Benicar

Benicar Uses, Dosage, Side Effects, Food Interaction and all others data.

Hydrochlorothiazide inhibits the reabsorption of Na in the distal tubules causing increased excretion of Na and water including K and hydrogen ions.

Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in vascular smooth muscle. Its action is therefore independent of the pathways for angiotensin II synthesis.

An AT2 receptor is also found in many tissues, but this receptor is not known to be associated with cardiovascular homeostasis. Olmesartan has more than a 12,500-fold greater affinity for the AT1 receptor than for the AT2 receptor.

​Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is a mechanism of many drugs used to treat hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because olmesartan medoxomil does not inhibit ACE, it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and circulating angiotensin II levels do not overcome the effect of olmesartan on blood pressure.

Trade Name Benicar
Generic Olmesartan + Hydrochlorothiazide
Weight 20mg, 40mg, 5mg,
Type Oral tablet
Therapeutic Class Combined antihypertensive preparations
Manufacturer
Available Country United States,
Last Updated: September 19, 2023 at 7:00 am
Benicar
Benicar

Uses

Treatment of essential hypertension. This fixed dose combination is used for adult patients whose blood pressure is not adequately controlled on Olmesartan Medoxomil alone.

Benicar is also used to associated treatment for these conditions: Acidosis, Renal Tubular, Calcium Nephrolithiasis, Cirrhosis of the Liver, Congestive Heart Failure (CHF), Diabetes Insipidus, Edema, High Blood Pressure (Hypertension), Hypertension,Essential, Hypokalemia caused by diuretics, Nephrotic Syndrome, Premenstrual tension with edema, Sodium retention, Stroke, Prophylaxis of preeclampsiaDiabetic Nephropathy, High Blood Pressure (Hypertension), Severe Hypertension, Moderate Hypertension

How Benicar works

Hydrochlorothiazide is transported from the circulation into epithelial cells of the distal convoluted tubule by the organic anion transporters OAT1, OAT3, and OAT4. From these cells, hydrochlorothiazide is transported to the lumen of the tubule by multidrug resistance associated protein 4 (MRP4).

Normally, sodium is reabsorbed into epithelial cells of the distal convoluted tubule and pumped into the basolateral interstitium by a sodium-potassium ATPase, creating a concentration gradient between the epithelial cell and the distal convoluted tubule that promotes the reabsorption of water.

Hydrochlorothiazide acts on the proximal region of the distal convoluted tubule, inhibiting reabsorption by the sodium-chloride symporter, also known as Solute Carrier Family 12 Member 3 (SLC12A3). Inhibition of SLC12A3 reduces the magnitude of the concentration gradient between the epithelial cell and distal convoluted tubule, reducing the reabsorption of water.

Olmesartan belongs to the angiotensin II receptor blocker (ARB) family of drugs, which also includes telmisartan, candesartan, losartan, valsartan, and irbesartan. ARBs selectively bind to angiotensin receptor 1 (AT1) and prevent the protein angiotensin II from binding and exerting its hypertensive effects. As the principal pressor agent of the renin-angiotensin system, Angiotensin II causes vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in vascular smooth muscle. Its action is, therefore, independent of the pathways for angiotensin II synthesis. Overall, olmesartan's physiologic effects lead to reduced blood pressure, lower aldosterone levels, reduced cardiac activity, and increased excretion of sodium.

Olmesartan also effects on the renin-angiotensin aldosterone system (RAAS) plays an important role in hemostasis and regulation of kidney, vascular, and cardiac functions. Pharmacological blockade of RAAS via AT1 receptor blockade inhibits negative regulatory feedback within RAAS, which is a contributing factor to the pathogenesis and progression of cardiovascular disease, heart failure, and renal disease. In particular, heart failure is associated with chronic activation of RAAS, leading to inappropriate fluid retention, vasoconstriction, and ultimately a further decline in left ventricular function. ARBs have been shown to have a protective effect on the heart by improving cardiac function, reducing afterload, increasing cardiac output and preventing ventricular hypertrophy and remodelling.

