Candesartan Cilexetil and Hydrochlorothiazide

CANDESARTAN CILEXETIL AND HYDROCHLOROTHIAZIDE- candesartan cilexetil and hydrochlorothiazide tablet
REMEDYREPACK INC.

WARNING: FETAL TOXICITY

  • When pregnancy is detected, discontinue candesartan cilexetil and hydrochlorothiazide tablets as soon as possible.
  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. See Warnings: Fetal Toxicity

DESCRIPTION

Candesartan Cilexetil and Hydrochlorothiazide Tablets USP combine an angiotensin II receptor (type AT 1 ) antagonist and a diuretic, hydrochlorothiazide.

Candesartan cilexetil, a nonpeptide, is chemically described as (±)-1-Hydroxyethyl 2-ethoxy-1-[ p -( o -1 H -tetrazol-5-ylphenyl)benzyl]-7-benzimidazolecarboxylate, cyclohexyl carbonate (ester).

Its empirical formula is C 33 H 34 N 6 O 6 and its structural formula is:

Chemical Structure for Candesartan cilexetil
(click image for full-size original)

Candesartan cilexetil is a white to off-white powder with a molecular weight of 610.67. It is practically insoluble in water and sparingly soluble in methanol. Candesartan cilexetil is a racemic mixture containing one chiral center at the cyclohexyloxycarbonyloxy ethyl ester group. Following oral administration, candesartan cilexetil undergoes hydrolysis at the ester link to form the active drug, candesartan, which is achiral.

Hydrochlorothiazide is 6-chloro-3,4-dihydro-2 H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C 7 H 8 ClN 3 O 4 S 2 and its structural formula is:

Chemical Structure for Hydrochlorothiazide

Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight of 297.72, which is slightly soluble in water, but freely soluble in sodium hydroxide solution.

Candesartan cilexetil and hydrochlorothiazide tablets are available for oral administration in three tablet strengths of candesartan cilexetil and hydrochlorothiazide.

Candesartan cilexetil and hydrochlorothiazide tablets contain 16 mg or 32 mg of candesartan cilexetil and 12.5 mg or 25 mg of hydrochlorothiazide providing for the following available combinations: 16 mg/12.5 mg, 32 mg/12.5 mg or 32 mg/25 mg. The inactive ingredients of the tablets are carboxymethylcellulose calcium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, corn starch, polyethylene glycol 8000, and ferric oxide (yellow). Ferric oxide (reddish brown) is also added to the 16 mg/12.5 mg and 32 mg/25 mg tablets as colorant.

CLINICAL PHARMACOLOGY

Mechanism of Action

Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Candesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT 1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is, therefore, independent of the pathways for angiotensin II synthesis.

There is also an AT 2 receptor found in many tissues, but AT 2 is not known to be associated with cardiovascular homeostasis. Candesartan has much greater affinity (>10,000-fold) for the AT 1 receptor than for the AT 2 receptor.

Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because candesartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Candesartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of candesartan on blood pressure.

Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so co‑administration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics.

The mechanism of the antihypertensive effect of thiazides is unknown.

Pharmacokinetics

General

Candesartan Cilexetil

Candesartan cilexetil is rapidly and completely bioactivated by ester hydrolysis during absorption from the gastrointestinal tract to candesartan, a selective AT 1 subtype angiotensin II receptor antagonist. Candesartan is mainly excreted unchanged in urine and feces (via bile). It undergoes minor hepatic metabolism by O-deethylation to an inactive metabolite. The elimination half-life of candesartan is approximately 9 hours. After single and repeated administration, the pharmacokinetics of candesartan are linear for oral doses up to 32 mg of candesartan cilexetil. Candesartan and its inactive metabolite do not accumulate in serum upon repeated once-daily dosing.

Following administration of candesartan cilexetil, the absolute bioavailability of candesartan was estimated to be 15%. After tablet ingestion, the peak serum concentration (C max ) is reached after 3 to 4 hours. Food with a high fat content does not affect the bioavailability of candesartan after candesartan cilexetil administration.

Hydrochlorothiazide

When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours.

Metabolism and Excretion

Candesartan Cilexetil

Total plasma clearance of candesartan is 0.37 mL/min/kg, with a renal clearance of 0.19 mL/min/kg. When candesartan is administered orally, about 26% of the dose is excreted unchanged in urine. Following an oral dose of 14 C-labeled candesartan cilexetil, approximately 33% of radioactivity is recovered in urine and approximately 67% in feces. Following an intravenous dose of 14 C-labeled candesartan, approximately 59% of radioactivity is recovered in urine and approximately 36% in feces. Biliary excretion contributes to the elimination of candesartan.

Hydrochlorothiazide

Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. At least 61% of the oral dose is eliminated unchanged within 24 hours.

Distribution

Candesartan Cilexetil

The volume of distribution of candesartan is 0.13 L/kg. Candesartan is highly bound to plasma proteins (>99%) and does not penetrate red blood cells. The protein binding is constant at candesartan plasma concentrations well above the range achieved with recommended doses. In rats, it has been demonstrated that candesartan crosses the blood-brain barrier poorly, if at all. It has also been demonstrated in rats that candesartan passes across the placental barrier and is distributed in the fetus.

Hydrochlorothiazide

Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

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