Olmesartan is an angiotensin II receptor blocker (ARB) that is FDA approved for the treatment of patients suffering from hypertension. Olmesartan can be combined with other antihypertensive medications or used alone. Olmesartan, like other ARBs, can be used as monotherapy for hypertension in the absence of comorbidities such as chronic kidney disease, cerebrovascular events, heart failure, diabetes, and ischemic heart disease. ARBs can be used in combination with a thiazide diuretic or calcium channel blocker to achieve normotensive goals in high-risk patients, including atherosclerotic cardiovascular disease [ASCVD] risk greater than or equal to 10% or stage 2 hypertension. Olmesartan should not be administered with other medications that interfere with the RAAS systems, such as angiotensin-converting enzyme inhibitors (ACE-I). ARBs have been a recommendation to help lower microalbuminuria in patients with diabetes mellitus.[1]

In clinic practice, ARBs can also lower cardiovascular events and mortality in ischemic heart disease. However, ARB medications are inferior when compared to the use of ACE inhibitors.[2] While ACE inhibitors are generally considered first-line agents in the treatment of hypertension, these inhibitors can cause a bradykinin-induced cough, which can deter patients away from its use. In patients who cannot tolerate ACE-inhibitor medications due to side effects, the recommendation is for a change in medication from ACE-I to ARB medication such as olmesartan.[2][3] Despite studies suggesting little cardiovascular protection, it is still prescribed off-label for stable coronary artery disease and secondary prevention of myocardial infarction.

More recently, the use of ARBs in the prevention of all-cause CV outcomes has been controversial and called into question. In a review of current literature performed by Flavio Danni Fuchs and James J DiNicolantonio published in the British Medical Journal (BMJ), the authors identified that ARBs as a class were ineffective in preventing CV outcomes in patients with high CV risk in multiple large studies. Five separate studies were evaluated and suggested that the use of ARB in the prevention of major CV events was not superior to placebo, some of which suggested a higher rate of CV mortality in those treated with an ARB.[4][5][6]

Mechanism

Olmesartan functions as an angiotensin-II receptor blocker to undermine the renin-angiotensin-aldosterone system.[7][8] Olmesartan is an antagonistic molecule that binds to angiotensin type I receptors (AT-I) and angiotensin type II receptors (AT-II).[8] Olmesartan is both reversible and selective, binding to AT-I receptor at an affinity of over 12000 times its affinity for AT-II subtypes. This molecule inhibits these receptors at the adrenal gland and vascular smooth muscle sites, specifically the arterioles. Physiologically, angiotensin II binds to the AT-I/AT-II receptors result in aldosterone release from the adrenal gland causing arteriolar vasoconstriction.[9] The competitive binding of Olmesartan antagonizes these effects to help lower blood pressure by decreasing arteriolar resistance through vasodilation, which in turn lowers blood pressure. Olmesartan competitively blocks the binding of AT-II to its receptor, thus inhibiting the release of aldosterone from zona glomerulosa of the adrenal cortex. The reduction in serum aldosterone, in turn, results in reduced expression of ENaC channels within the distal collecting tubule of the nephron leading to decreased sodium reabsorption.[9] Decreased expression of the ENaC channel results in natriuresis, accompanied by osmotic diuresis.[9] Other electrolytes such as calcium, chloride, magnesium, phosphate, and magnesium are also excreted, though to a lesser extent.

Absorption

• Gastrointestinal absorption of an oral pill
• The bioavailability is about 26% and unaltered with the consumption of food

Clearance

• Total plasma clearance is 1.3 Liters/hour
• Renal clearance is 0.6 Liters/hour

Elimination

• Biphasic elimination
• Half-life (T1/2) = 10 to 15 hours
• Route = 35 to 50% eliminated unchanged in the urine
  • Remainder eliminated in the feces

Metabolism

• Ester hydrolysis in the gastrointestinal tract activates olmesartan upon digestion 

Volume of Distribution[7]

• The VD approximates 17L as it has a high affinity for plasma proteins
• Does not enter red blood cells; animal studies also show poor penetration of the blood-brain barrier

Olmesartan is an antihypertensive agent that is administered orally as olmesartan-medoxomil.[7] This medication comes in either a 5 mg, 20 mg, or 40 mg tablet. Olmesartan administration can be without regard to food, and its sole administration route is oral. Initial adult dosing is generally 20 mg taken once daily though reduced doses may be useful in cases of symptomatic orthostatic hypotension associated with medication administration. If blood pressure responses are ineffective, patients can titrate up to 40 mg daily after two weeks of taking the medication. Pediatric and adolescent data is relatively limited, given the dominance of hypertension in older populations. While data is limited, pediatric patients less than five years of age should be initially dosed with 0.3 mg/kg/dose daily and can be titrated up to 0.6 mg/kg/dose daily as needed. Adolescents from age six to sixteen and between 20 to 35 kg should begin with 10 mg olmesartan daily and titrated up to 20 mg as needed. Patients in the six to sixteen age group and weigh over 35 kg can be dosed as an adult starting with 20 mg daily and titrated to a maximum of 40 mg daily.[10]

ARBs are known for their relatively mild side-effect profile in comparison to other antihypertensive medications.[11] While side effects are not exceptionally common, as with most drugs, olmesartan can produce a constellation of side effects.

