摘要:

Antipsychotic drugs (neuroleptics) are candidates for plasma concentration monitoring, but not all agents have the same potential in this respect. The present review analyses the available data on the kinetics and metabolism of fluphenazine, perphenazine, thiothixene, flupenthixol, clopenthixol, haloperidol, pimozide, penfluridol, sulpiride and clozapine.Although some of the drugs described in this review have been in use for many years, knowledge of their pharmacokinetics is still only approximate. This is primarily because determination in biological fluids is not always feasible. Accordingly, analytical methods useful for pharmacokinetic studies or plasma concentration monitoring of these antipsychotic drugs are discussed.With the exception of sulpiride, all the neuroleptics reviewed share some basic pharmacokinetic properties: good gastrointestinal absorption but reduced systemic availability because of hepatic first-pass metabolism, high hepatic clearance and a large apparent volume of distribution leading to an apparent elimination half-life of about 24 hours for most of these compounds. The renal elimination is negligible and it seems that these drugs do not possess active metabolites.The pharmacokinetic properties of antipsychotic drugs are important for the inclusion of a set of drugs in a psychiatric institution where there is a possibility of drug concentration monitoring. In addition, the availability of a depot preparation is of importance. These factors are discussed in view of the experience made during the last years in the University Psychiatric Institutions of Geneva.

ISSN:0312-5963    

出版商:ADIS    

年代:1987

数据来源: ADIS

摘要:

In the past few years an intense effort has been directed toward the development of new inotropic agents for the treatment of chronic cardiac failure. Traditionally, therapy of this disease has included treatment with digitalis glycosides, diuretics, sodium restriction and vasodilators. While digitalis has proven to be an effective inotropic agent, it possesses a low therapeutic index and many patients remain symptomatic or ‘refractory’ despite its inotropic effects. This review focuses on the pharmacokinetics and pharmacodynamics of newer inotropic agents that have been developed or which are currently undergoing investigation.Amrinone and milrinone are two bipyridine derivatives which have been shown to be effective in the short term treatment of cardiac failure. Milrinone is currently being evaluated for its long term efficacy. The mechanism of action of amrinone and milrinone appears to be unrelated to the cardiac glycosides and sympathomimetic agents, and they are rapidly and well absorbed following oral administration. The bioavailability of milrinone appears to be somewhat reduced in patients with chronic cardiac failure. The distribution of these drugs to extravascular tissues is very rapid; the volume of distribution suggests that they are not extensively bound to tissues. While the volume of distribution of amrinone appears to be unaffected by the presence of heart failure, that of milrinone appears to be somewhat enhanced. The major route of elimination of both drugs appears to be excretion into urine as unchanged drug. A substantial fraction of the amrinone dose, however, undergoes hepatic metabolism to many metabolites, including an N-acetyl derivative. Clearance of amrinone and milrinone is dramatically reduced in patients with chronic cardiac failure compared with normal volunteers, resulting in proportionate increases in the serum half-lives of these drugs. Studies examining the acute and chronic disposition of these agents in cardiac failure patients have not demonstrated changes in their pharmacokinetics secondary to improvements in cardiocirculatory function. Both drugs show strong correlations between mean improvements in haemodynamics and drug serum concentrations, although considerable intrapatient variability may exist. It is currently unclear as to whether the site for the pharmacological action of amrinone is pharmacokinetically distinguishable from plasma.Enoximone and its sulphoxide metabolite, piroximone, are two compounds currently undergoing investigation for the treatment of chronic cardiac failure. Like the bipyridine derivatives, the mechanism of action of these compounds appears to be unrelated to sodium-potassium ATPase inhibition or sympathomimetic activity. Following oral administration of enoximone a substantial fraction of the dose is converted to piroximone on the first pass through the liver. The volumes of distribution of enoximone and piroximone do not suggest extensive tissue distribution of these drugs. The major pathway for elimination of enoximone is conversion to piroximone with subsequent renal excretion. Discrepancies exist in the literature concerning the half-life of these drugs. This discrepancy may be explained by the existence of terminal phases of disposition which have only recently been recognised. Any relationships between the haemodynamic effects of these drugs and their serum concentrations remain to be determined.Dobutamine, a synthetic catecholamine, was the first inotropic agent to become available for therapeutic use after the advent of digoxin. The limited data examining dobutamine pharmacokinetics suggest that it possesses an extremely high clearance, a limited volume of distribution, and a very short half-life. Strong relationships exist between changes in mean haemodynamic parameters and mean plasma dobutamine concentrations.Ibopamine, the 3,4-di-isobutyryl ester derivative of deoxyadrenaline (deoxyepinephrine; epinine) is an orally active, positive inotropic drug with dopaminergic vasodilatory activity. Upon oral administration, deoxyadrenaline exists primarily in the conjugated state in plasma. Elimination of this drug is primarily through metabolism; homovanillic acid is the primary urinary metabolite. The time course of haemodynamic effects of ibopamine greatly exceed the plasma persistence of free deoxyadrenaline. The site of action of ibopamine may be in a physiological compartment which is pharmacokinetically distinguishable from plasma.The development and investigation of newer inotropic agents in the treatment of chronic cardiac failure is evolving. Many more studies are needed to fully elucidate the pharmacokinetics of these and future compounds, as well as the relationships between the pharmacokinetics of these drugs and their effects in patients.

