Journal of Psychosocial Nursing and Mental Health Services

Psychopharmacology 

Adverse Events, Drug Interactions, and Treatment Adherence

Barbara J. Limandri, PhD, PMHNP, BC

Abstract

Many clients do not take their medications as prescribed. One of the reasons may be the common adverse drug effects and drug–drug interactions of certain medications. This article reviews adverse drug effects (including less serious side effects), the pharmacokinetics and pharmacodynamics involved in adverse effects, and the pharmacokinetics of drug interactions. For medications to be effective in treating mental disorders, nurses need to carefully assess clients and their motivations for taking medications, routinely inquire about when and how they are taking their prescriptions, any adverse effects they are experiencing, and how they are managing common, less severe adverse effects. [Journal of Psychosocial Nursing and Mental Health Services, 58(2), 9–13.]

Abstract

Many clients do not take their medications as prescribed. One of the reasons may be the common adverse drug effects and drug–drug interactions of certain medications. This article reviews adverse drug effects (including less serious side effects), the pharmacokinetics and pharmacodynamics involved in adverse effects, and the pharmacokinetics of drug interactions. For medications to be effective in treating mental disorders, nurses need to carefully assess clients and their motivations for taking medications, routinely inquire about when and how they are taking their prescriptions, any adverse effects they are experiencing, and how they are managing common, less severe adverse effects. [Journal of Psychosocial Nursing and Mental Health Services, 58(2), 9–13.]

The major reasons people give for not taking medications as prescribed are side effects, forgetting to take and refill medications, and confusion about directions (Allison, Flowerdew, & Elsmlie, 2012). Adverse and side effects such as weight gain, sexual dysfunction, and cognitive fogging effect not only individuals' bodies but also how they perceive their recovery from the mental disorder for which they are taking the medication. Weight change may be a consequence of depression, which can affect the person's self-esteem, which adds to the depression. Similarly, not being able to think clearly influences how people interact with others. Therefore, even what may seem to the clinician as benign side effects may play a major role in recovery and willingness to seek and continue treatment.

The current article addresses the pharmacological explanations for adverse and side effects, the common side effects and serious adverse effects of psychotropic medications, and ways for clinicians to manage these effects with clients.

Pharmacokinetics and Pharmacodynamics

The three major processes in drug metabolism involve the cytochrome P 450 (CYP450) system, conjugation in the liver, and the P-glycoproteins in the intestinal epithelium. Although glucuronidation is a major metabolic pathway, there are few studies regarding how this pathway affects psychotropic medications; therefore, this article will focus on the CYP450 system and to a lesser extent on the P-glycoproteins.

The CYP450 enzymes are involved in the oxidative phase of metabolism and account for 75% of drug metabolism. Enzymes most involved in metabolism of psychotropic drugs are: 1A2, 2D6, 3A4, and 2C19. Enzyme substrates and inducers breakdown drugs, thereby reducing the concentration of the drug in the body, whereas enzyme inhibitors slow down the metabolism of the drug, thereby increasing the concentration of the drug (McDonnell & Dang, 2013). Drugs that induce enzymatic activity may have a time delay in both onset and offset of drug effects when starting and stopping a drug because enzymatic inductions involve protein synthesis. Therefore, the full effect may not be evident for several weeks after initiation and continue for several weeks after discontinuation (Brown, 2008). Table A (available in the online version of this article) shows these enzyme families and their effects on psychotropic medications. Because the CYP450 enzymes affect the bioavailability of drugs, they contribute to interactions of drugs to other drugs and foods and adverse effects of medications.

Cytochrome P-450 Enzymes Commonly Involved in Psychotropic Drug Metabolism (Adapted from Keltner & Folks, 2005; Stahl, 2013)Cytochrome P-450 Enzymes Commonly Involved in Psychotropic Drug Metabolism (Adapted from Keltner & Folks, 2005; Stahl, 2013)Cytochrome P-450 Enzymes Commonly Involved in Psychotropic Drug Metabolism (Adapted from Keltner & Folks, 2005; Stahl, 2013)

Table A:

Cytochrome P-450 Enzymes Commonly Involved in Psychotropic Drug Metabolism (Adapted from Keltner & Folks, 2005; Stahl, 2013)

