Tolol-XR Actions

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Actions of Tolol-XR in details

The action of the drug on the human body is called Pharmacodynamics in Medical terminology. To produce its effect and to change the pathological process that is happening the body and to reduce the symptom or cure the disease, the medicine has to function in a specific way. The changes it does to the body at cellular level gives the desired result of treating a disease. Drugs act by stimulating or inhibiting a receptor or an enzyme or a protein most of the times. Medications are produced in such a way that the ingredients target the specific site and bring about chemical changes in the body that can stop or reverse the chemical reaction which is causing the disease.
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Pharmacotherapeutic Group: Beta-receptor blocker, selective. ATC Code: C07A B02

Pharmacology: Pharmacodynamics: Tolol-XR is a beta1-selective receptor blocker, i.e. Tolol-XR affects the beta1-receptors of the heart in lower doses than needed to affect beta2-receptors in peripheral vessels and bronchi. At increasing doses the beta1-selectivity may decrease.

Tolol-XR has no beta-stimulating effect and has little membrane-stimulating effect. Beta-receptor blockers have negative inotropic and chronotropic effect.

Tolol-XR therapy reduces the effect of catecholamines in association with physical and psychic strain and gives lower heart rate, cardiac output and blood pressure. In stress situations with an increased release of adrenaline from the adrenal glands, Tolol-XR does not prevent the normal physiological vascular dilation. In therapeutic doses, Tolol-XR has less contractile effect on the bronchial muscles than non-selective beta-blockers. This property enables treatment of patients with bronchial asthma or other pronounced obstructive lung diseases with Tolol-XR in combination with beta2-receptor stimulants. Tolol-XR influences insulin release and carbohydrate metabolism to less extent than non-selective beta-blockers and therefore it can also be given to patients with diabetes mellitus. The cardiovascular reaction in hypoglycaemia eg, tachycardia, is less influenced by Tolol-XR and the return of blood sugar level to normal is faster than for non-selective beta-receptor blockers.

In hypertension, Tolol-XR lowers the blood pressure significantly for more than 24 hours both in lying and standing position as well as during exercise. In treatment with Tolol-XR an increase in the peripheral vascular resistance is observed initially. In long-term treatment, however, the obtained lowering in blood pressure may be due to reduced peripheral vascular resistance and unchanged cardiac output. In males with moderate/severe hypertension, Tolol-XR reduces the risk of cardiovascular death. There is no electrolyte imbalance.

In tachyarrhythmias the effect of increased sympatholytic activity is blocked and this gives a lower heart rate primarily by reduced automatisation in the pacemaker cells, but also through a prolonged supraventricular conduction time.

Tolol-XR reduces the risk of reinfarction and cardiac death, especially sudden death after myocardial infarction.

Pharmacokinetics: The bioavailability of Tolol-XR is 40-50%. Maximal beta-blockade is reached after 1-2 hours. After per oral once-daily dosage of 100 mg the effect on the heart rate is still pronounced after 12 hours. Tolol-XR is metabolised in the liver mainly by CYP2D6. Three main metabolites have been identified, though none has a beta-blocking effect of clinical importance. The half-life in plasma is 3-5 hours. Tolol-XR is excreted to approximately 5% in unchanged form via the kidneys, the remaining dose as metabolites.

How should I take Tolol-XR?

Take Tolol-XR only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. Your dose may need to be changed several times in order to find out what works best for you.

In addition to the use of Tolol-XR, treatment for your high blood pressure may include weight control and changes in the types of foods you eat, especially foods high in sodium (salt). Your doctor will tell you which of these are most important for you. You should check with your doctor before changing your diet.

Many patients who have high blood pressure will not notice any signs of the problem. In fact, many patients feel normal. It is very important that you take your medicine exactly as directed and that you keep your appointments with your doctor even if you feel well.

Remember that Tolol-XR will not cure your high blood pressure, but it does help control it. You must continue to take it as directed if you expect to lower your blood pressure and keep it down. You may have to take high blood pressure medicine for the rest of your life. If high blood pressure is not treated, it can cause serious problems such as heart failure, blood vessel disease, strokes, or kidney disease.

Take Tolol-XR with a meal or just after you eat. You may break the extended-release tablet into two pieces, but swallow the two pieces whole and do not crush or chew them.

Swallow the tablet whole with a glass of water. Do not crush, break, or chew it.

Dosing

The dose of Tolol-XR will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of Tolol-XR. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

Missed Dose

If you miss a dose of Tolol-XR, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Tolol-XR administration

Administration of drug is important to know because the drug absorption and action varies depending on the route and time of administration of the drug. A medicine is prescribed before meals or after meals or along with meals. The specific timing of the drug intake about food is to increase its absorption and thus its efficacy. Few work well when taken in empty stomach and few medications need to be taken 1 or 2 hrs after the meal. A drug can be in the form of a tablet, a capsule which is the oral route of administration and the same can be in IV form which is used in specific cases. Other forms of drug administration can be a suppository in anal route or an inhalation route.
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Oral:

Immediate release (Tolol-XR): Administer with or immediately following meals.

Extended release (Tolol-XR succinate): According to the manufacturer, it is preferable to administer with or immediately following meals; however, may also administer without regard to meals (Tangeman 2003; van den Berg 1990; Wikstrand 2003). May divide tablets in half; do not crush or chew.

