Barbiturates pharmacokinetics

The pharmacokinetics of batbitutates have been discussed by Chatney et al. (2001) and Harvey (1985). When used as hypnoticsotantianxiety agents, the barbiturates ate administeted otaUy. As anticonvulsants, they may be used either orally or intravenously, although the lattet toute of administtation may be problematic because these dtugs ate vety alkaline and nectosis and pain oc-cut at the site of injection. 

Pharmacodynamic tolerance to barbiturates develops over weeks to months, whereas pharmacokinetic tolerance occurs in a period of days. At maximum tolerance, the dosage of a barbiturate may be six times the original dosage. 

Nestorov lA, Aarons LJ, Rowland M. Physiologically based pharmacokinetic modeling of a homologous series of barbiturates in the rat a sensitivity analysis. / Pharmacokinet Biopharm 1997 25 413-47. 

Blakey GE, Nestorov lA, Arundel PA, Aarons LJ, Rowland M. Quantitative structure-pharmacokinetics relationships I. Development of a whole-body physiologically based model to characterize changes in pharmacokinetics across a homologous series of barbiturates in the rat. J Pharmacokinet Biopharm 1997 Jun 25(3) 277-312. Erratum in J Pharmacokinet Biopharm 1998 Feb 26(l) 131. 

Benzodiazepines are the evidence-based treatment of choice for uncomplicated alcohol withdrawal.17 Barbiturates are not recommended because of their low therapeutic index due to respiratory depression. Some of the anticonvulsants have also been used to treat uncomplicated withdrawal (particularly car-bamazepine and sodium valproate). Although anticonvulsants provide an alternative to benzodiazepines, they are not as well studied and are less commonly used. The most commonly employed benzodiazepines are chlordiazepoxide, diazepam, lorazepam, and oxazepam. They differ in three major ways (1) their pharmacokinetic properties, (2) the available routes for their administration, and (3) the rapidity of their onset of action due to the rate of gastrointestinal absorption and rate of crossing the blood-brain barrier. 

Toon, S., Rowland, M., Structure-pharmacokinetic relationships among the barbiturates in the rat, J. Pharmacol. Exp. Ther. 1983, 225, 752-763. 

Other barbiturates are also used as anticonvulsants. See Sedatives/Hvonotics section. Exhibits dose-dependent, nonlinear pharmacokinetics. 

Pharmacodynamic tolerance, probably on the basis of down-regulation of receptors, develops more rapidly to the effects of barbiturates on mood and sedation than to the anticonvulsant and lethal action. This results in a marked decrease in therapeutic index and the ratio of LD50 and ED50 can approach 1. Furthermore, barbiturates induce P450 enzymes and thus increase their own metabolism resulting in time dependent pharmacokinetic behavior. 

The straightforward step used to form the ring system means that the chemistry involved in the preparation of the scores of barbiturates that have been used clinically in fact devolves on the syntheses of the various malonic esters. It should be noted that little success has been achieved in changing the side effect spectrum of these dmgs. The main differences between the various agents involve their pharmacokinetic properties these in turn are manifested as variations in bioavailablity by parenteral and oral routes as well as in time to the onset and duration of action. 

Because most antidepressants require oxidative metabolism as a necessary step in their elimination, they can be the target of a pharmacokinetic drug-drug interaction, as well as the cause. The CYP enzymes mediating the biotransformation of the various antidepressants are also shown in Table 7-30. CYP 1A2 and 3A3/4 are induced by anticonvulsants such as barbiturates and carbamazepine. As expected, coadministration of these anticonvulsants has been shown to lower plasma levels of TCAs and would be predicted to have the same effect on nefazodone, sertraline, and venlafaxine. 