Individuals differ in their genetic expression of the CYP450 enzymes. Polymorphism or mutation of the enzymes may result in defective alleles to copy specific CYP450 enzymes resulting in variable responses to drugs. Genetic polymorphism results in slower metabolism (poor metabolizers) or more rapid metabolism (ultra-rapid metabolizers) of drugs. Persons who lack a specific CYP450 enzyme (poor metabolizers) will experience the effects of a drug that is a substrate of that enzyme to a greater extent at a lower dosage, including the side effects of that drug. Conversely, persons who are ultra-rapid metabolizers may seem to not be affected by a drug in ordinary doses and require a much higher dosage to achieve the same benefits as intermediate metabolizers (McDonnell & Dang, 2013). Curiously, however, both poor metabolizers and ultra-metabolizers may experience toxicity to drugs that have active metabolites of the prodrug (e.g., fluoxetine, norfluoxetine). Geno-typing has shed some light on CYP450 polymorphism and can help prescribers make clinical decisions when faced with clients who respond idiosyncratically.

Ethnicity and race play a role in biological response, as ethnopharmacological research has identified genetic polymorphism. For example, approximately 5% to 14% of Caucasian, 0.5% to 5% of African, and 0% to 1% of Asian, Pacific Islander individuals have reduced or nonfunctional CYP 2D6 alleles (Warren, 2013; Zhou, Liu, & Chowbay, 2009). In contrast 3% to 5% of Caucasian, 12% to 23% of Asian, and 38% to 79% of Polynesian individuals lack CYP 2C19 enzymes contributing to significant risk of toxicity to drugs metabolized by these enzymes and experience increased side effects at low dosages (Choi et al., 2014). Without considering polymorphism of CYP450, persons taking dopamine antagonists and/or serotonin dopamine antagonists may be at greater risk for tardive dyskinesia and receive excessively high doses even though the dose may be in therapeutic range for someone who is an extensive metabolizer.

The CYP450 system also influences interactions with other drugs taken concurrently and foods consumed. As many people who have mental disorders are also being treated for medical problems, they are likely to be taking medications in addition to psychotropic drugs. For example, protein pump inhibitors (e.g., omeprazole) may be prescribed for gastroesophageal reflux disease that inhibit 3A4 and induce 2C19, thereby interfering with the metabolism of several serotonin reuptake inhibitors (SRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and serotonin dopamine antagonists (SDAs) and hastening the breakdown of other SRIs, tricyclic antidepressants (TCAs), and SDAs (Table A). Cigarette smoking, charcoal-broiled foods, and certain cruciferous vegetables (e.g., brussels sprouts, broccoli, cabbage) can induce 1A2, which is the substrate for medications including duloxetine, clozapine, olanzapine, and imipramine. When people are taking these drugs and consuming these foods and/or smoking cigarettes, they require higher doses of the medication or experience a decrease in serum levels. Smoking cessation, while commendable, needs to take into consideration changing dosages of medication as well. Even innocuous grapefruit juice inhibits 3A4 and will raise the dose response to many psychotropic medications.

In addition to pharmacokinetic effects, combining different medications introduces potential pharmacodynamic effects resulting in drug–drug interactions. Prescribers may deliberately introduce these interactions as a way to improve response when reaching maximum dosage of a drug with continued symptoms. This is commonly the rationale for adding a third-generation antipsychotic to a regimen that already includes a second-generation antipsychotic to target additional neuronal activity. For example, aripiprazole has a moderate binding for dopamine 2 (D2), dopamine 3 (D3), and serotonin 5HT7 but less for histamine 1, serotonin 5HT2A, 5HT2C, 5HT3, or 5HT1B. When combined with olanzapine, which has a higher 5HT2A, lower D2 and D3, and higher histamine 1, there may be improved cognitive functioning and less negative symptoms with some sedation (Stahl, 2013). Similarly, aripiprazole, brexpiprazole, and cariprazine may be combined with SRIs and SNRIs in individuals with treatment-resistant depression or bipolar depression because different neurotransmitters are targeted by the different classes of medications (Thase, 2013). Aripiprazole, brexpiprazole, and cariprazine have minimal and brief D2 and D3 binding in addition to greater binding at 5HT2B, 5HT1A, and 5HT7 and lesser binding at 5HT1D and 5HT2A, which likely will improve depressive symptoms in conjunction with SRIs or SNRIs (Stahl, 2013). Polypharmacy, however, also increases the risk for adverse side effects including metabolic syndrome, extrapyramidal symptoms, and serotonin syndrome. These adverse side effects may be particularly dangerous in children and older clients (Mojtabai & Olfson, 2010; Piña, Di Palo, & Ventura, 2018).

