Metabolism and Pharmacodynamic Properties of Atenolol

Atenolol is a long-acting cardioselective β1-adrenoceptor blocker without intrinsic sympathomimetic activity or membrane-stabilizing properties. Its blocking effect on β1-adrenoceptors is similar to that of metoprolol, nadolol, and propranolol, and is about one-sixth that of pindolol and timolol; however, it does not inhibit the bronchodilator effects of isoproterenol. Atenolol is primarily used for the treatment of hypertension, angina pectoris, and myocardial infarction, and may also be used for arrhythmias, hyperthyroidism, and pheochromocytoma.

Figure1: Picture of Atenolol

Basic Introduction

Atenolol is one of the most widely used blockers clinically, and has often been used as a reference drug in randomised controlled trials of hypertension. However, questions have been raised about atenolol as the best reference drug for comparisons with other antihypertensives. Thus, our aim was to systematically review the effect of atenolol on cardiovascular morbidity and mortality in hypertensive patients. Atenolol is a hydrophilic β-adrenoceptor blocking drug whose properties of cardioselectivity and hydrophilicity can be predicted from its molecular structure. As a cardioselective beta blocker containing an oxypropranolamine side chain, atenolol features an amidic group at the para position of the benzene ring—a structural characteristic common to such compounds. This amidic function not only contributes to atenolol's cardioselectivity but also reduces its lipophilicity, making atenolol both cardioselective and predominantly hydrophilic. Due to its hydrophilic nature, atenolol tends not to undergo metabolism and is consequently excreted unchanged by the kidneys, and it reaches deeper body compartments only with relative difficulty. [1]

Metabolism

Lipophilic beta blockers, such as propranolol, metoprolol, or oxprenolol, fail to reach the systemic circulation after oral administration because they are taken up in the portal vein and removed from the bloodstream by the liver. In contrast, hydrophilic beta blockers like atenolol tend to be poorly metabolized. Atenolol is primarily eliminated by renal excretion, with only about 10% of the drug undergoing nonrenal elimination. Feces contain approximately 10% of an intravenously administered dose of atenolol, which is largely excreted unchanged, accompanied by only small amounts of nonpolar metabolites. These findings apply to both intravenous and oral administration of atenolol, although absorption after oral dosing is incomplete compared to the intravenous route. In humans, atenolol undergoes limited metabolism, with a non-conjugated hydroxylated metabolite isolated in urine. This metabolite accounts for only 2–3% of the radiolabeled material in urine after oral intake and 5.8% after intravenous administration. Since this metabolite does not appear in blood to any significant extent and possesses very low beta-blocking activity—approximately one-tenth that of the parent compound—atenolol itself is solely responsible for the observed pharmacological effects. Additionally, about 2% of an administered dose of atenolol recovered in urine is conjugated with glucuronic acid. Although these two metabolic pathways have been described for atenolol, they are so minor that they do not significantly influence the pharmacokinetic or pharmacological properties of the drug. [1]

Pharmacodynamic Properties

Atenolol is a selective and long acting {j,-adrenoceptor antagonist. In patients with hyperten sion, oral administration of atenolol significantly reduces resting systolic and diastolic blood pres sures and attenuates the blood pressure increase induced by exercise. Insome studies, long term administration ofatenolol 50 to 100mg daily improved left ventricular hypertrophy when present before treatment. In patients with coronary artery disease the antihypertensive effects ofatenolol are accompanied by reductions in heart rate (8 to 34%) and rate-pressure product (9 to 40%). Atenolol improves indices ofoxygen consumption in patients with acute myocardial infarction. Short or long term administration ofatenolol 50 to 100mg daily reduces blood pressure in preg nant women. Although impaired glucose tolerance and increased insulin resistance have been reported in some patients treated with atenolol, improved glucose tolerance has been reported in others. Increases in plasma total triglycerides and very low density lipoprotein triglycerides, and decreases in high density lipoprotein cholesterol generally occur after several months' treatment with at enolol, but these changes are less pronounced than those associated with propranolol and a trend towards a reduction in effect has been noted during long term administration. Atenolol 50 to 125mg impairs respiratory function in asthmatic patients, following single or multiple doses, to a lesser extent than propranolol, and does not significantly decrease the bronchodilatation effect of inhaled salbutamol during short or long term treatment. [2]

