General Principles Of Newer Antidepressants

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The newer antidepressants are a heterogeneous group of drugs that differ significantly in chemical structure, mechanism of action, pharmacokinetic characteristics, and adverse effect profile. Nonetheless, they also share many important similarities that are summarized in the following seven points. For brevity within this chapter, most of these points are not repeated for each individual drug:

1. These agents do not significantly inhibit cardiac sodium, calcium, or potassium ion channels. Therefore, they do not demonstrate the same cardiotoxicity or electrocardiographic conduction abnormalities typically seen with TCAs.

2. These agents do not inhibit monoamine oxidase activity and are not associated with tyramine-like reactions. The use of indirect sympathomimetics is not contraindicated.

3. They have negligible affinity for acetylcholine, dopamine, g-aminobutyric acid (GABA), glutamate, or b-adrenergic receptors. Although their exact mechanism of action remains poorly understood, it is traditionally attributed to inhibition of neurotransmitter reuptake (except mirtazapine).

4. Newer antidepressants (except bupropion) appear to have a much higher safety margin than the MAOIs and TCAs. Nonetheless, they can still cause fatalities, especially at very high doses or when combined with other drugs. Importantly, there is extremely limited human data on the "typical" presentation or optimal management of patients having overdosed on newer antidepressants. Therefore, current management recommendations may require modification as more information becomes available. Emergency physicians should routinely contact a regional poison control center (PCC) to report exposures to newer antidepressants. Also, consultation with a medical toxicologist is available through most regional PCCs.

5. Attempts at enhancing the elimination of newer antidepressants via hemodialysis, hemoperfusion, forced diuresis, or multiple-dose activated charcoal are unlikely to be successful and therefore not recommended. Whole bowel irrigation does not offer any advantage over single-dose activated charcoal in providing gastrointestinal decontamination to patients exposed to newer antidepressants.

6. The newer antidepressants are not detected by routine hospital serum and urine drug screens. Certain specialty laboratories do have the capability to measure parent drug and metabolite plasma levels, but this information is only useful for the confirmation of suspected drug overdose. Specific levels are not immediately available to emergency physicians nor do they affect the management of these patients. Postmortem drug redistribution is likely to occur with the newer antidepressants and, thus, postmortem drug level interpretation must take this factor into consideration.

7. Since all of the newer antidepressants are metabolized primarily by the liver, hepatic dysfunction can lead to elevated drug levels and subsequent drug toxicity. Also, drug interactions are possible when the newer antidepressants are combined with other drugs dependent on hepatic metabolism.

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