiazide should be used in treating hypertension, along with appropriate dietary restrictions.

Avoid consumption of a high-salt or high-sodium diet while taking Hydrochlorothiazide.

Avoid excessive consumption of alcohol, grapefruit or grapefruit juice while taking amlodipine, as it may interact with the medication.

Hydrochlorothiazide can lead to potassium loss. To prevent low potassium levels, consider including potassium-rich foods in your diet, such as bananas, oranges, potatoes, and spinach. 

While taking this combination, it is advised to stay hydrated, maintain a rich, balanced diet low in saturated fats and cholesterol, and consume plenty of vegetables, whole grains, fruits, and lean proteins.

The dietary restriction should be individualized as per patient requirements.

Olmesartan+Amlodipine+Hydrochlorothiazide may be contraindicated in patients with the following conditions:-

• Hypersensitivity (drug component or sulfonamide-derived substance)
• Anuria
• Pregnancy: Significant risk of fetal/neonatal morbidity and death during the second and third trimesters of pregnancy
• Co-administer aliskiren in patients with diabetes mellitus
• Severe Renal impairment (<30 mL/min)
• History of Angioedema
• Hypotension

The treating physician must closely monitor the patient and keep pharmacovigilance as follows.

• It might result in hypotension, especially if the volume or salt levels are low (fix before starting)
• Syncope or symptomatic hypotension may happen.
• Patients who have significant renal or hepatic impairment should be titrated cautiously.
• Be cautious of possible hypotension with severe aortic stenosis. If that happens, lie the patient down and consider giving them a saline infusion. Treatment may resume once a temporary dip in blood pressure is stabilized. Therefore, it is not always necessary to stop.
• Monitor acute hyperkalemia
• In individuals with significant coronary artery disease, use caution while starting or increasing calcium channel blocker medication since it may worsen angina or myocardial infarction. Yet the mechanism is still unknown.
• The medication's antihypertensive effects may be increased in post-sympathectomy patients.
• Photosensitivity could happen; advise patients to use sunblock and get frequent skin cancer screenings
• Use thiazides with caution if individuals have mild to moderate liver damage or progressing liver disease.
• Maintain fluid and electrolyte imbalance
• Olmesartan has been linked to digestive problems such as enteropathy with sprue-like symptoms. After starting the medication, some individuals may develop severe, ongoing diarrhoea and weight loss for months or years. Villous atrophy may be seen during biopsies. If such symptoms appear, rule out other potential reasons, and if none are identified, consider discontinuing olmesartan.

• Be cautious if you have hypertrophic cardiomyopathy, severe aortic stenosis (amlodipine), liver disease, or renal artery stenosis.
• In contrast to monotherapy, dual blockage of the renin-angiotensin system with ARBs, ACE inhibitors, or aliskiren is linked to an increased risk of hyperkalemia, hypotension, and abnormalities in renal function, including acute renal failure.
• Monitor for deteriorating heart failure, which might cause oliguria or progressive azotemia.
• Systemic lupus erythematosus has been seen to be aggravated or exacerbated by thiazide diuretics.
• Patients with severe obstructive CAD who begin calcium channel blockers run the risk of MI or have worsening angina.
• Acute transitory myopia and acute angle-closure glaucoma have been recorded, especially in people with a history of penicillin or sulfonamide allergies (Hydrochlorothiazide is a sulfonamide allergy). If the individual suddenly experiences changes in eyesight or eye discomfort, get medical help immediately. Stop taking Hydrochlorothiazide at this point and seek medical advice. Uncontrolled intraocular pressure may need immediate medical attention or surgery. An increased risk may exist for those with a history of penicillin or sulfonamide allergies.

It is unsafe to consume alcohol with Olmesartan+Amlodipine+Hydrochlorothiazide.

There is no sufficient scientific evidence traceable regarding the use and safety of Olmesartan+Amlodipine+Hydrochlorothiazide for breastfeeding populations.

Unsafe to use during pregnancy.

The adverse reactions related to Olmesartan+Amlodipine+Hydrochlorothiazide can be categorized as

• Common: Dizziness, headache, swelling of the ankles, feet, or legs (peripheral oedema) and flushing (redness of the skin, typically on the face)
• Less Common: Muscle cramps, altered kidney function and abnormal liver function tests
• Rare: Decreased potassium levels in the blood (hypokalemia), allergic reactions, elevated blood urea nitrogen (BUN), gout, changes in sodium levels and blood glucose levels.