Pharmacokinetic Properties

Following oral administration, about 50 to 60%ofan atenolol dose is absorbed with maximum plasma concentrations reached within 2 to 4 hours. Atenolol is widely distributed in the body (although only a small proportion ofan administered dose reaches the brain), and readily crosses the placenta. In adult patients with normal renal function the elimination half-life is about 5 to 7 hours and total clearance is about 6 Llh (100 ml/min) per 1.73m2. A shorter elimination half life (4.5 hours) has been observed in children. However, there are wide intra- and interindividual differences in the pharmacokinetic properties of atenolol. Most absorbed atenolol is excreted unchanged in the urine. Accumulation into breast milk has been reported but plasma concen trations are negligible in infants. In patients with renal dysfunction the elimination rate is de creased and is related to glomerular filtration rate. [2]

Therapeutic Efficacy

During long term follow-up trials with atenolol, generally 50 to 100mg once daily alone or in combination with a diuretic, goal blood pressures are achieved in about two-thirds of all patients with mild to moderate hypertension. The greatest reductions in blood pressure occur in the first 2 weeks oftreatment, and blood pressure remains within normal limits during extended therapy without major adjustment of dosage. Atenolol 50 to 100mg daily is clearly more effective than placebo in reducing blood pressure, and in comparative trials it reduced blood pressure in a similar proportion ofpatients, and to a similar extent, as usual therapeutic doses of other {j-adrenoceptor antagonists (acebutolol, celi prolol, betaxolol, indenolol, SR metoprolol, nadolol, SR pindolol, SR propranolol, tertatolol), ACE inhibitors [captopril (100mg), enalapril (20 to 40mg) and Iisinopril (20 to 80mg)], calcium antagonists [amlodipine (2.5 to IOmg), diltiazem (240 to 360mg), felodipine (10 to 20mg), isra dipine (5 to 20mg), SR nifedipine (20 to 40mg), SR verapamil (240mg) and nitrendipine (20 to 40mg)], doxazosin I to 16mg, ketanserin 40 to 80mg and a-methyldopa 1500mg daily. Elderly patients and women with hypertension associated with pregnancy respond well to treatment with atenolol 50 and 50 to 200mg daily, respectively. Inpatients with stable angina pectoris, oral atenolol 100mg daily was superior to placebo and at least as effective as usual therapeutic doses ofother antianginal agents in reducing the severity and frequency of anginal attacks, reducing glyceryl trinitrate consumption, improving exercise duration, and extending time to Imm ST-segment depression. Atenolol appears to eliminate the morning ischaemic episode peak in patients with silent ischaemia. [2]

Tolerability

The most frequently reported adverse effects experienced during oral atenolol therapy for hypertension, angina pectoris and arrhythmias are bradycardia (0.6 to 10%), cold extremities/ Raynaud's phenomenon (2 to 35%),gastrointestinal symptoms (0.5 to 32%),fatigue/weakness (I to 51%),nightmares/sleep disturbances (6 to 26%),headache (I to 18%), and sexual disturbances (I to 14%). In general these effects were mild, occurred more frequently during baseline phases, usually become less frequent with continued therapy and, in most studies, necessitated withdrawal of treatment from only 3 to 6% of patients. Data from comparative studies suggest that the tolerability profile of atenolol is similar to that of other antihypertensive agents although the pattern of effects differed between drug classes. Both hypotension and bradycardia have been observed after intravenous administration of atenolol in patients with myocardial infarction. At enolol therapy has not been associated with ophthalmological changes or clinically significant changes in haematological or biochemical indices. [2]

Reference

[1] Kirch, W., G?rg, K.G. Clinical pharmacokinetics of atenolol — A review. European Journal of Drug Metabolism and Pharmacokinetics 7, 81–91 (1982).

[2] Heel, R.C., Brogden, R.N., Speight, T.M. et al. Atenolol: A Review of its Pharmacological Properties and Therapeutic Efficacy in Angina Pectoris and Hypertension. Drugs 17, 425–460 (1979).

You may like