Common Side Effects and Adverse Events Associated with Psychotropic Medications

Any medication will have some side (i.e., unwanted) effects; however, adverse effects introduce potentially dangerous outcomes. Prescribers are responsible for informing clients of common side effects, the estimated likelihood of these effects, and some ways of managing side effects while waiting for them to subside and therapeutic effects of the medication to begin. Adverse effects require more attention as well as informing clients of their possibility and what to do if they arise. Some common side effects that clients are especially concerned about include weight changes, sexual dysfunction, and cognitive effects and are the most common reasons reported for not taking medications as prescribed (Ashton et al., 2005; Chapman & Horne, 2013). Weight gain is usually associated with histamine blockade (Hasnain & Vieweg, 2013), and sexual dysfunction is associated with blockade of 5HT2 and D2 effect on the tuberoinfundibular pathway (Osis & Bishop, 2010). Cognitive blunting and slowing is commonly associated with hypodopaminergic activity in the prefrontal cortex (Baune, Brignone, & Larsen, 2018). Confounding these three side effects is that depression can also be manifested by weight changes, sexual dysfunction, and cognitive impairment. The challenge to clinicians is making a thorough assessment of prodromal symptoms prior to introduction of medication and how medications may add to these symptoms.

Pharmacies are required to provide consumers with a description of common side effects of medications that are dispensed. In addition, consumers can view medication drug inserts regarding details of side effects and adverse events, including the percentage of occurrence in drug trials. Informing consumers of side effects may influence some to experience them, whereas others may find it helpful to know the possibility of occurrence. Prescribers are also required to fully inform clients of the benefits and detriments of treatments in helping clients decide on the course of action. Prescribers also need to provide clients with means of managing side effects, such as using sugarless gum to tolerate dry mouth, taking sedating medications at bedtime, and taking medication with food to help with nausea. Side effects commonly occur at the initiation of treatment and wane with time; however, these effects may be discouraging to clients who experience delays in therapeutic effects with most psychotropic medications.

The most detrimental adverse events associated with psychotropic medications include extrapyramidal symptoms and tardive dyskinesia, neuroleptic malignant syndrome, serotonin syndrome, metabolic syndrome, and Stevens-Johnson syndrome. These are all rare or unusual events that can be prevented with due caution.

Extrapyramidal Symptoms and Tardive Dyskinesia

Extrapyramidal symptoms (EPS) are associated with prolonged blockade of D2 in the substantia nigra (Janicak, Marder, & Pavuluri, 2011; Stanilla & Simpson, 2017). EPS are manifested by acute dystonic reactions, akathisia, pseudoparkinsonism, and tardive dyskinesia and dystonia. Dystonic reactions occur early in treatment, within 4 days of initiation and up to 10 days after, and akathisia may occur anytime but is usually early in treatment, whereas pseudoparkinsonian symptoms of bradykinesia, muscle rigidity, and resting tremors occur after a few weeks. Tardive dyskinesia and dystonia are long-term effects that begin months to years after initiation and may continue even after discontinuation of medication (Stanilla & Simpson, 2017). The best treatment of EPS and tardive dyskinesia and dystonia is prevention by avoiding prolonged D2 blockade with first-generation dopamine antagonists; however, when prevention is not possible, concurrent use of beta blockers, anticholinergic medications (e.g., benztropine, trihexyphenidyl) or anti-histamines (e.g., diphenydramine for akathisia) for akinesia, and antiparkinson dopaminergics (e.g., amantadine) is recommended. An alternative would be to switch to second-generation anti-psychotics that have a lower duration of dopamine blockage such as clozapine, iloperidone, and lurasidone (Stanilla & Simpson, 2017).

