摘要:

&bgr;-Adrenoceptor blocking drugs (&bgr;-blockers) have an established place in the management of patients with thyroid disease. Thyroid hormones, however, markedly alter hepatic, renal and cardiovascular function and thus may significantly influence drug disposition. In hyperthyroidism the clearance of propranolol following intravenous administration is increased by approximately 50%, an effect that may be attributed to the marked increase in liver blood flow that occurs in this condition. On the other hand, the increased clearance of propranolol during long term oral therapy is presumably due to increased hepatic drug metabolising enzyme activity. However, following single oral doses the clearance of propranolol has been reported both to be unchanged and increased in hyperthyroid patients. Both during single dose and long term therapy the elimination half-life of propranolol is unaltered, in part due to an increased apparent volume of distribution. The degree of plasma protein binding of propranolol appears to be slightly reduced in the hyperthyroid state.There is evidence to suggest that the clearance of metoprolol, which like propranolol undergoes extensive hepatic metabolism, is also increased in hyperthyroidism. In contrast, the oral clearance of renally excreted &bgr;-blockers such as sotalol and atenolol, and probably practolol also, is not altered in hyperthyroidism.In general, all &bgr;-blockers produce a similar degree of symptomatic response. Those with intrinsic sympathomimetic activity (e.g. oxprenolol) do not reduce heart rate to the same extent as propranolol. Recent studies have shown a significant relationship between plasma propranolol levels and the objective measures (reduction in exercise tachycardia, serum triiodothyronine concentration and weight change) but not the subjective measures of therapeutic response. Concentration-response relationships are also becoming apparent for other &bgr;-blockers such as metoprolol and nadolol. The 20-fold interindividual variation in propranolol plasma concentrations, which may be largely attributed to age and smoking habits, emphasises the need for individualisation of dosage. This may also explain the reported cases of thyroid crisis, particularly postoperatively in patients receiving a fixed dosage regimen. In the latter situation surgery may also markedly alter the handling of propranolol.The effect of hypothyroidism on the disposition of &bgr;-blockers has not been definitively studied. In hypothyroidism the elimination half-life of propranolol following a single oral dose may be prolonged although clearance is not affected. During long term therapy, preliminary evidence suggests that steady-state plasma propranolol levels are elevated. The clearance of practolol is reduced and its elimination half-life is prolonged compared with the hyperthyroid state.It is unlikely that the efficacy of newer &bgr;-blockers will exceed that of propranolol. However, in certain clinical situations a long acting or a cardioselective agent may be preferable. The influence of thyroid disorders on the kinetics and the concentration-response relationships of the newer agents will, however, require further study.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

