Pharmacokinetic drug interactions of synthetic opiate analgesics.

Earlier reviews have covered pharmacokinetic drug interactions of natural and semi-synthetic opioid analgesics. This review will focus on the pharmacokinetic drug-drug interactions of methadone, propoxyphene, levomethadyl, meperidine, other phenylpiperidines (such as fentanyl), pentazocine, diphenoxylate, loperimide, and tramadol. The authors present an extensive review of the current literature. These drugs, with a few exceptions, are, at least partially, if not primarily, metabolized by the cytochrome P450 isoenzyme system (CYP) 3A4, and the action/interaction of these enzymes can have an effect on outcome. Therefore, these drugs are likely to produce drug-drug interactions when the CYP3A4 system is inhibited or induced. Knowledge of these drug-drug interactions is important because such interactions may decrease drug efficacy or result in adverse effects.

Clozapine case series.

Clozapine is not a drug that is ever used casually. Patients generally are afflicted with severe illnesses and have demonstrated treatment resistance and/or intolerance to other therapeutic options before clozapine is seriously considered. When the clinical stakes are this high, it is especially important that physicians gain an appreciation for the various drug-drug interactions that can significantly increase or decrease clozapine blood levels; such pharmacokinetic changes can derail clozapine treatment by producing clozapine toxicity or loss of antipsychotic efficacy, respectively. The authors present a case series of five drug-drug interactions involving clozapine, each of which illustrates different mechanisms by which the metabolism of clozapine can be altered. Exploring these cases should help clinicians anticipate and avoid these undesirable drug-drug interactions.

Clinical guidelines for psychiatrists for the use of pharmacogenetic testing for CYP450 2D6 and CYP450 2C19.

Pharmacogenetics has arrived in clinical psychiatric practice with the FDA approval of the AmpliChip CYP450 Test that genotypes for two cytochrome P450 2D6 (CYP2D6) and 2C19 (CYP2C19) genes. Other pharmacogenetic tests, including those focused on pharmacodynamic genes, are far from ready for clinical application. CYP2D6 is important for the metabolism of many antidepressants and antipsychotics, and CY2C19 is important for some antidepressant metabolism. Poor metabolizers (PMs), lacking the enzyme, account for up to 7% of Caucasians for CYP2D6 and up to 25% of East Asians for CYP2C19. Patients having three or more active CYP2D6 alleles (up to 29% in North Africa and the Middle East), are called CYP2D6 ultra-rapid metabolizers (UMs). CYP2D6 phenotypes (particularly PMs) are probably important in patients taking tricyclic antidepressants (TCAs), venlafaxine, typical antipsychotics, and risperidone. The CYP2C19 PM phenotype is probably important in patients taking TCAs and perhaps citalopram, escitalopram, and sertraline. On the basis of the literature and the authors' clinical experience, the authors provide provisional recommendations for identifying and treating CYP2D6 PMs, CYP2C19 PMs, and CYP2D6 UMs. The next few years will determine whether CYP2D6 genotyping is beneficial for patients taking the new drugs aripiprazole, duloxetine, and atomoxetine. Practical recommendations for dealing with laboratories offering CYP2D6 and CYP2C29 genotyping are provided.

An overview of psychotropic drug-drug interactions.

The psychotropic drug-drug interactions most likely to be relevant to psychiatrists' practices are examined. The metabolism and the enzymatic and P-glycoprotein inhibition/induction profiles of all antidepressants, antipsychotics, and mood stabilizers are described; all clinically meaningful drug-drug interactions between agents in these psychotropic classes, as well as with frequently encountered nonpsychotropic agents, are detailed; and information on the pharmacokinetic/pharmacodynamic results, mechanisms, and clinical consequences of these interactions is presented. Although the range of drug-drug interactions involving psychotropic agents is large, it is a finite and manageable subset of the much larger domain of all possible drug-drug interactions. Sophisticated computer programs will ultimately provide the best means of avoiding drug-drug interactions. Until these programs are developed, the best defense against drug-drug interactions is awareness and focused attention to this issue.

The dosing of atypical antipsychotics.

