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Dutoprol

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Dutoprol

CLINICAL PHARMACOLOGY

Mechanism Of Action

The mechanism of the antihypertensive effects of beta adrenergic blockers 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.

The mechanism of the antihypertensive effect of thiazide diurectics is unknown.

Pharmacodynamics

Metoprolol

Clinical pharmacology studies have confirmed the beta adrenergic blocker activity of metoprolol, 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.

Metoprolol is a beta1-selective (cardioselective) adrenergic receptor blocker. This preferential effect is not absolute, however, and at higher plasma concentrations, metoprolol also inhibits beta2-adrenoreceptors, chiefly located in the bronchial and vascular musculature. Metoprolol has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is detectable only at plasma concentrations much greater than required for beta-blockade. Animal and human experiments indicate that metoprolol slows the sinus rate and decreases AV nodal conduction.

The relative beta1-selectivity of metoprolol is demonstrated by the following: (1) In healthy subjects, metoprolol is unable to reverse the beta2-mediated vasodilating effects of epinephrine. This contrasts with the effect of nonselective beta-blockers, which completely reverse the vasodilating effects of epinephrine. (2) In asthmatic patients, metoprolol reduces FEV1 and FVC significantly less than a nonselective beta-blocker, propranolol, at equivalent beta1-receptor blocking doses.

The relationship between plasma metoprolol levels and reduction in exercise heart rate is independent of the pharmaceutical formulation. Using an Emax model, the maximum effect is a 30% reduction in exercise heart rate, which is attributed to beta1-blockade. Beta1-blocking effects in the range of 30– 80% of the maximal effect (approximately 8–23% reduction in exercise heart rate) correspond to metoprolol plasma concentrations from 30-540 nmol/L. The relative beta 1-selectivity of metoprolol diminishes and blockade of beta2-adrenoceptors increases at higher plasma concentrations above 300 nmol/L.

Although beta-adrenergic receptor blockade is useful in the treatment of hypertension there are situations in which sympathetic stimulation is vital. In patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. In the presence of AV block, beta-blockade may prevent the necessary facilitating effect of sympathetic activity on conduction. Beta2adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bronchospasm and may also interfere with exogenous bronchodilators in such patients.

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equimolar 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.

After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.

The following pharmacodynamic drug interactions may occur with hydrochlorothiazide:

Alcohol, barbiturates, or narcotics: Orthostatic hypotension.

Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine): Possible increased responsiveness to the muscle relaxant.

Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia.

Pharmacokinetics

Metoprolol/hydrochlorothiazide

After single oral doses of DUTOPROL, plasma levels of metoprolol and of hydrochlorothiazide are similar to levels obtained after single doses of TOPROL XL and hydrochlorothiazide. Peak plasma concentrations (Cmax ) of metoprolol and hydrochlorothiazide occur within 10-12 hours and 2 hours of dose intake, respectively.

The rate and extent of absorption of metoprolol/ hydrochlorothiazide are similar in the fasting state and after a high-fat meal after administration of DUTOPROL.

Metoprolol

Absorption of metoprolol is complete following oral administration. The absolute bioavailability of metoprolol after oral administration of immediate release metoprolol is estimated to be about 50% because of pre-systemic metabolism. Plasma levels achieved are highly variable after oral administration of immediate release metoprolol.

Metoprolol is known to cross the blood brain barrier following oral administration and CSF concentrations close to that observed in plasma have been reported. About 12% of the drug is bound to human serum albumin.

Metoprolol is primarily metabolized by CYP2D6. Metoprolol is a racemic mixture of R-and Senantiomers, and when administered orally, it exhibits stereoselective metabolism that is dependent on oxidation phenotype. CYP2D6 is absent (poor metabolizers) in about 8% of Caucasians and about 2% of most other populations. CYP2D6 can be inhibited by a number of drugs. Concomitant use with CYP2D6 inhibitors or administration of metoprolol in poor metabolizers will increase blood levels of metoprolol several-fold, decreasing metoprolol's cardioselectivity [see DRUG INTERACTIONS].

Elimination is mainly by biotransformation in the liver, and the plasma half-life ranges from approximately 3 to 7 hours. Less than 5% of an oral dose and 10% of an intravenous dose of metoprolol is recovered unchanged in the urine; the rest is excreted by the kidneys as metabolites that appear to have no beta blocking activity.

