Anin Plus

Uses

Losartan, an angiotensin II receptor blocker (ARB) and hydrochlorothiazide, a diuretic used for:

• Treatment of hypertension, to lower blood pressure. 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

Anin Plus is also used to associated treatment for these conditions: Acidosis, Renal Tubular, Calcium Nephrolithiasis, Cirrhosis of the Liver, Congestive Heart Failure (CHF), Diabetes Insipidus, Edema, High Blood Pressure (Hypertension), Hypertension,Essential, Hypokalemia caused by diuretics, Nephrotic Syndrome, Premenstrual tension with edema, Sodium retention, Stroke, Prophylaxis of preeclampsiaDiabetic Nephropathy, Heart Failure, High Blood Pressure (Hypertension), Marfan Syndrome, Stroke

How Anin Plus works

Hydrochlorothiazide is transported from the circulation into epithelial cells of the distal convoluted tubule by the organic anion transporters OAT1, OAT3, and OAT4. From these cells, hydrochlorothiazide is transported to the lumen of the tubule by multidrug resistance associated protein 4 (MRP4).

Normally, sodium is reabsorbed into epithelial cells of the distal convoluted tubule and pumped into the basolateral interstitium by a sodium-potassium ATPase, creating a concentration gradient between the epithelial cell and the distal convoluted tubule that promotes the reabsorption of water.

Hydrochlorothiazide acts on the proximal region of the distal convoluted tubule, inhibiting reabsorption by the sodium-chloride symporter, also known as Solute Carrier Family 12 Member 3 (SLC12A3). Inhibition of SLC12A3 reduces the magnitude of the concentration gradient between the epithelial cell and distal convoluted tubule, reducing the reabsorption of water.

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

Anin Plus dosage

Hypertension:

• Usual starting dose: 50/12.5 mg once daily. Titrate as needed to a maximum dose of 100/25 mg.

Hypertensive Patients with Left Ventricular Hypertrophy:

• Not controlled on monotherapy: Initiate with 50/12.5 mg. Titrate as needed to a maximum of 100/25 mg.

Dosing must be individualised. The usual starting dose of Losartan is 50 mg once daily, with 25 mg recommended for patients with intravascular volume depletion (e.g., patients treated with diuretics) and patients with a history of hepatic impairment. Losartan can be administered once or twice daily at total daily doses of 25 to 100 mg. If the antihypertensive effect measured trough using once a day dosing is inadequate, a twice a day regimen at the same total daily dose or an increase in dose may give a more satisfactory response.

Hydrochlorothiazide is effective in doses of 12.5 to 50 mg once daily and can be given at doses of 12.5 to 25 mg. To minimise dose independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy

Side Effects

Abdominal pain, Edema/swelling, Palpitation, Back pain, Dizziness, Cough, Sinusitis, Upper respiratory tract infection, rash etc.

Toxicity

The oral LD₅₀ of hydrochlorothiazide is >10g/kg in mice and rats.

Patients experiencing an overdose may present with hypokalemia, hypochloremia, and hyponatremia. Treat patients with symptomatic and supportive treatment including fluids and electrolytes. Vasopressors may be administered to treat hypotension and oxygen may be given for respiratory impairment.

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

Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance: hyponatraemia, hypochloraemic alkalosis, and hypokalaemia. Because Losartan decreases uric acid, Losartan in combination with Hydrochlorothiazide attenuates the diuretic-induced hyperuricaemia. In diabetic patients dosage adjustments of Insulin or oral hypoglycaemic agents may be required. Hyperglycaemia may occur with thiazide diuretics. The antihypertensive effects of the drug may be enhanced in the post-sympathectomy patient. If progressive renal impairment becomes evident, consider withholding or discontinuing diuretic therapy. Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesaemia. Thiazides may decrease urinary calcium excretion. Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy

Interaction

Losartan, administered for 12 days, did not affect the pharmacokinetics or pharmacodynamics of a single dose of Warfarin. Losartan did not affect the pharmacokinetics of oral or intravenous Digoxin. Coadministration of Losartan and Cimetidine led to an increase of about 18% in AUC of Losartan but did not affect the pharmacokinetics of its active metabolite. Coadministration of Losartan and Phenobarbital led to a reduction of about 20% in the AUC of Losartan and that of its active metabolite. Hydrochlorothiazide when administered concurrently may interact with drugs like alcohol, barbiturates, or narcotics. Antidiabetic drugs (oral agents and insulin) require dosage adjustment. Lithium should not generally be given with diuretics. In some patients, the administration of NSAIDs can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics.

Volume of Distribution

The volume of distribution varies widely from one study to another with values of 0.83-4.19L/kg.

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

Elimination Route

An oral dose of hydrochlorothiazide is 65-75% bioavailable, with a T_max of 1-5 hours, and a C_max of 70-490ng/mL following doses of 12.5-100mg. When taken with a meal, bioavailability is 10% lower, C_max is 20% lower, and T_max increases from 1.6 to 2.9 hours.

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

The plasma half life of hydrochlorothiazide is 5.6-14.8h.

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

The renal clearance of hydrochlorothiazide in patients with normal renal function is 285mL/min. Patients with a creatinine clearance of 31-80mL/min have an average hydroxychlorothiazide renal clearance of 75mL/min, and patients with a creatinine clearance of ≤30mL/min have an average hydroxychlorothiazide renal clearance of 17mL/min.

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

Hydrochlorothiazide is eliminated in the urine as unchanged hydrochlorothiazide.

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

When pregnancy is detected, Losartan & Hydrochlorothiazide should be discontinued as soon as possible. It is not known whether Losartan is excreted in human milk. Thiazides appear in human milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Contraindication

This combination is contraindicated in patients who are hypersensitive to any component of this product. Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.

Special Warning

Use in pediatric patients: The safety and effectiveness in paediatric patients have not been established.

Use in patients with renal impairment: The usual regimens of therapy with Losartan & Hydrochlorothiazide may be followed as long as the patient’s creatinine clearance is >30 mL/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so Losartan & Hydrochlorothiazide is not recommended.

Patients with hepatic impairment: Losartan & Hydrochlorothiazide is not recommended for titration in patients with hepatic impairment because the appropriate 25 mg starting dose of losartan cannot be given.

Acute Overdose

Limited data are available in regard to overdosage of Losartan Potassium in humans. The most likely manifestations of overdosage would be hypotension, tachycardia, and bradycardia. If symptomatic hypotension occurs, supportive treatment should be instituted. Neither Losartan nor its active metabolite can be removed by hemodialysis. The most common signs and symptoms observed for Hydrochlorothiazide are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis.

Storage Condition

Store in a cool dry place protected from light. Keep out of reach of children.

Innovators Monograph

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