摘要:

The pharmacokinetics of ethanol after typical doses are described by a 1-compartment model with concentration-dependent elimination. The volume of distribution estimated from blood concentrations is about 37 L/70kg. Protein binding of ethanol has not been reported. Elimination is principally by metabolism in the liver with small amounts excreted in the breath (0.7%), urine (0.3%), and sweat (0.1%). Metabolism occurs, principally by alcohol dehydrogenase, in the liver to acetaldehyde.Models of ethanol input and absorption are crucial to the description and understanding of the effects of ethanol dose on bioavailability. Little attention has been paid to evaluation of potential models. First-pass extraction of ethanol is predicted to be dependent on hepatic blood flow and ethanol absorption rate, with a typical extraction ratio of 0.2.The overall elimination process can be described by a capacity-limited model similar to the Michaelis-Menten model for enzyme kinetics. The maximum rate of elimination of ethanol (elimination capacity or Vmaxis 8.5 g/h/70kg. This would be equivalent to a blood ethanol disappearance rate of 230 mg/L/h if metabolism took place at its maximum rate. The elimination rate is half of the elimination capacity at a peripheral blood ethanol concentration (Km) of about 80 mg/L.Ethanol is readily detectable in expired air. The usual blood: expired air ratio is 2300: 1 and breath clearance at rest is 0.16 L/h. The renal clearance of ethanol is 0.06 L/h and sweat clearance is 0.02 L/h.The use of a zero-order model of ethanol elimination has been widespread although the limitations of this model have been known for a long time. Much of the published work on ethanol pharmacokinetics must be regarded with suspicion because of this assumption.

ISSN:0312-5963    

出版商:ADIS    

年代:1987

数据来源: ADIS

摘要:

Lignocaine (lidocaine) and &bgr;-adrenoceptor antagonists are widely used after acute myocardial infarction. The therapeutic value of these agents depends on the achievement and maintenance of safe and effective plasma concentrations. Lignocaine pharmacokinetics after acute myocardial infarction (MI) are controlled by a number of variables. The single most important is left ventricular function, which affects both volume of distribution and plasma clearance. Other major factors include bodyweight, age, hepatic function, the presence of obesity, and concomitant drug therapy. Lignocaine is extensively bound to &agr;1-acid glycoprotein, a plasma protein which is also an acute phase reactant. Increases in &agr;1-acid glycoprotein concentration occur after an acute MI, decreasing the free fraction of lignocaine in the plasma and consequently decreasing total plasma lignocaine clearance without altering the clearance of non-protein-bound lignocaine. Complex changes in lignocaine disposition occur with long term infusions, and therefore early discontinuation of lignocaine infusions (within 24 hours) should be undertaken whenever possible. Because the risk of ventricular tachyarrhythmia declines rapidly after the onset of an acute MI, lignocaine therapy can be rationally discontinued within 24 hours in most patients.Lignocaine has a narrow toxic/therapeutic index, so that pharmacokinetic factors are critical in dose selection. In contrast, &bgr;-adrenoceptor antagonists' adverse effects are more related to the presence of predisposing conditions (such as asthma, heart failure, bradyarrhythmias, etc.) than to plasma concentration. The pharmacokinetics of &bgr;-adrenoceptor antagonists are important to help assure therapeutic efficacy, to provide information about the anticipated time course of drug action, and to predict the possible role of ancillary drug effects (such as direct membrane action) and loss of cardioselectivity. Lipid solubility is the main determinant of the pharmacokinetic properties of a &bgr;-adrenoceptor antagonist. Lipid-soluble agents like propranolol and metoprolol are well absorbed orally, and undergo rapid hepatic metabolism, with important presystemic clearance and a short plasma half-life. Water-soluble drugs like sotalol, atenolol, and nadolol are less well absorbed, and are eliminated more slowly by renal excretion. Clinical assessment of &bgr;-adrenoceptor antagonism is more valuable than plasma concentration determinations in evaluating the adequacy of the dose of a particular &bgr;-adrenoceptor antagonist.This review considers the factors that determine the pharmacodynamic and pharmacokinetic properties of lignocaine and &bgr;-adrenoceptor antagonists after acute MI. These factors are then related to the principles of rational dose selection for these agents.

ISSN:0312-5963    

出版商:ADIS    

年代:1987

数据来源: ADIS

摘要:

Penicillamine exists as 2 stereoisomers, but only the D-isomer is used therapeutically. Its chemical reactivity derives from its functional groups, of which the thiol group seems the most important.It is difficult to determine penicillamine in biological fluids because of its instability, the presence of endogenous compounds with a thiol function, and the various chemical forms in which it occurs, namely reduced free penicillamine, penicillamine bound to proteins, and internal (P-S-S-P) and mixed (P-S-S-C) disulphides. The earliest assay methods (colourimetry, isotopic methods, gas-phase chromatography) were neither sensitive nor specific. High performance liquid chromatography with electrochemical detection has led to a more specific assay for D-penicillamine, with detection based on either derivatisation reactions or on electro-oxidisation of the thiol function. With dual-electrode detectors (Au/Hg) disulphides can be assayed directly.D-penicillamine is absorbed rapidly but incompletely (40 to 70%) in the intestine, with wide interindividual variations. Food, antacids and, in particular, iron reduce absorption of the drug. Its bioavailability is also dramatically decreased in patients with malabsorption states. The peak plasma concentration occurs at 1 to 3 hours after ingestion, regardless of dose, and is of the order of 1 to 2 mg/L after an oral dose of 250mg; some investigators have reported a double peak in plasma, which is probably not due to an enterohepatic cycle. The concentration in plasma then decreases rapidly, generally following a biphasic curve. When long term treatment is discontinued, there is a slow elimination phase lasting 4 to 6 days, which suggests that there is a ‘deep compartment’ or ‘slow pool of the drug reversibly bound to tissues’, particularly the skin. This may explain the persistence of its therapeutic effect and the occurrence of undesirable side effects after treatment has been stopped.During long term treatment plasma concentrations are highly variable between individuals. They do not seem to be correlated with the activity or the toxicity of D-penicillamine in patients with rheumatoid arthritis. More than 80% of plasma D-penicillamine is bound to proteins, particularly albumin. The rest is mainly in the free reduced form or as disulphides. Only a small portion of the dose is metabolised in the liver to S-methyl-D-penicillamine. The route of elimination is mainly renal; disulphides represent the main compounds found in the urine. Faecal excretion corresponds mainly to the non-absorbed fraction of the drug.

ISSN:0312-5963    

出版商:ADIS    

年代:1987

数据来源: ADIS

摘要:

Tubular secretion appears to be a major route of the renal elimination of digoxin. Secretion of the drug by the tubules is modulated by renal blood flow, by a number of commonly coadministered drugs (e.g. quinidine, spironolactone, verapamil, amiodarone), and by age. The maximal transport capacity does not appear to be achieved with clinically relevant concentrations. The tubular transport of digoxin does not appear to be associated with the anionic or cationic transport systems, nor the Na+/K+-ATPase receptor.Further studies are needed to elucidate the exact mechanisms involved in the transtubular movement of the glycoside.

ISSN:0312-5963    

出版商:ADIS    

年代:1987

数据来源: ADIS