RiteMED Atenolol Mechanism of Action

Pharmacology: Pharmacodynamics: Atenolol is a beta₁-selective beta-adrenergic receptor blocker without membrane stabilizing or intrinsic sympathomimetic activities. This preferential effect is not absolute, however, and at higher doses, atenolol inhibits beta₂-adrenergic receptors particularly those located in the bronchial and vascular musculature. Atenolol is a racemic mixture and its activity resides in the S(-) enantiomer.
Atenolol's beta-adrenoceptor blocking activity has been demonstrated by reduction in resting and exercise heart rate and cardiac output, reduction of systolic and diastolic blood pressure at rest and on exercise, inhibition of isoproterenol-induced tachycardia, and reduction in reflex orthostatic tachycardia.
Atenolol's significant beta-blocking effect is apparent within one hour after oral administration of a single dose, as measured by reduction of exercise tachycardia. This effect is maximal at about 2 to 4 hours and persists for at least 24 hours.
The beta, selectivity of atenolol is demonstrated by its reduced ability to reverse the beta₂-mediated vasodilating effect of isoproterenol compared with equivalent beta-blocking doses of propranolol in normal subjects. A dose of atenolol producing a greater effect on resting heart rate than propranolol resulted in an adequate increase in airway resistance in patients with asthma. In a placebo-controlled comparison of approximately equipotent oral doses of several beta-blockers, atenolol produced a significantly smaller decrease of forced expiratory volume in 1 second (FEV₁) compared with nonselective beta-blockers such as propranolol and, unlike those agents, did not inhibit bronchodilation in response to isoproterenol.
Consistent with its negative chronotropic effect due to beta blockade of the sinoatrial node, atenolol increases sinus cycle length and sinus node recovery time. Also, conduction in the atrioventricular node is prolonged. Atenolol is devoid of membrane stabilizing activity, and increasing the dose well beyond that producing beta blockade does not further depress myocardial contractility. Studies have shown a moderate (about 10%) increase in stroke volume at rest and during exercise.
Atenolol, given as a single daily oral dose, provided 24-hour reduction in blood pressure. Atenolol's dose range is narrow and increasing the dose beyond 100 mg once daily is not associated with increased antihypertensive effects. The mechanism of the antihypertensive effect of beta-blockers has not been established. Several possible mechanisms have been proposed and include competitive antagonism of catecholamines at peripheral (particularly cardiac) adrenergic neuron sites resulting in reduced cardiac output, a central effect leading to reduced sympathetic outflow to the periphery, and suppression of renin activity. Atenolol has not shown diminution of its antihypertensive effect with prolonged use.
Atenolol's anti-anginal activity appears to be due to a reduction in left ventricular work and oxygen utilization resulting (mainly) from the decrease in heart rate and contractility. On the other hand, atenolol can increase oxygen requirements by increasing left ventricular fiber length and end diastolic pressure, particularly in patients with heart failure.
Pharmacokinetics: Atenolol's absorption after oral administration is consistent but incomplete (about 40 to 50%) with peak plasma concentrations occurring 2 to 4 hours after dosing. Atenolol blood levels are consistent and subject to little variability.
After a single oral dose of atenolol 100 mg tablet to fasted normal adults, mean peak atenolol plasma concentration (C_max) of 0.4833 ± 0.1929 mcg/mL was achieved in 3.36 ± 1.01 hours (T_max). The area under the plasma concentration-time curve (AUC0-36) was 4.0105 ± 1.8756 mcg·h/mL. The elimination half-life was 6.498 ± 1.6078 hours.
Atenolol is distributed throughout the body and into breast milk. It also crosses the placenta, with fetal serum atenolol concentrations approaching those of the mother. About 6 to 16% of atenolol is bound to plasma protein.
The serum half-life of atenolol in patients with normal renal function is 6 to 7 hours; half-life increases progressively as renal function worsens. Atenolol undergoes little or no metabolism by the liver. About 40 to 50% of an oral dose of atenolol is excreted in urine unchanged. The remainder is excreted unchanged in feces, principally as unabsorbed drug.
In elderly patients, total plasma atenolol clearance is reduced by about 50% compared with that in younger patients, resulting in higher concentrations of the drug. The decreased clearance in the elderly may be related to decreased renal function.
About 1 to 12% of atenolol is reportedly removed by hemodialysis.