Any breast-feeding mother could also be an ultrarapid metabolizer and not know it, and unwittingly pass on high levels of opioids to her nursing baby through breast milk.
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The problem with both codeine and tramadol is that some people are "ultrarapid metabolizers" whose livers metabolize the drugs much too quickly, causing dangerously high levels of opioids to build up, said Dr. Douglas Throckmorton, the deputy director for regulatory programs at the F.D.A.'s Center for Drug Evaluation and Research.
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"Because we can't easily determine which children or nursing mothers specifically are at greater risk of ultrarapid metabolism of codeine and tramadol, today we are requiring manufacturers of prescription codeine and tramadol products to make important labeling changes to protect those children who are at greater risk," Dr. Throckmorton said.
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The consortium also recommends considering an alternative drug not metabolized by CYP2C19 in patients who are CYP2C19 ultrarapid metabolizers. A reduction in starting dose is recommended for patients who are CYP2D6 intermediate metabolizers and CYP2C19 poor metabolizers. If use of amitriptyline is warranted, therapeutic drug monitoring is recommended to guide dose adjustments. The Dutch Pharmacogenetics Working Group also recommends selecting an alternative drug or monitoring plasma concentrations of amitriptyline in patients who are CYP2D6 poor or ultrarapid metabolizers, and selecting an alternative drug or reducing initial dose in patients who are CYP2D6 intermediate metabolizers.
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Most individuals (about 77–92%) are extensive metabolizers, and have "normal" metabolism of nortriptyline. Poor and intermediate metabolizers have reduced metabolism of the drug as compared to extensive metabolizers; patients with these metabolizer types may have an increased probability of experiencing side effects. Ultrarapid metabolizers use nortriptyline much faster than extensive metabolizers; patients with this metabolizer type may have a greater chance of experiencing pharmacological failure. The Clinical Pharmacogenetics Implementation Consortium recommends avoiding nortriptyline in persons who are CYP2D6 ultrarapid or poor metabolizers, due to the risk of a lack of efficacy and side effects, respectively.
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Due to increased metabolism of codeine to morphine, ultrarapid metabolizers (those possessing more than 2 functional copies of the CYP2D6 allele) are at increased risk of adverse drug effects related to morphine toxicity. Guidelines released by the Clinical Pharmacogenomics Implementation Consortium (CPIC) advise against administering codeine to ultrarapid metabolizers, where this genetic information is available. The CPIC also suggests that codeine use be avoided in poor metabolizers, due to its lack of efficacy in this group. Codeine and its salts are readily absorbed from the gastrointestinal tract and ingestion of codeine phosphate produces peak plasma concentrations in about one hour.
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Most individuals (about 77–92%) are extensive metabolizers, and have "normal" metabolism of amitriptyline. Poor and intermediate metabolizers have reduced metabolism of the drug as compared to extensive metabolizers; patients with these metabolizer types may have an increased probability of experiencing side effects. Ultrarapid metabolizers use amitriptyline much faster than extensive metabolizers; patients with this metabolizer type may have a greater chance of experiencing pharmacological failure. The Clinical Pharmacogenetics Implementation Consortium recommends avoiding amitriptyline in patients who are CYP2D6 ultrarapid or poor metabolizers, due to the risk for a lack of efficacy and side effects, respectively.
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A reduction in starting dose is recommended for patients who are CYP2D6 intermediate metabolizers. If use of nortriptyline is warranted, therapeutic drug monitoring is recommended to guide dose adjustments. The Dutch Pharmacogenetics Working Group recommends reducing the dose of nortriptyline in CYP2D6 poor or intermediate metabolizers, and selecting an alternative drug or increasing the dose in ultrarapid metabolizers.
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CYP2D6 and CYP2C19 belong to the Cytochrome P450 oxidase family. CYP2D6 has over 90 variants, 2C19 has mainly three. They are responsible for the majority of the inter-individual variability in the ability to metabolize drugs. There are four phenotypes of CYP2D6: Poor Metabolizer (PM), Intermediate Metabolizer (IM), Extensive (normal) Metabolizer (EM) and Ultrarapid Metabolizer (UM).
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The duration of mood swings also varies. They may last a few hours - ultrarapid - or extend over days - ultradian: clinicians maintain that only when four continuous days of hypomania, or seven days of mania, occur, is a diagnosis of bipolar disorder justified.S, Nassir Ghaemi, Mood Disorder (2007) p. 243-4 In such cases, mood swings can extend over several days, even weeks: these episodes may consist of rapid alternation between feelings of depression and euphoria.
