Clin Pharmacokinet
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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. ⋯ 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.
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Critically ill patients exhibit a range of organ dysfunctions and often require treatment with a variety of drugs including sedatives, analgesics, neuromuscular blockers, antimicrobials, inotropes and gastric acid suppressants. Understanding how organ dysfunction can alter the pharmacokinetics of drugs is a vital aspect of therapy in this patient group. Many drugs will need to be given intravenously because of gastrointestinal failure. ⋯ Failure of the central nervous system, muscle, the endothelial system and endocrine system may also affect the pharmacokinetics of specific drugs. Time-dependency of alterations in pharmacokinetic parameters is well documented for some drugs. Understanding the underlying pathophysiology in the critically ill and applying pharmacokinetic principles in selection of drug and dose regimen is, therefore, crucial to optimising the pharmacodynamic response and outcome.
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The pharmacokinetics and pharmacodynamics of sedatives and analgesics are significantly altered in the critically ill. These changes may account for the large differences in drug dosage requirements compared with other patient populations. Drugs that in other settings may be considered short-acting often have significantly altered onset and duration of action in critically ill patients, necessitating a change in dosage. ⋯ The costs of sedation and analgesia are very variable and closely linked to the pharmacokinetics and pharmacodynamics of the drug. Monitoring of sedation and analgesia is difficult in uncooperative patients in the intensive care unit. In the future, specific monitoring tools may assist clinicians in the regulation of infusions of sedative and analgesic agents.
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The potential for drug-drug interactions in psychiatric patients is very high as combination psychopharmacotherapy used to treat comorbid psychiatric disorders, to treat the adverse effects of a medication, to augment a medication effect or to treat concomitant medical illnesses. Interactions can be pharmacodynamic or pharmacokinetic in nature. This paper focuses on the metabolic kinetic interactions between selective serotonin reuptake inhibitors (SSRIs) and other central nervous system (CNS) drugs. ⋯ Paroxetine and citalopram are unlikely to cause interactions with benzodiazepines. The evidence is conflicting for an interaction between carbamazepine and the SSRIs fluoxetine and fluvoxamine. These combinations should be used cautiously, and be accompanied by monitoring for adverse events and carb
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Traditionally, opioids have been administered as fixed doses at fixed dose intervals. This approach has been largely ineffective. Patient-controlled analgesia (PCA) and upgraded traditional approaches incorporating flexibility in dose size and dose interval, and titration for an effect in individual patients with the monitoring of pain and sedation scores, can greatly improve the efficacy of opioid administration. ⋯ There is a clear kinetic preference for regimens with a rapid onset and short duration (e.g. intravenous PCA) for coping with incident pain. It is shown that, in general, titration is improved by the more frequent administration of smaller doses, but it is important to use additional doses to initially 'load' a patient. The titration of opioids should always be accompanied by the monitoring of pain and sedation scores and ventilation.