The currently available drugs for the treatment of systemic fungal infections are amphotericin B, flucytosine, miconazole and ketoconazole.Amphotericin B has to be given intravenously in the treatment of deep mycoses. The dose is gradually increased following a small initial dose, though this may delay the attainment of therapeutic concentrations. Amphotericin B serum concentrations are proportional to dose but only up to doses of 50mg. The serum pharmacokinetics fit a 3-compartment model, while cerebrospinal fluid pharmacokinetics fit a 2-compartment model. The precise identities of these compartments have not been determined. In the serum there is a relatively rapid initial half-life of 1 to 2 days, and a slower elimination phase of 15 days. Amphotericin B penetrates poorly into other body tissues, and concentrations are usually well below those in serum. This may partly be due to its high protein binding. The routes of amphotericin B elimination in man are unknown. Amphotericin B invariably causes dose-related renal damage, but this does not markedly alter its pharmacokinetics; mannitol infusions do not reduce this nephrotoxicity. Concurrent gentamicin administration and sodium depletion may enhance amphotericin B nephrotoxicity.Flucytosine may be given orally or intravenously. It has a high (greater than 80%) oral bioavailability, but this is lower in patients with renal failure. Flucytosine absorption is delayed in renal failure and by antacids. The serum pharmacokinetics fit a I-compartment model, and the apparent volume of distribution approximates to body water. Flucytosine has low protein binding and good tissue penetration. There is minimal metabolism in man; conversion to 5-fluorouracil may be the basis of flucytosine toxicity. Since flucytosine is largely eliminated by renal excretion, serum concentrations are markedly increased in the presence of renal impairment. The renal clearance of flucytosine closely parallels creatinine clearance, and in renal failure the half-life is considerably prolonged. Toxicity can be avoided by therapeutic monitoring of serum concentrations and reducing the dose when renal function is impaired.Miconazole is poorly absorbed from the gut; therefore intravenous administration is required for treatment of systemic fungal infections. Its serum pharmacokinetics fit a 3-compartment model with a short initial half-life of less than 1 hour, an intermediate half-life of 2 hours, and a terminal half-life of 20 hours. Despite this long terminal half-life, miconazole has to be given every 8 hours. It has a high apparent volume of distribution and is highly bound to plasma proteins. Adequate penetration only occurs into certain body tissues. Penetration into cerebrospinal fluid is poor and intrathecal injection may be required. Miconazole is oxidised in man and the inactive metabolites are excreted mainly in urine. Serum concentrations of miconazole are higher in renal failure, but dosage adjustment is rarely necessary. Miconazole toxicity is not related to pharmacokinetics, and the need for therapeutic monitoring of serum concentrations is unclear. Miconazole enhances the anticoagulant effect of warfarin.Ketoconazole is well absorbed from the gut. Food has been reported to both enhance and reduce ketoconazole absorption. Absorption is decreased in renal failure and when gastric acidity is reduced. Its pharmacokinetics fit a 2-compartment model. The initial half-life is between 1 and 4 hours and the terminal half-life ranges between 6 and 10 hours; both elimination phases are dose-dependent. Ketoconazole is almost completely protein bound, and penetration into body tissues is variable. It is extensively metabolised, mainly by oxidation, to metabolites without antifungal activity which are excreted in urine and faeces. Renal and hepatic disease do not appear to affect ketoconazole kinetics. Therapeutic failure is associated with low serum concentrations of the drug, therefore therapeutic monitoring is of use in such patients. Cimetidine, and presumably other H2-receptor antagonists, reduce ketoconazole serum concentrations by reducing absorption.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

The clinical pharmacokinetics of metronidazole following oral, intravenous, rectal, and intravaginal doses are described. Peak serum concentrations are quite similar after oral or intravenous administration and average approximately 10 &mgr;g/ml after a single 500mg dose. After an oral dose the peak serum concentration is reached approximately 1 hour after administration. Food does not significantly affect absorption, and the bioavailability of the dose approaches 100%. For both intravenous and oral administration, a linear doseconcentration curve pertained for usual therapeutic doses between 200 and 2000mg.Multiple oral or intravenous doses given every 6 to 8 hours result in some drug accumulation with higher serum concentrations as compared with single doses. On an intravenous dose regimen of 500mg every 8 hours, maximum metronidazole serum concentrations average 25 &mgr;g/ml and minimum concentrations 15 &mgr;g/ml. Rectal administration of metronidazole by suppository resulted in peak serum concentrations approximately one-half those following equivalent oral doses and occurred at 4 hours after administration; the bioavailability of the rectal suppository was approximately 80%. From the limited data available, the systemic absorption of intravaginal metronidazole is very slow with peak serum concentrations of approximately 2 &mgr;g/ml being attained 8 to 24 hours after administration of a 500mg dose.Metronidazole is excreted in the urine as unchanged drug and primarily oxidative metabolites, the major compounds being the hydroxy and acid metabolites. The degree of urinary excretion is dependent upon the assay used. By bioassay, 15 to 20% of the administered dose is excreted as bioactive drug. By high pressure liquid chromatography, in which unchanged metronidazole and the hydroxy and acid metabolites are measured separately, total excretion of these compounds after 48 hours is approximately 30%, with the hydroxy metabolite being the primary excretory product.Detailed pharmacokinetic analysis of metronidazole has been performed using 1-compartment and 2-compartment open models. The serum half-life of unchanged metronidazole averaged 8.2 hours, as determined by specific chemical methods, whereas using bioassay methods the half-life was somewhat longer. A 2-compartment open model analysis described the serum concentration-time curve with a rapid &agr; (distribution) phase (half-life 1.24 hours) and a slower &bgr; (elimination) phase (half-life 9.76 hours). Metronidazole has a large apparent volume of distribution and serum protein binding of 20% or less. In multiple-dose regimens the hydroxy metabolite of metronidazole may be present in concentrations up to 30% of those of the parent drug with a half-life of 9.7 hours. The acid metabolite is rarely detected in serum. Metronidazole is widely distributed throughout the body with tissue levels, in most cases, approximating serum levels. This is especially important in the central nervous system where the drug readily crosses both the blood-brain and blood-cerebrospinal fluid barriers.The pharmacokinetics of metronidazole do not appear to differ significantly in neonates, patients seriously ill with anaerobic infections, or during pregnancy. However, dose modification is necessary in neonates because of the slower elimination of the drug. In patients with renal failure, although the serum half-life of metronidazole does not change, the half-life of the hydroxy metabolite increases 4-fold and accumulates in the serum. Haemodialysis effectively removes metronidazole and, to a lesser extent, the hydroxy metabolite, reducing the half-life of the former to 2.6 hours and the latter to 7.8 hours. and diarrhoea, a reversible leucocytopenia, and various neurological toxicities (the latter generally associated with large doses over a prolonged period). Potentially serious toxicities including tumourigenicity, dysmorphogenicity, and mutagenicity inferred from certain animal models and bacterial test systems have not been confirmed in humans.The pharmacokinetic properties of metronidazole complement its excellent microbiological activity against anaerobic organisms, making it a very effective drug in the treatment of anaerobic infections.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

Measurement of drug levels is becoming increasingly popular to optimise the dosage of various drugs. In the case of antiarrhythmic drugs, the narrow therapeutic margin of most of these agents and a direct relationship between their pharmacological effects and plasma concentrations would justify more widespread use of monitoring. Optimum plasma concentration ranges have been described for lignocaine (lidocaine), procainamide, quinidine and, more recently, also for disopyramide, mexiletine, tocainide and other new antiarrhythmics. A critical analysis of the original data shows, however, that therapeutic and toxic levels are not so well defined as often assumed: small numbers of patients, marked interindividual variability, sometimes inadequate documentation of arrhythmias and lack of standardised blood sampling characterise many of these studies. Uncertainty about the reliability of concentration-effect relationships also arises when active drug metabolites are identified or there are marked concentration-dependent changes of drug protein-binding. In addition, abolition of various types of arrhythmias might require different drug concentrations. Nevertheless, therapeutic monitoring can be of practical value in patients with life-threatening ventricular arrhythmias and can also greatly facilitate dosage adjustment in cases with renal hepatic or severe cardiac failure. For a correct interpretation of drug levels, the time of blood sampling, dosage regimen, duration of treatment, pharmacokinetic principles, and the clinical condition of the patient must be taken into account.Further studies are needed to define the optimum therapeutic range for several drugs and to evaluate the usefulness of plasma concentration measurements in routine antiarrhythmic treatment.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

The rate and extent of accumulation of clobazam and its major metabolite, desmethylclobazam, during multiple dosage with clobazam were evaluated in 4 similarly sized groups of young male, young female, elderly male, and elderly female volunteers. Subjects received single 10mg doses of clobazam daily for 22 consecutive days. Plasma levels were measured during and after the period of dosage. Compared with the young male subjects, elderly males had slower rates of clobazam accumulation and washout, higher steady-state plasma levels, and lower steady-state clearance. Accumulation of desmethylclobazam also was slower and more extensive in the elderly male group. Among females, however, agerelated kinetic differences did not approach significance.Among all subjects, pharmacokinetic variables for clobazam determined in a previous single-dose study were highly consistent with the multiple-dose pharmacokinetic profile. Single-dosevspost-multiple dosage half-life, single-dosevssteady-state clearance, observedvspredicted accumulation ratios, and observedvspredicted steady-state plasma concentrations were all highly correlated, with regression line slopes close to unity. Thus, reduced single-dose clearance of clobazam in elderly men leads to slower and more extensive accumulation during multiple dosage. The single-dose pharmacokinetic profile of clobazam is highly predictive of drug behaviour during repeated dosage, suggesting that clobazam kinetics are dose- and concentration-independent within the range studied, and that self-induction or inhibition of clearance is not evident during 3 weeks of dosage.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS