Actions of Losagen Combi in details
Losagen Combi Gentech Healthcare is an anxiolytic drug (tranquilizer), a derivative of benzodiazepine. This medication has anxiolytic, sedative, hypnotic, anticonvulsant, muscle relaxant central, antiemetic effect. The mechanism of the anxiolytic, sedative and hypnotic action is associated with increased inhibitory effect of GABA in the CNS. Anticonvulsant action, apparently in part due to increased presynaptic inhibition; inhibited the spread of epileptogenic activity arising in the epileptogenic foci in the cortex, thalamus and limbic structures, but not removed the excited state of the hearth. Muscle relaxant effect is primarily associated with the suppression of spinal polysynaptic afferent pathways and, presumably, an inhibition of monosynaptic afferent pathways; possibly also a direct inhibitory effect on motor nerves and muscle function.
How should I take Losagen Combi?
Take Losagen Combi 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.
Take Losagen Combi with a full glass (8 ounces) of water.
Your blood pressure will need to be checked often. Your kidney function may also need to be checked.
You may have very low blood pressure while taking this medication. Call your doctor if you are sick with vomiting or diarrhea, or if you are sweating more than usual.
If you need surgery, tell the surgeon ahead of time that you are using Losagen Combi. You may need to stop using the medicine for a short time.
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 Losagen Combi at room temperature away from moisture and heat.
Losagen Combi administration
Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
Your doctor may occasionally change your dose to make sure you get the best results.
Take this medication with a full glass (8 ounces) of water.
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. Your kidney function may also need to be tested. Visit your doctor regularly.
If you need surgery or medical tests, tell the doctor ahead of time that you are taking medication that contains Hydrochlorothiazide (Losagen Combi). You may need to stop using the medicine for a short time.
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 and heat.
Losagen Combi pharmacology
Mechanism Of Action
Losartan (Losagen Combi) Potassium
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. Losartan (Losagen Combi) 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 AT 2 receptor found in many tissues but it is not known to be associated with cardiovascular homeostasis. Neither Losartan (Losagen Combi) nor its principal active metabolite exhibits any partial agonist activity at the AT 1 receptor, and both have much greater affinity (about 1000-fold) for the AT 1 receptor than for the AT 2 receptor. In vitro binding studies indicate that Losartan (Losagen Combi) is a reversible, competitive inhibitor of the AT 1 receptor. The active metabolite is 10 to 40 times more potent by weight than Losartan (Losagen Combi) and appears to be a reversible, non-competitive inhibitor of the AT 1 receptor.
Neither Losartan (Losagen Combi) 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.
Hydrochlorothiazide (Losagen Combi)
Hydrochlorothiazide (Losagen Combi) is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of Hydrochlorothiazide (Losagen Combi) reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics. The mechanism of the antihypertensive effect of thiazides is unknown.
Pharmacodynamics
Losartan (Losagen Combi) Potassium
Losartan (Losagen Combi) 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. Losartan (Losagen Combi) does not affect the response to bradykinin, whereas ACE inhibitors increase the response to bradykinin. Aldosterone plasma concentrations fall following Losartan (Losagen Combi) administration. In spite of the effect of Losartan (Losagen Combi) on aldosterone secretion, very little effect on serum potassium was observed.
The effect of Losartan (Losagen Combi) 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 Losartan (Losagen Combi) appeared to be maintained for up to a year. There is no apparent rebound effect after abrupt withdrawal of Losartan (Losagen Combi). There was essentially no change in average heart rate in Losartan (Losagen Combi)-treated patients in controlled trials.
Hydrochlorothiazide (Losagen Combi)
After oral administration of Hydrochlorothiazide (Losagen Combi), diuresis begins within 2 hours, peaks in about 4 hours, and lasts about 6 to 12 hours.
Drug Interactions
Hydrochlorothiazide (Losagen Combi)
Alcohol, barbiturates, or narcotics — potentiation of orthostatic hypotension may occur.
Other antihypertensive drugs — additive effect or potentiation.
Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine) — possible increased responsiveness to the muscle relaxant.
Corticosteroids, ACTH, or glycyrrhizin (found in liquorice) — intensified electrolyte depletion, particularly hypokalemia.
Pressor amines (e.g., norepinephrine) — possible decreased response to pressor amines but not sufficient to preclude their use.
