Losacor Actions

• Actions of Losacor in details
• Losacor administration
• Losacor pharmacology
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Actions of Losacor in details

Losacor (Losacor), the first of a new class of agents for the treatment of hypertension, is an angiotensin II receptor (type AT₁) antagonist. Losacor also provides a reduction in the combined risk of cardiovascular death, stroke and myocardial infarction in hypertensive patients with left ventricular hypertrophy and provides renal protection for type 2 diabetic patients with proteinuria.

Pharmacology: Pharmacodynamics: Losacor inhibits systolic and diastolic pressor responses to angiotensin II infusions. At peak, 100 mg of Losacor inhibits these responses by approximately 85%; 24 hrs after single and multiple-dose administration, inhibition is about 26-39%.

During Losacor administration, removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. Increases in plasma renin activity lead to increases in angiotensin II in plasma. During chronic (6 weeks) treatment of hypertensive patients with 100 mg/day Losacor, approximately 2-3 fold increases of plasma angiotensin II were observed at time of peak plasma drug concentrations. In some patients, greater increases were observed, particularly during short-term (2 weeks) treatment. However, antihypertensive activity and suppression of plasma aldosterone concentration were apparent at 2 and 6 weeks, indicating effective angiotensin II receptor blockade. After discontinuation of Losacor, plasma renin activity and angiotensin II levels declined to untreated levels within 3 days.

Since Losacor is a specific antagonist of the angiotensin II receptor type AT₁, it does not inhibit ACE (kininase II), the enzyme that degrades bradykinin. In a study which compared the effects of 20 mg and 100 mg of Losacor and an ACE inhibitor on responses to angiotensin I, angiotensin II and bradykinin, Losacor was shown to block responses to angiotensin I and angiotensin II without affecting responses to bradykinin. This finding is consistent with Losacor's specific mechanism of action. In contrast, the ACE inhibitor was shown to block responses to angiotensin I and enhance responses to bradykinin without altering the response to angiotensin II, thus providing a pharmacodynamic distinction between Losacor and ACE inhibitors.

Plasma concentrations of Losacor and its active metabolite and the antihypertensive effect of Losacor increase with increasing dose. Since Losacor and its active metabolite are both angiotensin II receptor antagonists, they both contribute to the antihypertensive effect.

In a single-dose study in normal males, the administration of 100 mg of Losacor, under dietary high- and low-salt conditions, did not alter glomerular filtration rate, effective renal plasma flow or filtration fraction. Losacor had a natriuretic effect which was more pronounced on a low-salt diet and did not appear to be related to inhibition of early proximal reabsorption of sodium. Losacor also caused a transient increase in urinary uric acid excretion.

In nondiabetic hypertensive patients with proteinuria (≥2 g/24 hrs) treated for 8 weeks, the administration of Losacor 50 mg titrated to 100 mg significantly reduced proteinuria by 42%. Fractional excretion of albumin and IgG also was significantly reduced. In these patients, Losacor maintained glomerular filtration rate and reduced filtration fraction.

In postmenopausal hypertensive women treated for 4 weeks, 50 mg of Losacor had no effect on renal or systemic prostaglandin levels.

Losacor has no effect on autonomic reflexes and no sustained effect on plasma norepinephrine.

Losacor, administered in doses of up to 150 mg once daily, did not cause clinically important changes in fasting triglycerides, total cholesterol or HDL-cholesterol in patients with hypertension. The same doses of Losacor has no effect on fasting glucose levels.

Generally, Losacor caused a decrease in serum uric acid (usually <0.4 mg/dL) which was persistent in chronic therapy. In controlled clinical trials in hypertensive patients, no patients were discontinued due to increases in serum creatinine or serum potassium.

In a 12-week, parallel-design study in patients with left ventricular failure (New York Heart Association Functional Classes II-IV), most of whom were receiving diuretics and/or digitalis, Losacor administered in once-daily doses of 2.5, 10, 25 and 50 mg was compared to placebo. The 25-mg and 50-mg doses produced positive hemodynamic and neurohormonal effects which were maintained for the length of the study. Hemodynamic responses were characterized by an increase in cardiac index and decreases in: Pulmonary capillary wedge pressure, systemic vascular resistance, mean systemic arterial pressure and heart rate. The occurrence of hypotension was dose related in these heart failure patients. Neurohormonal results were characterized by a reduction in circulating levels of aldosterone and norepinephrine.

