Beta adrenoceptor blocking drugs are relatively well tolerated and adverse reactions to them are not common. The ones that do occur are reviewed in this paper under the following headings: Short term adverse reactions, drug interactions, long term adverse reactions, risks in pregnancy and hazards of abrupt withdrawal. Predictable short term effects may be caused either by the actions of these drugs on the beta 1- or beta 2-receptors. The beta 1 adverse effects are hypotension, bradycardia and cardiac failure; these are best avoided by not giving beta-adrenoceptor blocking drugs to susceptible patients with cardiac disease. The beta 2 adverse effects on the bronchi, the peripheral arteries and various metabolic functions may be reduced to some extent by using a relatively cardioselective drug. Unpredictable short term effects such as fatigue, sexual dysfunction and gastrointestinal symptoms may occur but are not common problems with this group of drugs. Similarly, serious drug interactions are infrequent. Under the heading of long term adverse effects the practolol problem and the risk of causing malignant disorders have been considered. There is no evidence that any of the currently available drugs will cause either a practolol syndrome or malignant disease in man. However, the need for careful appraisal by drug regulatory bodies and continued vigilance by all prescribers of beta-adrenoceptor blocking drugs remains. The possible adverse effects of treatment during pregnancy are also considered. It now appears that beta-adrenoceptor drugs can be used safely in pregnancy but since neonatal bradycardia and hypoglycemia may occur, care should be taken to look for these complications. A serious deterioration may occur when beta-adrenoceptor drugs, given to patients with significant ischemic heart disease, are suddenly stopped. This is a rare occurrence but prescribers should be aware of it

Six healthy subjects were treated with 100 mg atenolol. After a therapy- free interval of 4 wk the same subjects received the same dose of atenolol with furosemide, 40 mg, with calcium (as the lactate gluconate and carbonate), 500 mg, or with aluminum hydroxide, 5.6 gm. Atenolol alone and in combination was administered first as a single oral dose; a long-term 6-day treatment began 48 hr later. Addition of furosemide did not influence atenolol kinetics, but aluminum hydroxide led to an insignificant reduction (P greater than 0.05) of mean peak plasma levels of about 20% and of the area under the plasma concentration-time curve (AUC -infinity) from 5818 to 4353 ng ml-1 hr (P greater than 0.05). Calcium altered atenolol kinetics distinctly mean peak plasma levels of atenolol fell 51% (P less than 0.001), AUC0-infinity fell from 5818 to 3935 ng ml-1 hr (P less than 0.01) and elimination half- life (t1/2) increased to a mean of 11.0 hr (compared to 6.2 hr with atenolol alone). The prolongation of t1/2 induced by calcium coadministration led to atenolol cumulation during the long-term dosage. Twelve hours after atenolol, 100 mg, and calcium, 500 mg, exercise tachycardia was lower than with atenolol alone (P less than 0.001). During the 4-wk treatment in six hypertensive patients, blood pressure values of those on atenolol alone were not different from those on the combination therapies (P greater than 0.05)

Propranolol is widely used in clinical practice and is frequently administered along with other drugs. The co-administration of propranolol and other drugs may result in either propranolol-induced changes in the disposition of other drugs or in effects of the other drugs on the pharmacokinetics of propranolol. These changes may be due to alteration in absorption, metabolism or to haemodynamic effects such as altered liver blood flow. Understanding the pharmacokinetics of propranolol is important to the rational interpretation of the effects of other drugs on propranolol´s disposition. The absorption, protein binding and metabolism of propranolol may all be affected by the co-administration of other drugs. Induction of propranolol´s metabolism by halofenate, phenytoin, phenobarbitone, rifampicin and alcohol have all been implicated in altering propranolol clearance, while inhibition of hepatic drug metabolising enzymes by chlorpromazine and cimetidine appear to reduce propranolol clearance. Propranolol may also affect the metabolism of other drugs such as antipyrine, chlorpromazine, theophylline and thyroid hormones. Suggestions that propranolol may alter quinidine´s elimination have not been substantiated. By reducing liver blood flow propranolol may reduce the systemic clearance of other high extraction drugs such as lignocaine

There is evidence, from human and animal studies, that drug-metabolising enzymes exist in multiple forms, the individual enzymes having selective, but not specific, substrate requirements. Consequently drug interactions may arise when two drugs bind to the same enzyme. The degree of enzyme inhibition will be partly dependent on the relative affinities of the drugs for the enzyme and on their rates of turnover. The decrease in drug clearance produced by enzyme inhibition is dependent on the fraction of the drug normally metabolised by the inhibited pathway(s). Cimetidine, a P-450 enzyme inhibitor, increases the systemic bioavailability of propranolol and labetalol, which undergo extensive metabolism, but does not affect the clearance of atenolol, which is excreted largely unchanged. In this situation, both the extent and type of biotransformation are important. Thus, cimetidine has no effect on the clearance of penbutolol, even though the drug is eliminated almost entirely by biotransformation. The major metabolite is penbutolol glucuronide, and it has been shown recently that cimetidine does not inhibit glucuronylation. Beta-adrenoceptor blockers also act as enzyme inhibitors themselves. For example, antipyrine clearance is decreased by propranolol and to a lesser extent by metoprolol, whereas atenolol has no effect. It has been suggested, therefore, that there is a relationship between the lipid-solubility of beta-adrenoceptor blockers and their ability to inhibit drug metabolism. The clearance of lipophilic beta-adrenoceptor blockers is dependent on hepatic enzyme activity, and is therefore sensitive to enzyme induction. For drugs with high hepatic clearance and subsequent high presystemic elimination, a moderate increase in the extraction ratio will produce a marked decrease in systemic bioavailability. (ABSTRACT TRUNCATED AT 250 WORDS)

Concomitant administration of antacid increased the maximum concentration (Cpmax) and the area under the plasma concentration-time curve (AUC) of 100 mg oral dose of metoprolol by 25 per cent (p less than 0.05) and 11 per cent (p less than 0.1) respectively. For atenolol the opposite effect was observed and Cpmax and AUC were decreased by 37 and 33 per cent respectively (p less than 0.02). In both cases the antacid did not affect the time-course of atenolol in the plasma or its bioavailability. Propantheline prolonged the absorption phase of atenolol and the time of peaking (tmax) was shifted from 2.1 to 4.5 h. Cpmax of atenolol was essentially unchanged by propantheline pretreatment while the AUC was increased by 36 per cent. It is concluded that the negative effect of the antacid on the bioavailability of atenolol is caused by a reduction in the in vivo dissolution rate due to increased gastric pH. The positive effect of propantheline might be due either to more efficient absorption of atenolol in the upper part of the intestine or more extensive dissolution of the drug as a result of prolonged contact with gastric juice or a combination of these factors