Actions of Tolol AM in details
Calcium-channel blocker.
Pharmacology: Pharmacodynamics: S(-) Tolol AM, the chirally pure form of Tolol AM, is a calcium channel antagonist belonging to the dihydropyridine class. The S(-) isomer of Tolol AM is found to possess greater pharmacological effects than R(+) Tolol AM. S(-) Tolol AM is 1000 times more potent than the R(+) isomer in binding to the dihydropyridine receptor. In humans, the dominant effects of Tolol AM are consequent to vasodilation. S(-) Tolol AM lowers peripheral vascular resistance without causing a reflex tachycardia. It is effective as a once-daily dosing in the control of hypertension.
Pharmacokinetics: Administration of S(-) Tolol AM 2.5 mg as a single dose in the fasting state produced maximum plasma concentration (Cmax) of 8.3 ± 1.071 ng/mL in 2.73 ± 0.88 hrs (Tmax). Tolol AM is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. The mean AUC0-t value (t=48 hrs) of Tolol AM 2.5 mg is 95.33 ± 14.45 ng·hr/mL. The AUC0-∞ value is recorded to be 140.91 ± 28.06 ng·hr/mL. The plasma elimination half-life of S(-) Tolol AM has been found to be in the range of 14.62-68.88 hrs.
How should I take Tolol AM?
Take Tolol AM 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 use this medicine in larger or smaller amounts or for longer than recommended.
You may take Tolol AM with or without food. Take the medicine at the same time each day.
Your blood pressure will need to be checked often.
Your chest pain may become worse when you first start taking Tolol AM or when your dose is increased. Call your doctor if your chest pain is severe or ongoing.
If you are being treated for high blood pressure, keep using Tolol AM even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medicine for the rest of your life.
Your hypertension or heart condition may be treated with a combination of drugs. Use all medications as directed by your doctor. Read the medication guide or patient instructions provided with each medication. Do not change your doses or stop taking any of your medications without your doctor's advice. This is especially important if you also take nitroglycerin.
Tolol AM is only part of a complete program of treatment that may also include diet, exercise, weight control, and other medications. Follow your diet, medication, and exercise routines very closely.
Store at room temperature away from moisture, heat, and light.
Tolol AM 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.
Tolol AM is usually taken once daily. Your doctor may occasionally change your dose to make sure you get the best results.
Your chest pain may become worse when you first start taking Tolol AM or when your dose is increased. Call your doctor if your chest pain is severe or ongoing.
Tolol AM is only part of a complete program of treatment that may also include diet, exercise, weight control, and other medications. Follow your diet, medication, and exercise routines very closely.
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, heat, and light.
Tolol AM pharmacology
Mechanism of Action
Tolol AM is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that Tolol AM binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Tolol AM inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by Tolol AM. Within the physiologic pH range, Tolol AM is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.
Tolol AM is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.
The precise mechanisms by which Tolol AM relieves angina have not been fully delineated, but are thought to include the following:
Exertional Angina: In patients with exertional angina, Tolol AM reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand, at any given level of exercise.
Vasospastic Angina: Tolol AM has been demonstrated to block constriction and restore blood flow in coronary arteries and arterioles in response to calcium, potassium epinephrine, serotonin, and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro. This inhibition of coronary spasm is responsible for the effectiveness of Tolol AM in vasospastic (Prinzmetal's or variant) angina.
Pharmacodynamics
Hemodynamics: Following administration of therapeutic doses to patients with hypertension, Tolol AM produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of Tolol AM decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of Tolol AM in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.
With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with Tolol AM is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105–114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90–104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/–2 mmHg).
In hypertensive patients with normal renal function, therapeutic doses of Tolol AM resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.
As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with Tolol AM have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, Tolol AM has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.
Electrophysiologic Effects: Tolol AM does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and H-V conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving Tolol AM and concomitant beta-blockers. In clinical studies in which Tolol AM was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed. In clinical trials with angina patients alone, Tolol AM therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.
Drug interactions
Sildenafil: When Tolol AM and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.
Pharmacokinetics
After oral administration of therapeutic doses of Tolol AM, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of Tolol AM is not altered by the presence of food.
Tolol AM is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Elimination from the plasma is biphasic with a terminal elimination half-life of about 30–50 hours. Steady-state plasma levels of Tolol AM are reached after 7 to 8 days of consecutive daily dosing.
The pharmacokinetics of Tolol AM are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.
Elderly patients and patients with hepatic insufficiency have decreased clearance of Tolol AM with a resulting increase in AUC of approximately 40–60%, and a lower initial dose may be required. A similar increase in AUC was observed in patients with moderate to severe heart failure.
Drug interactions
In vitro data indicate that Tolol AM has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.
Impact of other drugs on Tolol AM
Co-administered cimetidine, magnesium-and aluminum hydroxide antacids, sildenafil, and grapefruit juice have no impact on the exposure to Tolol AM.
CYP3A inhibitors: Co-administration of a 180 mg daily dose of diltiazem with 5 mg Tolol AM in elderly hypertensive patients resulted in a 60% increase in Tolol AM systemic exposure. Erythromycin co-administration in healthy volunteers did not significantly change Tolol AM systemic exposure. However, strong inhibitors of CYP3A (e.g., itraconazole, clarithromycin) may increase the plasma concentrations of Tolol AM to a greater extent.
Impact of Tolol AM on other drugs
Co-administered Tolol AM does not affect the exposure to atorvastatin, digoxin, ethanol and the warfarin prothrombin response time.
Simvastatin: Co-administration of multiple doses of 10 mg of Tolol AM with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone.
Cyclosporine: A prospective study in renal transplant patients (N=11) showed on an average of 40% increase in trough cyclosporine levels when concomitantly treated with Tolol AM.
Tacrolimus: A prospective study in healthy Chinese volunteers (N=9) with CYP3A5 expressers showed a 2.5- to 4-fold increase in tacrolimus exposure when concomitantly administered with Tolol AM compared to tacrolimus alone. This finding was not observed in CYP3A5 non-expressers (N= 6). However, a 3-fold increase in plasma exposure to tacrolimus in a renal transplant patient (CYP3A5 non-expresser) upon initiation of Tolol AM for the treatment of post-transplant hypertension resulting in reduction of tacrolimus dose has been reported. Irrespective of the CYP3A5 genotype status, the possibility of an interaction cannot be excluded with these drugs.
Pediatric Patients
Sixty-two hypertensive patients aged 6 to 17 years received doses of Tolol AM between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar to values in adults.
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).
- NCIt. "Amlodipine: 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).
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Information checked by Dr. Sachin Kumar, MD Pharmacology