Reports on Post-marketing

Extrapyramidal disorder (associated with amlodipine), acute renal failure, elevated blood creatinine, jaundice, and hepatic enzyme abnormalities (most often associated with cholestasis or hepatitis)

Hydrochlorothiazide: melanoma-free skin cancer

The clinically relevant drug interactions of Olmesartan+Amlodipine+Hydrochlorothiazide are briefly summarized here.

• CYP3A Inhibitors: Amlodipine's systemic exposure increases when it is administered concurrently with CYP3A inhibitors, both mild and potent, and may necessitate dosage reduction. When using Amlodipine with CYP3A inhibitors, monitor for signs of hypotension and oedema to evaluate whether a dosage change is necessary.
• Sildenafil: Monitor closely for hypotension when sildenafil is co-administered with Amlodipine.
• Simvastatin: Co-administration of simvastatin with Amlodipine raises the systemic exposure of simvastatin. Limit the simvastatin dose in patients on Amlodipine to 20 mg daily.
• Lithium: Lithium toxicity and blood lithium concentration increase when angiotensin II receptor antagonists, such as olmesartan, are used concurrently with lithium. When using lithium concurrently, maintain a close watch on the blood levels.
• Agents Increasing Serum Potassium: Olmesartan may cause increases in serum potassium when used concurrently with other renin-angiotensin system blockers, potassium-sparing diuretics (such as spironolactone, triamterene, or amiloride), potassium supplements, potassium-containing salt substitutes, or other medications that may raise potassium levels (such as heparin). It is advised to monitor serum potassium levels if co-medication is essential.
• Antidiabetic drugs (oral agents and insulin) dosage adjustment of the antidiabetic drug may be required.
• Cholestyramine and colestipol resins: Cholestyramine and colestipol resins bind Hydrochlorothiazide and reduce it by up to 85% and 43%, respectively, in the gastrointestinal system.
• Non-steroidal anti-inflammatory drugs: Non-steroidal anti-inflammatory drugs (NSAIDs) can decrease the intended benefits of diuretics like Hydrochlorothiazide when used concurrently. A thorough observation is recommended to determine how effective a diuretic is in this combination. Combining NSAIDs with angiotensin II receptor antagonists, such as olmesartan medoxomil, may cause renal problems in older individuals, those with low fluid volume, or patients with impaired kidney function. These problems, however, may be treatable. When taking olmesartan medoxomil plus NSAIDs, such as selective COX-2 inhibitors, it is advisable to have regular renal function tests since olmesartan medoxomil's antihypertensive impact might be decreased by NSAIDs.

• Headache
• Dizziness
• Nausea
• An upper respiratory infection
• Fatigue
• Infected urinary tract
• Diarrhoea
• A joint swell
• Localized swelling
• Nasopharyngitis (inflammation of the nasal passages and the throat)
• Muscle spasm

Olmesartan+ Amlodipine+ Hydrochlorothiazide should be prudent in the following group of special populations.

• Pregnancy:

Olmesartan: Pregnancy Category D; Use in LIFE-THREATENING situations when no better alternatives are available.

The use of renin-angiotensin system-affecting medications in the later stages of pregnancy might result in decreased foetal renal function, increasing the risk of foetal and neonatal problems, including death. This might lead to disorders like oligohydramnios linked to fetal skeletal and lung abnormalities. Skull underdevelopment, anuria, low blood pressure, renal failure, and even death are all possible newborn complications. It's critical to stop taking Olmesartan as soon as pregnancy is confirmed. Even though these unfavourable effects are predominantly associated with usage in the second and third trimesters, it can be challenging to discriminate between medications that influence the renin-angiotensin system and other antihypertensive medicines in early pregnancy studies. Maternal hypertension during pregnancy must be well managed for the mother and foetus to have the best possible results. Mothers should be warned of potential foetal risks if there is, in rare circumstances, no viable alternative to medications that impact the renin-angiotensin system. To examine the amniotic environment, routine ultrasound examinations are indicated. If oligohydramnios is found, stopping Olmesartan is advised unless judged essential for the mother's health. Furthermore, knowing that oligohydramnios may become visible after irreparable foetal injury is critical. Infants with a history of in-utero Olmesartan exposure should be closely monitored for hypotension, decreased urine production, and high potassium levels.

