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Evidence-Based Reviews


How to prevent adverse drug events

Enhanced awareness, vigilant monitoring can reduce morbidity and mortality

Vol. 10, No. 07 / July 2011

Dr. Yu: How to assess for possible drug-drug interactions

Medication errors due to system-, provider-, or patient-related factors contribute significantly to increased costs, adverse drug events (ADEs), and morbidity and mortality.1 One study found >60% of ADEs that led to hospitalization could have been prevented by strategies such as adequate monitoring or appropriate prescribing.2 Psychiatrists have an opportunity to reduce rates of ADEs; however, the possibility of disease symptoms overlapping with these adverse events is 1 of many obstacles prescribing clinicians face.1 Prescribers also must contend with adverse effects of polypharmacy, which are common among psychiatric patients. Patient-related factors of concern include:

  • seeing multiple prescribers
  • medication nonadherence
  • failure to communicate use of herbal or over-the-counter products
  • lack of insight
  • comorbid medical and psychiatric diagnoses, such as dementia.1

This article highlights potential ADEs and major medication safety concerns that may contribute to morbidity and mortality among patients taking psychotropics. Although many factors are beyond the prescribing clinician’s control—such as medication dispensing and administration errors—psychiatrists can substantially reduce ADEs. We will cover potential adverse events associated with key medications or medication classes, drug interactions with potentially devastating consequences, and strategies to minimize risks of ADEs, including enhanced awareness and monitoring (Table 1).

Table 1

How to avoid ADEs with psychotropics

Establish a collaborative practice among physicians, pharmacists, nurses, and social workers to enhance patient care and reduce the risk of medication errors and negative outcomes

Educate patients to increase their understanding of psychiatric diseases and medications and increase compliance with therapy. This may lead the patient to self-monitor drug efficacy and adverse effects

Be aware of psychotropic medications’ ‘black-box’ warnings that guide their safe use

Pay particular attention to drugs with a narrow therapeutic index, such as lithium and tricyclic antidepressants, which have small safety margins and are lethal in overdose

Avoid using 1 drug to treat the side effects of another. Minimizing polypharmacy can reduce medication errors, DDIs, and ADEs

Remain vigilant for DDIs, which can be serious and life-threatening. Examples include sudden cardiac death from additive QTc prolongation effects and NMS. Early detection of NMS and discontinuing the offending agent(s) can help prevent patient morbidity and mortality

Stay up-to-date on literature and drug warnings to employ best practices and avoid potentially serious adverse and/or lethal outcomes

Encourage patients to disclose any prescription drugs, over-the-counter medications, and herbal therapies they are taking

Develop strategies to prevent ADEs, such as personal formularies, suicide assessments, prescribing limited quantities, ‘eyes on’ medication administration, therapeutic drug monitoring, utilizing databases and resources for drug information, and patient education

ADEs: adverse drug events; DDIs: drug-drug interactions;
NMS: neuroleptic malignant syndrome

Prescription drug overdose

Each year, unintentional drug overdoses account for >20,000 deaths in the United States.3 Prescription medications, particularly opioid analgesics, have contributed to the doubling of overdose mortality rates in recent years. A recent study reported that nearly 50% of unintentional drug overdose deaths were associated with psychotropics and one-third of these deaths were associated with benzodiazepines, many of which were not prescribed to the individual.4

The risk of mortality from intentional drug overdose also must be assessed. Tricyclic antidepressants (TCAs) are a particularly lethal class of medications in suicide attempts and may result in arrhythmias, coma, seizures, respiratory failure, and death.5 Venlafaxine and mirtazapine are associated with greater risk of death and toxicity in overdose, respectively, than selective serotonin reuptake inhibitors (SSRIs).6 Lithium toxicity in overdose may lead to bradycardia, seizure, coma, hyperventilation, serotonin syndrome, respiratory failure, or death.5 The risk of death with lithium or benzodiazepine monotherapy is low when these agents are taken as prescribed. However, prescribers must exercise caution when these agents are used in combination. Interactions involving drugs with a narrow therapeutic index—such as lithium and TCAs—are more likely to be clinically significant because small increases in drug concentration can lead to serious adverse effects or death. See Related Resources for a review article on appropriate use and monitoring of lithium.

Drug-drug interactions

Many Americans take multiple prescription and nonprescription drugs, and psychiatric patients are more likely than other individuals to have more complex medication regimens.7 This can result in polypharmacy and drug-drug interactions (DDIs), which can lead to undesired medication effects and serious, potentially fatal ADEs.

