Actions of Metoprololtartraat CF in details
S(-)Metoprololtartraat CF is a β1-selective blocker. Metoprololtartraat CF has an insignificant membrane stabilizing effect and does not display partial agonistic activity.
Pharmacology: Pharmacodynamics: Metoprololtartraat CF is a β1-selective β-blocker ie, it blocks β1-receptors at doses much lower than those needed to block β2-receptors. S-Metoprololtartraat CF is an active enantiomer of racemic Metoprololtartraat CF which has been shown to have higher binding affinity for β1-adrenergic receptors. The mechanism of antihypertensive effect of β-blocking agent 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 central sympathetic outflow to the periphery; and (3) inhibition of renin release from the juxtaglomerular apparatus in kidneys.
Metoprololtartraat CF interferes less with insulin release and carbohydrate metabolism than do nonselective β-blockers. Metoprololtartraat CF interferes much less with the cardiovascular response to hypoglycaemia than do nonselective β-blockers.
Pharmacokinetics: S-Metoprololtartraat CF is almost completely absorbed after oral administration. Maximum plasma concentration is achieved in approximately 7 hrs. Metoprololtartraat CF exhibits stereoselective pharmacokinetics and undergoes oxidative metabolism in the liver. Majority of an oral dose can be recovered in the urine.
Significant reduction in systolic and diastolic blood pressure was noticed at 7 days of S(-)Metoprololtartraat CF therapy in 1 randomized control clinical trial (SMART study).
How should I take Metoprololtartraat CF?
Take Metoprololtartraat CF exactly as prescribed by your doctor. Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.
Take the medicine at the same time each day.
Metoprololtartraat CF should be taken with a meal or just after a meal.
A Metoprololtartraat CF tablet can be divided in half if your doctor has told you to do so. The half tablet should be swallowed whole, without chewing or crushing.
While using Metoprololtartraat CF, you may need frequent blood tests at your doctor's office. Your blood pressure will need to be checked often.
If you need surgery, tell the surgeon ahead of time that you are using Metoprololtartraat CF.
You should not stop using Metoprololtartraat CF suddenly. Stopping suddenly may make your condition worse.
If you are being treated for high blood pressure, keep using this medication even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.
Store Metoprololtartraat CF at room temperature away from moisture and heat.
Metoprololtartraat CF administration
Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
Take Metoprololtartraat CF at the same time every day.
Metoprololtartraat CF should be taken with food or just after a meal.
A Metoprololtartraat CF tablet can be divided in half if your doctor has told you to do so. The half tablet should be swallowed whole, without chewing or crushing. Chewing or crushing the pill could cause too much of the drug to be released at one time.
Do not skip doses or stop taking Metoprololtartraat CF without first talking to your doctor. Stopping suddenly may make your condition worse.
Your blood pressure will need to be checked often. Visit your doctor regularly.
If you need surgery, tell the surgeon ahead of time that you are using Metoprololtartraat CF.
Metoprololtartraat CF is only part of a complete program of treatment for hypertension that may also include diet, exercise, and weight control. Follow your diet, medication, and exercise routines very closely if you are being treated for hypertension.
If you are being treated for high blood pressure, keep using this medication even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.
Store at room temperature away from moisture and heat.
Metoprololtartraat CF pharmacology
Mechanism of Action
Metoprololtartraat CF is a beta1-selective (cardioselective) adrenergic receptor blocking agent. This preferential effect is not absolute, however, and at higher plasma concentrations, Metoprololtartraat CF also inhibits beta2-adrenoreceptors, chiefly located in the bronchial and vascular musculature.
Metoprololtartraat CF 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 Metoprololtartraat CF slows the sinus rate and decreases AV nodal conduction.
The relative beta1-selectivity of Metoprololtartraat CF has been confirmed by the following: (1) In normal subjects, Metoprololtartraat CF 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, Metoprololtartraat CF reduces FEV1 and FVC significantly less than a nonselective beta-blocker, propranolol, at equivalent beta1-receptor blocking doses.
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.
Angina Pectoris: By blocking catecholamine-induced increases in heart rate, in velocity and extent of myocardial contraction, and in blood pressure, Metoprololtartraat CF reduces the oxygen requirements of the heart at any given level of effort, thus making it useful in the long-term management of angina pectoris.
Heart Failure: The precise mechanism for the beneficial effects of beta-blockers in heart failure has not been elucidated.
Pharmacodynamics
Clinical pharmacology studies have confirmed the beta-blocking activity of Metoprololtartraat CF 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 relationship between plasma Metoprololtartraat CF levels and reduction in exercise heart rate is independent of the pharmaceutical formulation. Beta1-blocking effects in the range of 30 to 80% of the maximal effect (approximately 8 to 23% reduction in exercise heart rate) correspond to Metoprololtartraat CF plasma concentrations from 30 to 540 nmol/L. The relative beta1‑selectivity of Metoprololtartraat CF diminishes and blockade of beta2-adrenoceptors increases at plasma concentration above 300 nmol/L.
In five controlled studies in normal healthy subjects, extended-release Metoprololtartraat CF succinate administered once a day, and immediate-release Metoprololtartraat CF administered once to four times a day, provided comparable total beta1-blockade over 24 hours (area under the beta1-blockade versus time curve) in the dose range 100 to 400 mg. In another controlled study, 50 mg once daily for each product, extended-release Metoprololtartraat CF succinate produced significantly higher total beta1-blockade over 24 hours than immediate-release Metoprololtartraat CF. For extended-release Metoprololtartraat CF succinate, the percent reduction in exercise heart rate was relatively stable throughout the entire dosage interval and the level of beta1-blockade increased with increasing doses from 50 to 300 mg daily.