Pharmacokinetics
Losartan (Losagen Combi) Potassium
Absorption
Following oral administration, Losartan (Losagen Combi) is well absorbed and undergoes substantial first-pass metabolism. The systemic bioavailability of Losartan (Losagen Combi) is approximately 33%. Mean peak concentrations of Losartan (Losagen Combi) and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. While maximum plasma concentrations of Losartan (Losagen Combi) 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 Losartan (Losagen Combi). A meal slows absorption of Losartan (Losagen Combi) and decreases its C max but has only minor effects on Losartan (Losagen Combi) AUC or on the AUC of the metabolite (~10% decrease). The pharmacokinetics of Losartan (Losagen Combi) and its active metabolite are linear with oral Losartan (Losagen Combi) doses up to 200 mg and do not change over time.
Distribution
The volume of distribution of Losartan (Losagen Combi) and the active metabolite is about 34 liters and 12 liters, respectively. Both Losartan (Losagen Combi) 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 Losartan (Losagen Combi) crosses the blood-brain barrier poorly, if at all.
Metabolism
Losartan (Losagen Combi) 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 Losartan (Losagen Combi) treatment. About 14% of an orally-administered dose of Losartan (Losagen Combi) 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 Losartan (Losagen Combi) to its metabolites.
Elimination
Total plasma clearance of Losartan (Losagen Combi) 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 Losartan (Losagen Combi) is about 2 hours and of the metabolite is about 6-9 hours. After single doses of Losartan (Losagen Combi) 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 Losartan (Losagen Combi) and its metabolites. Following oral C-labeled Losartan (Losagen Combi), about 45% of radioactivity is recovered in the urine and 50% in the feces. Neither Losartan (Losagen Combi) nor its metabolite accumulate in plasma upon repeated once-daily dosing.
Hydrochlorothiazide (Losagen Combi)
Hydrochlorothiazide (Losagen Combi) is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide (Losagen Combi) crosses the placental but not the blood-brain barrier and is excreted in breast milk.
Special Populations
Geriatric and Gender
Losartan (Losagen Combi) pharmacokinetics have been investigated in the elderly (65-75 years) and in both genders. Plasma concentrations of Losartan (Losagen Combi) and its active metabolite are similar in elderly and young hypertensives. Plasma concentrations of Losartan (Losagen Combi) were about twice as high in female hypertensives as male hypertensives, but concentrations of the active metabolite were similar in males and females.
Race
Pharmacokinetic differences due to race have not been studied.
Hepatic Insufficiency
Following oral administration in patients with mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of Losartan (Losagen Combi) 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 Losartan (Losagen Combi) in patients with hepatic insufficiency was about 50% lower, and the oral bioavailability was about doubled. The lower starting dose of Losartan (Losagen Combi) recommended for use in patients with hepatic impairment cannot be given using Losagen Combi. Its use in such patients as a means of Losartan (Losagen Combi) titration is, therefore, not recommended.
Renal Insufficiency
Losartan (Losagen Combi)
Following oral administration, plasma concentrations and AUCs of Losartan (Losagen Combi) 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 Losartan (Losagen Combi) and its active metabolite in patients with mild or moderate renal insufficiency. Neither Losartan (Losagen Combi) nor its active metabolite can be removed by hemodialysis.
Hydrochlorothiazide (Losagen Combi)
Following oral administration, the AUC for Hydrochlorothiazide (Losagen Combi) is increased by 70 and 700% for patients with mild and moderate renal insufficiency, respectively. In this study, renal clearance of Hydrochlorothiazide (Losagen Combi) decreased by 45 and 85% in patients with mild and moderate renal impairment, respectively.
Use the usual regimens of therapy with Losagen Combi as long as the patient's creatinine clearance is greater than 30 mL/min. Safety and effectiveness of Losagen Combi in patients with severe renal impairment (creatinine clearance less than 30 mL/min) have not been established.
Drug Interactions
Losartan (Losagen Combi) Potassium
No clinically significant drug interactions have been found in studies of Losartan (Losagen Combi) potassium with Hydrochlorothiazide (Losagen Combi), digoxin, warfarin, cimetidine and phenobarbital. However, rifampin has been shown to decrease the AUC of Losartan (Losagen Combi) 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 Losartan (Losagen Combi) by approximately 70% following multiple doses. Conversion of Losartan (Losagen Combi) to its active metabolite after intravenous administration is not affected by ketoconazole, an inhibitor of P450 3A4.The AUC of active metabolite following oral Losartan (Losagen Combi) was not affected by erythromycin, an inhibitor of P450 3A4, but the AUC of Losartan (Losagen Combi) was increased by 30%.
