Dorin 2

Uses

Indapamide & Perindopril combination is used for essential hypertension.

Dorin 2 is also used to associated treatment for these conditions: High Blood Pressure (Hypertension), Recurrent Nephrolithiasis, Sodium and fluid retentionCardiovascular Events, Diabetic Nephropathy, High Blood Pressure (Hypertension), Hypertension,Essential, Myocardial Infarction, NYHA Class I Congestive heart failure, Stroke, Chronic heart failure with reduced ejection fraction (NYHA Class II), Chronic heart failure with reduced ejection fraction (NYHA Class III)

How Dorin 2 works

Indapamide acts on the nephron, specifically at the proximal segment of the distal convoluted tubule where it inhibits the Na+/Cl- cotransporter, leading to reduced sodium reabsorption. As a result, sodium and water are retained in the lumen of the nephron for urinary excretion. The effects that follow include reduced plasma volume, reduced venous return, lower cardiac output, and ultimately decreased blood pressure.

Interestingly, it is likely that thiazide-like diuretics such as indapamide have additional blood pressure lowering mechanisms that are unrelated to diuresis. This is exemplified by the observation that the antihypertensive effects of thiazides are sustained 4-6 weeks after initiation of therapy, despite recovering plasma and extracellular fluid volumes.

Some studies have suggested that indapamide may decrease responsiveness to pressor agents while others have suggested it can decrease peripheral resistance. Although it is clear that diuresis contributes to the antihypertensive effects of indapamide, further studies are needed to investigate the medication’s ability to decrease peripheral vascular resistance and relax vascular smooth muscle.

There are two isoforms of ACE: the somatic isoform, which exists as a glycoprotein comprised of a single polypeptide chain of 1277; and the testicular isoform, which has a lower molecular mass and is thought to play a role in sperm maturation and binding of sperm to the oviduct epithelium. Somatic ACE has two functionally active domains, N and C, which arise from tandem gene duplication. Although the two domains have high sequence similarity, they play distinct physiological roles. The C-domain is predominantly involved in blood pressure regulation while the N-domain plays a role in hematopoietic stem cell differentiation and proliferation. ACE inhibitors bind to and inhibit the activity of both domains, but have much greater affinity for and inhibitory activity against the C-domain. Perindoprilat, the active metabolite of perindopril, competes with ATI for binding to ACE and inhibits and enzymatic proteolysis of ATI to ATII. Decreasing ATII levels in the body decreases blood pressure by inhibiting the pressor effects of ATII as described in the Pharmacology section above. Perindopril also causes an increase in plasma renin activity likely due to a loss of feedback inhibition mediated by ATII on the release of renin and/or stimulation of reflex mechanisms via baroreceptors.

Dosage

Dorin 2 dosage

2 mg perindopril / 0.625 mg indapamide is indicated for the initial treatment of mild to moderate essential hypertension.

4 mg perindopril / 1.25 mg indapamide and 8 mg perindopril / 2.5 mg indapamide) are indicated in the treatment of mild to moderate essential hypertension in patients for whom combination therapy is appropriate.

4 mg perindopril / 1.25 mg indapamide and 8 mg perindopril / 2.5 mg indapamide are not indicated for initial therapy. Patients in whom perindopril and indapamide are initiated simultaneously can develop symptomatic hypotension.

Patients should be titrated on the individual drugs. If the fixed combination represents the dosage determined by this titration, the use of (4 mg perindopril / 1.25 mg indapamide) and (8 mg perindopril / 2.5 mg indapamide) may prove to be more convenient in the management of patients. If during maintenance therapy dosage adjustment is necessary, it is advisable to use individual drugs

The safety and efficacy of perindopril / indapamide in renovascular hypertension and in congestive heart failure have not been established and therefore, their use in this condition is not recommended.

Geriatrics (> 65 years of age): Although the blood pressure response and safety profile of in patients >65 years old were comparable to those of the younger adult patients, greater sensitivity of some elderly patients cannot be ruled out.

Pediatrics: The safety and effectiveness of in children have not been established. Its use in this age group, therefore, is not recommended.

Side Effects

Asthenia, dizziness, headache, mood swings and/or sleep disturbances, cramps, hypotension, allergic reactions, skin rashes, gastrointestinal disorders, dry cough, dry mouth, risk of dehydration in the elderly and in patients suffering from heart failure; changes in blood test results may occur.

