ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Patients with renal insufficiency commonly require the administration of an opioid analgesic to provide adequate pain relief. The handling of morphine, pethidine (meperidine) and dextropropoxyphene in patients with renal insufficiency is complicated by the potential accumulation of metabolites. While morphine itself remains largely unaffected by renal failure, accumulation, as denoted by an increase in both mean peak concentrations and the area under the concentrationtime curve, of both the active metabolite (morphine-6-glucuronide) and the principal metabolite (morphine-3-glucuronide, thought to possess opiate antagonist properties) have been reported. The increased elimination half-lives of the toxic metabolites norpethidine and norpropoxyphene in patients with poor renal function administered pethidine and dextropropoxyphene, respectively, makes their routine use ill advised.Case reports of prolonged narcosis associated with the use of both codeine and dihydrocodeine in patients with renal insufficiency call for care to be used when prescribing these agents under such conditions. Although the pharmacokinetics of buprenorphine, alfentanil, sufentanil and remifentanil change little in patients with renal failure, the continuous administration of fentanyl can lead to prolonged sedation.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Sedation is currently administered to neonates experiencing pain and stress during intensive care for medical diseases, as well as postoperatively. Drugs commonly used for sedation in neonates include benzodiazepines (midazolam and lorazepam), chloral hydrate and opioids (fentanyl and morphine). Sedation protocols and dosage schedules are, in most cases, adapted from those which have been developed in children and even adults. The effectiveness and safety of the sedative agents remain underevaluated, however, due to the difficulties of quantifying pain and stress in neonates, and because of the limited use of validated scoring methods by practitioners.Among the benzodiazepines, midazolam is probably the drug of choice for continuous sedation. However, its elimination is delayed in the neonatal period and hypotension may occur when given as a bolus injection or when taken with opioids. Lorazepam requires further evaluation to exclude severe neurotoxicity. Chloral hydrate is administered orally, but because of its delayed elimination and risk of accumulation, a single administration for short term sedation is recommended.Among opioids, fentanyl (which was initially administered for postoperative analgesia) is now prescribed for sedation during mechanical ventilation. Tolerance and dependence may develop rapidly, limiting its usefulness for prolonged sedation. Although extensively studied in neonates, the efficacy and safety of morphine are not clearly determined, because of the limited number of patients included in individual studies. In addition, important interindividual differences in metabolism render dosage recommendations difficult. Alfentanil and sufentanil need further investigations to define their pharmacokinetic-pharmacodynamic properties in neonates.Although the choice of drug is important, the way the drug is used and monitored is equally important. All the drugs used for the sedation of neonates have large inter-and intraindividual differences in disposition, justifying specific pharmacological knowledge and individual dosage adjustments based on clinical evaluation of the patient and the monitoring of drug concentrations.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

The recently introduced antidepressants, the selective serotonin reuptake inhibitors (SSRIs) [citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline], are known for their clinical efficacy, good tolerability and relative safety. They differ from each other in chemical structure, metabolism and pharmacokinetic properties. Therapeutic drug monitoring of these compounds is not widely used, as the plasma concentration ranges within which clinical response with minimal adverse effects appears to be optimal are not clearly defined.Almost all recent assays developed for the quantitative determination of SSRIs and their metabolites in blood are based either on the separation of SSRIs by high performance liquid chromatography (HPLC) or gas chromatography (GC). Citalopram and fluoxetine have been introduced as racemic compounds. There are some differences in the pharmacological profile, metabolism and pharmacokinetics between the enantiomers of the parent compounds and their demethylated metabolites. Stereoselective chromatographic methods for their analysis in blood are now available.With regard to the SSRIs presently available, no clearcut plasma concentration-clinical effectiveness relationship in patients with depression has been shown, nor any threshold which defines toxic concentrations. This may be explained by their low toxicity and use at dosages where serious adverse effects do not appear.SSRIs vary widely in their qualitative and quantitative interaction with cytochrome P450 (CYP) isozymes in the liver. CYP2D6 is inhibited by SSRIs, in order of decreasing potency paroxetine, norfluoxetine, fluoxetine, sertraline, citalopram and fluvoxamine. This may have clinical consequences with some but not all SSRIs, when they are taken with tricyclic antidepressants. Except for citalopram and paroxetine, little is known about the enzymes which control the biotransformation of the SSRIs.There have been many reports on marked pharmacokinetic interactions between fluoxetine and tricyclic