Several chemically unrelated agents has been developed and introduced in the past decade, to supplement the earlier antidepressants. These include inhibitors of the reuptake of serotonin [the selective serotonin reuptake inhibitors (SSRI)] or noradrenaline (reboxetine) or both (milnacipran and venlafaxine), as well as drugs with distinct neurochemical profiles such as mirtazapine, nefazodone, moclobemide and tianeptine. Like the earlier drugs, these newer antidepressants are almost totally biotransformed before excretion, except for milnacipran whose clearance appears to be due equally to both urinary excretion and metabolism. Sometimes — as in the case of moclobemide — up to 20 metabolites have been identified in body fluids. In some cases, however, only a few metabolites have been detected, and a substantial proportion of the dose remains unaccounted for (e.g. fluoxetine and fluvoxamine). Metabolism generally proceeds through sequential or parallel oxidative pathways. These may be affected to varying degrees by physiological and pathological factors and those mediated by cytochrome P450 (CYP) 2D6 and CYP2C19 through genetic polymorphism. Some are influenced by chirality (e.g. the dealkylation of citalopram and fluoxetine), although information on this aspect of disposition is still lacking for other drugs existing as racemates (e.g. mirtazepine and tianeptine) and milancipran, which is probably a mixture of 4 stereoisomers. Others again are saturable within the therapeutic range of doses (e.g. some pathways of metabolism of fluoxetine, fluvoxamine, nefazodone, paroxetine and venlafaxine). This may explain the individual variability with all these drugs which, from the pharmacokinetic point of view, is the same as with tricyclic agents. Our knowledge of the isoenzymes involved in the various oxidation pathways and their relevance for potential drug interactions varies from a considerable amount for most of the SSRI and nefazodone, to minimal for reboxetine and tianeptine. This information is useful for predicting the pharmacokinetic interactions mediated through inhibition of specific isoenzymes. This would be better appreciated if the enzymatic mechanisms involved in the biotransformation of the metabolite(s), and their role in drug interactions, were also known. This information is still lacking for some drugs, although metabolites may exhibit in vitro inhibitory potencies of similar to (paroxetine and its M2 metabolite as inhibitors of CYP2D6) or even greater than that of the parent drug (norfluoxetine is more potent than fluoxetine as an inhibitor of CYP3A3/4, and in view of the longer half-life (t1/2) of the metabolite the potential for interactions may persist for weeks after discontinuation of the parent drug). While we do know something about the biological activity of the metabolites of some of these drugs, we know very little about others. With few exceptions this knowledge refers only to the major metabolite(s) and regards the main in vitro effects as exerted by the parent drug. However, in vitro potency and selectivity may not translate directly into in vivo, and either major or minor metabolites may have characteristic in vitro and in vivo properties. For example, unlike the parent drug some minor ring-opened metabolites of moclobemide have monoamine oxidase-B inhibitory activity in the rat, and the nefazodone metabolite m-chlorophenyl-piperazine shows activity on 5-HT2C receptors in rats and humans. Data on the brain-to-blood partition of metabolites compared with their parent drug are available only in a few cases. They are still not known for the main metabolites of fluvoxamine, milnacipran, mirtazapine, moclobemide, nefazodone, paroxetine, reboxetine and venlafaxine, despite the fact that total blood concentrations do not always reflect the metabolite: parent drug ratio in brain. Thus, in most cases, we do not really know what part hepatic metabolism plays in the overall effect of the administered parent drug.

Metabolism of the newer antidepressants. An overview of the pharmacological and pharmacokinetic implications.

Depression and anxiety are among the most common comorbid illnesses in people with end-stage renal disease (ESRD). Patients with ESRD face many challenges which increase the likelihood that they will develop depression or anxiety or worsen these conditions. These include a general feeling of unwellness; specific symptoms caused by ESRD or the patient's treatment; major disruptions in lifestyle; the need to comply with treatment regimens, including dialysis schedules, diet prescription, and water restriction; ancillary treatments and hospitalizations; and the fear of disability, morbidity, and shortened lifespan. Depression has been studied extensively in patients on maintenance dialysis, and much effort has been done to validate the proper screening tools to diagnose depression and to define the treatment options for patients on maintenance dialysis with depression. Anxiety is less well studied in this population of patients. Evidence indicates that anxiety is also common in maintenance dialysis. More attention should be paid to measuring the incidence and prevalence and developing methods of diagnosis and treatment approaches for anxiety in patients with ESRD. In this review, we attempted to underscore those aspects of depression and anxiety that have not been investigated extensively, especially with regard to anxiety. The interaction between racial/ethnic characteristics of patients on maintenance dialysis with depression and anxiety needs to be studied more extensively, in order to assess better approaches to healthcare for these individuals.

/pdf/mental-health-depression-and-anxiety-in-patients-on-5fbhzmfise.pdf

Mental health, depression, and anxiety in patients on maintenance dialysis.