ISSN:0312-5963    

出版商:ADIS    

年代:1987

数据来源: ADIS

摘要:

The pharmacokinetics of bisoprolol were investigated following oral administration of 10mg once daily for 7 days in 8 healthy subjects, in 14 patients with different degrees of renal impairment and in 18 patients with liver disease.In healthy subjects peak and trough steady-state concentrations of 52 μg/L and 11 μg/L, respectively, an elimination half-life of 10.0 hours and total body clearance of 14.2 L/h were observed. 5.21 mg/24 hours of unchanged bisoprolol were recovered following urinary excretion during the dosage interval. In 11 patients with renal impairment (mean CLCR=28 ± 5 ml/min/1.72m2) half-life was prolonged to 18.5 hours, and peak and trough concentrations were 74 and 32 μg/L, respectively. Correspondingly, urinary excretion decreased to 3.35 mg/24 hours and total body clearance to 7.8 L/h. In uraemic patients (CLCR<5 ml/min/1.73m2) the total clearance of bisoprolol was 5.0 L/h and the elimination half-life was 24.2 hours. In patients with liver cirrhosis half-life increased to 13.5 hours, steady-state peak and trough concentrations increased to 62 and 22 μg/L, respectively, and total body clearance decreased to 10.8 L/h.The present study indicates that in patients with impairment of kidney or liver function accumulation of bisoprolol above a factor of 2 did not occur. However, in the terminal stages of insufficiency of kidney or liver function bisoprolol dosage should not exceed 10mg.

ISSN:0312-5963    

出版商:ADIS    

年代:1987

数据来源: ADIS

摘要:

The absorption characteristics of 3 sustained release quinidine formulations were assessed in 12 healthy male volunteers in a randomised 3-way crossover trial. Each formulation (‘Quinidex’ 300mg, ‘Biquin Durules’ 250mg and ‘Quinaglute Dura-Tabs’ 324mg) was administered as a single tablet every 12 hours for 5 days. Peak quinidine serum concentrations of 2.7 ± 0.8 mg/L occurred 2.5 ± 1.1 hour after ‘Quinaglute’ administration, significantly higher (p < 0.01) than concentrations of 1.6 ± 0.4 mg/L achieved 4.2 ± 1.1 hours following ‘Biquin’ dosing and 1.7 ± 0.6 mg/L attained 3.9 ± 2.7 hours after ‘Quinidex’ ingestion. The extent of absorption based on AUC∞and normalised for the anhydrous quinidine content was similar for the 3 products. Following multiple dosing, the mean steady-state trough concentration of quinidine was 2.06 ± 0.56 mg/L for ‘Quinidex’, significantly greater (p < 0.05) than that of ‘Biquin’ (1.18 ± 0.67 mg/L) or ‘Quinaglute’ (1.58 ± 0.58 mg/L).The rate of absorption was found to be much slower for ‘Quinidex’ than for the other 2 sustained release quinidine formulations. Comparison of the residual sums of squares from simple linear regression of Wagner-Nelson plots did not demonstrate a preference for a zero- or first-order absorption model. Nevertheless, the absorption of ‘Quinidex’ was twice as prolonged as that of ‘Biquin’ and ‘Quinaglute’ regardless of model; first-order absorption half-lives were 2.83 ± 1.02 hours, 1.25 ± 0.6 hours and 1.43 ± 0.88 hours, respectively. The data also suggest that ‘Quinidex’ absorption may continue beyond 12 hours in some subjects.These results indicate that the rate of quinidine absorption from various sustained release formulations may be markedly different. Since these formulations also differ in their anhydrous quinidine content, prescribers should not view these products as equivalent or interchangeable.

ISSN:0312-5963    

出版商:ADIS    

年代:1987

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1987

数据来源: ADIS