Metoz L

Uses

Losartan is an angiotensin II receptor blocker (ARB) used for:

• Treatment of hypertension, to lower blood pressure in adults and children greater than 6 years old. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.
• Reduction of the risk of stroke in patients with hypertension and left ventricular hypertrophy. There is evidence that this benefit does not apply to Black patients.
• Treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria in patients with type 2 diabetes and a history of hypertension.

Metolazone is used for the treatment of salt and water retention including:

• Edema accompanying congestive heart failure
• Edema accompanying renal diseases, including the nephrotic syndrome and states of diminished renal function.

Metolazone is also used for the treatment of hypertension, alone or in combination with other antihypertensive drugs of a different class.

Metoz L is also used to associated treatment for these conditions: Diabetic Nephropathy, Heart Failure, High Blood Pressure (Hypertension), Marfan Syndrome, StrokeEdema, Mild Hypertension, Moderate Hypertension

How Metoz L works

Losartan reversibly and competitively prevents angiotensin II binding to the AT₁ receptor in tissues like vascular smooth muscle and the adrenal gland. Losartan and its active metabolite bind the AT₁ receptor with 1000 times more affinity than they bind to the AT₂ receptor. The active metabolite of losartan is 10-40 times more potent by weight than unmetabolized losartan as an inhibitor of AT₁ and is a non-competitive inhibitor. Losartan's prevention of angiotensin II binding causes vascular smooth muscle relaxation, lowering blood pressure.

Angiotensin II would otherwise bind to the AT₁ receptor and induce vasoconstriction, raising blood pressure.

The actions of metolazone result from interference with the renal tubular mechanism of electrolyte reabsorption. Metolazone acts primarily to inhibit sodium reabsorption at the cortical diluting site and to a lesser extent in the proximal convoluted tubule. Sodium and chloride ions are excreted in approximately equivalent amounts. The increased delivery of sodium to the distal tubular exchange site results in increased potassium excretion. Metolazone does not inhibit carbonic anhydrase. The antihypertensive mechanism of action of metolazone is not fully understood but is presumed to be related to its saluretic and diuretic properties.

Dosage

Metoz L dosage

Hypertension:

• Usual adult dose: 50 mg once daily.
• Usual pediatric starting dose: 0.7 mg per kg once daily (up to 50 mg).

Hypertensive Patients with Left Ventricular Hypertrophy:

• Usual starting dose: 50 mg once daily.
• Add hydrochlorothiazide 12.5 mg and/or increase Losartan to 100 mg followed by an increase to hydrochlorothiazide 25 mg if further blood pressure response is needed.

Nephropathy in Type 2 Diabetic Patients:

• Usual dose: 50 mg once daily.
• Increase dose to 100 mg once daily if further blood pressure response is needed.

Use in elderly:

• Patients up to 75 years: No initial dosage adjustment is necessary for this group of patients.
• Patients over 75 years: A lower starting dose of 25 mg once daily is recommended.

Effective dosage of Metolazone tablets should be individualized according to indication and patient response. A single daily dose is recommended. Therapy with Metolazone tablets should be titrated to gain an initial therapeutic response and to determine the minimal dose possible to maintain the desired therapeutic response.

Usual Single Daily Dosage Schedules: Suitable initial dosages will usually fall in the ranges given.

Edema of Cardiac Failure: Metolazone tablets 5 to 20 mg once daily.

Edema of Renal Disease: Metolazone tablets 5 to 20 mg once daily.

Mild to Moderate Essential Hypertension: Metolazone tablets 2.5 to 5 mg once daily.New patients- If considered desirable to switch patients currently on Zaroxolyn tablets and other formulations of Metolazone that share its slow and incomplete bioavailability to Mykrox , the dose should be determined by titration starting at one tablet (0.5 mg) once daily and increasing to two tablets (1 mg) once daily if needed.

Treatment Of Edematous States: The time interval required for the initial dosage to produce an effect may vary.Diuresisand saluresis usually begin within one hour and persist for 24 hours or longer. When a desired therapeutic effect has been obtained, it may be advisable to reduce the dose if possible. The daily dose depends on the severity of the patient's condition, sodium intake, and responsiveness. A decision to change the daily dose should be based on the results of thorough clinical and laboratory evaluations. If antihypertensive drugs or diuretics are given concurrently with Metolazone tablets, more careful dosage adjustment may be necessary. For patients who tend to experience paroxysmal nocturnaldyspnea, it may be advisable to employ a larger dose to ensure prolongation of diuresis and saluresis for a full 24-hour period.

Treatment Of Hypertension: The time interval required for the initial dosage regimen to show effect may vary from three or four days to three to six weeks in the treatment of elevated blood pressure. Doses should be adjusted at appropriate intervals to achieve maximum therapeutic effect.

Side Effects

In controlled clinical trials in patients with essential hypertension, dizziness was the only side effect reported that occurred with an incidence greater than placebo in 1% or more of patients treated with Losartan. Rarely, rash was reported although the incidence in controlled clinical trials was less than placebo. Angioedema, involving swelling of the face, lips and/or tongue has been reported rarely in patients treated with Losartan. Serious hypotension (particularly on initiating treatment in salt-depleted patients) or renal failure (mainly in patients with renal artery stenosis) may be encountered during Losartan treatment.