Amlodipine: Pregnancy Category C; Use with caution if benefits outweigh risks.

There haven't been any controlled studies conducted on pregnant women. Amlodipine should only be used during pregnancy if the benefits exceed the hazards to the developing foetus. Amlodipine maleate was given orally to pregnant rats and rabbits during critical organ development periods at doses up to 10 mg amlodipine/kg/day (8 times and 23 times the maximum recommended human dose of 10 mg on a mg/m2 basis, respectively), and no teratogenicity or other embryo/fetal toxicity was found. The litter size significantly decreased by nearly 50% during mating and gestation in rats receiving 10 mg of amlodipine/kg/day for 14 days before mating. In contrast, intrauterine mortality dramatically increased (about 5-fold). Additionally, the rats' gestation and labour times were prolonged by this dosage.

Amlodipine's postmarketing data lacks info on congenital disabilities or miscarriage risks. Poorly controlled hypertension during pregnancy poses maternal and fetal risks.

Hydrochlorothiazide: Pregnancy Category B; Could be acceptable. Either no danger has been shown by animal research, but human studies have not been conducted, or some risk has been shown by animal studies but not by human studies.

Teratogenic Effects

Thiazides can cross the placenta, and the quantities in the umbilical vein are similar to those in maternal plasma. Like other diuretics, hydrochlorothiazide can result in placental hypoperfusion. With observed amounts up to 19 times higher than in umbilical vein plasma, it accumulates in the amniotic fluid. Pregnancy-related thiazide use has been linked to an increased risk of thrombocytopenia or jaundice in the foetus or newborn. These medications shouldn't be used to treat hypertension in pregnant women since they don't stop or change the progression of EPH (Oedema, Proteinuria, Hypertension) or Gestosis (pre-eclampsia). It is recommended to avoid using Hydrochlorothiazide during pregnancy for any other conditions, such as heart disease.

Due to the high potential risk to the foetus, avoid the Olmesartan + Amlodipine + Hydrochlorothiazide combination when pregnant. If pregnancy is detected, stop immediately and control hypertension according to pregnancy recommendations. High blood pressure during pregnancy raises the chances of complications for both the mother and the baby, including conditions like pre-eclampsia and premature birth. Close monitoring and proper management are essential.

If hypotension or oliguria develops, take precautions to maintain healthy blood pressure and renal perfusion; exchange transfusions or dialysis may be needed to reverse hypotension and sustain renal function.

When using this drug while expecting or planning a pregnancy, use caution and consult a physician.

• Lactating Mothers

Olmesartan: Although its excretion in human milk is unknown, olmesartan is released in small amounts in the milk of nursing rats. Given the possibility of harmful effects on the nursing child, a choice should be taken on whether to discontinue breastfeeding or stop taking the drug, considering the significance of the medication to the mother.

Amlodipine: Amlodipine may pass into breast milk; however, this is unknown. Nursing should be stopped while Amlodipine is provided if this information is lacking.

Hydrochlorothiazide: Breast milk contains thiazide excretion. Considering the significance of the medication to the mother, a choice should be taken on whether to stop nursing or to stop taking Hydrochlorothiazide due to potential significant adverse effects in nursing infants.

It is recommended that nursing mothers avoid breastfeeding while on Olmesartan+ Amlodipine+ Hydrochlorothiazide treatment. This precaution is crucial due to potentially severe adverse effects on the breastfed infant, including hypotension, hyperkalemia, and renal impairment

• Pediatric Use

As per FDA, safety and effectiveness in the pediatric population have not been established.

Neonates with a history of olmesartan exposure in utero should be closely monitored for hypotension, oliguria, and hyperkalemia.

• Geriatric Use

Geriatric people should have their use of Olmesartan+Amlodipine+Hydrochlorothiazide closely monitored. Elderly people may be more vulnerable to adverse drug reactions and drug interactions. It is essential to closely monitor liver and kidney function and any possible medication interactions. Depending on the individual's medical situation and drug regimen, dosage modifications may be required. It's crucial to monitor patients and consult with medical professionals regularly.