A controlled cross-over study in heart failure patients compared the plasma concentrations and beta1-blocking effects of 50 mg immediate-release Metoprololtartraat CF administered t.i.d., and 100 mg and 200 mg extended-release Metoprololtartraat CF succinate once daily. Extended-release Metoprololtartraat CF succinate 200 mg once daily produced a larger effect on suppression of exercise-induced and Holter-monitored heart rate over 24 hours compared to 50 mg t.i.d. of immediate-release Metoprololtartraat CF.
In other studies, treatment with Metoprololtartraat CF succinate produced an improvement in left ventricular ejection fraction. Metoprololtartraat CF succinate was also shown to delay the increase in left ventricular end-systolic and end-diastolic volumes after 6 months of treatment.
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.
Pharmacokinetics
The peak plasma levels following once-daily administration of extended release Metoprololtartraat CF succinate are reduced by 50 to 75% on average compared to a corresponding dose of immediate-release Metoprololtartraat CF tartrate, both when administered once daily or in divided doses. At steady state the average bioavailability of Metoprololtartraat CF following administration of Metoprololtartraat CF succinate, across the dosage range of 50 to 400 mg once daily, was reduced by 25% relative to the corresponding single or divided doses of immediate-release Metoprololtartraat CF tartrate. The bioavailability of Metoprololtartraat CF shows a dose-related, although not directly proportional, increase with dose. The exposure (Cmax and AUC) of Metoprololtartraat CF succinate extended-release capsule are similar to that of TOPROL-XL® tablet.
Absorption
Plasma levels following oral administration of Metoprololtartraat CF tablet approximate 50% of levels following intravenous administration, indicating about 50% first-pass metabolism. Peak plasma concentration of Metoprololtartraat CF is attained at 10 hours following administration of Metoprololtartraat CF succinate extended-release capsule.
Effect of food
Compared to fasted state administration, high-fat, high-calorie meal (54.3% fat, 15.6% proteins and 30.1% carbohydrates) did not have a significant effect on the absorption of Metoprololtartraat CF succinate extended-release capsule.
200 mg Metoprololtartraat CF succinate extended release capsule administered under fasting conditions to healthy adults by sprinkling the entire contents on one-tablespoon (15 mL) of applesauce did not significantly affect Tmax, Cmax, and AUC of Metoprololtartraat CF.
Distribution
About 12% of the drug is bound to human serum albumin.
Metoprololtartraat CF crosses the blood-brain barrier and has been reported in the CSF in a concentration 78% of the simultaneous plasma concentration.
Elimination
Elimination is mainly by biotransformation in the liver, and the plasma half-life ranges from approximately 3 to 7 hours.
Metabolism
Metoprololtartraat CF 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.
Excretion
Less than 5% of an oral dose of Metoprololtartraat CF 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 Metoprololtartraat CF, the urinary recovery of unchanged drug is approximately 10%.
Specific Populations
Pediatric Patients
The pharmacokinetic profile of Metoprololtartraat CF succinate was studied in 120 pediatric hypertensive patients (6 to 17 years of age) receiving doses ranging from 12.5 to 200 mg once daily. The pharmacokinetics of Metoprololtartraat CF were similar to those described previously in adults. Age, gender, race, and ideal body weight had no significant effects on Metoprololtartraat CF pharmacokinetics. Metoprololtartraat CF apparent oral clearance (CL/F) increased linearly with body weight. Metoprololtartraat CF pharmacokinetics have not been investigated in patients < 6 years of age.
Drug Interactions
CYP2D6
Metoprololtartraat CF is metabolized predominantly by CYP2D6. In healthy subjects with CYP2D6 extensive metabolizer phenotype, coadministration of quinidine 100 mg, a potent CYP2D6 inhibitor, and immediate-release Metoprololtartraat CF 200 mg tripled the concentration of S-Metoprololtartraat CF and doubled the Metoprololtartraat CF elimination half-life. In four patients with cardiovascular disease, coadministration of propafenone 150 mg t.i.d. with immediate-release Metoprololtartraat CF 50 mg t.i.d. resulted in steady-state concentration of Metoprololtartraat CF 2- to 5-fold what is seen with Metoprololtartraat CF alone. Extensive metabolizers who concomitantly use CYP2D6 inhibiting drugs will have increased (several-fold) Metoprololtartraat CF blood levels, decreasing Metoprololtartraat CF's cardioselectivity.
Alcohol
An in vitro dissolution study was conducted to evaluate the impact of alcohol (5, 10, 20 and 40%), on the extended-release characteristics of Metoprololtartraat CF succinate extended-release capsules. The in vitro study showed that about 89% of the total Metoprololtartraat CF succinate dose was released at 2 hour at the highest alcohol level (40%), and about 17% of total drug was released at 2 hour with 5% alcohol. Alcohol causes a rapid release of Metoprololtartraat CF succinate from the extended-release capsules that may increase the risk for above events associated with Metoprololtartraat CF succinate extended-release capsules. Consumption of alcohol is not recommended when taking Metoprololtartraat CF succinate extended-release capsules 25 mg, 50 mg, 100 mg and 200 mg.
Pharmacogenomics
CYP2D6 is absent in about 8% of Caucasians (poor metabolizers) and about 2% of most other populations. CYP2D6 can be inhibited by several drugs. Poor metabolizers of CYP2D6 will have increased (several-fold) Metoprololtartraat CF blood levels, decreasing Metoprololtartraat CF's cardioselectivity.
References
- DailyMed. "METOPROLOL FUMARATE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- NCIt. "Metoprolol Fumarate: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
- EPA DSStox. "Metoprolol: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
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Information checked by Dr. Sachin Kumar, MD Pharmacology