Dosage

Benicar dosage

The usual recommended starting dose of Olmesartan Medoxomil is 20 mg once daily when used as monotherapy in patients who are not volume-contracted. For patients requiring further reduction in blood pressure after 2 weeks of therapy, the dose may be increased to 40 mg. No initial dosage adjustment is recommended for elderly patients, for patients with moderate to marked renal impairment (creatinine clearance<40 ml/min) or with moderate to marked hepatic dysfunction.

Hydrochlorothiazide is effective in doses between 12.5 mg and 50 mg once daily.

Replacement Therapy: Olmesartan & Hydrochlorothiazidemay be substituted for its titrated components.

Dose Titration by Clinical Effect: The dose of Olmesartan & Hydrochlorothiazide tablet is one tablet once daily. More than one tablet daily is not recommended. Olmesartan & Hydrochlorothiazide tablet may be administered with other antihypertensive agents. A patient whose blood pressure is inadequately controlled by Olmesartan or Hydrochlorothiazide alone may be switched to once daily Olmesartan & Hydrochlorothiazide tablet. Dosing should be individualized. Depending on the blood pressure response, the dose may be titrated at intervals of 2-4 weeks. If blood pressure is not controlled by Olmesartan alone, Hydrochlorothiazide may be added starting with a dose of 12.5 mg and later titrated to 25 mg once daily.

If a patient is taking Hydrochlorothiazide, Olmesartan may be added starting with a dose of 20 mg once daily and titrated to 40 mg, for inadequate blood pressure control. If large doses of hydrochlorothiazide have been used as monotherapy and volume depletion or hyponatremia is present, caution should be used when adding Olmesartan or switching to Olmesartan & Hydrochlorothiazide tablet, as marked decreases in blood pressure may occur. Consideration should be given to reducing the dose of Hydrochlorothiazide to 12.5 mg before adding Olmesartan. The antihypertensive effect of Olmesartan & Hydrochlorothiazide is related to the dose of both components over the range of 10 mg/12.5 mg to 40 mg/25 mg

Side Effects

This combination tablet has been evaluated for safety in 1,243 hypertensive patients. It was well tolerated, with an incidence of adverse events similar to placebo. Events generally were mild, transient and had no relationship to the dose of this combination tablet. Some common side effects include: headache, urinary tract infection, chest pain, back pain, peripheral edema, vertigo, abdominal pain, dyspepsia, gastroenteritis, diarrhoea, SGOT increased, GGT increased, SGPT increased, hyperlipemia, creatine phosphokinase increased, hyperglycemia, arthritis, arthralgia, myalgia, coughing, rash etc.

Toxicity

The oral LD50 of hydrochlorothiazide is >10g/kg in mice and rats.

Patients experiencing an overdose may present with hypokalemia, hypochloremia, and hyponatremia. Treat patients with symptomatic and supportive treatment including fluids and electrolytes. Vasopressors may be administered to treat hypotension and oxygen may be given for respiratory impairment.

The reported LD50 of olmesartan in dogs was reported to be greater of 1500 mg/kg. Overdose is expressed as hypotension, tachycardia, and bradycardia when there is parasympathetic stimulation. In case of overdose, supportive treatment is recommended.

Olmesartan was shown to be safe on carcinogenic and fertility studies. However, in in vitro mutagenic studies showed a potential to induce chromosomal aberrations in cells and it tested positive for thymidine kinase mutations in the mouse lymphoma assay.

Precaution

Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of Olmesartan Medoxomil-Hydrochlorothiazide.

Interaction

Olmesartan Medoxomil: No significant drug interactions were reported in studies in which Olmesartan Medoxomil was coadministered with hydrochlorothiazide, digoxin or warfarin in healthy volunteers.

