CLINICAL PHARMACOLOGY
General:
Metoprolol and hydrochlorothiazide have been used individually and in combination for the treatment of hypertension. The antihypertensive effects of these agents are additive.
Metoprolol is a beta1-selective (cardioselective) adrenergic receptor-blocking agent. 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.
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.
The relative beta1-selectivity of metoprolol has been confirmed by the following: (1) In normal 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 beta1-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 angina, hypertension, and heart failure 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. Beta2-adrenergic 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 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.
Pharmacokinetics
Metoprolol succinate extended release/hydrochlorothiazide
After single oral doses of DUTOPROL tablets, the peak plasma concentrations (Cmax) of metoprolol and hydrochlorothiazide are observed within 10-12 hours and 2.0 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 when given as DUTOPROL tablets. (See DOSAGE AND ADMINISTRATION.)
Single dose pharmacokinetics of metoprolol/hydrochlorothiazide given as DUTOPROL tablets is similar to that of each drug given individually as TOPROL-XL and a formulation of hydrochlorothiazide created for the clinical trial.
Metoprolol
In man, absorption of metoprolol is rapid and complete. Plasma levels following oral administration of immediate release metoprolol tablets, however, approximate 50% of levels following intravenous administration, indicating about 50% first-pass metabolism. Metoprolol crosses the blood brain barrier and has been reported in the CSF in a concentration 78% of the simultaneous plasma concentration.
Plasma levels achieved are highly variable after oral administration of immediate release metoprolol. 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, and is primarily metabolized by CYP2D6. When administered orally, it exhibits stereoselective metabolism that is dependent on oxidation phenotype. 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 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. Following intravenous administration of metoprolol, the urinary recovery of unchanged drug is approximately 10%. The systemic availability and half-life of metoprolol in patients with renal failure do not differ to a clinically significant degree from those in normal subjects. (See DOSAGE AND ADMINISTRATION.)
Metoprolol is metabolized predominantly by CYP2D6, an enzyme that is absent in about 8% of Caucasians (poor metabolizers) and about 2% of most other populations. CYP2D6 can be inhibited by a number of drugs. Concomitant use of inhibiting drugs in poor metabolizers will increase blood levels of metoprolol several-fold, decreasing metoprolol's cardioselectivity. (See PRECAUTIONS, Drug Interactions, Metoprolol.)
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. 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, ß1-blockade is similar and dose-related (see CLINICAL PHARMACOLOGY). The bioavailability of metoprolol shows a dose-related, although not directly proportional, increase with dose and is not significantly affected by food following TOPROL-XL administration.
Hydrochlorothiazide
Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract with a bioavailability of about 60-80%.
Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.
Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. At least 61% of the oral dose is eliminated unchanged within 24 hours.
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. In a study of patients with impaired renal function (mean creatinine clearance of 19 mL/min), the half-life of hydrochlorothiazide elimination was lengthened to 21 hours (See DOSAGE AND ADMINISTRATION). The bioavailability of hydrochlorothiazide is not significantly affected by food following DUTOPROL administration.
Hypertension
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.
The mechanism of the antihypertensive effect of thiazide is unknown.
Clinical Trials
Metoprolol succinate extended release and hydrochlorothiazide
A randomized, double-blind, placebo-controlled, 8-week, unbalanced factorial study (N=1571) evaluated the antihypertensive effects of various doses 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 contribute to the antihypertensive effect, 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.
Blood pressure declines were apparent within 2 weeks and were maintained throughout the 8-week study. The blood pressure lowering 24 hours post dosing retained approximately 96% of the peak (6 hours post dosing) effect. The antihypertensive effect was similar regardless of age or gender, and the response to the metoprolol succinate extended release and hydrochlorothiazide combination appears similar in black and non-black patients.
Table 1. Placebo-corrected Predicted Values
for Change from Baseline in SBP/DBP | TOPROL-XL Dosage |
|---|
| HCT Dosage | 0 mg SBP/DBP | 25 mg SBP/DBP | 50 mg SBP/DBP | 100 mg SBP/DBP | 200 mg SBP/DBP |
|---|
|
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
|
|
