摘要:

The pharmacological effect of a drug is partly dependent upon its concentration at its site of action, which in turn is partly dependent upon its rate of elimination. The rate of elimination of many lipophilic drugs is governed by the activity of the hepatic microsomal mixed-function oxidases. Consequently any alteration in the activity of these enzymes may result in a modification of drug action.A wide range of chemically unrelated substances may stimulate the activity of the mixedfunction oxidases by enzyme induction. The drugs most frequently encountered as enzymeinducing agents in man are barbiturates, rifampicin and phenytoin. Enhancement of drug metabolism by ethanol, tobacco smoking and diet may also involve enzyme induction. Enzyme induction is normally associated with a reduction in drug efficacy but may also alter the toxicity of certain substances.Enzyme induction has been assessed in man by measuring changes in the pharmacokinetics of a marker drug, or changes in the disposition of endogenous compounds such as &ggr;-glutamyltranspeptidase, D-glucaric acid and 6&bgr;-hydroxycortisol.The therapeutic problems associated with enzyme inhibition have received much less attention than those associated with enzyme induction. The effect on the rate of elimination of a particular drug will depend upon the fraction of the dose that is normally metabolised by the inhibited enzyme and on the affinity of the enzyme for the drug and the inhibitor. An alteration in the dosage schedule is usually only necessary for drugs with a small therapeutic ratio.

ISSN:0312-5963    

出版商:ADIS    

年代:1981

数据来源: ADIS

摘要:

Muscle relaxants are of great benefit to the anaesthetist as adjuncts to anaesthesia. These drugs are used to facilitate endotracheal intubation and to reduce muscle tone during surgery, and may also find application in assisting ventilator care in the intensive care situation.The pharmacological effect of the relaxants may be readily assessed by the anaesthetist by means of a variety of techniques to quantify muscular activity in response to electrical stimulation. A number of factors may modify the effects of the muscle relaxants including anaesthetic agents, hypothermia, patient age and disease status and a variety of drugs.The disposition kinetics of the muscle relaxants have been well characterised although information on protein binding and placental transfer is somewhat scanty. A common characteristic of their pharmacokinetics is multicompartmental behaviour. Clearance of the relaxants ranges from total elimination by the kidneys (gallamine) to substantial hepatic clearance (fazadinium), and thus their clearance may be adversely affected by renal or hepatic disease.Dosage regimens have been designed using knowledge of the disposition kinetics of the relaxants to provide for continuous adequate relaxation during prolonged surgical procedures.With the use of sophisticated pharmacokinetic and pharmacodynamic models good relationships have been demonstrated between plasma concentrations of the relaxants throughout the entire range of relaxant response.

ISSN:0312-5963    

出版商:ADIS    

年代:1981

数据来源: ADIS

摘要:

Intravenous agents used in anaesthetic practice comprise three different groups of compounds: intravenous general anaesthetics, narcotic analgesics and skeletal muscle relaxants. All these drugs are characterised by a rapid onset of action and a short duration of action. These properties are the result of a number of common physicochemical and pharmacokinetic characteristics. The high lipid solubility of general anaesthetics and of narcotic analgesics explains their rapid onset of action when they are administered intravenously. The short duration of action corresponds to a rapid decline of the plasma concentration due to tissue distribution for most agents. The influence of elimination processes must also be considered, especially for long lasting operative procedures at the end of which a high cumulative dose of narcotic analgesics and muscle relaxants has been administered.Knowledge of the pharmacokinetics of the agents used may be of some help in the understanding of two serious anaesthetic accidents: (1) hypotension and cardiac.arrest during induction of anaesthesia which is due to an overdose of intravenous general anaesthetic; and (2) respiratory depression and respiratory arrest which can be attributed to a prolonged effect of narcotic analgesics and muscle relaxants. Thus, special attention must be focussed on the factors influencing the initial blood concentration for general anaesthetics and those influencing elimination processes for narcotic analgesics and muscle relaxants.For thiopentone, an excessive initial blood concentration results in hypotension. It may be related to an excessively rapid rate of injection, a reduced volume in which the drug initially distributes and/or a reduced protein-bound fraction. Distribution processes will mostly influence the duration of action of anaesthetics. Hepatic biotransformation of general anaesthetics will hardly influence their duration of action because of the relatively long elimination half-life of about 2 to 6 hours except for althesin, this drug being more rapidly metabolised with an elimination half-life of 0.5 hours.In contrast, elimination processes may influence the duration of action of narcotic analgesics and muscle relaxants. Knowledge about the pharmacokinetics of narcotic analgesics is incomplete and contradictory, especially for morphine. The elimination half-lives of morphine, pethidine (meperidine), pentazocine and fentanyl are similar (2.5 to 3.5 hours). Narcotics are eliminated by hepatic biotransformation. In liver parenchymal disease, prolongation of the elimination half-life has only been demonstrated for pethidine.In contrast to general anaesthetics and narcotic analgesics, muscle relaxants are highly hydrophilic compounds. Their volume of distribution is limited approximately to that of the extracellular fluids. Non-depolarising muscle relaxants are mainly excreted unchanged through the kidneys according to an ultrafiltration process. Biliary excretion represents an accessory pathway of excretion for all these compounds, except gallamine. Hepatic biotransformation is negligible. Their elimination half-lives are of about 2 to 3 hours. Higher values have, however, been reported for d-tubocurarine. Renal failure is the main cause of prolongation of action of non-depolarising relaxants. A less important cause of prolongation of the elimination half-life, for at least some relaxants, is the presence of hepatic parenchymal disease or cholestasis.

ISSN:0312-5963    

出版商:ADIS    

年代:1981

数据来源: ADIS

摘要:

A method is presented by which chloramphenicol clearance (CI) can be estimated from a single serum sample obtained 6 hours after the initial intravenous dose. The method was evaluated prospectively in 20 infants and children who received intravenous chloramphenicol sodium succinate. Agreement between predicted and observed clearance was excellent (r = 0.914, p < 0.001). The equation of the observed regression line was: observed = 0.886x predicted + 0.019. The method appears to provide reasonably accurate estimates of clearance which can be used for rapid clinical adjustment of dose.

ISSN:0312-5963    

出版商:ADIS    

年代:1981

数据来源: ADIS