Pharmacokinetic interactions typically affect drug concentrations and occur when 1 drug interferes with the absorption, distribution, metabolism, or excretion of another drug. Many common pharmacokinetic interactions involve the liver cytochrome P450 (CYP) system, which is responsible for metabolizing many medications.8 DDIs can occur when CYP enzymes are modified by inhibitors or inducers, which can decrease or increase drug clearance, respectively. Table 2 5,7,9 provides examples of common CYP450 substrates, inhibitors, and inducers. Polymorphisms in the pharmacogenetics of CYP450 also can affect overall drug clearance and the impact of DDIs.8

Pharmacodynamic interactions are caused by additive or competing effects of multiple drugs. The most serious of these involve medications that increase a patient’s risk of serotonin syndrome or neuroleptic malignant syndrome (NMS); both are medical emergencies that require immediate hospitalization.

Although any medication with serotonergic activity can induce serotonin syndrome, combinations of serotonergic drugs in particular are associated with increased risk.10 Serotonin syndrome is characterized by hyperthermia, altered muscle tone, altered mental status, and autonomic instability; rhabdomyolysis and disseminated intravascular coagulation are potential lethal complications.10 A high index of suspicion can help clinicians rapidly detect serotonin syndrome, discontinue offending agents, and initiate supportive treatments.

NMS is a life-threatening complication of antipsychotics characterized by fever, delirium, muscle rigidity, autonomic instability, and abnormal laboratory findings that include elevated white blood count and increased creatinine kinase from muscle injury. In early stages, NMS may be mistaken for extrapyramidal symptoms. Although NMS can occur with any antipsychotic as monotherapy, additive antidopaminergic effects increase the risk. Patients with a compromised CNS as a result of mental retardation, traumatic brain injury, or metabolic abnormalities also are at increased risk of developing NMS.11

Other pharmacodynamic interactions involve medications that may have additive effects on prolonging QTc intervals. For example, TCAs are pro-arrhythmic and have quinidine-like effects, which can cause cardiac conduction abnormalities and prolonged PR and QTc intervals.12 Employ routine ECG monitoring when prescribing multiple medications known to cause QTc prolongation, such as TCAs (Table 3).13,14 The Arizona Center for Education and Research on Therapeutics (www.azcert.org) provides a searchable list of QT-prolonging drugs (see Related Resources).

Medications also can interact with food, disease states, and herbal supplements. Alcohol interacts with many CNS-active medications, including many psychotropics. Patients taking benzodiazepines may experience oversedation and respiratory depression from alcohol’s additive sedating effects.5 Advise patients to limit their alcohol intake while taking CNS-depressing psychotropics such as benzodiazepines, antipsychotics, and some antidepressants. Monoamine oxidase inhibitors (MAOIs) and tyramine-containing food—such as cheese, beer, preserved meat, and soy sauce—can lead to a dangerous hypertensive crisis that requires immediate medical intervention to prevent life-threatening complications.5 Hypertensive crisis may be more significant in patients who have pre-existing hypertension. Finally, herbal supplements also can interact with medications. Patients who take St. John’s wort for depressive symptoms might not realize that it can reduce the efficacy of other drugs or increase their risk of serotonin syndrome.9

Table 2

Cytochrome P450 substrates, inhibitors, and inducers

 

3A4

2D6

2C9

2C19

1A2

Substrates

Carbamazepine
Citalopram
Fluoxetine
Haloperidol
Mirtazapine
Oxcarbazepine
Quetiapine
Sertraline
Ziprasidone

Aripiprazole
Citalopram
Duloxetine
Fluoxetine
Haloperidol
Mirtazapine
Paroxetine
Risperidone
Sertraline
Venlafaxine
TCAs

Amitriptyline
Carbamazepine
Sertraline
Valproic acid

Citalopram
Clomipramine
Sertraline
Valproic acid

Carbamazepine
Clozapine
Olanzapine

Inhibitors

Amiodarone
Aprepitant
Azole antifungals
Carbamazepine
Cimetidine
Diltiazem
Erythromycin
Fluoxetine (norfloxetine)
Grapefruit juice
Imatinib
Paroxetine
Ritonavir
Sertraline
Verapamil

Amiodarone
Bupropion
Cimetidine
Duloxetine
Fluoxetine
Methadone
Paroxetine
Ritonavir
Sertraline

Amiodarone
Fluconazole
Isoniazid
Sertraline
Trimethoprim-sulfamethoxazole
Valproic acid

Cimetidine
Fluoxetine
Ketoconazole
Omeprazole
Sertraline
Valproic acid

Amiodarone
Cimetidine
Fluoroquinolones

Inducers

Carbamazepine
Phenobarbital
Phenytoin
Rifampin
St. John’s wort

Rifampin

Phenobarbital
Rifampin

Carbamazepine
Rifampin

Nafcillin
Phenobarbital
Rifampin
Smoking

TCAs: tricyclic antidepressants
Source: References 5,7,9

Table 3

Psychotropics associated with QT prolongation

Class

Agents

Antidepressants

Mirtazapine, SNRIs (desvenlafaxine, venlafaxine), SSRIs (citalopram, fluoxetine, paroxetine, sertraline), TCAs (amitriptyline, clomipramine, desipramine, doxepin, imipramine, protriptyline, trimipramine), trazodone

Typical antipsychotics

Chlorpromazine, fluphenazine, haloperidol, perphenazine, thioridazine, trifluoperazine

Atypical antipsychotics

Aripiprazole, asenapine, clozapine, iloperidone, paliperidone, quetiapine, risperidone, ziprasidone

Mood stabilizers

Lithium

Miscellaneous agents

Amantadine, atomoxetine, chloral hydrate, diphenhydramine, galantamine

Stimulants

Amphetamine/dextroamphetamine products, methylphenidate/dexmethylphenidate

SNRIs: serotonin-norepinephrine reuptake inhibitors; SSRIs: selective serotonin reuptake inhibitors; TCAs: tricyclic antidepressants
Source: Adapted from references 13,14

Black-box warnings

“Black-box” warnings issued by the FDA are included in the package insert to highlight a medication’s risks of dangerous and potentially lethal adverse effects. Table 4 highlights current black-box warnings for various psychotropics.5,14-16

Antidepressants and suicide. All medications with antidepressant indications carry a black-box warning for risk of suicidal ideation and behavior in children, adolescents, and young adults during the early months of medication therapy. This includes not only SSRIs and serotonin-norepinephrine reuptake inhibitors, but also anticonvulsants and atypical antipsychotics indicated for treating mood disorders. Monitor young patients carefully and advise family members to alert clinicians of any signs of suicidality or unusual behavior.

Lamotrigine and aseptic meningitis. Aseptic meningitis—inflammation of the meninges that is not caused by bacteria—is a rare but serious adverse effect of lamotrigine. Symptoms include headache, fever, stiff neck, nausea and vomiting, delirium, rash, and sensitivity to light.5 Forty cases of aseptic meningitis in children and adults were reported over 15 years, representing <.01% of all lamotrigine prescriptions.5 Most of these patients required hospitalization, but symptoms resolved after lamotrigine was discontinued. Prompt identification and management of aseptic meningitis are necessary to prevent permanent brain damage and death. Other complications of aseptic meningitis include long-term neurologic sequelae such as cognitive impairment, seizure disorders, and behavioral disturbances.

Table 4

Which psychotropics carry ‘black-box’ warnings?

Warning

Class or medication affected

Comments

Suicidality

Antidepressants Antipsychotics indicated for mood disorders Anticonvulsants

See ‘Black-box warnings

Serious, life-threatening rashes such as Stevens-Johnson syndrome or toxic epidermal necrolysis

Lamotrigine Carbamazepine

Lamotrigine’s risk of severe dermatologic reactions necessitates slow titration during drug initiation Carbamazepine warning includes a recommendation for genetic screening in Asian patients because Stevens-Johnson syndrome is associated with the HLA-B*1502 allele found primarily in the Asian population

Increased mortality in elderly patients with dementia-related psychosis

Antipsychotics

A study of >10,000 geriatric patients with dementia showed mortality rates of 22.6% to 29.1% among those who took antipsychotics compared with 14.6% for patients taking other psychiatric medications. When antipsychotics are used in older adults, well-documented informed consent from the patient or substitute decision-maker is required

Other effects

Clozapine

Agranulocytosis occurs in 1% to 2% of clozapine patients, necessitating WBC/ANC monitoring Clozapine-induced myocarditis, generally accompanied by peripheral eosinophilia, usually occurs within the first 2 months of treatment, and can result in significant mortality from resultant cardiomyopathy. Early warning signs of fever, fatigue, and tachycardia are easily mistaken for the more benign effects of clozapine titration Seizures are more likely with higher doses. Cautious use is advised with patients who have an underlying seizure disorder Other cardiovascular and respiratory effects: Hypotension has been associated with rapid initial titration. Cardiac and respiratory arrest and circulatory collapse have occurred rarely. Respiratory complications are more likely when clozapine is used in combination with benzodiazepines

ANC: absolute neutrophil count; WBC: white blood cell
Source: References 5,14-16

Other complications

Hematologic effects. All classes of psychotropics carry a risk (1 to 2 cases per year per 100,00 patients) of serious hematologic complications, including neutropenia, agranulocytosis, eosinophilia, thrombocytopenia, purpura, and anemia.17 Agranulocytosis has been associated most commonly with clozapine, carbamazepine, and typical antipsychotics.17 SSRIs, which are widely prescribed, are associated with increased risk of bruising and bleeding. Patients with bleeding or platelet disorders are at an increased risk for these complications.17

Continued...
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