The pharmacodynamic consequences of concomitant use of Losartan (Losagen Combi) and inhibitors of P450 2C9 have not been examined. Subjects who do not metabolize Losartan (Losagen Combi) to active metabolite have been shown to have a specific, rare defect in cytochrome P450 2C9. These data suggest that the conversion of Losartan (Losagen Combi) to its active metabolite is mediated primarily by P450 2C9 and not P450 3A4.
Clinical Studies
Losartan (Losagen Combi) Monotherapy
Reduction in the Risk of Stroke: The LIFE study was a multinational, double-blind study comparing Losartan (Losagen Combi) and atenolol in 9193 hypertensive patients with ECG-documented left ventricular hypertrophy. Patients with myocardial infarction or stroke within six months prior to randomization were excluded. Patients were randomized to receive once daily Losartan (Losagen Combi) 50 mg or atenolol 50 mg. If goal blood pressure ( < 140/90 mmHg) was not reached, Hydrochlorothiazide (Losagen Combi) (12.5 mg) was added first and, if needed, the dose of Losartan (Losagen Combi) or atenolol was then increased to 100 mg once daily. If necessary, other antihypertensive treatments (e.g., increase in dose of Hydrochlorothiazide (Losagen Combi) therapy to 25 mg or addition of other diuretic therapy, calcium channel blockers, alpha-blockers, or centrally acting agents, but not ACE inhibitors, angiotensin II antagonists, or beta-blockers) were added to the treatment regimen to reach the goal blood pressure.
In efforts to control blood pressure, the patients in both arms of the LIFE study were coadministered Hydrochlorothiazide (Losagen Combi) the majority of time they were on study drug (73.9% and 72.4% of days in the Losartan (Losagen Combi) and atenolol arms, respectively).
Of the randomized patients, 4963 (54%) were female and 533 (6%) were Black. The mean age was 67 with 5704 (62%) age ≥ 65. At baseline, 1195 (13%) had diabetes, 1326 (14%) had isolated systolic hypertension, 1469 (16%) had coronary heart disease, and 728 (8%) had cerebrovascular disease. Baseline mean blood pressure was 174/98 mmHg in both treatment groups. The mean length of follow-up was 4.8 years. At the end of study or at the last visit before a primary endpoint, 77% of the group treated with Losartan (Losagen Combi) and 73% of the group treated with atenolol were still taking study medication. Of the patients still taking study medication, the mean doses of Losartan (Losagen Combi) and atenolol were both about 80 mg/day, and 15% were taking atenolol or Losartan (Losagen Combi) as monotherapy, while 77% were also receiving Hydrochlorothiazide (Losagen Combi) (at a mean dose of 20 mg/day in each group). Blood pressure reduction measured at trough was similar for both treatment groups but blood pressure was not measured at any other time of the day. At the end of study or at the last visit before a primary endpoint, the mean blood pressures were 144.1/81.3 mmHg for the group treated with Losartan (Losagen Combi) and 145.4/80.9 mmHg for the group treated with atenolol [the difference in SBP of 1.3 mmHg was significant (p < 0.001), while the difference of 0.4 mmHg in DBP was not significant (p=0.098)].
The primary endpoint was the first occurrence of cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction. Patients with nonfatal events remained in the trial, so that there was also an examination of the first event of each type even if it was not the first event (e.g., a stroke following an initial myocardial infarction would be counted in the analysis of stroke). Treatment with Losartan (Losagen Combi) resulted in a 13% reduction (p=0.021) in risk of the primary endpoint compared to the atenolol group; this difference was primarily the result of an effect on fatal and nonfatal stroke. Treatment with Losartan (Losagen Combi) reduced the risk of stroke by 25% relative to atenolol (p=0.001).
