Olmesartan


Article Author:
Connor Kerndt


Article Editor:
Michael Soos


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
9/3/2019 4:03:21 PM

Indications

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 medication 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 recommended to help lower microalbuminuria in diabetic patients.[1]

In clinic practice, ARBs are also used to 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 of Action

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 

The 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

Administration

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 prescribed as a 20 mg tablet to be 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]

Adverse Effects

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

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 diabetic patients 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 be given 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 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]  

Monitoring

In 2014 during the Eight Joint Nation Committee (JNC-8) established goals for hypertension management. The therapeutic index should be indirectly monitored through blood pressure control and evaluation for side effects. Typically well-tolerated mild side effects have been previously reported including but not limited to dizziness, headache, drowsiness, nausea, vomiting, diarrhea, and electrolyte disturbances, for instance, hyperkalemia. When discontinuing olmesartan, recommendations that addition antihypertensive medications be considered according to provider preference to maintain blood pressure goals as established in JNC-8. Also, renal function tests (CrCl) and liver function may require monitoring as dose adjustments may be necessary in cases of significant renal impairment, guidelines for which appear below. A complete metabolic panel can also be utilized to monitor for any possible derangement of potassium, sodium, calcium, chloride, magnesium, phosphate, and magnesium.

History of Renal dysfunction[7][10]:

  • CrCl greater than equal to 40 mL/min: Dose adjustment unnecessary
  • CrCl 20 mL/min to less than 40 mL/min: Adjustment not needed upon initiation, consider lowering dose-dependent on patient response
  • CrCl less than 20 mL/min: Consider lowering dose due to impaired excretion (Less than 20mg/day)

History of Hepatic impairment[7][10]:

  • Mild impairment: No dosing adjustment needed
  • Moderate to severe: No need for initial dose modification; may consider depending on patient response

Toxicity

While data of olmesartan's toxicity is limited, given the mechanism of action, the likely presenting toxic symptoms would include hypotension and tachycardia. The toxicity could also manifest with altered vision, angina, vertigo, lightheadedness, and diaphoresis. These possible toxicities mimic the side effect profile of the medication.[23] While no antidote exists, activated charcoal may be appropriate if consumption of olmesartan was within four hours for decontamination. Supportive measures include monitoring vital signs every six hours post-consumption to monitor for marked hypotension or hemodynamic instability. The patient should perform leg raising while lying supine to improve venous return to the heart.[23] If severe hypotension persists, vasopressors are a treatment option in extreme circumstances. Another possible cleansing method would include hemodialysis if a patient was remarkable unstable and refractory to vasopressor medication, although rarely necessary. Also, as always, cardiac life support is indicated if cardiac arrest occurs and preservation of an airway with an endotracheal tube in situations with a threatened airway.

Enhancing Healthcare Team Outcomes

A patient's primary care provider will most often manage medications prescribed for the treatment of hypertension; however, various specialties, including cardiology and nephrology, are often consulted for the management of treatment-resistant disease. Patients undergoing treatment for hypertension frequently have concomitant pathologies include obesity, diabetes, and coronary artery disease. A patient may be referred to cardiology to manage severe hypertension and may suggest a more suitable alternative in patients with a significant cardiac health history based on ongoing studies. Similarly, in patients with impaired renal function, nephrology may be able to contribute by suggesting different medication to improve kidney health and patient outcomes. Nurse-practitioners, physician assistants, nurses, and medical assistants can perform medication reviews to determine in the patient has been experiencing any harmful or unwanted side effects while taking olmesartan. Communication between specialties and levels of different level of providers, including the pharmacist, can assist in ensuring that patients can safely take olmesartan or more appropriate medication. Nursing can monitor blood pressure and other monitoring parameters to evaluate treatment effectiveness and check for any adverse reactions, reporting these to the healthcare team should they occur. Pharmacists shall verify dosing and also check for drug-drug interactions, particularly with other RAAS-targeting medications, as at one time there was a school of thought that ACE-inhibitors and ARBs could be prescribed together, but that is no longer the case based on more recent data. The pharmacist shall communicate any findings to the treating physician or nursing staff.

Though its use remains controversial based on current literature and more effective alternatives exist within the ARB class at this time,[24] olmesartan remains a useful medication to consider in the treatment of hypertension. In summary, olmesartan therapy requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level V]


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Olmesartan - Questions

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Which of the following drugs block the aldosterone secreting effects of angiotensin II by binding to the AT1 angiotensin II receptor?



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In which class is olmesartan correctly placed?



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A patient comes to the office. His blood pressure normally reads in the 140s/90s mmHg but today is 90/72 mmHg. He says he feels lightheaded and feels his heart racing. Upon further questioning, he says he has been urinating much more frequently than usual. When reviewing his medications, he says he has been taking olmesartan twice daily although you only prescribed him to take it once daily. A complete metabolic panel is ordered to evaluate his electrolytes. Which of the following might be anticipated?



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Olmesartan - References

References

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