Drug-drug interactions or genetic variability may require using doses different from those recommended for atypical antipsychotics. Dosage alterations of olanzapine and clozapine, dependent on cytochrome P450 1A2 (CYP1A2) for clearance, and quetiapine, dependent on cytochrome P450 3A (CYP3A), may be necessary when used with other drugs that inhibit or induce their metabolic enzymes. Smoking cessation can significantly increase clozapine, and perhaps olanzapine, levels. Ziprasidone pharmacokinetic drug-drug interactions are not likely to be important. Genetic variations of cytochrome P450 2D6 (CYP2D6) and drug-drug interactions causing inhibition (CYP2D6 and/or CYP3A) or induction (CYP3A) may be important for risperidone, and perhaps for aripiprazole, dosing. Adding inhibitors may cause side effects more easily in drugs with a narrow therapeutic window, such as clozapine or risperidone, than in those with a wide therapeutic window, such as olanzapine or aripiprazole. Adding inducers may be associated with a gradual development of lost efficacy.

Med-psych drug-drug interactions update. Antiretrovirals, part III: antiretrovirals and drugs of abuse.

The third in a series reviewing the HIV/AIDS antiretroviral drugs, this report summarizes the interactions between antiretrovirals and common drugs of abuse. In an overview format for primary care physicians and psychiatrists, the metabolism and drug interactions in the context of antiretroviral therapy are presented for the following drugs of abuse: alcohol, benzodiazepines, cocaine, GHB (liquid X), ketamine (special K), LSD (acid), MDMA (Ecstasy), opiates, PCP (angel dust), and THC (marijuana).

Antiretrovirals, Part II: focus on non-protease inhibitor antiretrovirals (NRTIs, NNRTIs, and fusion inhibitors).

The second in a series reviewing the HIV/AIDS antiretroviral drugs. This review summarizes the non-protease inhibitor antiretrovirals: nucleoside and nucleotide analogue reverse transcriptase inhibitors (NRTIs), the nonnucleoside reverse transcriptase inhibitors (NNRTIs), and cell membrane fusion inhibitors. In an overview format for primary care physicians and psychiatrists, this review presents the mechanism of action, side effects, toxicities, and drug interactions of these agents.

Immunosuppressants.

Immunosuppressants are prescribed to prevent rejection of transplanted tissues and organs and are also used in the treatment of autoimmune disorders. Consultation-liaison psychiatrists increasingly encounter patients taking these agents as the number of transplant recipients increases and the indications for the use of immunosuppressants expands. These drugs have potentially deleterious physical, mental, and biochemical side effects. In addition, transplant recipients and patients with autoimmune disorders commonly have comorbid illnesses that require pharmacologic treatment. The management of these patients is challenging secondary to the severity of these illnesses, the number of medications prescribed, and the potential for adverse drug-drug interactions. Knowledge of the pharmacokinetic properties of these drugs and the potential for serious drug-drug interactions that cause alterations in serum levels of the immunosuppressant medications is essential. Increased serum levels may cause serious toxic effects and decreased serum levels may lead to rejection of the transplanted organ or worsening of the autoimmune disorder. Adverse events may also occur when serum levels of medications prescribed for comorbid illnesses are altered by administration of immunosuppressants. The pharmacokinetic drug-drug interaction profiles of the glucocorticoids, cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, azathioprine, and monoclonal antibodies are discussed in this review.

Antiretrovirals, part 1: overview, history, and focus on protease inhibitors.

This column is the first in a series on HIV/AIDS antiretroviral drugs. This first review summarizes the history of HIV/AIDS and the development of highly active antiretroviral therapy (HAART) and highlights why it is important for non-HIV specialists to know about these drugs. There are four broad classes of HIV medications used in varying combinations in HAART: the protease inhibitors, nucleoside analogue reverse transcriptase inhibitors, the non-nucleoside reverse transcriptase inhibitors, and cell membrane fusion inhibitors. This paper reviews the mechanism of action, side effects, toxicities, and drug interactions of the protease inhibitors.

Ecstasy: pharmacodynamic and pharmacokinetic interactions.

At "raves," young people dance and ingest illicit drugs, the most common of which is MDMA (N-methyl-3,4,-methylenedioxymethamphetamine) or "ecstasy." This drug is metabolized principally through the cytochrome P450 (CYP450) 2D6 enzyme. Pharmacokinetic drug-drug interactions can occur if MDMA is combined with other recreational or therapeutic drugs that are 2D6 inhibitors. Ecstasy concentration may increase to cause toxicity. Since ecstasy is pro-serotonergic, it may also be involved in pharmacodynamic drug-drug interactions when other pro-serotonergic drugs are combined with it, leading to a central serotonin syndrome. Some drugs are both pro-serotonergic and CYP450 2D6 inhibitors and, if co-administered with ecstasy, may cause both pharmacokinetic and pharmacodynamic drug-drug interactions.

Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: theory and clinical reality, Part II.

Pharmacokinetic drug-drug interactions with codeine, dihydrocodeine, hydrocodone, oxycodone, and buprenorphine are reviewed in this column. These compounds have a very similar chemical structure to morphine. Unlike morphine, which is metabolized chiefly through conjugation reactions with uridine diphosphate glucuronosyl transferase (UGT) enzymes, these five drugs are metabolized both through oxidative reactions by the cytochrome P450 (CYP450) enzyme and conjugation by UGT enzymes. There is controversy as to whether codeine, dihydrocodeine, and hydrocodone are actually prodrugs requiring activation by the CYP450 2D6 enzyme or UGT enzymes. Oxycodone and buprenorphine, however, are clearly not prodrugs and are metabolized by the CYP450 2D6 and 3A4 enzymes, respectively. Knowledge of this metabolism assists in the understanding for the potential of drug-drug interactions with these drugs. This understanding is important so that clinicians can choose the proper dosages for analgesia and anticipate potential drug-drug interactions.

Antihistamines.

Antihistamines and their drug-drug interactions are reviewed in depth. The metabolism of "classic" or sedating antihistamines is coming to light through in vivo and in vitro studies. The polymorphic CYP 2D6 metabolic enzyme appears to be potently inhibited by many of these over-the-counter medications. The history of the discontinued "second-generation" antihistamines terfenadine and astemizole is reviewed to remind the reader why the understanding of the cytochrome P450 system became increasingly important when the cardiotoxicity of these drugs became apparent. The "third-generation" nonsedating antihistamines are also listed and compared. They have been exhaustively scrutinized for drug-drug interactions and cardiotoxicity, and they appear to have no serious drug-drug interactions at recommended doses.

Six patterns of drug-drug interactions.

The literature on pharmacokinetic drug-drug interactions usually focuses on various interactions relating to the cytochrome p450 system, phase II glucuronidation, and P-glycoprotein function. However, there has been relatively little examination of how the modes or patterns that govern these interactions can be systematically characterized to better anticipate drug-drug interactions in clinical practice. This article details a schema of six core patterns of pharmacokinetic drug-drug interaction relating to processes of induction and inhibition and the action of substrates. Case examples illustrating each pattern are provided.

Pharmacokinetic drug interactions of morphine, codeine, and their derivatives: theory and clinical reality, part I.

Pharmacokinetic drug-drug interactions with morphine, hydromorphone, and oxymorphone are reviewed in this column. Morphine is a naturally occurring opiate that is metabolized chiefly through glucuronidation by uridine diphosphate glucuronosyl transferase (UGT) enzymes in the liver. These enzymes produce an active analgesic metabolite and a potentially toxic metabolite. In vivo drug-drug interaction studies with morphine are few, but they do suggest that inhibition or induction of UGT enzymes could alter morphine and its metabolite levels. These interactions could change analgesic efficacy. Hydromorphone and oxymorphone, close synthetic derivatives of morphine, are also metabolized primarily by UGT enzymes. Hydromorphone may have a toxic metabolite similar to morphine. In vivo drug-drug interaction studies with hydromorphone and oxymorphone have not been done, so it is difficult to make conclusions with these drugs.

Triptans.

Triptans are potent serotonin (5-HT) 1B/1D receptor agonists used to abort and treat migraine headaches. Although the triptans share pharmacodynamic characteristics at 5-HT(1B/1D) receptors, they differ pharmacokinetically. This column reviews how the triptans are metabolized. Generally, the triptans are metabolized by phase I monoamine oxidases (MAOs) and by various cytochrome p450 enzymes. However, each triptan has a unique metabolic profile, leading to significant differences in each triptan's potential for drug-drug interactions. These differences are detailed in this review.

Immunosuppressants.

This edition of the Med-Psych Drug-Drug Interactions Update begins a change in format. Starting with this column, each column will feature one drug-drug interaction (DDI) topic that will be explored in depth. This edition features DDIs associated with the commonly used immunosuppressants. These drugs are frequently encountered by consultation-liaison psychiatrists in tertiary care settings. Generally, most of these drugs have narrow safety and therapeutic windows; therefore, other drugs that change their serum levels can have deleterious effects. In this review, the DDI profiles of cyclosporine, tacrolimus, sirolimus, and the corticosteroids are explored.