Atenolol kinetics were investigated in six healthy subjects after 100 mg orally, as monotherapy a 6-day treatment began 48 hr later. After a therapy-free interval of 4 wk, the same subjects received the same dose of atenolol with 1 gm ampicillin, 500 mg aspirin, and with 300 mg allopurinol. Allopurinol and aspirin did not substantially alter the kinetics of atenolol. After a single oral dose of 100 mg atenolol combined with 1 gm ampicillin, the bioavailability of atenolol was reduced to 36 +/- 5% compared to 60 +/- 8% after monotherapy. During long-term treatment with atenolol and ampicillin the bioavailability of atenolol fell to 24% (P less than 0.01). Mean peak plasma levels were lowered from 511 +/- 59 ng/ml on monotherapy to 344 +/- 33 ng/ml after the combination with ampicillin. The area under the plasma level-time curve, mean steady-state concentration, and urinary recovery were reduced, also. Twelve hours after 100 mg atenolol and 1 gm ampicillin, exercise tachycardia was significantly higher than after atenolol alone. During the 4-wk treatment in six hypertensive patients blood pressure levels of those on atenolol alone were not different from those on the combination therapy with ampicillin

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

In ten hospitalized, hypertensive male patients (WHO stage I or II) an acetylsalicylic acid (ASA) pretreatment (p.o. 5.0 g/24 h) prevented the acute blood pressure (BP) lowering effect of pindolol (1 mg i.v.) as compared with a placebo pretreatment. Similarly in six other hospitalized male patients (four normotensive, two slightly hypertensive) a single dose of ASA (1.0 or 1.5 g orally), which alone tended to raise the BP, reduced the decrease in systolic BP and led to an increase in diastolic BP following propranolol (5 mg i.v.). The ASA pretreatment did not affect the decrease in heart rate and cardiac contractility (measured by systolic time intervals) after the application of pindolol and propranolol, respectively. In conformity with data in the literature, the results suggest a possible connection between endogenous prostaglandins and the hypotensive, but not negative chronotropic and inotropic activity of the beta-blocking agents investigated

Nonsteroidal anti-inflammatory drugs (NSAIDs) can induce an increase in blood pressure (BP) and may potentially reduce the efficacy of several antihypertensive drugs. Probably the main mechanism of action is inhibition of prostaglandin (PG) synthesis since NSAIDs have higher propensity to increase BP as the regulation of BP (and renal function) is more PG-dependent and to interact with drugs (diuretics, beta- blockers and ACE inhibitors) that may act through the increase of PG formation. In contrast, NSAIDs do not interact with calcium antagonists and central acting drugs which actions are apparently unrelated with renal/extrarenal production of PG. It has been claimed that inhibition of natriuretic PGs could explain the pressure effects of NSAIDs in treated hypertensive patients, but sodium retention may be not the single explanation for such an interaction. We found that despite indomethacin produced sodium retention after being added either to enalapril or nifedipine-GITS, it only attenuated (by 45%) the antihypertensive effects of enalapril. In alternative, since PG enhances vasodilatation and attenuates vasoconstrictor influences, some NSAIDs may counteract the PG-dependent vasodilatory tone in renal and extrarenal vascular beds that mediate the antihypertensive action of some drugs. Thus, since calcium antagonists are probably not affected by NSAIDs, they may be preferable to drugs like diuretics, beta- blockers and ACE inhibitors for the treatment of high blood pressure control in hypertensive patients who are clinically suitable for NSAIDs therapy

OBJECTIVE: To provide a comprehensive review of the pharmacokinetic and pharmacodynamic interactions between antipsychotics and antihypertensive and to provide recommendations for the selection of antihypertensive in patients receiving antipsychotic therapy. DATA SOURCES: A MEDLINE search of the English-language literature was used to identify pertinent human and animal studies, reviews, and case reports. STUDY SELECTION: All available sources were reviewed. DATA EXTRACTION: Background information was obtained from comprehensive reviews. Individual case reports were assimilated, and pertinent data were extracted. DATA SYNTHESIS: Because hypertension is common in patients with psychiatric illness and antihypertensive agents are used for a multiplicity of indications, significant numbers of patients receive concurrent therapy with antihypertensives and antipsychotics. Many antipsychotics may block the antihypertensive efficacy of guanethidine and related drugs. The interaction between clonidine and antipsychotics is defined less clearly. Limited data suggest possible additive hypotensive effects when chlorpromazine and methyldopa are given in combination. Increased plasma concentrations of thioridazine with a resultant increase in adverse effects have been reported when propranolol or pindolol are added to the regimen. A similar increase in chlorpromazine concentrations has been reported when propranolol was added. Although there are no reports documenting an interaction between a calcium-channel antagonist and an antipsychotic, the possible inhibition of oxidative metabolism of antipsychotics, additive calcium-blocking activity, and additive pharmacodynamic effects are theorized. Hypotension and postural syncope were reported in a patient given therapeutic dosages of chlorpromazine and captopril, and in 2 patients when clozapine was added to enalapril therapy. CONCLUSIONS: No antipsychotic-antihypertensive combination is absolutely contraindicated, but no combination should be considered to be completely without risk. Antihypertensives with no centrally acting activity, such as diuretics, may be the least likely to result in adverse reactions. The combination of the beta-antagonists propranolol or pindolol with thioridazine or chlorpromazine should be avoided if possible. Scrupulous patient monitoring for attenuated or enhanced activity of either agent is essential whenever antipsychotics and antihypertensives are given concurrently

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)