Bariatric surgery: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. ER tablet (Tolol-XR succinate) may be divided in half but not crushed or chewed. IR tablet, oral solution, and injectable formulations are available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery; however, selection of IR formulation or alternative therapy is advised for cardiovascular and other high-risk labeled and off-label indications.

Sprinkle capsule: May be swallowed whole or the capsule may be opened and contents sprinkled on a small amount (1 teaspoonful) of soft food (eg, applesauce, pudding, or yogurt) to be used within 60 minutes (do not store for future use).

Nasogastric tube administration: Open capsule and add contents to an all plastic oral tip syringe; add 15 mL of water. Gently shake the syringe for ~10 seconds. Immediately deliver mixture through a ≥12 French nasogastric tube. No granules should remain in the syringe; rinse syringe with additional water if necessary.

IV: May administer undiluted by rapid infusion (IV push) over 1 minute for acute treatment. May also be administered by slow infusion (ie, 5 to 10 mg of Tolol-XR in 50 mL of fluid) over ~30 to 60 minutes during less urgent situations (eg, substitution for oral Tolol-XR).

Tolol-XR pharmacology

Pharmacokinetics of a drug can be defined as what body does to the drug after it is taken. The therapeutic result of the medicine depends upon the Pharmacokinetics of the drug. It deals with the time taken for the drug to be absorbed, metabolized, the process and chemical reactions involved in metabolism and about the excretion of the drug. All these factors are essential to deciding on the efficacy of the drug. Based on these pharmacokinetic principles, the ingredients, the Pharmaceutical company decides dose and route of administration. The concentration of the drug at the site of action which is proportional to therapeutic result inside the body depends on various pharmacokinetic reactions that occur in the body.
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Mechanism of Action

Tolol-XR is a beta1-selective (cardioselective) adrenergic receptor blocking agent. This preferential effect is not absolute, however, and at higher plasma concentrations, Tolol-XR also inhibits beta2-adrenoreceptors, chiefly located in the bronchial and vascular musculature.

Tolol-XR 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 Tolol-XR slows the sinus rate and decreases AV nodal conduction.

The relative beta1-selectivity of Tolol-XR has been confirmed by the following: (1) In normal subjects, Tolol-XR 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, Tolol-XR 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, Tolol-XR 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 Tolol-XR 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 Tolol-XR 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 Tolol-XR plasma concentrations from 30 to 540 nmol/L. The relative beta1‑selectivity of Tolol-XR diminishes and blockade of beta2-adrenoceptors increases at plasma concentration above 300 nmol/L.

In five controlled studies in normal healthy subjects, extended-release Tolol-XR succinate administered once a day, and immediate-release Tolol-XR 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 Tolol-XR succinate produced significantly higher total beta1-blockade over 24 hours than immediate-release Tolol-XR. For extended-release Tolol-XR 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 Tolol-XR administered t.i.d., and 100 mg and 200 mg extended-release Tolol-XR succinate once daily. Extended-release Tolol-XR 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 Tolol-XR.

In other studies, treatment with Tolol-XR succinate produced an improvement in left ventricular ejection fraction. Tolol-XR 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 Tolol-XR succinate are reduced by 50 to 75% on average compared to a corresponding dose of immediate-release Tolol-XR, both when administered once daily or in divided doses. At steady state the average bioavailability of Tolol-XR following administration of Tolol-XR 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 Tolol-XR. The bioavailability of Tolol-XR shows a dose-related, although not directly proportional, increase with dose. The exposure (Cmax and AUC) of Tolol-XR succinate extended-release capsule are similar to that of TOPROL-XL® tablet.

Absorption

Plasma levels following oral administration of Tolol-XR tablet approximate 50% of levels following intravenous administration, indicating about 50% first-pass metabolism. Peak plasma concentration of Tolol-XR is attained at 10 hours following administration of Tolol-XR 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 Tolol-XR succinate extended-release capsule.

200 mg Tolol-XR 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 Tolol-XR.

Distribution

About 12% of the drug is bound to human serum albumin.

Tolol-XR 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

Tolol-XR 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 Tolol-XR 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 Tolol-XR, the urinary recovery of unchanged drug is approximately 10%.

Specific Populations

Pediatric Patients

The pharmacokinetic profile of Tolol-XR 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 Tolol-XR were similar to those described previously in adults. Age, gender, race, and ideal body weight had no significant effects on Tolol-XR pharmacokinetics. Tolol-XR apparent oral clearance (CL/F) increased linearly with body weight. Tolol-XR pharmacokinetics have not been investigated in patients < 6 years of age.

Drug Interactions

CYP2D6

Tolol-XR 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 Tolol-XR 200 mg tripled the concentration of S-Tolol-XR and doubled the Tolol-XR elimination half-life. In four patients with cardiovascular disease, coadministration of propafenone 150 mg t.i.d. with immediate-release Tolol-XR 50 mg t.i.d. resulted in steady-state concentration of Tolol-XR 2- to 5-fold what is seen with Tolol-XR alone. Extensive metabolizers who concomitantly use CYP2D6 inhibiting drugs will have increased (several-fold) Tolol-XR blood levels, decreasing Tolol-XR'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 Tolol-XR succinate extended-release capsules. The in vitro study showed that about 89% of the total Tolol-XR 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 Tolol-XR succinate from the extended-release capsules that may increase the risk for above events associated with Tolol-XR succinate extended-release capsules. Consumption of alcohol is not recommended when taking Tolol-XR 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) Tolol-XR blood levels, decreasing Tolol-XR's cardioselectivity.



References

  1. 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).
  2. 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).
  3. 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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