The most commonly affected organ systems are[11]:

• Nervous system
• Respiratory system
• Endocrine system
• Gastrointestinal system
• Genitourinary system
• Musculoskeletal systems

Studies show the most common side effect is associated headache, which up to 7% of patients may experience, and 3% may have associated dizziness. Respiratory complaints from the medication include upper respiratory infections(up to 5%), influenza (up to 3.5%), and sinusitis (up to 1%). Endocrine abnormalities may also result from olmesartan, including hyperglycemia (greater than 1%), and hypertriglyceridemia (more than 1%). The gastrointestinal system may also exhibit side effects, including abdominal pain, diarrhea (over 1%), increased ALT (1%), and increase GGT (approximately 2.5%). Of note, long term olmesartan use can result in sprue enteropathy like symptoms.[12] This condition includes significant weight-loss and osmotic diarrhea resulting from induced villous atrophy. Genitourinary complaints include hematuria (approximately 2.5%) and urinary tract infections(less than 2%).[13] Musculoskeletal complaints include back pain (more than 1%), arthralgia(greater than 1%), and bone pain (1%).[14] Very rare potential side effects include acute renal failure, alopecia, anaphylaxis, anxiety, chest pain, dyspepsia, eczema, erectile dysfunction, hyperbilirubinemia, hyperkalemia, hypotension, insomnia, and syncope. Olmesartan also has a couple of rare, life-threatening side effects, including anaphylaxis, angioedema, and severe renal failure.[11]

Contraindications

• Concurrent use of ACE inhibitors
• Previous reaction to olmesartan 
• Pregnancy (especially second/third trimester)
• Use of aliskiren with diabetes
• Severe renal impairment
• History of hypotension
• Hyperkalemia

Patients should not take olmesartan if they have previous hypersensitivity reactions to the medication in the past or any components of the formulation. While research is limited, allergic reactions to other angiotensin receptor blockers could exhibit cross-reactivity to olmesartan due to a similar mechanism of action and chemical composition. Additionally, the use of olmesartan is contraindicated in patients with diabetes mellitus with concomitant aliskiren use(direct renin inhibitor), during pregnancy, renal impairment, hypotension, and hyperkalemic patients. Also, olmesartan is not to be used with aliskiren in patients with diabetes mellitus due to the risk of cardiovascular and renal events. The ALTITUDE study suggests that the combination of this medication with concomitant diabetes can result in severe adverse events, including stroke, hyperkalemia, and hypotension.[15][16] Olmesartan contraindications include pregnancy due to teratogenicity. Olmesartan is especially teratogenic during second and third trimesters as it can cause in anuria and oligohydramnios, leading to limb defects, pulmonary hypoplasia, and craniofacial abnormalities. FDA, under its prior pregnancy classification system, classified olmesartan as a pregnancy class C medication during the first semester and as Class D medication during the second and third trimester respectfully.[17][18][19] No data has analyzed the safety of olmesartan while breastfeeding. Children below the age of one should not take olmesartan, as undeveloped kidneys can suffer damage from the medication.[20] Also, olmesartan is contraindicated in patients with renal impairment, especially with creatine clearance of less than 60 mL/min. Olmesartan should be avoided as the medication can result in dangerous electrolyte abnormalities, including hyperkalemia.[7] Patients with a significant history of persistent hypotension should also abstain from using olmesartan. Olmesartan increased urinary flow and the natriuretic nature of the medication. This combination can worsen hypotension.[7]

Cautious Use

• Coadministration of mTOR inhibitors
• Renal stenosis (bilateral)
• Liver disease

Patients using mTOR inhibitors such as sirolimus and everolimus should be cautious with the use of olmesartan.  Studies show an increased risk of angioedema when using these medications concomitantly.[21] Olmesartan should be prescribed cautiously to patients with know renal artery stenosis, as studies have shown an increased risk of acute renal failure for these patients.[22] Patients with a history of liver disease should be cautious when using olmesartan because of partial hepatic clearance. Liver function tests should be monitored in the weeks following initiation to ensure therapeutic values.[7]