Depressive and anxiety disorders appear during the transplant process due to psychological stressors, medications and physiological disturbances Treatment is necessary to prevent impact on patient compliance, morbidity and mortality Psychotropic medications provide an effective option, although most are only available as oral formulations Because of this, they are more susceptible to alterations in pharmacokinetic behaviour arising from organ dysfunction in the pretransplant period Kinetics are also an issue when considering potential drug-drug interactions before and after transplantation Prior to transplant, organ dysfunction can change the pharmacokinetic behaviour of some psychotropic agents, requiring adjustment of dosage and schedules Thoracic or abdominal organ failure may reduce drug absorption through disturbances in intestinal motility, perfusion and function Cirrhotic patients experience increased drug bioavailability due to portosystemic shunting, and thus dosage is adjusted downward In contrast, dosage needs to be raised when peripheral oedema expands the drug distribution volume for hydrophilic and protein-bound agents Drug clearance for most psychotropic medications is dependent upon hepatic metabolism, which is often disrupted by endstage organ disease Selection of drugs or their dosage may need to be adjusted to lower the risk of drug accumulation Further adjustments in dosage may be called for when renal failure accompanies thoracic or abdominal organ failure, resulting in further impairment of clearance Studies regarding the treatment of anxiety and depressive disorders in the medically ill are limited in number, but recommendations are possible by review of clinical and pharmacokinetic data Selective serotonin reuptake inhibitors are well tolerated and efficacious for depression, panic disorder and post-traumatic stress disorder Adjustments in dosage are required when renal or hepatic impairment is present Among them, Citalopram and escitalopram appear to have the least risk of drug-drug interactions Paroxetine has demonstrated evidence supporting its use with generalised anxiety disorder Venlafaxine is an alternative option, beneficial in depression, post-traumatic stress and generalised anxiety disorders Nefazodone may also be considered, but there is some risk of hepatotoxicity and interactions with immunosuppressant drugs Mirtazapine still needs to be studied further in anxiety disorders, but can be helpful for depression accompanied by anorexia and insomnia Bupropion is effective in the treatment of depression, but data are sparse about its use in anxiety disorders Psychostimulants are a unique approach if rapid onset of antidepressant action is desired Acute or short-term anxiolysis is obtained with benzodiazepines, and selection of particular agents entails consideration of distribution rate, half-life and metabolic route

Treatment of anxiety and depression in transplant patients: Pharmacokinetic considerations

Buspirone: An Updated Review of its Clinical Pharmacology and Therapeutic Applications

Update on psychotropic medication use in renal disease.

12 patients with mild to moderate impairment of renal function and 12 healthy subjects each received 20mg buspirone as a single dose in this acute study. Six anuric patients with chronic renal failure were given two 20mg doses of buspirone, the first 2 days before haemodialysis (between dialyses) and the second during hemodialysis (2 hours before dialysis began). The differences between the median pharmacokinetic values of buspirone for healthy subjects, patients with mild to moderate renal impairment, and anuric patients were not statistically significant. Similarly, there were no significant differences between values in mild to moderate renal failure vs healthy subjects. Some of the median pharmacokinetic values for the active buspirone metabolite l-(2-pyrimidinyl)-piperazine (1-PP), however, differed significantly for anuric patients, compared with healthy subjects or patients with mild to moderate renal impairment. When assessed between and during haemodialysis, the anuric patients had significantly (p < 0.05) greater pharmacokinetic median values: half life (t
 ½ = 15.2 vs 9.8 hours; area under the concentration-time curve (AUC) = 604 vs 404 nmol/L · h; and mean residence time (MRT) = 9.28 vs 6.96 hours. No firm recommendation for specific dosage can be made based on the present data. However, it does appear that in patients with mild to moderate renal impairment, the pharmacokinetics of buspirone and its active metabolite 1-PP are similar to those in individuals with normal renal function. For anuric patients higher concentrations of the 1-PP metabolite are attained while they are not undergoing haemodialysis. A dosage reduction of 25 to 50% might be necessary when buspirone is given to anuric patients.

Clinical pharmacokinetics of oral buspirone in patients with impaired renal function

The pharmacokinetics of a single oral dose of buspirone (20 mg) were determined in 12 patients with cirrhosis and 12 normal subjects. The mean AUC of buspirone was 55 +/- 38 s.d. ng ml-1 h in cirrhotics and 3.5 +/- 2.4 s.d. ng ml-1 h in normals. The time until maximum concentration (tmax) attained was similar in the two groups (0.6 vs 0.7 h), but mean maximum concentration Cmax was higher in patients (18.8 +/- 16.3 s.d. ng ml-1) than in normals (1.2 +/- 0.8 s.d. ng ml-1). Mean elimination half-life of buspirone was greater in cirrhotics, but this difference was marginally significant statistically (cirrhotics, 6.1 +/- 3.5 s.d. h, normals 3.2 +/- 1.5 s.d. h, P = 0.05). Eight of 12 patients and seven of 12 normal subjects had a second peak in the plasma concentrations of buspirone. In patients this occurred at 10.8 +/- 7.4 s.d. h after the dose, and its mean concentration was 3.1 +/- 6.6 ng ml-1. In normal subjects the second peak occurred at 4.3 +/- 2.1 h after the dose and its mean concentration was 0.5 +/- 0.3 ng ml-1. On the kinetic evidence buspirone should be used with caution in liver disease.

/pdf/buspirone-pharmacokinetics-in-patients-with-cirrhosis-33xye3zitj.pdf

Buspirone pharmacokinetics in patients with cirrhosis.

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Clinical pharmacokinetics of oral buspirone in patients with impaired renal function

Buspirone pharmacokinetics in patients with cirrhosis.