ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

Many drugs have a low degree of oral bioavailability even though their gastrointestinal absorption is complete. This is because they undergo extensive presystemic metabolic transformation during the first passage of the drug through the gastrointestinal mucosa and the liver. In addition to effects on the absorption of some drugs, food intake has been found to influence the bioavailability of drugs with extensive presystemic metabolic clearance.Extensive presystemic clearance occurs commonly with compounds that are lipophilic bases, e.g. propranolol and amitriptyline, but rarely if ever with lipophilic acids, e.g. salicylic acid and penicillin, except for esters of such acids, e.g. acetylsalicylic acid (aspirin) and pivampicillin. While presystemic clearance of (esterified) acidic drugs is unaffected by food, concurrent food intake markedly reduces presystemic clearance, and thus enhances bioavailability, of several lipophilic bases. Among these are propranolol, metoprolol, labetalol, dixyrazine and hydralazine, which are presystemically metabolised by hydroxylation, glucuronidation and acetylation enzyme systems. In contrast, the bioavailability of lipophilic bases which undergo presystemic dealkylation (amitriptyline, codeine, dextropropoxyphene, prazosin, zimelidine) is unaffected by concurrent food intake. Food intake reduces presystemic clearance of hydralazine and propranolol when these drugs are administered in conventional rapid-release tablets but not when they are given in slow-release formulations. Likewise, coadministration of hydralazine reduces presystemic clearance of rapid-release but not slow-release propranolol. These and other observations favour the view that food may reduce presystemic clearance of (certain) lipophilic basic drugs via transient, complex effects on splanchnic-hepatic blood flow and/or shunt processes, and that the extent of this effect is influenced by the rate of drug delivery to the liver. In addition, these findings refute the notion that the reduced presystemic clearance results from (long-lasting) hepatic enzyme inhibition by some nutrient. On the other hand, repeated intake of specific nutrients (protein) and food contaminants (benzpyrene) can enhance presystemic drug clearance by enzyme induction. Thus, food may exert a dual effect on presystemic drug clearance. A complete evaluation of the influence of food on presystemic drug clearance necessitates bioavailability studies carried out following both single and repeated meals, including different kinds of food prepared by various cooking methods.The influence of food on the presystemic clearance of drugs is most likely to be clinically relevant with drugs having narrow therapeutic margins and/or steep dose-response curves. Its importance may be minimised by stipulating that drugs always be taken in the same relation to meals. Alternatively, the problem can be circumvented by employing formulations that minimise the food influence, or by the use of drugs that have little or no presystemic clearance.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

The number of non-steroidal anti-inflammatory drugs (NSAIDs) available for clinical use has dramatically increased during the last decade. As a general rule, NSAIDs are well absorbed from the gastrointestinal tract, with the exception of aspirin (and possibly diclofenac, tolfenamic acid and fenbufen) which undergoes presystemic hydrolysis to form salicylic acid. Concomitant administration of NSAIDs with food or antacids may in some cases lead to delayed or even reduced absorption. The NSAIDs are highly bound to plasma proteins (mainly albumin), which limits their body distribution to the extracellular spaces. Apparent volumes of distribution of NSAIDs are, therefore, very low and usually less than 0.2 L/kg. The elimination of these drugs depends largely on hepatic biotransformation; renal excretion of unchanged drug is usually small (< 5% of the dose). Total body clearance is low and for most NSAIDs is less than 200 ml/min.The effect of age and disease on the disposition of NSAIDs has not been extensively studied. Due to the central role of the liver in the overall elimination of the majority of these compounds, hepatic disease will most likely lead to a significant alteration in their pharmacokinetic behaviour.NSAIDs have been reported to be involved in numerous pharmacokinetic drug interactions. Aspirin decreases the plasma concentrations of many other NSAIDs, although the clinical significance of this is uncertain. Due to the extremely high plasma protein binding of NSAIDs (around 99% in many cases), competition for the same binding sites on plasma proteins may be at least partly responsible for some interactions of NSAIDs with other highly bound drugs; however, another mechanism such as decreased metabolism or decreased urinary elimination is usually involved as well. The most important interactions with NSAIDs are those involving the oral anticoagulants and oral hypoglycaemic agents, though not all NSAIDs have been found to interact with these drugs.In clinical practice, there appear to be no clear-cut guidelines to assist the clinician in the selection of the most appropriate drug for an individual patient. The selection of an anti-inflammatory drug should be based on clinical experience, patient convenience (e.g. once or twice daily dosage schedule), side effects and cost. Since a marked interindividual variability exists in the clinical response to a given NSAID, clinicians prescribing these agents may try several of them sequentially until an adequate response is obtained.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

