Actions of Losacard in details
Losacard (Losacard potassium), the first of a new class of agents for the treatment of hypertension, is an angiotensin II receptor (type AT1) antagonist. Losacard 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: Losacard inhibits systolic and diastolic pressor responses to angiotensin II infusions. At peak, 100 mg of Losacard potassium inhibits these responses by approximately 85%; 24 hrs after single and multiple-dose administration, inhibition is about 26-39%.
During Losacard 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 Losacard, 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 Losacard, plasma renin activity and angiotensin II levels declined to untreated levels within 3 days.
Since Losacard 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 Losacard potassium and an ACE inhibitor on responses to angiotensin I, angiotensin II and bradykinin, Losacard was shown to block responses to angiotensin I and angiotensin II without affecting responses to bradykinin. This finding is consistent with Losacard'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 Losacard and ACE inhibitors.
Plasma concentrations of Losacard and its active metabolite and the antihypertensive effect of Losacard increase with increasing dose. Since Losacard 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 Losacard potassium, under dietary high- and low-salt conditions, did not alter glomerular filtration rate, effective renal plasma flow or filtration fraction. Losacard 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. Losacard 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 Losacard potassium 50 mg titrated to 100 mg significantly reduced proteinuria by 42%. Fractional excretion of albumin and IgG also was significantly reduced. In these patients, Losacard maintained glomerular filtration rate and reduced filtration fraction.
In postmenopausal hypertensive women treated for 4 weeks, 50 mg of Losacard potassium had no effect on renal or systemic prostaglandin levels.
Losacard has no effect on autonomic reflexes and no sustained effect on plasma norepinephrine.
Losacard potassium, 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 Losacard has no effect on fasting glucose levels.
Generally, Losacard 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, Losacard potassium 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, Losacard is well absorbed and undergoes first-pass metabolism, forming an active carboxylic acid metabolite and other inactive metabolites. The systemic bioavailability of Losacard tablets is approximately 33%. Mean peak concentrations of Losacard 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 Losacard when the drug was administered with a standardized meal.
Distribution: Both Losacard and its active metabolite are ≥99% bound to plasma proteins, primarily albumin. The volume of distribution of Losacard is 34 L. Studies in rats indicate that Losacard crosses the blood-brain barrier poorly, if at all.
Biotransformation: About 14% of an IV or orally-administered dose of Losacard is converted to its active metabolite. Following oral and IV administration of 14C-labeled Losacard potassium, circulating plasma radioactivity primarily is attributed to Losacard and its active metabolite. Minimal conversion of Losacard 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 Losacard and its active metabolite is about 600 mL/min and 50 mL/min, respectively. Renal clearance of Losacard and its active metabolite is about 74 mL/min and 26 mL/min, respectively. When Losacard 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 Losacard and its active metabolite are linear with oral Losacard potassium doses up to 200 mg.
Following oral administration, plasma concentrations of Losacard 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 Losacard nor its active metabolite accumulates significantly in plasma.
Both biliary and urinary excretion contribute to the elimination of Losacard and its metabolites. Following an oral dose of 14C-labeled Losacard 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 Losacard and its active metabolite were, respectively, 5-fold and 1.7-fold greater than those seen in young male volunteers.
Neither Losacard nor the active metabolite can be removed by hemodialysis.
How should I take Losacard?
Take Losacard 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 Losacard 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 Losacard 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.
Losacard 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 Losacard 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.
Losacard 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. Losacard 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 Losacard 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 Losacard is a reversible, competitive inhibitor of the AT1 receptor. The active metabolite is 10 to 40 times more potent by weight than Losacard and appears to be a reversible, non-competitive inhibitor of the AT1 receptor.
Neither Losacard 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
Losacard 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. Losacard does not affect the response to bradykinin, whereas ACE inhibitors increase the response to bradykinin. Aldosterone plasma concentrations fall following Losacard administration. In spite of the effect of Losacard on aldosterone secretion, very little effect on serum potassium was observed.
The effect of Losacard 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 Losacard appeared to be maintained for up to a year. There is no apparent rebound effect after abrupt withdrawal of Losacard. There was essentially no change in average heart rate in Losacard-treated patients in controlled trials.
Pharmacokinetics
Absorption: Following oral administration, Losacard is well absorbed and undergoes substantial first-pass metabolism. The systemic bioavailability of Losacard is approximately 33%. Mean peak concentrations of Losacard and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. While maximum plasma concentrations of Losacard 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 Losacard. A meal slows absorption of Losacard and decreases its Cmax but has only minor effects on Losacard AUC or on the AUC of the metabolite (~10% decrease). The pharmacokinetics of Losacard and its active metabolite are linear with oral Losacard doses up to 200 mg and do not change over time.
Distribution: The volume of distribution of Losacard and the active metabolite is about 34 liters and 12 liters, respectively. Both Losacard 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 Losacard crosses the blood-brain barrier poorly, if at all.
Metabolism: Losacard 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 Losacard treatment. About 14% of an orally-administered dose of Losacard 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 Losacard to its metabolites.
Elimination: Total plasma clearance of Losacard 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 Losacard is about 2 hours and of the metabolite is about 6-9 hours. After single doses of Losacard 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 Losacard and its metabolites. Following oral 14C-labeled Losacard, about 35% of radioactivity is recovered in the urine and about 60% in the feces. Following an intravenous dose of 14C-labeled Losacard, about 45% of radioactivity is recovered in the urine and 50% in the feces. Neither Losacard nor its metabolite accumulates in plasma upon repeated once-daily dosing.
Special Populations
Pediatric: Pharmacokinetic parameters after multiple doses of Losacard (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 Losacard 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 | |
| ||||
| 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 Losacard tablets in healthy adults. The suspension and tablet are similar in their bioavailability with respect to both Losacard and the active metabolite.
Geriatric and Gender: Losacard pharmacokinetics have been investigated in the elderly (65-75 years) and in both genders. Plasma concentrations of Losacard and its active metabolite are similar in elderly and young hypertensives. Plasma concentrations of Losacard 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 Losacard 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 Losacard and its active metabolite in patients with mild or moderate renal insufficiency. Neither Losacard 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 Losacard 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 Losacard 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. Losacard has not been studied in patients with severe hepatic impairment.
Drug Interactions
No clinically significant drug interactions have been found in studies of Losacard potassium with hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital. However, rifampin has been shown to decrease the AUC of Losacard 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 Losacard by approximately 70% following multiple doses. Conversion of Losacard to its active metabolite after intravenous administration is not affected by ketoconazole, an inhibitor of P450 3A4. The AUC of active metabolite following oral Losacard was not affected by erythromycin, an inhibitor of P450 3A4, but the AUC of Losacard was increased by 30%.
The pharmacodynamic consequences of concomitant use of Losacard and inhibitors of P450 2C9 have not been examined. Subjects who do not metabolize Losacard to active metabolite have been shown to have a specific, rare defect in cytochrome P450 2C9. These data suggest that the conversion of Losacard to its active metabolite is mediated primarily by P450 2C9 and not P450 3A4.
References
- 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).
- 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).
- 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
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Information checked by Dr. Sachin Kumar, MD Pharmacology
