Zione Ds L

Uses

Chlorthalidone is used for the management of hypertension. Chlorthalidone is used for adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis and corticosteroid and estrogen therapy.

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.

Zione Ds L is also used to associated treatment for these conditions: Calcium NephrolithiasisDiabetic Nephropathy, Heart Failure, High Blood Pressure (Hypertension), Marfan Syndrome, Stroke

How Zione Ds L works

Chlorthalidone prevents reabsorption of sodium and chloride through inhibition of the Na+/Cl- symporter in the cortical diluting segment of the ascending limb of the loop of Henle. Reduction of sodium reabsorption subsequently reduces extracellular fluid and plasma volume via an osmotic, sodium-driven diuresis. By increasing the delivery of sodium to the distal renal tubule, Chlorthalidone indirectly increases potassium excretion via the sodium-potassium exchange mechanism. The exact mechanism of chlorthalidone's anti-hypertensive effect is under debate, however, it is thought that increased diuresis results in decreased plasma and extracellular fluid volume which therefore requires decreased cardiac output and overall lowers blood pressure. Chlorthalidone has also been shown to decrease platelet aggregation and vascular permeability, as well as promote angiogenesis in vitro, which is thought to be partly the result of reductions in carbonic anhydrase–dependent pathways. These pathways may play a role in chlorthalidone's cardiovascular risk reduction effects.

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.

Dosage

Zione Ds L dosage

Therapy should be initiated with the lowest possible dose and then titrated according to individual patient response. A single dose given in the morning with food is recommended; divided doses are unnecessary.

Edema: Up to 50 mg daily.

Hypertension: 25 mg daily in the morning, increased to 50 mg daily if necessary.

Heart failure: 25-50 mg daily in the morning, increased if necessary to 100-200 mg daily (reduce to lowest effective dose for maintenance).

Maintenance doses may often be lower than initial doses and should be adjusted according to the individual patient.

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.

Side Effects

Dry mouth, thirst, nausea, vomiting, feeling weak, drowsy, restless, or light-headed, fast or uneven heartbeat, muscle pain or weakness, urinating less than usual or not at all, easy bruising or bleeding, unusual weakness, red or purple spots on skin, numbness or tingly feeling, nausea, stomach pain, low fever, loss of appetite, dark urine, clay-colored stools.

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.

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.

Precaution

Renal impairment: Chlorthalidone dosage should be reduced in moderate renal failure - every 24 or 48 h - and should not be used in advanced renal failure.

Liver disease: There is a risk of precipitating hepatic encephalopathy in patients with liver cirrhosis and ascites.

Use in pregnancy: It is better to avoid Chlorthalidone as it crosses the placenta.

Use in Lactation: In lactating mother, significant amount of Chlorthalidone enter breast milk; like other long-acting thiazides, it can suppress lactation. Chlorthalidone should not be prescribed for lactating mother.

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

Interaction

Chlorthalidone may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs with ganglionic peripheral adrenergic blocking drugs.

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.

Volume of Distribution

Chlorthalidone has been shown to rapidly concentrate within erythrocytes and subsequently equilibrate via a slow diffusion back into the serum compartment, resulting in a large 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.

Half Life

40-50 hours

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.

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

Approximately 50% of the administered dose is excreted unmetabolized through the kidney, and excretion is characterized by biphasic elimination with a rapid phase followed by a slow secretory phase.

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.

Pregnancy & Breastfeeding use

Pregnancy category B. Thiazides are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from chlorthalidone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

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.

Contraindication

Patients with anuria and known hypersensitivity to Chlorthalidone or other sulfonamide-derived drugs.

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.

Special Warning

Pediatric Use: Safety and effectiveness of Chlorthalidone tablets in pediatric patients have not been established.

Geriatric Use: Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

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

Symptoms of acute overdosage include nausea, weakness, dizziness, and disturbances of electrolyte balance. The oral LD50 of the drug in the mouse and the rat is more than 25,000 mg/kg body weight. The minimum lethal dose (MLD) in humans has not been established. There is no specific antidote, but gastric lavage is recommended, followed by supportive treatment. Where necessary, this may include intravenous dextrose-saline with potassium, administered with caution.

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.

Storage Condition

Store in a cool & dry place, away from children

Store between 15-30°C

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