Non-linear pharmacokinetics are much less common than linear kinetics. They occur when drug concentrations are sufficiently high to saturate the ability of the liver enzymes to metabolise the drug. This occurs with ethanol, therapeutic concentrations of phenytoin and salicylates, or when high doses of barbiturates are used for cerebral protection. The kinetics of conventional doses of thiopentone are linear. With non-linear pharmacokinetics, the amount of drug eliminated per unit time is constant rather than a constant fraction of the amount in the body, as is the case for the linear situation. Non-linear kinetics are also referred to as zero order or saturation kinetics. The rate of drug decline is governed by the Michaelis-Menton equation ... 

The ideal intravenous anaesthetic agent Mechanism(s) of intravenous anaesthesia Pharmacokinetics and metabolism Rapidly acting intravenous anaesthetics Non-barbiturate intravenous anaesthetics Slower-acting intravenous anaesthetics Other drugs INTRODUCTION... 

The general pharmacology of the barbiturates is discussed in Chapter 22. Thiopental is a barbiturate commonly used for induction of anesthesia. Thiamylal is structurally almost identical to thiopental and has the same pharmacokinetic and pharmacodynamic profile. 

Nifedipine was one of the first CYP3A4 substrates to be identified (167,168) and has been the subject of a large number of drug-drug interaction studies both in vitro and in vivo. Pharmacokinetic studies with nifedipine clearly identify inhibitors, such as itraconazole (169) and grapefruit juice (170), and inducers, such as the barbiturates (171) and rifampin (172). 

In explaining the variance in pharmacokinetic parameters, log Poet. is not always a sufficient descriptor. The failure to correlate the kinetics of distribution and the storage of barbiturates in adipose tissue with log Poet. can serve as an example. Again, other descriptors have been investigated [90]. 

At times of physiological change, corresponding alterations can occur in pharmacokinetics. This can be reflected in variability in response and the need for dosage adjustment. Unusual, paradoxical pharmacodynamic differences can occur in children, for example. While antihistamines and barbiturates generally sedate adults,... 

Numerous applications of pharmacokinetic-dynamic models incorporating a biophase (or effect) compartment for a variety of drugs that belong to miscellaneous pharmacological classes, e.g., anesthetic agents [419], opioid analgesics [420-422], barbiturates [423,424], benzodiazepines [425], antiarrhyth-mics [426], have been published. The reader can refer to a handbook [427] or recent reviews [405] for a complete list of the applications of the biophase distribution model. 

A further consideration is which barbiturate to employ. We recommend the use of barbital because this substance, in contrast to many other barbiturates, undergoes no metabolism (Remmer 1972 Simon et al. 1992). For this reason, results obtained can be more readily interpreted in terms of a pharmacological interaction without confounding by pharmacokinetic or metabolic factors. 

Being one of the long-time standards in basic psychopharmacology, there are few major variants to the procedure apart from the kind of barbiturate employed. Several barbiturates undergo clear hepatic metabolism, for example pentobarbital and phenobarbital, thereby confounding interpretations because of pharmacokinetic and metabolic factors. Indeed, one modification of the method has been specifically employed to estimate enzyme induction in the liver as indicated by more rapid barbiturate metabolism. Animals given a pre-exposure to a test substance are then exposed to a standard dose of phenobarbital (80 mg/kg i.p.) 24 hours later and assessed for sleep duration. The presence or absence of a decrease in sleep duration is taken as an index of the hepatic enzyme induction produced by the test substance (Kushikata et al. 2003). 

Note. For a review of the clinical pharmacokinetics of barbiturates see D. D. Breimer, Clin. Pharmacokinet., 1977, 2, 93-109. 

GC-MS methods provide greater specificity and in many cases sensitivity when compared with more conventional techniques. They offer increased scope for the study of pharmacokinetics and of plasma concentration in relation to biological effect. SIM assay has been applied to the investigation of placental transfer of lipid soluble drugs and their subsequent elimination in the newborn (barbiturates, diphenylhydantoin, caffeine, pethidine and diazepam [122,408] diphenylhydantoin [411] amylobarbitone and 3 -hydroxyamylobarbitone [83,423]). 

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