Chest pain, palpitation, necrotising angiitis, orthostatic hypotension, syncope, venous thrombosis, vertigo, volume depletion; depression, dizziness, chills, drowsiness, fatigue, restlessness, headache, lightheadedness; petechiae, photosensitivity, hypersensitivity reactions; gout attacks, electrolyte disturbances; abdominal bloating, diarrhoea, abdominal pain, anorexia, constipation, epigastric distress, nausea, xerostomia, pancreatitis, vomiting; impotence; aplastic anaemia, thrombocytopenia, haemoconcentration, leukopenia; cholestatic jaundice, hepatitis; joint pain, muscle cramps, weakness, neuropathy, paraesthesia; blurred vision; increased BUN, glucosuria.

Toxicity

The oral TDLO in mice is 1000mg/kg and in rats is 2000mg/kg. In humans the TDLO for men is 10mg/kg/2W and for women is 1mg/kg/1D.

Symptoms of overdose are likely to include hypotension, tachycardia, or bradycardia due to vagal stimulation. Supportive treatment should be instituted for symptomatic hypotension. Hemodialysis will not remove losartan or its active metabolite due to their high rates of protein binding.

Symptoms of overdose include difficulty breathing, dizziness, dizziness on standing up, drowsiness, fainting, irritation of the stomach and intestines, and lethargy leading to coma.

Precaution

A lower dose should be considered for patients with a history of hepatic and renal impairment. Losartan should not be used with potassium-sparing diuretic

Pre-diabetes or DM; gout; SLE; hepatic and renal impairment; hypercholesterolaemia. Correct electrolyte disturbances prior to therapy. Risk of cross-sensitivity with sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides and loop diuretics. Lactation.

Interaction

No drug interaction of clinical significance has been identified. Compounds which have been studied in clinical pharmacokinetic trials include hydrochlorothiazide, digoxin, warfarin, cimetidine, ketoconazole and phenobarbital.

Hypotensive and nephrotoxic effects of ACE inhibitors may be enhanced. Absorption may be reduced with bile acid sequestrants. Hyperglycaemic effect may be enhanced with diazoxide. May increase serum concentration and QTc-prolonging effect of dofetilide. May reduce lithium excretion. Hypotensive effect may be increased with alcohol.

Volume of Distribution

The volume of distribution of losartan is 34.4±17.9L and 10.3±1.1L for the active metabolite (E-3174).

Elimination Route

Losartan is approximately 33% orally bioavailable. Losartan has a T_max of 1 hour and the active metabolite has a T_max of 3-4 hours. Taking losartan with food decreases the C_max but does only results in a 10% decrease in the AUC of losartan and its active metabolite. A 50-80mg oral dose of losartan leads to a C_max of 200-250ng/mL.

Peak blood levels are obtained within 2 to 4 hours of oral administration. The rate and extent of absorption are formulation dependent.

Half Life

The terminal elimination half life of losartan is 1.5-2.5 hours while the active metabolite has a half life of 6-9 hours.

Approximately 14 hours.

Clearance

Losartan has a total plasma clearance of 600mL/min and a renal clearance of 75mL/min. E-3174, the active metabolite, has a total plasma clearance of 50mL/min and a renal clearance of 25mL/min.

Elimination Route

A single oral dose of losartan leads to 4% recovery in the urine as unchanged losartan, 6% in the urine as the active metabolite. Oral radiolabelled losartan is 35% recovered in urine and 60% in feces. Intravenous radiolabelled losartan is 45% recovered in urine and 50% in feces.

Most of the drug is excreted in the unconverted form in the urine.

Pregnancy & Breastfeeding use

Although there is no experience with the use of Losartan in pregnant women, animal studies with Losartan potassium have demonstrated fetal and neonatal injury and death, the mechanism of which is believed to be pharmacologically mediated through effects on the renin angiotensinaldosterone system. Losartan should not be used in pregnancy and if pregnancy is detected Losartan should be discontinued as soon as possible.

It is not known whether Losartan is excreted in human breast milk. However, significant level of Losartan found in rat milk which suggests that the drug should not be used in lactating mother.

Pregnancy Category B: Either animal-reproduction studies have not demonstrated a foetal risk but there are no controlled studies in pregnant women or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the 1st trimester (and there is no evidence of a risk in later trimesters).

If used in gestational HTN: Pregnancy Category D: There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Contraindication

It is also contraindicated to patients who are hypersensitive to any component of this product. In patients who are intravenously volume depleted (e.g. those treated with high dose diuretics), symptomatic hypotension may occur. These conditions Losartan potassium should be corrected prior to administer Losartan or a lower starting dose (usually 25 mg) should be used.

Anuria; hepatic coma or pre-coma. Pregnancy.

Special Warning

No initial dosage adjustment is necessary in patients with mild renal impairment (CrCl 20-50 ml/min). For patients with moderate to severe renal impairment (CrCl <20 ml/min) or patients on dialysis, a lower starting dose of 25 mg is recommended.

Acute Overdose

Limited data are available regarding overdose in humans. The most likely manifestation of overdose would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. Supportive treatment should include repletion of the intravascular volume. Neither Losartan nor the active metabolite can be removed by hemodialysis.

Symptoms: Orthostatic hypotension, dizziness, drowsiness, syncope, haemoconcentration and haemodynamic changes due to plasma volume depletion.

Management: Symptomatic and supportive.

Storage Condition

Store between 15-30°C

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