Dosage Adjustment in Kidney Impairment Patient

CrCl >30 mL/min: No dosage adjustment is necessary for mild to moderate

CrCl 30 mL/min or less: Avoid usage. With severe renal impairment, loop diuretics are recommended over thiazides because they are less likely to cause azotemia.

CrCl 20 mL/min or less: Approximately quadrupled olmesartan AUC

Dosage Adjustment in Hepatic Impairment Patient

Moderate to mild impairment: Use caution; unknown

Severe hepatic impairment: Do not use; needs Amlodipine starting at 2.5 mg when the combination is not accessible.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Amlodipine + Telmisartan. Overconsumption of Olmesartan+ Amlodipine+ Hydrochlorothiazide could lead to symptoms such as severe hypotension (low blood pressure) and electrolyte imbalances.

There is no specific antidote or treatment for excessive intake of Olmesartan+ Amlodipine+ Hydrochlorothiazide. However, immediate medical attention is essential.

Olmesartan+Amlodipine+Hydrochlorothiazide should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake. Management typically involves supportive measures and symptomatic treatment. Supportive therapy should be given, addressing any symptoms that persist or worsen. Activated charcoal may also be considered if the overdose is detected shortly after ingestion to reduce absorption. Monitoring the patient's vital signs and correcting any electrolyte imbalances, especially hyperkalemia (high potassium levels), is crucial. In severe cases, gastric lavage may be performed if ingestion occurs within the previous hour. Physical treatment might be added if necessary.

Pharmacodynamic of Olmesartan+ Amlodipine+ Hydrochlorothiazide

Olmesartan: Angiotensin I infusion's pressure effects are limited by 2.5 mg to 40 mg of olmesartan. Olmesartan levels greater than 40 mg inhibit at 24 hours, indicating the inhibitory effect was prolonged over time. After giving Olmesartan to individuals with high blood pressure once or more, angiotensin I and angiotensin II plasma concentrations increase. Up to 80 mg of olmesartan administered repeatedly had little effect on blood potassium levels and only a negligible impact on aldosterone levels.

Amlodipine: Amlodipine binds to cell membranes with a high affinity and inhibits specific membrane calcium channels to modulate calcium influx. Long-acting effects and a less frequent dose schedule are made possible by this medication's unique binding qualities.

Hydrochlorothiazide: Thiazides have been shown to have acute antihypertensive effects secondary to a natriuretic impact on blood volume and cardiac output; however, a direct vasodilatory mechanism has also been hypothesized. Plasma volume returns to normal after prolonged dosing, although peripheral vascular resistance is reduced. Hydrochlorothiazide has an antihypertensive impact. However, the specific mechanism is unknown. Normal blood pressure is unaffected by thiazides. Within two hours of the dose, the effects start to manifest, reaching their peak at around four hours and lasting up to 24 hours.

Pharmacokinetics of Olmesartan+Amlodipine+Hydrochlorothiazide

Absorption

Olmesartan: When olmesartan medoxomil is absorbed from the gastrointestinal system, it rapidly and completely bioactivates by hydrolyzing with its ester to become olmesartan. Olmesartan has a bioavailability of about 26%. One to two hours after delivery, olmesartan reaches its maximal plasma concentration.

Amlodipine: Amlodipine is slowly and almost entirely absorbed from the digestive tract. Peak plasma concentrations are reached 6 to 12 hours after oral dosing. Amlodipine's bioavailability is estimated to be between 64 - 90%. After 7-8 days of regular medication, steady-state plasma amlodipine levels are attained. Food does not affect absorption.

Hydrochlorothiazide: Hydrochlorothiazide is well absorbed (65% to 75%) after oral administration. Absorption of Hydrochlorothiazide is lower in patients with congestive heart failure.

Distribution

Olmesartan: Olmesartan's distribution volume is roughly 17 L. Olmesartan does not penetrate red blood cells because it is linked to plasma proteins. At plasma olmesartan concentrations that are significantly greater than those attained with advised dosages, the protein binding remains constant.

Amlodipine: The plasma protein binding of Amlodipine is approximately 98%.

Hydrochlorothiazide: The given dosage has a linear relationship with plasma concentrations. In comparison to plasma, whole blood has hydrochlorothiazide concentrations that are 1.6–1.8 times greater. Serum protein binding has been estimated to range from 40% to 68%. According to reports, the plasma elimination half-life is between 6 and 15 hours.