Pharmacokinetics: Absorption: Following oral administration, Losacor is well absorbed and undergoes first-pass metabolism, forming an active carboxylic acid metabolite and other inactive metabolites. The systemic bioavailability of Losacor tablets is approximately 33%. Mean peak concentrations of Losacor and its active metabolite are reached in 1 hr and in 3-4 hrs, respectively. There was no clinically significant effect on the plasma concentration profile of Losacor when the drug was administered with a standardized meal.

Distribution: Both Losacor and its active metabolite are ≥99% bound to plasma proteins, primarily albumin. The volume of distribution of Losacor is 34 L. Studies in rats indicate that Losacor crosses the blood-brain barrier poorly, if at all.

Biotransformation: About 14% of an IV or orally-administered dose of Losacor is converted to its active metabolite. Following oral and IV administration of ¹⁴C-labeled Losacor, circulating plasma radioactivity primarily is attributed to Losacor and its active metabolite. Minimal conversion of Losacor to its active metabolite was seen in about 1% of individuals studied.

In addition to the active metabolite, inactive metabolites are formed, including 2 major metabolites formed by hydroxylation of the butyl side chain and a minor metabolite, an N-2 tetrazole glucuronide.

Elimination: Plasma clearance of Losacor and its active metabolite is about 600 mL/min and 50 mL/min, respectively. Renal clearance of Losacor and its active metabolite is about 74 mL/min and 26 mL/min, respectively. When Losacor is administered orally, about 4% of the dose is excreted unchanged in the urine, and about 6% of the dose is excreted in the urine as active metabolite. The pharmacokinetics of Losacor and its active metabolite are linear with oral Losacor doses up to 200 mg.

Following oral administration, plasma concentrations of Losacor and its active metabolite decline polyexponentially with a terminal half-life of about 2 hrs and 6-9 hrs, respectively. During once-daily dosing with 100 mg, neither Losacor nor its active metabolite accumulates significantly in plasma.

Both biliary and urinary excretion contribute to the elimination of Losacor and its metabolites. Following an oral dose of ¹⁴C-labeled Losacor in man, about 35% of radioactivity is recovered in the urine and 58% in the feces.

Characteristics in Patients: Following oral administration in patients with mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of Losacor and its active metabolite were, respectively, 5-fold and 1.7-fold greater than those seen in young male volunteers.

Neither Losacor nor the active metabolite can be removed by hemodialysis.

How should I take Losacor?

Take Losacor exactly as prescribed by your doctor. Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.

You may take Losacor with or without food.

Call your doctor if you have ongoing vomiting or diarrhea, or if you are sweating more than usual. You can easily become dehydrated while taking this medication, which can lead to severely low blood pressure or a serious electrolyte imbalance.

Your blood pressure will need to be checked often. Visit your doctor regularly.

It may take 3 to 6 weeks of using Losacor before your blood pressure is under control. For best results, keep using the medication as directed. Talk with your doctor if your symptoms do not improve after 3 weeks of treatment.

If you are being treated for high blood pressure, keep using this medication even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.

Store at room temperature away from moisture, heat, and light.

Losacor administration

Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.

You may take Losacor with or without food.

Call your doctor if you have ongoing vomiting or diarrhea, or if you are sweating more than usual. You can easily become dehydrated while taking this medication, which can lead to severely low blood pressure or a serious electrolyte imbalance.

Your blood pressure will need to be checked often. Visit your doctor regularly.

It may take 3 to 6 weeks of using this medicine before your blood pressure is under control. For best results, keep using the medication as directed. Talk with your doctor if your symptoms do not improve after 3 weeks of treatment.

If you are being treated for high blood pressure, keep using this medication even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.

Store at room temperature away from moisture, heat, and light.