The systemic availability and half-life of metoprolol in patients with renal failure do not differ to a clinically significant degree from those in healthy subjects.

Metoprolol Succinate Extended Release

The metoprolol component of DUTOPROL is bioequivalent to TOPROL-XL. In comparison to immediate release metoprolol, the plasma metoprolol levels following administration of TOPROL-XL are characterized by lower peaks, longer time to peak and significantly lower peak to trough variation (PTT ratio). The peak plasma levels following once-daily administration of TOPROL-XL average one-fourth to one-half the peak plasma levels obtained following a corresponding dose of immediate release metoprolol, administered once daily or in divided doses. At steady state the average bioavailability of metoprolol following administration of TOPROL-XL, across the dosage range of 50 to 400 mg once daily, was 77% relative to the corresponding single or divided doses of immediate release metoprolol. Nevertheless, over the 24-hour dosing interval, 1-blockade is similar and dose-related.

Pharmacokinetic Drug Interactions

In healthy subjects with CYP2D6 extensive metabolizer phenotype, coadministration of quinidine 100 mg and immediate-release metoprolol 200 mg tripled the concentration of S-metoprolol and doubled the metoprolol elimination half-life. Coadministration of propafenone 150 mg t.i.d. with immediate-release metoprolol 50 mg t.i.d. resulted in two-to five fold increases in the steady-state concentration of metoprolol. These increases in plasma concentration would decrease the cardioselectivity of metoprolol.

Hydrochlorothiazide

The pharmacokinetics of hydrochlorothiazide is dose proportional in the range of 12.5 to 75 mg.

The estimated absolute bioavailability of hydrochlorothiazide after oral administration is about 70%. Peak plasma hydrochlorothiazide concentrations (Cmax ) are reached within 2 to 5 hours after oral administration. There is no clinically significant effect of food on the bioavailability of hydrochlorothiazide.

Hydrochlorothiazide binds to albumin (40 to 70%) and distributes into erythrocytes. Following oral administration, plasma hydrochlorothiazide concentrations decline bi-exponentially, with a mean distribution half-life of about 2 hours and an elimination half-life of about 10 hours.

About 70% of an orally administered dose of hydrochlorothiazide is eliminated in the urine as unchanged drug.

Pharmacokinetic Drug Interactions

Absorption of hydrochlorothiazide is impaired in the presence of ionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.

Clinical Studies

A randomized, double-blind, placebo-controlled, 8-week, factorial study (Study 1) (N=1571) evaluated the antihypertensive effects of various doses (given once daily) of metoprolol succinate extended release (25, 50, 100 and 200 mg) and hydrochlorothiazide (6.25, 12.5 and 25 mg), and 9 of their combinations. The trial established that metoprolol succinate extended release and hydrochlorothiazide both contributed to the antihypertensive effect, as measured by the change from baseline to week 8 in sitting diastolic (p= 0.0015) and systolic (p=0.0006) blood pressure. The predicted values for the drugs' effects are shown in Table 1.

Table 1: Placebo-corrected Change from Baseline* in SBP/DBP at Week 8 in Study 1

    Metoprolol
0 mg 25 mg 50 mg 100 mg 200 mg
HCTZ 0 mg 0/0 -2.0/-1.4 -3.7/-2.6 -6.1/-4.5 -7.0/-6.1
6.25 mg -3.5/-1.9 -5.5/-3.3 -7.2/-4.5 -9.6/-6.4 -10.5/-8.0†
12.5 mg -5.9/-3.3 -7.9/-4.7 -9.6/-5.9 -12.0/-7.8 -12.9/-9.3
25 mg -7.7/-4.3 -9.7/-5.7† -11.4/-6.9† -13.8/-8.8 -14.7/-10.4
*Predicted values from a least-squares quadratic regression model.
†These doses were not studied.
SBP = systolic blood pressure; DBP = diastolic blood pressure

Blood pressure declines were apparent within 2 weeks and were maintained throughout the 8-week study. The blood pressure lowering effect 24 hours post-dosing retained approximately 96% of the peak effect (6 hours post-dosing). The antihypertensive effect was similar regardless of age or gender, and the blood pressure response to the metoprolol succinate extended release and hydrochlorothiazide combination appears similar in black and non-black patients.

Last reviewed on RxList: 11/3/2014
This monograph has been modified to include the generic and brand name in many instances.

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