Malignant Neuroleptic Syndrome

Malignant neuroleptic syndrome (MNS) is acute thermodysregulation and neuromotor loss of control that is fatal 21% of the time if untreated (Janicak et al., 2011). MNS is manifested by fever greater than 104°F, severe muscle rigidity, altered sensorium, and autonomic changes including fluctuating blood pressure, tachypnea, and diaphoresis. MNS can occur with any dopamine blocking agents and antiparkinsonian agents, including second-generation antipsychotics, and can occur anytime during treatment with these medications. It is best treated early with dopamine agonists such as dantrolene, bromocriptine, and amantadine. Symptomatic management is also essential, including reducing fever and mechanical ventilation (Janicak et al., 2011).

Serotonin Syndrome

Serotonin syndrome is a rare and possibly underrecognized condition due to serotonin toxicity. It is similar to MNS in that it manifests as a combination of neuromuscular, autonomic, and sensorium alterations including myoclonus, fever, agitation, confusion, cardiovascular collapse, and death (Stahl, 2013). In milder presentations, clients may have muscle rigidity, dilated pupils, headache, and disorientation. The cause is excessive serotonergic medications, sometimes unintentional, because of combining medications such as SRIs, tramadol, or monoamine oxidase inhibitors. Treatment requires immediate discontinuation of the serotonergic agents, medically supportive crisis intervention, and possibly benzodiazepines in the short term (Garlow, Weigel, & D'Orio, 2018). After remission of symptoms, the serotonergic agent can be carefully reintroduced with avoidance of drug–drug interactions and additive effects. Clients need to be fully informed of the effects of combining serotonin agents and must tell their providers of all medications currently prescribed.

Stevens-Johnson Syndrome

Stevens-Johnson syndrome (SJS) is an unusual skin disease that occurs as a reaction to medication. It is manifested by a target-like skin rash with eventual blistering and desquamation, flu-like symptoms of fever, sore throat, and muscle aches. Blistering can affect mucous membranes of the mouth, tongue, nose, and eyes. The incidence of SJS is between 0.4 and 1.2 per 1 million people with an estimated mortality rate of 1% to 30% depending on the population (Yang et al., 2016). SJS is usually associated with lamotrigine but can also occur with other anti-epileptic, nonsteroidal anti-inflammatory, and anti-gout drugs. The HLA-B12 gene is likely implicated in the development of the syndrome (Deng et al., 2018; Zhang et al., 2019), and genetic testing may assist clinicians in averting the development of this adverse reaction. SJS is best treated with early recognition, immediate discontinuation of the offending drugs, symptomatic treatment to prevent complications, and careful monitoring. As it is likely to occur within the first few days to weeks of initiation of the offending drug, slow and gradual tapering of medication over 6 weeks' time is necessary for prevention. Similarly, slow tapering off the medication is necessary and if there is abrupt discontinuation, the client needs to be monitored for occurrence over several weeks. It is possible to re-challenge on the medication after several months of abstinence with careful and slow tapering.

Other Adverse Reactions

Another adverse reaction with psychotropic drugs is QT prolongation with several SRIs, ziprasidone, amitriptyline, and buspirone (Stock et al., 2018). Risk increases with age and number of drugs prescribed. Prior to prescribing these medications, prescribers should obtain an electrocardiogram (EKG) with QT correction and repeat the EKG after 1 month of taking the prescription and then annually as long as the client takes the medication.

Summary and Clinical Recommendations

Side effects occur with all medications and are usually mild and time limited. Adverse effects are more serious and require careful preliminary assessment, ongoing monitoring, and immediate treatment when encountered. Prior to prescribing any medication, prescribers must fully explain the potential for adverse and side effects, how to manage them, and when to seek medical attention. This information needs to be provided verbally and in writing. Often clients will have questions and may resist necessary pharmacological treatments because of the possible adverse effects, and prescribers need to provide careful and nonjudgmental consultation about the risks and benefits of treatment. It is also beneficial to establish a supportive therapeutic alliance with clients and family members and return to previously resisted treatments as needed. Internet information is readily available and easily misunderstood by consumers; it is useful to encourage clients to discuss their independent information search and provide neutral explanations based on evidence in the research literature.

Some clinical recommendations for clinicians to consider in making treatment decisions include:

  • In the initial assessment, inquire about weight changes over the course of the mental disorder (i.e., decreased appetite, weight gain/loss with early depressive symptoms) as well as libido changes and cognitive variations. This information helps clarify effects related to the disorder and those related to drug side effects.
  • Consider the client's race and ethnicity when evaluating responses to specific medications (i.e., what CYP450 enzymes are involved and might this client have a polymorphism of any of these enzymes?).
  • Seek physical and laboratory assessment, including EKG, weight, and vital signs prior to starting medication to establish a baseline for reference. Repeat necessary labs and vital signs at least after 1 month of new drug treatment or more often as necessary by client presentation.
  • Periodically ask questions specific to possible side and adverse effects, especially about sensitive topics such as libido and sexual function.
  • Collaborate fully with clients and their family members regarding changes in dosage, dosing, and discontinuation of medication, even if against the clinician's better judgment.

Clients change their medications and discontinue medications due to their experience with the medication and sense of alliance with their provider. They may conceal their nonadherence to medication if they believe the provider will disapprove. Ultimately, the effectiveness of pharmacotherapy depends on the client actually taking the medication.

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Cytochrome P-450 Enzymes Commonly Involved in Psychotropic Drug Metabolism (Adapted from Keltner & Folks, 2005; Stahl, 2013)

Enzyme Substrates Inducers Inhibitors
2D6 Antidepressants: Secondary tricyclics, venlafaxine, duloxetine fluoxetine, paroxetine, trazodone, mirtazapine, atomoxetine Antipsychotics: thioridazine, risperidone, perphenazine, haloperidol, clozapine, aripiprazole, iloperidone Beta-Blockers: propranolol, metoprolol, timolol Analgesics: oxycodone, dextromethorphan, codeine No known inducers Paroxetine, fluoxetine, fluphenazine, sertraline (>100 mg), duloxetine, bupropion, asenapine haloperidol, thioridazine, amitriptyline, clomipramine, desipramine, norfluoxetine, norduloxetine
1A2 Acetaminophen, caffeine, theophylline, amitriptyline, imipramine, clomipramine, duloxetine, clozapine, fluvoxamine, haloperidol, mirtazapine, olanzapine, asenapine, zotepine, phenothiazines, verapamil, phenacetin, estrogen Cigarettes, omeprazole, charcoal-broiled foods, some cruciferous vegetables, cabbage Fluvoxamine, fluoxetine and paroxetine at high doses, ciprofloxacin, beta-estradiol
3A3/4 Antidepressants: amitriptyline, imipramine, clomipramine, sertraline, mirtazapine, nefazodone, fluoxetine, bupropion Benzodiazepines: midazolam, alprazolam, diazepam, triazolam Anticonvulsants: carbamazepine, valproate, lamotrigine, ethosuximide Antipsychotics: lurasidone, iloperidone, aripiprazole, sertindole, quetiapine, clozapine Other: cyclosporine, dexamethasone, codeine, pimozide, zolpidem, buspirone, prednisone, alfentanil, lovastatin, pravastatin, fluvastatin, atorvastatin, oral contraceptives, testosterone, diltiazem, dextromethorphan, codeine Steroids, rifampin, carbamazepine, phenobarbital, phenytoin, some reverse transcriptase inhibitors Nefazodone, fluvoxamine, sertraline (>100 mg), cimetidine, diltiazem, verapamil, ketoconazole, erythromycin, fluoxetine, paroxetine, protease inhibitors, grapefruit juice
2C19 Aripiprazole, citalopram, clomipramine, clozapine, desipramine, diazepam, diphenhydramine, doxepin, escitalopram, fluoxetine, imipramine, lansoprazole, methadone, moclobemide, olanzapine, omeprazole, pantoprazole, phenobarbital, phenytoin, propranolol, sertraline, R-warfarin Barbiturates, carbamazepine, phenytoin, primidone, St. John's wort Chloramphenicol, cimetidine, clopidogrel, efavirenz, esomeprazole, fluconazole, isoniazid, modafinil, moclobemide, omeprazole, oxcarbazepine
Authors

Dr. Limandri is Professor Emerita, Linfield College, School of Nursing, McMinnville, Oregon.

The author has disclosed no potential conflicts of interest, financial or otherwise.

Address correspondence to Barbara J. Limandri, PhD, PMHNP, BC, Professor Emerita, 9136 SW 36th Avenue, Portland, OR 97219; e-mail: limandribj@gmail.com.

10.3928/02793695-20200117-02

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