Hydrochlorothiazide: When administered concurrently the following drugs may interact with thiazide diuretics: alcohol, barbiturates or narcotics, antidiabetic drugs, other antihypertensive drugs, cholestyramine and colestipol resins, corticosteroids, pressor amines (e.g. Norepinephrine), skeletal muscle relaxants (e.g. Tubocurarine), lithium, NSAIDs etc.

Volume of Distribution

The volume of distribution varies widely from one study to another with values of 0.83-4.19L/kg.

17 L[L5566]

Elimination Route

An oral dose of hydrochlorothiazide is 65-75% bioavailable, with a Tmax of 1-5 hours, and a Cmax of 70-490ng/mL following doses of 12.5-100mg. When taken with a meal, bioavailability is 10% lower, Cmax is 20% lower, and Tmax increases from 1.6 to 2.9 hours.

When taken orally, the prodrug olmesartan medoxomil is rapidly absorbed in the gastrointestinal tract and metabolized to olmesartan. The esterification with medoxomil was created with the intention of increasing olmesartan bioavailability from 4.5% to 28.6%.

Oral administration of 10-160 mg of olmesartan has been shown to reach peak plasma concentration of 0.22-2.1 mg/L after 1-3 hours with an AUC of 1.6-19.9mgh/L. The pharmacokinetic profile of olmesartan has been observed to be nearly linear and dose-dependent under the therapeutic range. The steady-state level of olmesartan is achieved after once a day dosing during 3 to 5 days.[L5566]

Half Life

The plasma half life of hydrochlorothiazide is 5.6-14.8h.

The mean plasma olmesartan half-life is reported to be from 10-15 hours after multiple oral administration.

Clearance

The renal clearance of hydrochlorothiazide in patients with normal renal function is 285mL/min. Patients with a creatinine clearance of 31-80mL/min have an average hydroxychlorothiazide renal clearance of 75mL/min, and patients with a creatinine clearance of ≤30mL/min have an average hydroxychlorothiazide renal clearance of 17mL/min.

Total plasma clearance is 1.3 L/h and the renal clearance is 0.6 L/h.[L5566]

Elimination Route

Hydrochlorothiazide is eliminated in the urine as unchanged hydrochlorothiazide.

The main elimination route of olmesartan is in the unchanged form through the feces. From the systemically bioavailable dose, about 10-16% is eliminated in the urine.

Pregnancy & Breastfeeding use

Pregnancy Categories C (first trimester) and D (second and third trimesters). This combination drug should not be used during pregnancy.

Lactation: It is not known whether Olmesartan is excreted in human milk, but Olmesartan is secreted at low concentration in the milk of lactating rats. Thiazides appear in human milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Contraindication

This combination tablet is contraindicated in patients who are hypersensitive to any component of this product. Because of the Hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.

Special Warning

Renal impairment: The usual regimens of therapy with Olmesartan & Hydrochlorothiazide tablet may be followed provided the patient's creatinine clearance>30 ml/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so this combination tablet is not recommended.

Patients with Hepatic Impairment: No dosage adjustment is necessary with hepatic impairment.

Paediatric population: The safety and efficacy of Olmesartan & Hydrochlorothiazide in children and adolescents below 18 years has not been established. No data are available.

Acute Overdose

The most likely manifestations of Olmesartan Medoxomil overdose are expected to be hypotension and tachycardia; bradycardia might also occur. Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloraemia) and dehydration resulting from excessive diuresis. The most common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in muscle spasm and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalis glycosides or certain anti-arrhythmic medicinal products. No specific information is available on the effects or treatment of Olmesartan Medoxomil-Hydrochlorothiazide overdose. The patient should be closely monitored and the treatment should be symptomatic and supportive. Management depends upon the time since ingestion and the severity of the symptoms. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdose. Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a supine position, with salt and volume replacements given quickly.

Storage Condition

Store in a cool and dry place, protected from light.

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