Losacor pharmacology

Mechanism of Action

Angiotensin II [formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II)] is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system, and an important component in the pathophysiology of hypertension. It also stimulates aldosterone secretion by the adrenal cortex. Losacor and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor found in many tissues, (e.g., vascular smooth muscle, adrenal gland). There is also an AT2 receptor found in many tissues but it is not known to be associated with cardiovascular homeostasis. Neither Losacor nor its principal active metabolite exhibits any partial agonist activity at the AT1 receptor, and both have much greater affinity (about 1000-fold) for the AT1 receptor than for the AT2 receptor. In vitro binding studies indicate that Losacor is a reversible, competitive inhibitor of the AT1 receptor. The active metabolite is 10 to 40 times more potent by weight than Losacor and appears to be a reversible, non-competitive inhibitor of the AT1 receptor.

Neither Losacor nor its active metabolite inhibits ACE (kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin), nor do they bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Pharmacodynamics

Losacor inhibits the pressor effect of angiotensin II (as well as angiotensin I) infusions. A dose of 100 mg inhibits the pressor effect by about 85% at peak with 25-40% inhibition persisting for 24 hours. Removal of the negative feedback of angiotensin II causes a doubling to tripling in plasma renin activity and consequent rise in angiotensin II plasma concentration in hypertensive patients. Losacor does not affect the response to bradykinin, whereas ACE inhibitors increase the response to bradykinin. Aldosterone plasma concentrations fall following Losacor administration. In spite of the effect of Losacor on aldosterone secretion, very little effect on serum potassium was observed.

The effect of Losacor is substantially present within one week but in some studies the maximal effect occurred in 3-6 weeks. In long-term follow-up studies (without placebo control) the effect of Losacor appeared to be maintained for up to a year. There is no apparent rebound effect after abrupt withdrawal of Losacor. There was essentially no change in average heart rate in Losacor-treated patients in controlled trials.

Pharmacokinetics

Absorption: Following oral administration, Losacor is well absorbed and undergoes substantial first-pass metabolism. The systemic bioavailability of Losacor is approximately 33%. Mean peak concentrations of Losacor and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. While maximum plasma concentrations of Losacor and its active metabolite are approximately equal, the AUC (area under the curve) of the metabolite is about 4 times as great as that of Losacor. A meal slows absorption of Losacor and decreases its Cmax but has only minor effects on Losacor AUC or on the AUC of the metabolite (~10% decrease). The pharmacokinetics of Losacor and its active metabolite are linear with oral Losacor doses up to 200 mg and do not change over time.

Distribution: The volume of distribution of Losacor and the active metabolite is about 34 liters and 12 liters, respectively. Both Losacor and its active metabolite are highly bound to plasma proteins, primarily albumin, with plasma free fractions of 1.3% and 0.2%, respectively. Plasma protein binding is constant over the concentration range achieved with recommended doses. Studies in rats indicate that Losacor crosses the blood-brain barrier poorly, if at all.

Metabolism: Losacor is an orally active agent that undergoes substantial first-pass metabolism by cytochrome P450 enzymes. It is converted, in part, to an active carboxylic acid metabolite that is responsible for most of the angiotensin II receptor antagonism that follows Losacor treatment. About 14% of an orally-administered dose of Losacor is converted to the active metabolite. In addition to the active carboxylic acid metabolite, several inactive metabolites are formed. In vitro studies indicate that cytochrome P450 2C9 and 3A4 are involved in the biotransformation of Losacor to its metabolites.

Elimination: Total plasma clearance of Losacor and the active metabolite is about 600 mL/min and 50 mL/min, respectively, with renal clearance of about 75 mL/min and 25 mL/min, respectively. The terminal half-life of Losacor is about 2 hours and of the metabolite is about 6-9 hours. After single doses of Losacor administered orally, about 4% of the dose is excreted unchanged in the urine and about 6% is excreted in urine as active metabolite. Biliary excretion contributes to the elimination of Losacor and its metabolites. Following oral 14C-labeled Losacor, about 35% of radioactivity is recovered in the urine and about 60% in the feces. Following an intravenous dose of 14C-labeled Losacor, about 45% of radioactivity is recovered in the urine and 50% in the feces. Neither Losacor nor its metabolite accumulates in plasma upon repeated once-daily dosing.