Metabolism

Olmesartan: After the rapid and complete conversion of olmesartan medoxomil to olmesartan in the course of absorption, there is no further metabolism of olmesartan.

Amlodipine: Amlodipine is primarily (approximately 90%) converted to inactive metabolites via hepatic breakdown with 10% of the parent compound and 60% of the metabolites.

Hydrochlorothiazide: Hydrochlorothiazide is eliminated primarily by renal pathways.

Excretion

Olmesartan: The total plasma clearance of olmesartan is 1.3 L/h, and total renal clearance of 0.6 L/h. About 50% of the absorbed dose is recovered in urine, while the leftover is eliminated in faeces via the bile.

Amlodipine: Approximately 10% of a given dose is excreted in the urine.

Hydrochlorothiazide: More than 95% of the absorbed dosage is excreted in urine as an unaltered substance at oral doses of 12.5 to 100 mg, with 55% to 77% of the given dose appearing in the urine.

Therapeutic benefits of a combination of Olmesartan +Amlodipine+ Hydrochlorothiazide

• The combination effectively reduces hypertension or high blood pressure. Together, Olmesartan, Amlodipine, and Hydrochlorothiazide relax blood vessels, decrease fluid retention, and block angiotensin II receptors to lower blood pressure.
• This combination can considerably lower the risk of cardiovascular events, including strokes and heart attacks, by lowering blood pressure. It reduces the workload on the cardiovascular system while protecting the heart and blood vessels.

• Punzi, Henry A. “Efficacy and safety of olmesartan/amlodipine/hydrochlorothiazide in patients with hypertension not at goal with mono, dual or triple drug therapy: results of the CHAMPiOn study.” Therapeutic advances in cardiovascular disease vol. 8,1 (2014): 12-21. doi:10.1177/1753944713520062
• Kereiakes, D.J., Chrysant, S.G., Izzo, J.L. et al. Olmesartan/amlodipine/hydrochlorothiazide in participants with hypertension and diabetes, chronic kidney disease, or chronic cardiovascular disease: a subanalysis of the multicenter, randomized, double-blind, parallel-group TRINITY study. Cardiovasc Diabetol 11, 134 (2012). https://doi.org/10.1186/1475-2840-11-134
• Bramlage P, Fronk E, Wolf W, Smolnik R, Sutton G, Schmieder R. Safety and effectiveness of a fixed-dose combination of olmesartan, amlodipine, and Hydrochlorothiazide in clinical practice. Vasc Health Risk Manag. 2015;11:1-8 https://doi.org/10.2147/VHRM.S75380

• Pregnancy: Women of childbearing age should be informed of the dangers of taking valsartan and hydrochlorothiazide pills during pregnancy. Explain to pregnant women their treatment choices. Pregnancies should be reported as soon as possible by patients to their doctors.
• Symptomatic Hypotension: It is important to warn patients using valsartan and hydrochlorothiazide pills that dizziness might happen, especially in the first few days of treatment, and that it should be reported to the prescribing doctor. Patients should be informed that stopping valsartan and hydrochlorothiazide pills is best if syncope develops until after consulting a doctor. All patients should be informed that insufficient fluid intake, severe sweating, diarrhoea, or vomiting can cause a significant drop in blood pressure, which has the same effects as dizziness and the potential for syncope.
• Non-melanoma Skin Cancer: Advise hydrochlorothiazide-using patients to protect their skin from the sun and get frequent skin cancer screenings.
• Suppose a patient exhibits signs of acute myopia or secondary angle-closure glaucoma. In that case, they should be advised to stop using olmesartan medoxomil, Amlodipine, and hydrochlorothiazide pills and get medical attention immediately.
• Potassium Supplements: A patient taking hydrochlorothiazide and valsartan pills should be advised not to utilise potassium supplements or salt substitutes without consulting the doctor.

https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020850s032lbl.pdf

https://www.researchgate.net/publication/49793014

https://pubmed.ncbi.nlm.nih.gov/23889722/

https://classic.clinicaltrials.gov/ct2/show/NCT00902538

https://pubmed.ncbi.nlm.nih.gov/21275446/