摘要:

Hydrallazine is widely used as a peripheral vasodilator antihypertensive drug. During recent years, knowledge has accumulated on the pharmacokinetics of hydrallazine in man. It is subjected to polymorphic N-acetylation, with phenotypically slow acetylators having higher steady state plasma concentrations and higher bioavailability of the drug in single dose studies, compared with subjects who are fast acetylators. However, the terminal elimination half-life of hydrallazine is only slightly longer among slow acetylators, thus it does not seem very likely that polymorphic N-acetylation can represent the major metabolic pathway of the drug in man. Hydrallazine is subject to significant first-pass metabolism and there are indications that the N-acetylation process involved may be capacity-limited.About 10% of a single oral dose can be recovered from the urine as the parent drug, but in spite of the apparent independence of renal function for its elimination thus suggested, hydrallazine is eliminated at a considerably slower rate in uraemic patients; possibly as a consequence of impaired hepatic metabolism or underestimation of the amount excreted unchanged in subjects with normal renal function. In spite of very high steady state plasma concentrations and prolonged clearance of hydrallazine in renal failure, no harmful effects have been reported. At least 2 active metabolites have been identified, but their clinical importance and kinetic properties have not been elucidated.The duration of the hypotensive effect of hydrallazine exceeds that predicted from the rate of elimination of the parent compound from plasma. Since there is no clear-cut correlation between the plasma concentration of the drug and its effect upon blood pressure, there is at present no reason to routinely measure plasma levels of hydrallazine in treated hypertensive patients.

ISSN:0312-5963    

出版商:ADIS    

年代:1977

数据来源: ADIS

摘要:

Muscle relaxants are commonly used as an adjunct to general anaesthesia and to facilitate ventilator care in the intensive care unit. The muscle relaxants are unique in that the degree of neuromuscular blockade can be directly measured. Thus, for some of the muscle relaxants it is possible to correlate the degree of neuromuscular blockade with the plasma concentration of drug. This quantitative pharmacokinetic approach has been applied primarily to d-tubocurarine and to a lesser extent to suxamethonium (succinylcholine), gallamine and pancuronium. The pharmacokinetic information for the other relaxants is mostly descriptive and incomplete.The variation in drug concentration over time is influenced by the distribution, metabolism and excretion of drug. Metabolism by plasma cholinesterase plays a major role in the termination of action of suxamethonium. Although pancuronium is partly metabolised its major metabolites have moderate pharmacological activity. The other relaxants are excreted through the kidney. For gallamine and dimethyl-tubocurarine, renal excretion appears to be the only means of elimination. However, biliary excretion probably provides an alternative route of elimination for d-tubocurarine and pancuronium. In patients with impaired renal function the duration of neuromuscular blockade may be markedly prolonged following standard doses of gallamine or dimethyl-tubocurarine, may be slightly prolonged following standard doses of pancuronium, and is near normal following standard doses of d-tubocurarine. Following large or repeated doses of pancuronium or d-tubocurarine, the duration of neuromuscular blockade may be markedly prolonged.Because of their relatively large extracellular fluid volume, infants require more suxamethonium on a weight basis than do adults to produce equal neuromuscular blockade. At a single equipotent dose of suxamethonium, the time to recover full neuromuscular transmission is the same in infants, children and probably adults. Neonates appear to be sensitive to non-depolarising muscle relaxants; dosage criteria are unpredictable.

ISSN:0312-5963    

出版商:ADIS    

年代:1977

数据来源: ADIS

摘要:

Intravenous anaesthetics comprise a variety of drugs that differ in chemical structure but share a suitable combination of physical properties that confer ready penetration of the blood-brain barrier. Lipid solubility is particularly important in this respect. Rapid entry into the brain is associated with rapid distribution and redistribution in the body for most of these drugs. They all readily cross the placenta to the fetus. Rate of metabolism varies between the rapidly biotransformed drugs like propanidid to the slowly metabolised ones like thiopentone. The liver is the main site of biotransformation, with the exception of propanidid which is hydrolysed by plasma pseudocholinesterase. Recovery of mental and psychomotor functions is protracted compared with inhalation anaesthetics, except after propanidid.Thiopentone confers a two- or three-compartment open model system on the body, with an average elimination half-life of 6.2 hours. Rapid initial recovery is due to redistribution to the muscle mass. Distribution is modified by the state of ionisation of the drug and its magnitude of binding to plasma proteins.Methohexitone has an elimination half-life of 70 to 125 minutes, which is the result of a high plasma clearance rate. However, complete psychomotor recovery seems to take the same length of time after the use of thiopentone and methohexitone in equianeasthetic doses.Droperidol exhibits two-compartment open model kinetics with a mean elimination half-life of 2.2 hours. It is 85 to 90% bound to plasma proteins at therapeutic levels and accumulates in certain brain areas. Fentanyl has a half-life of 1 to 4 hours or more, depending on the dosage given. The drug can therefore accumulate in the body after large or multiple doses, in spite of its reputation as a short-acting narcotic.Ketamine has a half-life of 4 hours or longer. It is poorly bound to plasma proteins. Some of its metabolites are pharmacologically active. The relation between the plasma levels of the drug and its metabolites and incidence of post-drug hallucinations and dreams need to be studied.The kinetics of propanidid follow a one-compartment open model. It is rapidly hydrolysed in plasma and the duration of anaesthesia is influenced by pseudocholinesterase activity.Althesin (alphadione) is a mixture of 2 steroids (alphaxalone and alphadolone). Alphaxalone is rapidly metabolised in the liver and then excreted in the urine. The pharmacokinetics of alphadolone have not been studied. The accumulation of Althesin after repeated doses and late impairment of driving skills have initial recovery may suggest the formation of pharmacologically active metabolites.Plasma level data of intravenous diazepam can be fitted with a three-compartment open model system. It has an elimination half-life of 21 to 37 hours which is age dependent and is prolonged in patients with liver disease. It is highly bound to plasma proteins and occasionally fluctuations in plasma concentrations may coincide with subjective recurrence of drowsiness.Etomidate is a new carboxylated imidazole derivative. Return of the drug to the central compartment from the deep peripheral compartment may be the rate controlling step in elimination of the drug. The major metabolic pathway is hydrolysis of the ethyl ester, which probably occurs mainly in the liver.

ISSN:0312-5963    

出版商:ADIS    

年代:1977

数据来源: ADIS

摘要:

To ascertain whether the renal clearance of disopyramide (pK&agr;= 8.36) is affected by urine pH, the disposition kinetics of disopyramide were compared during excretion of acidic and alkaline urine following both single dose intravenous (2mg/kg) and oral (5mg/kg) administration to 4 healthy male volunteers. No significant difference was observed in the plasma concentration-time curve of disopyramide. The mean 72 hour recovery of disopyramide and its N-deisopropyl metabolite (MND) in urine was 55.1 and 20.3% of the dose respectively, with no apparent difference between the two routes of administration or pH of urine. Renal clearance of disopyramide was found to vary with time, which is partly the result of a concentration dependent change in plasma protein binding. The unbound fraction of drug in plasma varied from 0.32 to 0.72 between 0.4 to 4&mgr;g/ml concentration. However, time-dependent change in renal clearance of disopyramide persists even after correction for plasma protein binding.

ISSN:0312-5963    

出版商:ADIS    

年代:1977

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1977

数据来源: ADIS