Adpep R

Adpep R Uses, Dosage, Side Effects, Food Interaction and all others data.

Losartan, the first of a new class of antihypertensives, is a specific and selective antagonist of angiotensin II at the AT1 sites. Angitensin II is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system and an important component in the pathophysiology of hypertension. Losartan and its principal active metabolite block the vasoconstriction and aldosterone secreting effects of angiotensin II to the AT1 receptor found in many tissues. Losartan is now regarded as the first-line therapy option for treating high blood pressue.

Losartan is an angiotensin II receptor blocker used to treat hypertension, diabetic nephropathy, and to reduce the risk of stroke. Losartan has a long duration of action as it is given once daily. Patients taking losartan should be regularly monitored for hypotension, renal function, and potassium levels.

Perindopril is an ACE inhibitor. It works by blocking the action of angiotensin converting enzyme (ACE). ACE produces angiotensin II, as part of the body's natural control of blood pressure. Angiotensin II causes blood vessels to constrict and narrow, which increases the pressure within the blood vessels. Perindopril blocks the action of ACE, it reduces the production of angiotensin II, thus allows the blood vessels to relax and widen. The overall effect of this is a drop in blood pressure.

Perindopril is a nonsulfhydryl prodrug that is metabolized via first pass effect (62%) and systemic hydrolysis (38%) to perindoprilat, its active metabolite, following oral administration. Perindoprilat lowers blood pressure by antagonizing the effect of the RAAS. The RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from the granular cells of the juxtaglomerular apparatus in the kidneys. In the blood stream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE. ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Third, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of the Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. Inhibiting the deactivation of bradykinin increases bradykinin levels and may sustain the effects of perindoprilat by causing increased vasodilation and decreased blood pressure.

Adpep R
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Adpep R
Generic	Perindopril + Losartan
Type	Tablet
Therapeutic Class
Manufacturer
Available Country	India
Last Updated:	September 19, 2023 at 7:00 am

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.

Perindopril is a long-acting ACE (Angiotensin Converting Enzyme) inhibitor and is used for Essential hypertension, Stable coronary artery disease, Congestive heart failure.

Adpep R is also used to associated treatment for these conditions: Diabetic Nephropathy, Heart Failure, High Blood Pressure (Hypertension), Marfan Syndrome, StrokeCardiovascular 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 Adpep R 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.

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

Adpep R 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.

Hypertension: One Perindopril 4 tablet once daily preferably in the morning. If necessary, the dose may be increased to 8 mg after 1 month of treatment. Perindopril should be taken before food.

Stable coronary artery disease: Perindopril 4 once daily for two weeks, then increased to 8 mg once daily, depending on renal function and provided that the 4 mg dose is well tolerated. Elderly patients should receive Perindopril 2 mg once daily for one week, then Perindopril 4 once daily the next week, before increasing the dose up to 8 mg once daily, depending on renal, function. The dose should be increased only if the previous lower dose is well tolerated.

Congestive heart failure: Perindopril should be started under close medical supervision at a starting dose of 2 mg in the morning. If necessary dose may be increased to 4 mg.

Elderly patients: Start treatment at Perindopril 2 mg daily.

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.

Rare and mild: usually at the start of treatment cough, fatigue, asthenia, headache, disturbances of mood and/or sleep have been reported.

Less often: Taste impairment, epigastric discomfort, nausea, abdominal pain and rash. Reversible increase in blood urea and creatinine may be observed. Proteinuria has occurred in some patients.

Rarely: Angioneurotic edema and decrease in hemoglobin, red cells and platelets have been reported.

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.

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

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

In the following cases, Perindopril should be used with caution:

Renovascular hypertension
Surgery/Anesthesia
Renal failure: The dose should be cautiously adjusted in accordance with the creatinine clearance
Symptomatic hypotension is rarely seen, but is more likely in volume-depleted patients, those receiving diuretics, or with the first two doses
In diuretic-treated patients: stop the diuretic 3 days before starting Perindopril. A diuretic may later be given in combination if necessary; potassium-sparing diuretics are not recommended
Combination with neuroleptics or imipramine-type drugs may increase the hypotensive effect. Serum lithium concentrations may rise during lithium therapy

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.

May enhance hypotensive effect with diuretics. Additive hyperkalaemic effect with K supplements, K-sparing diuretics, and other drugs (e.g. ciclosporin, heparin, indometacin). May increase serum levels and toxicity of lithium. Antihypertensive effect may be reduced by aspirin or other NSAIDs. Coadministration with NSAIDs may also increase the risk of renal impairment. Increased risk of hypoglycaemia with antidiabetic agents. Rarely, nitritoid reactions occur with concomitant use of gold (Na aurothiomalate).

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.

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

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.

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

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.

219 - 362 mL/min [oral administration]

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.

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

Perindopril should not be used during pregnancy & lactation.

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.

Perindopril is contraindicated in patients with a history of hypersensitivity to Perindopril. This drug is contraindicated in case of management of hypertension of Children, during Pregnancy & Lactation.

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: Hypotension, bradycardia, circulatory shock, renal failure, hyperventilation, electrolyte disturbances, tachycardia, palpitations, dizziness, anxiety, and cough.

Management: Symptomatic and supportive. IV infusion of NaCl 0.9%. Treatment with angiotensin II infusion and/or IV catecholamines may also be considered. Haemodialysis may be beneficial.