Special Populations

Pediatric: Pharmacokinetic parameters after multiple doses of Losacor (average dose 0.7 mg/kg, range 0.36 to 0.97 mg/kg) as a tablet to 25 hypertensive patients aged 6 to 16 years are shown in Table 4 below. Pharmacokinetics of Losacor and its active metabolite were generally similar across the studied age groups and similar to historical pharmacokinetic data in adults. The principal pharmacokinetic parameters in adults and children are shown in the table below.

Table 2: Pharmacokinetic Parameters in Hypertensive Adults and Children Age 6-16 Following Multiple Dosing

	Adults given 50 mg once daily for 7 days N=12		Age 6-16 given 0.7 mg/kg once daily for 7 days N=25
	Parent	Active Metabolite	Parent	Active Metabolite
* Mean ± standard deviation † Harmonic mean and standard deviation ‡ Median
AUC0-24 (ng∙hr/mL)*	442 ± 173	1685 ± 452	368 ± 169	1866 ± 1076
CMAX (ng/mL)*	224 ± 82	212 ± 73	141 ± 88	222 ± 127
T1/2 (h)†	2.1 ± 0.70	7.4 ± 2.4	2.3 ± 0.8	5.6 ± 1.2
TPEAK (h)‡	0.9	3.5	2.0	4.1
CLREN (mL/min)*	56 ± 23	20 ± 3	53 ± 33	17 ± 8

The bioavailability of the suspension formulation was compared with Losacor tablets in healthy adults. The suspension and tablet are similar in their bioavailability with respect to both Losacor and the active metabolite.

Geriatric and Gender: Losacor pharmacokinetics have been investigated in the elderly (65-75 years) and in both genders. Plasma concentrations of Losacor and its active metabolite are similar in elderly and young hypertensives. Plasma concentrations of Losacor were about twice as high in female hypertensives as male hypertensives, but concentrations of the active metabolite were similar in males and females. No dosage adjustment is necessary.

Race: Pharmacokinetic differences due to race have not been studied.

Renal Insufficiency: Following oral administration, plasma concentrations and AUCs of Losacor and its active metabolite are increased by 50-90% in patients with mild (creatinine clearance of 50 to 74 mL/min) or moderate (creatinine clearance 30 to 49 mL/min) renal insufficiency. In this study, renal clearance was reduced by 55-85% for both Losacor and its active metabolite in patients with mild or moderate renal insufficiency. Neither Losacor nor its active metabolite can be removed by hemodialysis.

Hepatic Insufficiency: Following oral administration in patients with mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of Losacor and its active metabolite were, respectively, 5-times and about 1.7-times those in young male volunteers. Compared to normal subjects the total plasma clearance of Losacor in patients with hepatic insufficiency was about 50% lower and the oral bioavailability was about doubled. Use a starting dose of 25 mg for patients with mild to moderate hepatic impairment. Losacor has not been studied in patients with severe hepatic impairment.

Drug Interactions

No clinically significant drug interactions have been found in studies of Losacor with hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital. However, rifampin has been shown to decrease the AUC of Losacor and its active metabolite by 30% and 40%, respectively. Fluconazole, an inhibitor of cytochrome P450 2C9, decreased the AUC of the active metabolite by approximately 40%, but increased the AUC of Losacor by approximately 70% following multiple doses. Conversion of Losacor to its active metabolite after intravenous administration is not affected by ketoconazole, an inhibitor of P450 3A4. The AUC of active metabolite following oral Losacor was not affected by erythromycin, an inhibitor of P450 3A4, but the AUC of Losacor was increased by 30%.

The pharmacodynamic consequences of concomitant use of Losacor and inhibitors of P450 2C9 have not been examined. Subjects who do not metabolize Losacor to active metabolite have been shown to have a specific, rare defect in cytochrome P450 2C9. These data suggest that the conversion of Losacor to its active metabolite is mediated primarily by P450 2C9 and not P450 3A4.

References

1. DailyMed. "LOSARTAN POTASSIUM: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
2. NCIt. "Losartan: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
3. EPA DSStox. "Losartan: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).

Reviews

The results of a survey conducted on ndrugs.com for Losacor are given in detail below. The results of the survey conducted are based on the impressions and views of the website users and consumers taking Losacor. We implore you to kindly base your medical condition or therapeutic choices on the result or test conducted by a physician or licensed medical practitioners.

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Information checked by Dr. Sachin Kumar, MD Pharmacology