Tolol AM Actions
Pharmacology: Tolol AM is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.
Mechanism of Action: The mechanism of the antihypertensive action of Tolol AM is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which Tolol AM relieves angina has not been fully determined but Tolol AM reduces total ischemic burden by the following 2 actions:
Tolol AM dilates peripheral arterioles and thus, reduces the total peripheral resistance against which the heart works. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements.
The mechanism of action of Tolol AM also probably involves dilatation of the main coronary arteries and coronary arterioles, both in normal and ischemic regions. This dilatation increases myocardial oxygen delivery in patients with coronary artery spasm.
Oral administration of therapeutic doses of Tolol AM produces peak plasma concentrations between 6-12 hrs. Absolute bioavailability has been estimated to be between 64-80%. The bioavailability of Tolol AM when administered alone is not altered by the presence of food.
Distribution: Approximately 97.5% of the circulating Tolol AM drug is bound to plasma proteins in hypertensive patients. The volume of distribution is approximately 21 L/kg. Steady-state plasma levels of Tolol AM are reached after 7-8 days of consecutive daily dosing.
Metabolism: Tolol AM is extensively (90%) converted to inactive metabolites via hepatic metabolism.
Excretion: Elimination from the plasma is biphasic with a terminal t½ of about 35-50 hrs, 10% of the parent Tolol AM compound and 60% of the metabolites of Tolol AM are excreted in the urine.
Special Populations: Elderly:
Elderly:In elderly hypertensive patients there was a decrease in clearance of Tolol AM from plasma as compared to young volunteers with a resulting increase in the AUC of about 60%.
Hepatic Insufficiency: Following single oral administration of 5 mg Tolol AM, patients with chronic mild to moderate hepatic insufficiency showed about 40% increase in AUC of Tolol AM as compared to normal volunteers.
Take Tolol AM exactly as directed even if you feel well and do not notice any chest pain. 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. Do not miss any doses.
For patients taking Tolol AM for high blood pressure:
You may take Tolol AM with or without food.
Take Tolol AM at the same time each day.
The dose of Tolol AM 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 AM. 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.
If you miss a dose of Tolol AM, 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.
Do not take Tolol AM if it has been more than 12 hours since you missed your last dose.
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.
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 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.
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.
Sildenafil: When Tolol AM and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.
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.
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.
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.
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Information checked by Dr. Sachin Kumar, MD Pharmacology