METOPROLOL TARTRATE AND HYDROCHLOROTHIAZIDE- metoprolol tartrate and hydrochlorothiazide tablet
Mylan Pharmaceuticals Inc.
Metoprolol tartrate and hydrochlorothiazide tablets, USP have the antihypertensive effect of metoprolol tartrate, a selective beta1 -adrenoreceptor blocking agent, and the antihypertensive and diuretic actions of hydrochlorothiazide. It is available as tablets for oral administration. The 50 mg/25 mg tablets contain 50 mg of metoprolol tartrate and 25 mg of hydrochlorothiazide; the 100 mg/25 mg tablets contain 100 mg of metoprolol tartrate and 25 mg of hydrochlorothiazide; and the 100 mg/50 mg tablets contain 100 mg of metoprolol tartrate and 50 mg of hydrochlorothiazide. Metoprolol tartrate is (±)-1-(Isopropylamino)-3-[p -(2-methoxyethyl)phenoxy]-2-propanol L-(+)-tartrate (2:1) salt, and its structural formula is:
Metoprolol tartrate, USP is a white, crystalline powder. It is very soluble in water; freely soluble in methylene chloride, in chloroform, and in alcohol; slightly soluble in acetone; and insoluble in ether. Its molecular weight is 684.81.
Hydrochlorothiazide is 6-Chloro-3,4-dihydro-2H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, and its structural formula is:
Hydrochlorothiazide, USP is a white, or practically white, practically odorless, crystalline powder. It is freely soluble in sodium hydroxide solution, in n -butylamine, and in dimethylformamide; sparingly soluble in methanol; slightly soluble in water; and insoluble in ether, in chloroform, and in dilute mineral acids. Its molecular weight is 297.74.
Inactive Ingredients: Anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, FD&C Yellow No. 6 Aluminum Lake, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch (corn) and sodium lauryl sulfate.
Metoprolol tartrate is a beta-adrenergic receptor blocking agent. In vitro and in vivo animal studies have shown that it has a preferential effect on beta1 adrenoreceptors, chiefly located in cardiac muscle. This preferential effect is not absolute, however, and at higher doses, metoprolol tartrate also inhibits beta2 adrenoreceptors, chiefly located in the bronchial and vascular musculature.
Clinical pharmacology studies have confirmed the beta-blocking activity of metoprolol in man, as shown by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2) reduction of systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4) reduction of reflex orthostatic tachycardia.
Relative beta1 selectivity has been confirmed by the following: (1) In normal subjects, metoprolol tartrate is unable to reverse the beta2 -mediated vasodilating effects of epinephrine. This contrasts with the effect of nonselective (beta1 plus beta2 ) beta blockers, which completely reverse the vasodilating effects of epinephrine. (2) In asthmatic patients, metoprolol tartrate reduces FEV1 and FVC significantly less than a nonselective beta blocker, propranolol at equivalent beta1 -receptor blocking doses.
Metoprolol tartrate has no intrinsic sympathomimetic activity and only weak membrane-stabilizing activity. Metoprolol tartrate crosses the blood-brain barrier and has been reported in the CSF in a concentration 78% of the simultaneous plasma concentration. Animal and human experiments indicate that metoprolol tartrate slows the sinus rate and decreases AV nodal conduction.
In controlled clinical studies, metoprolol tartrate has been shown to be an effective antihypertensive agent when used alone or as concomitant therapy with thiazide-type diuretics, at dosages of 100-450 mg daily. In controlled, comparative, clinical studies, metoprolol tartrate has been shown to be as effective an antihypertensive agent as propranolol, methyldopa, and thiazide-type diuretics, and to be equally effective in supine and standing positions.
The mechanism of the antihypertensive effects of beta-blocking agents has not been elucidated. However, several possible mechanisms have been proposed: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output; (2) a central effect leading to reduced sympathetic outflow to the periphery; and (3) suppression of renin activity.
In man, absorption of metoprolol tartrate is rapid and complete. Plasma levels following oral administration, however, approximate 50% of levels following intravenous administration, indicating about 50% first-pass metabolism.
Plasma levels achieved are highly variable after oral administration. Only a small fraction of the drug (about 12%) is bound to human serum albumin. Metoprolol is a racemic mixture of R- and S-enantiomers. Less than 5% of an oral dose of metoprolol tartrate is recovered unchanged in the urine; the rest is excreted by the kidneys as metabolites that appear to have no clinical significance. The systemic availability and half-life of metoprolol tartrate in patients with renal failure do not differ to a clinically significant degree from those in normal subjects. Consequently, no reduction in dosage is usually needed in patients with chronic renal failure.
In elderly subjects with clinically normal renal function, there are no significant differences in metoprolol tartrate pharmacokinetics compared to young subjects.
Metoprolol tartrate is extensively metabolized by the cytochrome P450 enzyme system in the liver. The oxidative metabolism of metoprolol tartrate is under genetic control with a major contribution of the polymorphic cytochrome P450 isoform 2D6 (CYP2D6). There are marked ethnic differences in the prevalence of the poor metabolizers (PM) phenotype. Approximately 7% of Caucasians and less than 1% of Asians are poor metabolizers.
Poor CYP2D6 metabolizers exhibit several-fold higher plasma concentrations of metoprolol tartrate than extensive metabolizers with normal CYP2D6 activity. The elimination half-life of metoprolol is about 7.5 hours in poor metabolizers and 2.8 hours in extensive metabolizers. However, the CYP2D6 dependent metabolism of metoprolol tartrate seems to have little or no effect on safety or tolerability of the drug. None of the metabolites of metoprolol tartrate contribute significantly to its beta-blocking effect.
Significant beta-blocking effect (as measured by reduction of exercise heart rate) occurs within 1 hour after oral administration, and its duration is dose-related. For example, a 50% reduction of the maximum registered effect after single oral doses of 20, 50, and 100 mg occurred at 3.3, 5.0, and 6.4 hours, respectively, in normal subjects. After repeated oral dosages of 100 mg twice daily, a significant reduction in exercise systolic blood pressure was evident at 12 hours.
There is a linear relationship between the log of plasma levels and reduction of exercise heart rate. However, antihypertensive activity does not appear to be related to plasma levels. Because of variable plasma levels attained with a given dose and lack of a consistent relationship of antihypertensive activity to dose, selection of proper dosage requires individual titration.
Thiazides affect the renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage, all thiazides are approximately equal in their diuretic potency. Thiazides increase excretion of sodium and chloride in approximately equivalent amounts. Natriuresis causes a secondary loss of potassium.
The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not affect normal blood pressure.
All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.