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CYP2D6 also activates some prodrugs. This enzyme also metabolizes several endogenous substances, such as hydroxytryptamines, neurosteroids, and both m-tyramine and p-tyramine which CYP2D6 metabolizes into dopamine in the brain and liver. Considerable variation exists in the efficiency and amount of CYP2D6 enzyme produced between individuals. Hence, for drugs that are metabolized by CYP2D6 (that is, are CYP2D6 substrates), certain individuals will eliminate these drugs quickly (ultrarapid metabolizers) while others slowly (poor metabolizers).
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Naltrexone therapy, which critics claim lacks long-term efficacy and can actually be detrimental to a patient's long-term recovery, has led to controversy. Additionally, there have been many questions raised about the ethics as well as safety of rapid detox following a number of deaths resulting from the procedure.Hamilton, R. J., Olmedo, R. E., Shah, S., Hung, O. L., Howland, M. A., Perrone, J., Nelson, L. S., Lewin, N. L. and Hoffman, R. S. (2002), Complications of Ultrarapid Opioid Detoxification with Subcutaneous Naltrexone Pellets. Academic Emergency Medicine, 9: 63–68.
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Nortriptyline is metabolized in the liver by the hepatic enzyme CYP2D6, and genetic variations within the gene coding for this enzyme can affect its metabolism, leading to changes in the concentrations of the drug in the body. Increased concentrations of nortriptyline may increase the risk for side effects, including anticholinergic and nervous system adverse effects, while decreased concentrations may reduce the drug's efficacy. Individuals can be categorized into different types of CYP2D6 metabolizers depending on which genetic variations they carry. These metabolizer types include poor, intermediate, extensive, and ultrarapid metabolizers.
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Since doxepin is mainly metabolized by CYP2D6, CYP2C9, and CYP2C19, genetic variations within the genes coding for these enzymes can affect its metabolism, leading to changes in the concentrations of the drug in the body. Increased concentrations of doxepin may increase the risk for side effects, including anticholinergic and nervous system adverse effects, while decreased concentrations may reduce the drug's efficacy. Individuals can be categorized into different types of cytochrome P450 metabolizers depending on which genetic variations they carry. These metabolizer types include poor, intermediate, extensive, and ultrarapid metabolizers.
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Since amitriptyline is primarily metabolized by CYP2D6 and CYP2C19, genetic variations within the genes coding for these enzymes can affect its metabolism, leading to changes in the concentrations of the drug in the body. Increased concentrations of amitriptyline may increase the risk for side effects, including anticholinergic and nervous system adverse effects, while decreased concentrations may reduce the drug's efficacy. Individuals can be categorized into different types of CYP2D6 or CYP2C19 metabolizers depending on which genetic variations they carry. These metabolizer types include poor, intermediate, extensive, and ultrarapid metabolizers.
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CYP2D6 converts codeine into morphine, which then undergoes glucuronidation. Life-threatening intoxication, including respiratory depression requiring intubation, can develop over a matter of days in patients who have multiple functional alleles of CYP2D6, resulting in ultra-rapid metabolism of opioids such as codeine into morphine. Studies on codeine's analgesic effect are consistent with the idea that metabolism by CYP2D6 to morphine is important, but some studies show no major differences between those who are poor metabolizers and extensive metabolizers. Evidence supporting the hypothesis that ultrarapid metabolizers may get greater analgesia from codeine due to increased morphine formation is limited to case reports.
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It is not known whether hERG-KCNE3 complexes occur in vivo. KCNE3 interacts with Kv2.1 in vitro and forms complexes with it in rat heart and brain. KCNE3 slows Kv2.1 activation and deactivation. KCNE3 can also regulate channels of the Kv3 subfamily, which are best known for permitting ultrarapid firing of neurons because of the extremely fast gating (activation and deactivation). KCNE3 moderately slows Kv3.1 and Kv3.2 activation and deactivation, and moderately speeds their C-type inactivation. It is possible that KCNE3 (and KCNE1 and 2) regulation of Kv3.1 and Kv3.2 helps to increase functional diversity within the Kv3 subfamily.
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Most people are extensive metabolizers, and have "normal" metabolism of doxepin. Poor and intermediate metabolizers have reduced metabolism of the drug as compared to extensive metabolizers; patients with these metabolizer types may have an increased probability of experiencing side effects. Ultrarapid metabolizers break down doxepin much faster than extensive metabolizers; patients with this metabolizer type may have a greater chance of experiencing pharmacological failure. A study assessed the metabolism of a single 75 mg oral dose of doxepin in healthy volunteers with genetic polymorphisms in CYP2D6, CYP2C9, and CYP2C19 enzymes. In CYP2D6 extensive, intermediate, and poor metabolizers, the mean clearance rates of (E)-doxepin were 406, 247, and 127 L/hour, respectively (~3-fold difference between extensive and poor).
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