Toxicity

Indapamide overdose symptoms may include but are not limited to nausea, vomiting, gastrointestinal disorders, electrolyte disturbances and weakness. Other signs of overdose include respiratory depression and severe hypotension. In cases of overdose, supportive care interventions may be necessary to manage symptoms. Emesis and gastric lavage may be recommended to empty the stomach; however, patients should be monitored closely for any electrolyte or fluid imbalances.

The most likely symptom of overdose is severe hypotension. The most common adverse effects observed in controlled clinical trials include cough, digestive symptoms, fatigue, headache, and dizziness.

Precaution

Disorders of electrolyte balance, diabetes, gout, hypotension, or strict sodium-free diets, heart or renal failure, atherosclerosis, renal artery stenosis, elderly.

Interaction

Increased risk of lithium toxicity. May cause and potentiate orthostatic hypotension when used with alcohol, barbiturates, neuroleptics, narcotics or other antihypertensives. Increased risk of acute renal insufficiency in dehydrated patients when used with systemic NSAIDs or high dose salicylates. May increase risk of hypoglycaemia in patients on concurrent treatment with hypoglycaemic sulfonamides/insulin. Concurrent use with baclofen may potentiate antihypertensive effect. May reduce antihypertensive effect when used with corticosteroids or tetracosactide. Increased risk of hyperkalaemia when used with potassium-sparing diuretics or potassium supplements. May increase hypotensive effect of certain anaesthetic drugs. Increased risk of leucopenia when used with allopurinol, immunosuppressants, procainamide or systemic corticosteoids. Additive hypotensive effect when used with other antihypertensives.

Volume of Distribution

Some sources report an apparent volume of distribution of 25 L for indapamide, while others report a value of approximately 60 L.

Elimination Route

The bioavailability of indapamide is virtually complete after an oral dose and is unaffected by food or antacids. Indapamide is highly lipid-soluble due to its indoline moiety - a characteristic that likely explains why indapamide’s renal clearance makes up less than 10% of its total systemic clearance. The Tmax occurs approximately 2.3 hours after oral administration. The Cmax and AUC_0-24 values are 263 ng/mL and 2.95 ug/hr/mL, respectively.

Rapidly absorbed with peak plasma concentrations occurring approximately 1 hour after oral administration. Bioavailability is 65-75%. Following absorption, perindopril is hydrolyzed to perindoprilat, which has an average bioavailability of 20%. The rate and extent of absorption is unaffected by food. However, food decreases the extent of biotransformation to peridoprilat and reduces its bioavailability by 35%.

Half Life

Indapamide is characterized by biphasic elimination. In healthy subjects, indapamide's elimination half-life can range from 13.9 to 18 hours. The long half-life is conducive to once-daily dosing.

Perindopril, 1.2 hours; Peridoprilat, 30-120 hours. The long half life of peridoprilat is due to its slow dissociation from ACE binding sites.

Clearance

Indapamide's renal and hepatic clearance values are reported to be 1.71 mL/min and 20-23.4 mL/min, respectively.

• 219 - 362 mL/min [oral administration]

Elimination Route

An estimated 60-70% of indapamide is eliminated in the urine, while 16-23% is eliminated in the feces.

Perindopril is extensively metabolized following oral administration, with only 4 to 12% of the dose recovered unchanged in the urine.

Pregnancy & Breastfeeding use

There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women OR Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester.

Contraindication

Absolute: Known allergy to perindopril Erbumine, indapamide, or sulfonamides; history of Quincke's edema linked to previous ACE inhibitor therapy; severe renal failure; serious liver disorder; hypokalemia; pregnancy; lactation.

Relative: Combination therapy with lithium, potassium salts, potassium-sparing diuretics, and certain medicines which can cause heart rhythm disorders.

Special Warning

Renal failure:

• Creatinine clearance (CrCl) >30 ml/min: No dosage modification.
• Creatinine clearance (CrCl) <30 ml/min: Treatment contraindicated.

Acute Overdose

Symptoms include hypotension, nausea, vomiting, cramps, dizziness, sleepiness mental confusion, oliguria which may progress to anuria. Salt and water disturbances (low sodium levels, low potassium levels) may also occur. Gastric lavage or administration of activated charcoal may be used to remove the ingested drug. Monitor and maintain fluid and electrolyte balance.

Storage Condition

Store below 30° C.

Innovators Monograph

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