摘要:

Anticonvulsant therapy was among the first areas to benefit from clinical pharmacokinetic studies. The most important advantage is that the frequent interindividual variation in the plasma level/dose ratio for these drugs can be circumvented by plasma level monitoring. For several anticonvulsants the brain concentration is shown to parallel the plasma concentration.Phenytoin(diphenylhydantoin) is still the most important anticonvulsant and the one for which kinetics have been thoroughly investigated in man. These investigations have revealed several reasons for the wellknown difficulties in using this drug clinically. The absorption rate and fraction are very much dependent on the pharmaceutical preparation, and changes of brand may alter the plasma level of phenytoin in spite of unaltered dose. The elimination capacity is saturable causing dose dependent kinetics, which again means disproportional changes in plasma level with changes in dose. Great individual variations exist in the rate of metabolism, and several pharmacokinetic drug interactions are known. As an optimum therapeutic plasma concentration range has been established monitoring plasma levels must be strongly advocated. Interpretation of plasma levels in uraemic patients must take into account decreased protein binding of the drug.Carbamazepineis probably as effective as phenytoin. The elimination is a first order process, but the rate of metabolism increases after a few weeks' treatment. An active metabolite (epoxide) may be the cause of some side-effects. Combined treatment with other anticonvulsant drugs decreases the half-life and more frequent dosing may be necessary. An optimum therapeutic concentration range has been suggested and plasma monitoring is advocated, along with that of the active metabolite, the epoxide.Phenobarbitoneis still much used but its kinetics have been investigated to a lesser extent. The main problem is the variability in the rate of elimination. In children the half-life of phenobarbitone is only half of that in adults. An optimum therapeutic plasma range has been established and monitoring is recommended.Primidonemay have an anticonvulsant activity in itself, but its main metabolite is phenobarbitone. The relatively rapid elimination of primidone is offset by the long half-life of phenobarbitone. An optimum therapeutic range has been suggested, but plasma level monitoring must include determination of phenobarbitone.Ethosuximide.The clinical pharmacokinetics of this important petit mal anticonvulsant is not well known. It has a relatively long half-life (in adults 2 to 3 days; in children shorter). An optimum therapeutic range has been suggested, and routine monitoring of plasma levels may be recommended.Diazepamexerts a rapid anticonvulsant activity when the plasma concentration exceeds approximately 500ng/ml after intravenous injection. The kinetic pattern is complex in man.Clonazepam.The clinical pharmacokinetics are still not fully investigated but a therapeutic range has been suggested. Monitoring of plasma levels may be carried out on special occasions.Di-n-propylacetic acid(valproic acid) is a new anticonvulsant, which is kinetically not sufficiently investigated in man. With a half-life of about 10 hours greater fluctuations in the plasma concentration may be seen. Plasma monitoring cannot yet be recommended as a routine procedure.

ISSN:0312-5963    

出版商:ADIS    

年代:1976

数据来源: ADIS

摘要:

Drugs are usually given orally. They are not absorbed to any extent from the stomach but may be absorbed very rapidly from the small intestine. Thus factors influencing the rate of gastric emptying may alter the rate of absorption of most if not all orally administered drugs. Food, hormones, posture, peritoneal irritation, severe pain, gastric ulcer, diabetes and other metabolic diseases, as well as drugs such as alcohol, anticholinergics, narcotic analgesics, ganglion blocking drugs, antacids and metoclopramide all influence the rate of gastric emptying and they will, in turn, change the rate of absorption of another drug.In most instances, increasing the rate of gastric emptying and gastro-intestinal motility increases the rate of absorption of a drug but, for digoxin and riboflavine, increased gastrointestinal motility is associated with a decrease in the rate of absorption. Delayed drug absorption due to altered gastric emptying usually results in therapeutic failure, especially if the drug has a short biological half-life. At present it is not possible to predict accurately the magnitude and clinical relevance of all drug absorption interactions.

ISSN:0312-5963    

出版商:ADIS    

年代:1976

数据来源: ADIS

摘要:

The volume of distribution of a drug (Vd) is a useful pharmacokinetic parameter for relating drug concentration in the plasma to the total amount of drug in the body. Diseaseinduced changes in Vdmay well result in a change in the therapeutic or toxic significance of a given plasma level. For the different factors under consideration, especially plasma protein binding, the weight and the age of the patient plays an important role. Plasma binding of many drugs is lower in patients with renal or liver disease and binding capacity can be decreased in neonates and elderly individuals. Since the heart, liver and kidney are the major organs determining the distribution and elimination of drugs, it is not surprising that alterations in their function will influence the pharmacokinetic properties of drugs.When comparing the Vdin different groups of patients one should use Vd(ss), since this is the only meaningful term as it is independent from elimination processes. Drugs which are strongly bound to plasma constituents (e.g. phenytoin, diazepam) demonstrate an increased Vdin patients with liver or kidney disease, since plasma binding is lowered. A reduced Vdseems to be a general phenomenon associated with renal failure and pronounced changes are most likely for drugs that are eliminated by a renal excretory mechanism (e.g. digoxin).From these disease-induced changes in Vdit follows, that plasma level monitoring should be done more extensively in patients with kidney, liver or heart disease and that arbitrary dosing regimens are only of limited value in these patients. It is also recommended that dosage should be adjusted according to the severity of the disease.

ISSN:0312-5963    

出版商:ADIS    

年代:1976

数据来源: ADIS

摘要:

This review illustrates current approaches to the study of the disposition in man of the strong analagesics morphine and methadone and the narcotic antagonist naloxone.Morphine administered orally is rapidly absorbed but equally rapidly metabolised to morphine glucuronide. This contributes to the diminished oral efficacy of morphine. Following intramuscular administration morphine is very rapidly absorbed. After intravenous injection, the serum levels of morphine during the first 10 minutes are higher and more variable in older patients. The half-life of morphine between 20 minutes and 6 hours is 2 to 3 hours and this value does not appear to be influenced by the age of the patient. Similar half-lives for morphine have been reported to normal volunteers and in anaesthetised patients who received morphine. Thus, surgical anaesthesia may not markedly influence morphine half-life and disposition. Based on urinary excretion data in man, accelerated morphine metabolism and excretion do not contribute to morphine tolerance.Methadone is now widely used in the treatment of narcotic abuse. The half-life of methadone averages 25 hours. The prolonged retention of methadone in the plasma may be related to its extensive binding to plasma proteins. With chronic dosing, studies in both animals and man indicate an increase in the metabolism of methadone. Unlike morphine, the urinary excretion of methadone increases with acidification of the urine. Women may metabolise methadone to a greater extent than do men. With the exception of pupillary effects, the plasma levels of methadone correlate poorly with its pharmacological activity. There is a marked variation in methadone plasma levels between patients and within the same patient.Naloxone rapidly disappears from the serum in man and the initial distribution phase has a half-life of 4 minutes. The half-life of naloxone in serum following distribution is 64 minutes. Based on animal studies, the rapid onset of the narcotic antagonist action of naloxone can be related to its rapid entry into the brain, whereas its potency stems in part from its high lipid solubility which allows a high brain concentration to be achieved. The short duration of action of naloxone may result from its rapid egress from the brain.

ISSN:0312-5963    

出版商:ADIS    

年代:1976

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1976

数据来源: ADIS