Lithium steady-state levels

For some psychotropic drugs (e.g., lithium and some antidepressants) a good correlation exists between plasma levels and therapeutic or toxic effects. Optimum steady-state levels can now be predicted from single-dose blood level data of some drugs (lithium, nortriptyline, desipramine). Altered PK behavior in children has to be taken into consideration in using psychotropic drugs. With development of suitable drug... 

Kramer MS, Cutler NR, Ballenger JC, et al A placebo-controUed trial of L-365,260, a CCKB antagonist, in panic disorder. Biol Psychiatry 37 462-466, 1995 Krauss GL, Fisher RS Cerebellar and thalamic stimulation for epilepsy, in Electrical and Magnetic Stimulation of the Brain and Spinal Cord. Edited by Devinsky O, Beric A. New York, Raven, 1993, pp 231-245 Krell RD, Goldberg AM Effect of acute and chronic administration of lithium on steady-state levels of mouse brain choline and acetylcholine. Biochem Pharmacol 22 3289-3291, 1973... 

Lithium is an alkali metal in group lA and shares many properties with similar elements such as sodium and potassium. As a compound it is rapidly absorbed and reaches peak blood levels in approximately 1 to 3 hours (6 to 8 hours with sustained release preparations), with absorption being completed in approximately 8 hours. Unlike other psychotropics, it is not protein-bound and steady-state levels are usually achieved after 4 to 6 days on a fixed dose. Table 10-16 lists the pharmacokinetic properties of lithium, as well as those of the other two commonly used mood stabilizers, VPA and CBZ. 

Absorption/Disthbution - Lithium is readily absorbed from the Gl tract. Peak serum levels occur in 0.5 to 3 hours and absorption is complete within 8 hours. Onset of action is slow (5 to 14 days). Until the desired therapeutic effect is attained, maintain a steady-state serum level of 0.8 to 1.4 mEq/L, then slowly decrease the lithium dose to a maintenance level. The therapeutic serum level range is from 0.4 to 1 mEq/L. 

Parameters to monitor Perform the following laboratory tests prior to and periodically during lithium therapy Serum creatinine complete blood count urinalysis sodium and potassium fasting glucose electrocardiogram and thyroid function tests. Check lithium serum levels twice weekly until dosage is stabilized. Once steady state has been reached, monitor the level weekly. Once the patient is on maintenance therapy, the level may be checked every 2 to 3 months. 

Lithium is readily absorbed from the gastrointestinal tract, reaching a peak plasma level in 2 to 4 hours. Distribution occurs throughout the extracellular fluid with no evidence of protein binding. Passage through the blood-brain barrier is limited, so that cerebrospinal fluid levels are 50% of plasma levels at steady state. 

Geller, B. and Fetner, H.H. (1989a) Children s 24-hour serum lithium level after a single dose predicts initial dose and steady-state plasma level [letter]. / Clin Psychopharmacol 9 155. 

Lithium carbonate is completely absorbed by the gastrointestinal tract and reaches peak plasma levels in 1-2 hours. The elimination half-life is approximately 24 hours. Steady-state lithium levels are achieved in approximately 5 days. Therapeutic plasma levels range from 0.5 to 1.2 mEq/L. Lower plasma levels are associated with less troubling side effects, but levels of at least 0.8 mEq/L are often required in the treatment of acute manic episodes. Therefore, when intolerable side effects have not intervened, treatment of acute mania with lithium should not be considered a failure until plasma levels of 1.0-1.2 mEq/L have been reached and have been maintained for 2 weeks. As discussed at the end of this chapter (see Treatment of Mania or Mixed Episodes ), more severely ill patients may require combination treatment. 

Ragheb M, Ban TA, Buchanan D, et al. Interaction of indomethacin and ibuprofen with lithium in manic patients under a steady-state lithium level. J Clin Psychiatry 1980 41 397-398. 

Because lithium has a half-life of approximately 24 hours and it takes four to five half-lives to achieve steady-state at a fixed dose, blood levels should be obtained every 5 days until an adequate therapeutic concentration is achieved or adverse effects preclude further increases. Attempts to develop dose prediction formulae to obtain therapeutic concentrations more rapidly have been promising, but they have not enjoyed widespread utilization ( 101, 102 and 103). While premature monitoring may lead to higher than necessary dosing, more frequent measuring of levels may be warranted in patients with known sensitivity to lithium or if... 

Lithium is rapidly absorbed, reaching peak serum concentrations in 2-3 hours. It is not protein-bound and is excreted unchanged by the kidney at a rate proportional to the glomerular filtration rate. It is best given as a single daily dose around 22.00 hours and steady state serum levels are reached after 5-7 days of dosing, with the elimination half-life being around 10-24 hours for most people. Most proprietary formulations of lithium in current use are in the form of a slow-release preparation. There can be variations in kinetics between different proprietary brands and it is therefore best for individual patients to remain on the same brand. 

An initial determination of serum lithium concentration should be obtained about 5 days after the start of treatment, at which time steady-state conditions should have been attained. If the clinical response suggests a change in dosage, simple arithmetic (new dose equals present dose times desired blood level divided by present blood level) should produce the desired level. The serum concentration attained with the adjusted dosage can be checked after another 5 days. Once the desired concentration has been achieved, levels can be measured at increasing intervals unless the schedule is influenced by intercurrent illness or the introduction of a new drug into the treatment program. 

Apseloff G, Mullet D, Wilner KD, Anziano RJ, Tensfeldt TG, Pelletier SM, Gerber N. The effects of ziprasidone on steady-state lithium levels and renal clearance of lithium. Br J Chn Pharmacol 2000 49(Suppl 1) 61S-4S. 

With chronic use the plasma t) of lithium is 15-30 h. Lithium is usually given 12-hourly to avoid unnecessary fluctuation (peak and trough concentrations) and maintain a plasma concentration just below the toxic level. A steady-state plasma concentration will be attained after about 5-6 days (i.e. 5 x t) ) in patients with normal renal... 

When lithinm is first started, a non-steady-state serum concentration is recommended every 2 to 3 days in patients prone to toxicity. Once a desired serum concentration has been achieved, levels should be drawn every 1 to 2 weeks for 2 months or until lithium concentrations are stabilized. 

The absorption of lithium is rapid and complete within 6 to 8 hours. The absorption rate of slow-release capsules is slower and the total amount of lithium absorbed lower than with other dosage forms. Lithium is not protein bound. The elimination half-life for elderly patients (39 hours) is longer than that for adult patients (24 hours), which in turn is longer than that for adolescent patients (18 hours). The time to peak serum concentration for lithium carbonate is dependent on the dosage form (tablets, 1-3 hours extended tab, 4 hours slow release, 3 hours). Steady-state serum concentrations are reached in 4 days, with the desirable dose targeted to give a maintenance lithium ion plasma concentration range of 0.6 to 1.2 mEq/L, with a level... 

Switching between the citrate, capsnle, and tablet dosage forms should not result in significantly different 12-h steady-state lithinm levels. Sustained-release formulations, developed in an attempt to decrease the adverse effects, are associated with peak and rapidly rising serum lithium concentrations. 

The steady-state serum lithium levels of 10 patients with schizophrenia, or schizoaffective or bipolar disorders were studied before, during, and afier the concurrent use of quetiapine 250 mg three times daily. The lithium AUCo-12 and the maximum serum levels were raised by 12% and 4.5%, respectively, by quetiapine, and concurrent use was well tolerated. This small rise was not statistically or clinically significant. 

A randomised, placebo-controlled study in 25 healthy subjects taking lithium carbonate 450 mg twice daily for 15 days, found that ziprasidone 20 mg twice daily on days 9 to 11, followed by 40 mg twice daily on days 12 to 15 caused only a small increase in the steady-state serum-lithium levels (14% compared with 11% in the placebo group). A 5% reduction in renal clearance was seen in the ziprasidone group and a 9% reduction was seen in the placebo group. These differences were neither statistically nor clinically significant. No special precautions would therefore seem to be necessary if ziprasidone is given to patients taking lithium. 

In a study in 12 healthy subjects, nefazodone 200 mg twice daily was given alone for 5 days. After a washout period, lithium was given for 11 days, in escalating doses from 250 mg twice daily to 500 mg twice daily. When therapeutic steady-state lithium levels were achieved nefazodone 200 mg twice daily was added for 5 days. The pharmacokinetics of both nefazodone and lithium were unaltered by concurrent use, although there were some small changes in the pharmacokinetics of the nefazodone metabolites. However, since the combination was well tolerated, no dosage adjustments were considered necessary on concurrent use. ... 

In a randomised, placebo-controlled study, 16 healthy subjects were given lithium 600 mg twice daily for 9 days. On day 8, half of the subjects received two 100-mg doses of sertraline 8 hours apart, while the other half received placebo. Sertraline caused a statistically insignificant fall of 1.4% in steady-state lithium levels, and a statistically insignificant rise in renal lithium excretion. However, there was a high incidence of adverse effects (mainly tremor and nausea) with the combined treatment tremor occurred in 7 out of the 8 taking sertraline, whereas no adverse effects were reported in the placebo group. ... 

In a steady-state study 10 healthy women with average plasma-lithium levels of 0.63 mmol/L had a slight 6% rise in their renal excretion of lith-... 

Hughes BM, Small RE, Brink D, McKenzie ND. The effect of flurbiprofen on steady-state plasma lithium levels. Pharmacotherapy 1991) 17,113-20. 

A study in 9 healthy subjects given lithium carbonate 300 mg every 12 hours to achieve steady state, followed by the addition of650 mg of paracetamol every 6 hours for 5 days, found no evidence that paracetamol increased serum-lithium levels. Six subjects had no change in lithium levels, one subject had a 0.1 mmol/L decrease, and two had a 0.1 mmol/L increase. One patient whose serum lithium level doubled while taking rofecoxib was later given paracetamol without any problems. No precautions seem necessary on concurrent use. 

The serum-lithium levels of 10 healthy subjects taking lithium carbonate 900 mg daily fell by 20 to 30%, and the urinary clearance increased by 30%, when they were given theophylline (Theo-dur). Steady-state theophylline levels of 5.4 to 12.7 mierograms/mL were aehieved, and it was noted that higher theophylline levels were strongly eorrelated with increased lithium clearance. This study has been reported in brief elsewhere. ... 

The equilibrium concentration in the coolant after a longer time of steady-state operation of the plant is controlled by the production rate and the penetration rate, on the one hand, and by the removal rate on the other. For this reason it can vary considerably from plant to plant. In PWR plants, the equilibrium activity concentration in the primary coolant usually is within the range of 10 to 30 GBq/ Mg, in BWR plants it is considerably lower (about two orders of magnitude). In a PWR, the most important source is the generation from the B dissolved in the coolant in addition, in the case of insufficient LiOH isotopic purity the Li reaction may become important. In BWR plants which contain neither boron nor lithium in the coolant (with the possible exception of inadvertently introduced impurities), neutron capture in deuterium is usually the main somce. Due to the low base level of activity in the BWR reactor water, the penetration from fuel and control rods gains a greater significance, the extent of which depends on plant-specific parameters. 

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