Anticonvulsants pharmacokinetics

Cohen AF, Land GS, Breimer DD, Yuen WC, Winton C, Peck AW. Lamotrigine, a new anticonvulsant Pharmacokinetics in normal humans. CHn Pharmacol Ther 1987 42 535-41. 

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. 

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. 

TABLE 36-5. Pharmacokinetics and Therapeutic Serum Concentrations of Lithium and Anticonvulsants Used in the Treatment of Bipolar Disorder... 

Relating the Time-Course of Plasma Concentrations to the Time-Course of Effect A critical decision to be made after the first human study is whether the compound s speed of onset and duration of action are likely to be consistent with the desired clinical response. Speed of onset is clearly of interest for treatments which are taken intermittently for symptoms rehef, for example, acute treatments for migraine, analgesics, or antihistamines for hay fever. Duration of action phase I is particularly important when the therapeutic effect needs to be sustained continuously, such as for anticonvulsants. The first information on the probable time course of action often comes from the plasma pharmacokinetic profile. However, it has become increasingly evident that the kinetic profile alone may be misleading, with the concentration-time and the effect-time curves being substantially different. Some reasons for this, with examples, include... 

A series of branched aliphatic amides were prepared to evaluate the role of amide hydrolysis on the pharmacokinetics and anticonvulsant activity of valpromide analogues. Table 4.1 summarizes the structures investigated, the fraction of amide hydrolyzed (/m), and the stability in blood. These results were obtained after intravenous administration to dogs [6], The structures are classified here in order of decreasing fm. 

B. D. Potts, S. Gabriel, C. J. Parli, Metabolism, Disposion, and Pharmacokinetics of a Potent Anticonvulsant, 4-Amino-A-(2,6-dimethylphenyl)benzamide (LY201116), in Rats , Drug Metab. Dispos. 1989,17, 656-661. 

S. W. Martin, F. E. Bishop, B. M. Kerr, M. Moor, M. Moore, P. Sheffels, M. Rashed, J. G. Slatter, L. Berthon-Cedille, F. Lepage, J.-J. Descombe, M. Picard, T. A. Baillie, R. H. Levy, Pharmacokinetics and Metabolism of the Novel Anticonvulsant Agent N-(2,6-Dimethylphenyl)-5-methyl-3-isoxazolecarboxamide (D2624) in Rats and Humans , Drug Metab. Dispos. 1997, 25, 40-46. 

Little is known as yet about the pharmacokinetics of carbamazepine in humans although preliminary reports suggest slow absorption (M21) and marked variations in blood levels during a day in some subjects (M15). Blood levels varying from trace quantities to 12 /ig/ml have been found in patients taking 400-1000 mg daily (P3), but no relation between the level observed and the dose was apparent. In the studies so far published carbamazepine blood levels have not correlated with seizure control (P3), but all the subjects wore receiving additional anticonvulsant drugs. 

Pharmacokinetics IM injection results in therapeutic plasma levels within 60 minutes and persists for 3 to 4 hours. IV doses provide immediate effects that last for 30 minutes. Effective anticonvulsant serum levels range from 2.5 to 7.5 mEq/L. Magnesium is excreted by the kidneys at a rate proportional to the plasma concentration and glomerular filtration. 

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

Pharmacokinetics Approximately 1 % to 2% of total body magnesium is located in the extracellular fluid space. Magnesium is 30% bound to albumin. With IV use, the onset of anticonvulsant action is immediate and lasts approximately 30 minutes. With IM use, onset occurs in 1 hour and persists for 3 to 4 hours. Magnesium is excreted by the kidney. 

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. 

Mecfianism of Action An anticonvulsant that inhibits burst firing without affecting normal neuronal excitability. Therapeutic Effect Prevents seizure activity. Pharmacokinetics Rapidly and almost completely absorbed through the GI tract. Protein binding less than 10%. Insignificant amount metabolized in liver. Excreted in urine. Removed by hemodialysis. Half-life 7 hr. 

Mectianism of Action An anticonvulsant that blocks sodium channels, resulting in stabilization of hyperexcited neural membranes, inhibition of repef if ive neuronal firing, and diminishing synapfic impulses. Therapeutic Effect Prevenfs seizures. Pharmacokinetics Complefely absorbed from GI tract and extensively metabolized in the liver to active metabolite. Protein binding 40%. Primarily excreted in urine. Half-life 2 hr metabolite, 6-10 hr. 

In this chapter we review the mechanisms of action, pharmacokinetics, side effects, and uses of lithium and the anticonvulsants as they apply to child psychiatric clinical practice. 

Carbamazepine (CBZ) and divalproex sodium (DVP) are the most common anticonvulsant agents prescribed for adult BD (Bowden et ah, 1994) Post et ah, 1998b) and pediatric epileptic disorders (Trimble, 1990 Dunn et al., 1998). As a consequence of their documented efficacy in these populations, their use has been extended to pediatric behavioral and mood disorders (Biederman et ah, 1998). We review here their mechanisms of action, pharmacokinetics, side effects, and pediatric uses. The multiple cytochrome P450 (CYB)-mediated potential drug interactions of CBZ and DVP are not covered in detail in this chapter. For a comprehensive review of this subjects the reader is referred to a recent publication by Flockhart and Oesterheld (2000). 

Gabapentin does not bind to plasma proteins, is not appreciably metabolized, nor induces hepatic enzyme activity (AHFS, 2000) Consequently, it does not appear to alter the pharmacokinetics of commonly used anticonvulsant drugs or oral contraceptives (Ketter et al.,... 

The pharmacokinetics of topiramate are linear with peak plasma concentrations (occurring in about 2 hours) of 25 pM after 400 mg daily (Shank et al., 2000). Topiramate is poorly bound to plasma proteins (15%) and it binds to erythrocytes. In rats the maximal concentration in the brain when administered at 10 mg/kg was 10 pM (Shank et ah, 2000). It is not extensively metabolized in humans and is eliminated (70%) unchanged in urine. Six minor metabolites have been identified, none with anticonvulsant activity. The average elimination half-life is 21 hours (Shank et ah, 2000). 

In partially responsive or nonresponsive patients, the first issue is to determine whether an individual is truly treatment-resistant, because many receive nontherapeutic doses and the potential for improvement may not be adequately tested. Thus, in some situations, more aggressive treatment (dose increase, augmentation) may be appropriate, if not precluded by adverse effects. In selected cases, it may also be helpful to monitor plasma levels to ensure that they are in a reasonable range (see Pharmacokinetics/Plasma Levels earlier in this chapter). If a patient continues to demonstrate significant symptoms after a sufficient trial (2 to 3 weeks), alternatives to switching to another antipsychotic may include the addition of lithium, an anticonvulsant, or a second antipsychotic agent. An antidepressant or anxiolytic may also be helpful, especially if affective or anxiety symptoms are prominent. 

When antipsychotics are used in conjunction with a variety of anticonvulsants, their plasma levels may be significantly altered due to pharmacokinetic interactions. For example, when CBZ and haloperidol are coadministered, their interaction may cause a significant decrease in the neuroleptic s serum levels, sometimes resulting in clinical decompensation (516). Conversely, the cessation of CBZ may lead to increased antipsychotic plasma levels. 

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. 

The relative anti-anxiety potencies of the different BDZs correlate with their relative potencies as agonists at the BDZ receptor. The resultant inhibitory effects in the brain are responsible for their anti-anxiety, sedative and anticonvulsant effects. Inhibition of spinal pathways results in relaxation of skeletal muscles. The therapeutic use of particular BDZs is as much related to their potency and solubility as to inherent pharmacokinetic differences. 

J. R., Nakamura, L., Monaghan, E. P., Ramu, K. Characterization of the anticonvulsant and pharmacokinetic properties of Co102862, a novel blocker of voltage-gated sodium channels, Epilepsia 1997, 28, suppl 8, 1038. 

Wilbur K, Ensom MH. Pharmacokinetic drug interactions between oral contraceptives and second-generation anticonvulsants. Clin Pharmacokinet 2000 38(4) 355-65. 

Nonlinear pharmacokinetics. Nonlinear pharmacokinetics simply means that the relationship between dose and Cp is not directly proportional for all doses. In nonlinear pharmacokinetics, drug concentration does not scale in direct proportion to dose (also known as dose-dependent kinetics). One classic drug example of nonlinear pharmacokinetics is the anticonvulsant drug phenytoin.38 Clinicians have learned to dose pheny-toin carefully in amounts greater than 300 mg/day above this point, most individuals will have dramatically increased phenytoin plasma levels in response to small changes in the input dose. 

Unlike most classes of psychotropic drugs where there is no direct correlation between the blood concentration and the therapeutic effect, for most of the commonly used anticonvulsants there is a high degree of correlation between the blood and brain concentrations and the therapeutic effect. A knowledge of the pharmacokinetic properties of the anticonvulsant drugs is therefore essential if their therapeutic efficacy is to be maximized and side effects minimized. 

It can be concluded that no significant differences exist between anticonvulsive and neurotoxic effects for this series of derivatives. The variation in the anticonvulsive effect seems to be determined by drug-membrane interactions and not by the pharmacokinetics of these compounds. 

M. Giaccone, Effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics in epileptic patients. Br. J. Clin. Pharmacol. 41 575-579, 1996. 

The individual benzodiazepines show small differences in their relative anxiolytic, anticonvulsant, and sedative properties. However, the duration of action varies widely among this group, and pharmacokinetic considerations are often important in choice of drug. 

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