Losartan (Losagen Combi) Potassium-Hydrochlorothiazide (Losagen Combi)
The 3 controlled studies of Losartan (Losagen Combi) and Hydrochlorothiazide (Losagen Combi) included over 1300 patients assessing the antihypertensive efficacy of various doses of Losartan (Losagen Combi) (25, 50 and 100 mg) and concomitant Hydrochlorothiazide (Losagen Combi) (6.25, 12.5 and 25 mg). A factorial study compared the combination of Losartan (Losagen Combi)/Hydrochlorothiazide (Losagen Combi) 50/12.5 mg with its components and placebo. The combination of Losartan (Losagen Combi)/Hydrochlorothiazide (Losagen Combi) 50/12.5 mg resulted in an approximately additive placebo-adjusted systolic/diastolic response (15.5/9.0 mmHg for the combination compared to 8.5/5.0 mmHg for Losartan (Losagen Combi) alone and 7.0/3.0 mmHg for Hydrochlorothiazide (Losagen Combi) alone). Another study investigated the dose-response relationship of various doses of Hydrochlorothiazide (Losagen Combi) (6.25, 12.5 and 25 mg) or placebo on a background of Losartan (Losagen Combi) (50 mg) in patients not adequately controlled (Sitting Diastolic Blood Pressure [SiDBP] 93-120 mmHg) on Losartan (Losagen Combi) (50 mg) alone. The third study investigated the dose-response relationship of various doses of Losartan (Losagen Combi) (25, 50 and 100 mg) or placebo on a background of Hydrochlorothiazide (Losagen Combi) (25 mg) in patients not adequately controlled (SiDBP 93-120 mmHg) on Hydrochlorothiazide (Losagen Combi) (25 mg) alone. These studies showed an added antihypertensive response at trough (24 hours post-dosing) of Hydrochlorothiazide (Losagen Combi) 12.5 or 25 mg added to Losartan (Losagen Combi) 50 mg of 5.5/3.5 and 10.0/6.0 mmHg, respectively. Similarly, there was an added antihypertensive response at trough when Losartan (Losagen Combi) 50 or 100 mg was added to Hydrochlorothiazide (Losagen Combi) 25 mg of 9.0/5.5 and 12.5/6.5 mmHg, respectively. There was no significant effect on heart rate.
There was no difference in response for men and women or in patients over or under 65 years of age.
Black patients had a larger response to Hydrochlorothiazide (Losagen Combi) than non-Black patients and a smaller response to Losartan (Losagen Combi). The overall response to the combination was similar for Black and non-Black patients.
Severe Hypertension (SiDBP ≥ 110 mmHg)
The safety and efficacy of Losagen Combi as initial therapy for severe hypertension (defined as a mean SiDBP ≥ 110 mmHg confirmed on 2 separate occasions off all antihypertensive therapy) was studied in a 6-week double-blind, randomized, multicenter study. Patients were randomized to either Losartan (Losagen Combi) and Hydrochlorothiazide (Losagen Combi) (50/12.5 mg, once daily) or to Losartan (Losagen Combi) (50 mg, once daily) and followed for blood pressure response. Patients were titrated at 2-week intervals if their SiDBP did not reach goal ( < 90 mmHg). Patients on combination therapy were titrated from Losartan (Losagen Combi) 50 mg/Hydrochlorothiazide (Losagen Combi) 12.5 mg to Losartan (Losagen Combi) 50 mg/Hydrochlorothiazide (Losagen Combi) 12.5 mg (sham titration to maintain the blind) to Losartan (Losagen Combi) 100 mg/Hydrochlorothiazide (Losagen Combi) 25 mg. Patients on monotherapy were titrated from Losartan (Losagen Combi) 50 mg to Losartan (Losagen Combi) 100 mg to Losartan (Losagen Combi) 150 mg, as needed. The primary endpoint was a comparison at 4 weeks of patients who achieved goal diastolic blood pressure (trough SiDBP < 90 mmHg).
The study enrolled 585 patients, including 264 (45%) females, 124 (21%) blacks, and 21 (4%) ≥ 65 years of age. The mean blood pressure at baseline for the total population was 171/113 mmHg. The mean age was 53 years. After 4 weeks of therapy, the mean SiDBP was 3.1 mmHg lower and the mean SiSBP was 5.6 mmHg lower in the group treated with Losagen Combi. As a result, a greater proportion of the patients on Losagen Combi reached the target diastolic blood pressure (17.6% for Losagen Combi, 9.4% for Losartan (Losagen Combi); p=0.006). Similar trends were seen when the patients were grouped according to gender, race or age ( <, ≥ 65).
After 6 weeks of therapy, more patients who received the combination regimen reached target diastolic blood pressure than those who received the monotherapy regimen (29.8% versus 12.5%).
References
- DailyMed. "AMLODIPINE BESYLATE; HYDROCHLOROTHIAZIDE; OLMESARTAN MEDOXOMIL: 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).
- 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).
Reviews
The results of a survey conducted on ndrugs.com for Losagen Combi 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 Losagen Combi. 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.User reports
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Information checked by Dr. Sachin Kumar, MD Pharmacology