antidepressants. Fluoxetine has a stronger effect on their hydroxylation than on their demethylation. Interactions observed between fluoxetine and alprazolam, midazolam and carbamazepine seem to occur on the level of CYP3A.Fluvoxamine strongly inhibits theN-demethylation of some tricyclic antidepressants of the tertiary amine type and of clozapine. This may lead to adverse effects but augmentation with fluvoxamine can also improve response in very rapid metabolisers, as it increases the bioavailability of the comedication. Fluvoxamine inhibits with decreasing potency, CYP1A2, CYP2C19, CYP2D6 and CYP1A1, but it is also an inhibitor of CYP3A. Fluoxetine and fluvoxamine have shown to increase methadone plasma concentrations in dependent patients.Some authors warn about a combination of monoamine oxidase (MAO) inhibitors with SSRIs, as this could lead to a serotonergic syndrome. Studies with healthy volunteers suggest, however, that a combination of moclobemide and SSRIs, such as fluvoxamine, should not present serious risks in promoting a serotonin syndrome. A combination of moclobemide and fluvoxamine has successfully been used in refractory depression, but more studies are needed, including plasma-concentration monitoring, before this combined treatment can be recommended.Paroxetine is a substrate of CYP2D6, but other enzyme(s) could also be involved. Its pharmacokinetics are linear in poor metabolisers of sparteine, and non-linear in extensive metabolisers. Due to its potent CYP2D6 inhibiting properties, comedication with this SSRI can lead to an increase of tricyclic antidepressants in plasma, as shown with amitriptyline and trimipramine. CYP3A has been claimed to be involved in the biotransformation of sertraline to norsertraline. Clinical investigations (with desipramine) confirmedin vitrofindings that CYP2D6 inhibition by sertraline is only moderate.The SSRIs are known to be effective and generally well tolerated antidepressants. None of the SSRIs has had a clearcut plasma concentration-clinical effectiveness relationship demonstrated. Therefore, therapeutic drug monitoring may be useful in situations where poor compliance is suspected and in special populations (elderly patients, patients with liver or renal disease, etc.). However, there are only a few case reports which describe such situations. More studies are needed to clarify the role of CYP isozymes in the metabolism of SSRIs, especially of fluoxetine, fluvoxamine and sertraline.Knowledge has increased on the role of the CYP isozymes CYP2D6, CYP2C19, CYP1A2 and CYP3A in the interactions which have been observed between SSRIs and other drugs. The risk of interaction with negative clinical consequences is highest with fluoxetine, paroxetine and fluvoxamine, and of little clinical significance with citalopram and sertraline, but in some situations, a combination treatment may favour clinical response. More studies on the combined use of reversible MAO-inhibitors and SSRIs are needed, including plasmaconcentration monitoring.The effect of other drugs on the metabolism and pharmacokinetics of SSRIs has been poorly investigated.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Antiepileptic drug interactions represent a common clinical problem which has been compounded by the introduction of many new compounds in recent years. Most pharmacokinetic interactions involve the modification of drug metabolism; the propensity of antiepileptic drugs to interact depends on their metabolic characteristics and action on drug metabolic enzymes.Phenobarbital, phenytoin, primidone and carbamazepine are potent inducers of cytochrome P450 (CYP), epoxide hydrolase and uridine diphosphate glucuronosyltransferase (UDPGT) enzyme systems; oxcarbazepine is a weak inducer of CYP enzymes, probably acting on a few specific isoforms only. All stimulate the rate of metabolism and the clearance of the drugs which are catabolised by the induced enzymes.Valproic acid (valproate sodium) inhibits to different extents many hepatic enzyme system activities involved in drug metabolism and is able to significantly displace drugs from plasma albumin. Felbamate is an inhibitor of some specific CYP isoforms and mitochondrial &bgr;-oxidation, whereas it is a weak inducer of other enzyme systems.Topiramate is an inducer of specific CYP isoforms and an inhibitor of other isoforms. Ethosuximide, vigabatrin, lamotrigine, gabapentin and possibly zonisamide and tiagabine have no significant effect on hepatic drug metabolism.Apart from vigabatrin and gabapentin, which are mainly eliminated unchanged by the renal route, all other antiepileptic drugs are metabolised wholly or in part by hepatic enzymes and their disposition may be altered by metabolic changes.Some interactions are clinically unremarkable and some need only careful clinical monitoring, but others require prompt dosage adjustment. From a practical point of view, if valproic acid is added to lamotrigine or phenobarbital therapy, or if felbamate is added to phenobarbital, phenytoin or valproic acid therapy, a significant rise in plasma concentrations of the first drug is expected with a corresponding increase in clinical effects. In these cases a concomitant reduction of the dosage of the first drug is recommended to avoid toxicity. Conversely, if a strong inducer is added to carbamazepine, lamotrigine, valproic acid or ethosuximide monotherapy, a significant decrease in their plasma concentrations is expected within days or weeks, with a possible reduction in efficacy. In these cases a dosage increase of the first drug may be required.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS