Lithium pharmacodynamics

Medications that have been used as treatment for anxiety and depression in the postwithdrawal state include antidepressants, benzodia2epines and other anxiolytics, antipsychotics, and lithium. In general, the indications for use of these medications in alcoholic patients are similar to those for use in nonalcoholic patients with psychiatric illness. However, following careful differential diagnosis, the choice of medications should take into account the increased potential for adverse effects when the medications are prescribed to alcoholic patients. For example, adverse effects can result from pharmacodynamic interactions with medical disorders commonly present in alcoholic patients, as well as from pharmacokinetic interactions with medications prescribed to treat these disorders (Sullivan and O Connor 2004). 

PHARMACODYNAMIC USES OF METAL COMPLEX DRUGS 9.18.5.1 Lithium Carbonate... 

SSRIs can provoke 5HT neurotoxicity (the 5HT syndrome) through pharmacodynamic interactions with other drugs that also potentiate 5HT function. Often the ability of the interacting drug to facilitate 5HT function is well known, as is the case, for example, when SSRIs are combined with monoamine oxidase inhibitors or lithium. In other cases, however, the potential 5HT activity of the co-administered drug is not widely known. The ability of the antibiotic linezolid to inhibit MAO and thereby to cause 5HT neurotoxicity in combination with SSRIs has been noted previously (SEDA-27, 14), and further cases have now been reported. 

Drug interactions with lithium have been reviewed (569-573) another review focused on interactions in the elderly (573). A review of drug interactions with lithium considered both pharmacokinetic interactions [for example diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs)] and pharmacodynamic interactions (for example antipsychotic drugs, SSRIs) and summarized the most important ones in tabular form (569). 

A pharmacodynamic drug interaction could not be excluded when a 60-year-old man developed delirium at a serum lithium concentration of 0.97 mmol/1 when taking lithium and haloperidol (158). 

Pharmacokinetic and pharmacodynamic profiles of olanzapine have been extensively reviewed (266). Olanzapine does not inhibit CYP isozymes, and no clinically significant metabolic interactions were found of olanzapine with aminophylline, biperiden, diazepam, ethanol, fluoxetine, imipramine, lithium, or R/S-warfarin. 

Some ethnic differences in therapeutic doses and side effects of various psychotropic medications, including neuroleptics, lithium, and TCAs, have also been explained by pharmacodynamic factors such as tissue or receptor sensitivity (Kalow 1989 Lin et al. 1995 Pi 1998). 

In the fourth chapter, Drs. Edmond H. Pi and Gregory E. Gray review the pharmacokinetics, pharmacodynamics, and sociocultural influences on the psychotropic responses among Asian American populations. Particular consideration is given to anti-psychotics, antidepressants, benzodiazepines, and lithium. The authors stress the importance of prescribing the lowest possible effective dose, to minimize untoward side effects and thus ensure treatment compliance. 

In a prospective study designed to investigate the pharmacodynamic effects of Uthium treatment on GSK-3 activity in patients with mild Alzheimer s disease, 71 patients received either lithium or a placebo for 10 weeks. Patients where assessed for cerebrospinal fluid (CSF) phospho-tau levels and cognitive function was assessed by Alzheimer s disease assessment scale (ADAS-Cog). No effect of lithium on CSF phosphorylated tau levels could be shown. However, a clinically significant effect on cognition was measured by ADAS-Cog [101]. It is feasible that a 10-week lithium treatment might not be sufficient to see an effect on phosphorylated tau or that GSK-3 inhibition will not be reflected in the CSF phospho-tau or total tau levels. CSF turnover is quite rapid (about 6 h) and a more predictive readout might be the tau/beta amyloid ratio that has been shown to be more sensitive [ 102]. 

Another example of pharmacodynamic differences is that of reports on lithium in the manic phase of bipolar depression. Asian patients, including Japanese, are reported to have therapeutic blood levels at 0.5 0.8m.eg/l compared to required levels in US Caucasian patients of 0.8-1.2m.eg/l (Jefferson et al 1987 Yang 1987 Takahashi 1979) these findings, however, are disputed by Chang et al (1985). African-Americans require less drug, but this is because of higher levels due to a slower clearance rate than Caucasians (Jefferson et al 1987 Lin et al 1986). 

The case reports detailed above suggest that some patients may develop a pharmacodynamic interaction. Concurrent use of lithium and olanzapine need not be avoided but be aware that there is some risk of developing adverse reactions to the combination. The presence of other serotonergic drugs (e.g. antidepressants such as SSRIs) or dopamine antagonists (e.g. antipsychotics such as haloperidol) is likely to increase the risk of an interaction. 

No pharmacokinetic or pharmacodynamic interactions appeared to occur between lithium and mirtazapine in one study in healthy subjects. 

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