Narcotic agonist-antagonist drugs are able specifically to reverse the effects of morphine and other opiate agonists in some pharmacological preparations. They also have some agonist properties which in some cases may be extensive and provide useful clinical properties such as analgesia, or may be minimal. Thus pentazocine, buprenorphine, nalbuphine and butorphanol all demonstrate definite analgesic properties. Naltrexone, in contrast, has only limited agonist action, as shown for example in pupil constriction, and is perhaps better regarded as an antagonist.After intravenous administration of buprenorphine there is an initially rapid early distribution phase with a half-life of about 2 minutes. Studies on butorphanol and pentazocine had insufficient early samples to allow accurate analysis of this phase. Otherwise, the intravenous pharmacokinetics for all these drugs show bi- or tri-exponential decay with terminal half-lives of between 3 and 5 hours, plasma clearances of between 1200 and 2800 ml/min, and apparent volumes of distribution of 200 to 400L. These values for plasma clearance and terminal half-life have been confirmed in oral and intramuscular studies.There is only limited information about the rate or extent of absorption after intramuscular administration. For buprenorphine peak plasma concentrations are reached between 2 and 5 minutes; for pentazocine and butorphanol the peak is later, at between 15 and 60 minutes for pentazocine and 45 minutes for butorphanol. Systemic availability of intramuscular buprenorphine is in the range of 40 to 100%, but is generally greater than 90%. Availability of intramuscular butorphanol has been reported to be complete.Oral systemic availability for drugs with a high plasma clearance is predictably low because of a significant first-pass effect through the liver. The oral availabilities of pentazocine and nalbuphine have been calculated to be about 20%, and although there are no pharmacokinetic data, some evidence of clinical efficacy suggests a similar figure for butorphanol and buprenorphine. For naltrexone however, the available data suggest that this drug is completely absorbed after oral administration.Only buprenorphine has been studied by the sublingual route. The systemic availability was variable (16 to 94%), but on average it was 55% in a study of long duration; the absorption half-life from the buccal cavity was estimated to be 76 minutes. Over a limited dose range there appeared to be linear increases in the maximum rise in plasma concentration and AUC with buprenorphine administered by this route. There have been no pharmacokinetic studies of the narcotic agonist-antagonist drugs by other routes of administration, such as after intrathecal or extradural administration, or rectally or transcutaneously.Pharmacodynamic data for these drugs are incomplete. Analgesia in man appears to be dose-related for pentazocine, butorphanol, buprenorphine and nalbuphine; morphine antagonism is dose-related for naltrexone. The appearance of opiate side effects (nausea and drowsiness) is reported to be dose-related for pentazocine, butorphanol and buprenorphine. ‘Ceiling’ effects on respiratory depression in man are found for pentazocine, butorphanol, buprenorphine and nalbuphine. For pupillary effects, there is evidence for a ceiling effect for nalbuphine and naltrexone, but dose-related effects for buprenorphine. Some of the neuroendocrine effects of buprenorphine and butorphanol appear to be dose-related, but there has been little work done in this area.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

Published results of pharmacokinetic studies (terminal half-life, t½&bgr;; elimination constant, kel; apparent volume of distribution in &bgr;-phase, Vd&bgr;and plasma clearance, CLp) in pregnant and non-pregnant women have been compiled and compared. Most of the data relate to the results of pharmacokinetic studies with 20 drugs in women at full-term pregnancy, i.e. about 40 weeks gestation. A review of these data failed to reveal any consistent overall trend in any of the pharmacokinetic parameters listed and no generally applicable changes in the disposition of the drugs as a result of pregnancy can be characterised. However, pregnancy associated changes appear to be discernable in the elimination patterns of certain drugs, for example, ampicillin, caffeine, diazepam, phenytoin and thiopentone, but the factors producing these changes can still only be suggested.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

Previously reported routine phenytoin clinical pharmacokinetic data from Japan, England, and Germany were analysed to estimate population pharmacokinetic parameters. There were 780 steady-state phenytoin concentrations and associated dosage rates (mg/day) from 322 patients. The patient group spanned paediatric and adult ages, mean age being 18.4 ± 17.3 (SD) years; 53% were males. The data were analysed using NONMEM, a computer programme designed for population pharmacokinetic analysis. Estimates of the influence of age, gender, data source, height and weight on the maximum elimination rate (Vm) and Michaelis-Menten constant (Km) were obtained. The Vm and Km of a 70kg adult male European were estimated to be 415 mg/day and 5.7 mg/L, respectively. Vm is not influenced by gender, age or data source. The parameters of a power function of height and weight were estimated to adjust Vm for body size. The best function adjusts Vm in proportion to weight to the 0.6 power; height contains no useful information.Km is not influenced by gender. The Km for patients less than 15 years old is 43% less than that of older patients. The Km of Japanese patients appears to be 23% less than that for European patients.Even after adjustments for age, etc., apparent Vm and Km vary unpredictably among individuals with a coefficient of variation between 10 to 20%, and approximately 50% respectively.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS

摘要:

Several methods have been published for estimating creatinine clearance from serum creatinine concentrations. Such estimates of creatinine clearance are widely used for dosage adjustments of drugs which are primarily eliminated through the kidneys in patients with reduced renal function. Most of these methods involve the use of equations, requiring a few steps of calculations. A simple and easy-to-use nomogram is presented for estimating creatinine clearance from serum creatinine concentration, plus the age, sex, and bodyweight of the individual patient. This nomogram is based on the linear relationship between creatinine clearance and the reciprocal value of the serum creatinine concentration, where the slope of this relationship is determined by the rate of creatinine production. The rate of creatinine production, however, is related to age, sex, and bodyweight. These physical characteristics are therefore used to scale the slopes of the relationships between creatinine clearance and serum creatinine concentration.The validity of the nomogram was tested in 50 consecutive hospitalised patients for which creatinine clearance was measured. There was an excellent correlation (r = 0.903) between predicted and observed creatinine clearance values.

ISSN:0312-5963    

出版商:ADIS    

年代:1983

数据来源: ADIS