REVIEW: COMBINED CANDESARTAN CILEXETIL AND PIOGLITAZONE HYDROCHLORIDE THERAPY IN METABOLIC SYNDROME

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This review article presents the pharmacology of combined Candesartan Cilexetil and Pioglitazone Hydrochloride therapy specially in Metabolic syndrome. Candesartan Cilexetil is a antihypertensive agent. Pioglitazone Hydrochloride is a selectively stimulates nuclear receptor peroxisome proliferator activated receptor gamma (PPAR-gamma). The use of Candesartan Cilexetil in combination with Pioglitazone Hydrochloride has been proved to provide beneficial effect (Synergistic effect) in metabolic syndrome. The mechanism of Candesartan Cilexetil and Pioglitazone Hydrochloride is quite different. The combination of both also have anti inflammatory and enhanced organ protective effects. The main objective of this review article is to provide pharmacological information of combined therapy of Candesartan Cilexetil and Pioglitazone Hydrochloride to researcher in development of combined dosage form of this combination.

I) Insulin resistance

The most accepted hypothesis to describe the pathophysiology of the metabolic syndrome is insulin resistance. That is why the metabolic syndrome is also known as the insulin resistance syndrome. Insulin resistance has been defined as a defect in insulin action that results in hyperinsulinaemia, necessary to maintain euglycaemia. Concept of insulin resistance provides a conceptual framework with which to place a substantial number of apparently unrelated biological events into a pathophysiological construct. A major contributor to the development of insulin resistance is an overabundance of circulating fatty acids, released from an expanded adipose tissue mass. FFA reduce insulin sensitivity in muscle by inhibiting insulin-mediated glucose uptake. Increased level of circulating glucose increases pancreatic insulin secretion resulting in hyperinsulinemia. In the liver, FFA increase the production of glucose, triglycerides and secretion of very low density lipoproteins (VLDL). The consequence is the reduction in glucose transformation to glycogen and increased lipid accumulation in triglyceride (TG). Insulin is an important antilipolytic hormone. In the case of insulin resistance, the increased amount of lipolysis of stored triacylglycerol molecules in adipose tissue produces more fatty acids, which could further inhibit the antilipolytic effect of insulin, creating additional lipolysis.

II) Hypertension 

The relation between insulin resistance and hypertension is well established. Several different mechanisms are proposed. First, insulin is a vasodilator when given intravenously to people of normal weight, with secondary effects on sodium reabsorption in the kidney. In the setting of insulin resistance, the vasodilatory effect of insulin can be lost, but the renal effect on sodium reabsorption preserved. Fatty acids themselves can mediate relative vasoconstriction. Hyperinsulinaemia may result in increased sympathetic nervous system (SNS) activity and contribute to the development of hypertension.

III) Obesity and increased waist circumference 

Metabolic syndrome include abdominal obesity, pathogenesis of the metabolic syndrome and its components is complex, abdominal obesity is a key causative factor, metabolically obese, normal-weight individuals, having increased amount of visceral adipose tissue. According to some theories, with increases in visceral adipose tissue, a higher rate of flux of adipose tissue-derived free fatty acids to the liver through the splanchnic circulation would be expected, while increases in abdominal subcutaneous fat could release lipolysis products into the systemic circulation and avoid more direct effects on hepatic metabolism.

CANDESARTAN CILEXETIL

Chemical name:- (1RS)-1-(cyclohexyloxycarbonyloxy)ethyl-2-ethoxy-1-{[2’-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-benzo[d]imidazole-7-carboxylate. A Imidazole derivativeappearsas White crystals or white crystalline powder. [4] The drug is Practically insoluble in water and Sparingly soluble in methanol.Melting point about 163 ºC [5]. The pKa value is about 5.3

PHARMACOKINETIC AND PHARMACODYNAMIC PROFILE

Absorption
Candesartan cilexetil is a prodrug. It rapidly and completely bioactivated by ester hydrolysis during absorption from the gastrointestinal tract to candesartan. The absolute bioavaibility of Candesartan was estimated to be 15% after administration of the Candesartan cilexetil available as prodrug. Food with a high fat content has no affect on the bioavaibility of candesartan from candesartan cilexetil.

Distribution
The volume of distribution of candesartan is 0.13 L/kg. Candesartan is highly bound to plasma proteins about >99% and does not penetrate Red Blood Cells.

Metabolism and Excreation
Total plasma clearance of Candesartan is 0.37 ml/min/kg and renal clearance about 0.19 ml/min/kg. Candesartan when administered orally, about 26% of the dose is excreated unchanged in urine. For oral dose of 14C-labled Candesartan about 33% of radioactivity is recovered in urine and about 67% in feces. For Intravenous dose of it shows 59% of radioactivity is recovered in urine and about 36% in feces. Biliary system also contributes in elimination of candesartan.

Pharmacodynamic

Candesartan inhibits the pressur effects of angiotensin II infusion in a dose-dependent manner. After 1 week of once-daily dosing with 8 mg of candesartan cilexetil, the effect of pressur was inhibited by approximately 90% at peak with approximately 50% inhibition persisting for 24 h. In a dose dependent manner after single and repeated administration of Candesartan cilexetil to healthy subjects and hypertensive patients increases plasma concentrations of angiotensin I and angiotensin II as well as plasma rennin activity. Plasma aldosterone concentrations did not influence by the once-daily administration of up to 16 mg of Candesartan cilexetil to healthy subjects, but when 32 mg of Candesartan cilexetil was administered to hypertensive patients it was observed that decrease in the plasma concentration of aldosterone.

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