Walker C. Brown, PharmD Candidate

SS, a 63-year-old woman, is complaining of involuntary and repetitive movements in her arms and legs, along with facial grimacing. She is concerned that she has Parkinson disease, which runs in her family. SS has scheduled an appointment to see a neurologist next week but is asking for a consult in the meantime to see if any of her medications may be causing these symptoms. She gives you the following medication list: atorvastatin for cholesterol; lisinopril for kidney protection; metformin for type 2 diabetes (T2D); metoclopramide for diabetic gastroparesis; sertraline for depression; and Toujeo (insulin glargine) for T2D. 

SS's symptoms sound consistent with dopamine (D

) antagonism. Based on her medication list, metoclopramide seems to be the most probable cause. As a D

 antagonist, this agent can cause tardive dyskinesia (TD), a potentially irreversible disorder characterized by involuntary movements of the extremities, face, or tongue, and it carries a black box warning for this adverse effect. The risk of developing TD increases with duration of treatment and total cumulative dose. Risk is further increased in the elderly, patients with diabetes, and women. SS has these risk factors, and her symptoms correlate with TD. She should reach out to her provider immediately to discuss discontinuation of metoclopramide. Her symptoms should remit within several weeks to months after metoclopramide is withdrawn.

CJ is a 20-year-old man with a history of treatment refractory schizophrenia. He recently was initiated on clozapine at 25 mg, and his dose was titrated to 200 mg over 3 weeks. He is presenting 1 month later with low-grade fever (temperature, 99.9°F), chest tightness, and congestion. Because of his symptoms, the health care team agrees to order an electrocardiogram, which shows that CJ is experiencing sinus tachycardia. Furthermore, when his cardiac enzymes were tested, his troponin level was 900 ng/mL. The team stopped CJ's clozapine, which led to subsequent symptom resolution. 

CJ likely experienced clozapine-induced myocarditis. Such symptoms can occur within the first 3 months of treatment, according to its black box warnings; close monitoring is recommended in the early stages of clozapine initiation, as it is often difficult to diagnose. Other causes of myocarditis should be ruled out before attributing it solely to clozapine. Using the Naranjo scale, it is "probable" that clozapine caused the symptoms. The reaction followed a reasonable temporal sequence after a drug, followed a recognized response to the suspected drug, was confirmed by withdrawal but not by exposure to the drug, and could not be reasonably explained by the known characteristics of the patient's clinical state. Clozapine should never be rechallenged after this condition occurs.

 is an associate clinical professor at the University of Connecticut in Storrs.

 are PharmD candidates at Massachusetts College of Pharmacy and Health Sciences in Boston.

Articles

What could be causing this patient's involuntary, repetitive movements in her arms and legs?

Case Studies (January 2020)

AB is a 24-year-old woman who goes to her primary care provider (PCP) for a follow-up on a hospitalization 2 days ago. AB says she started several new medications during her hospitalization but that she got confused when she went home and accidentally took several of the same pills, although she can't remember which ones. Her PCP is helping the pharmacist identify the medication. AB appears agitated and restless. During her physical exam, her blood pressure is 172/99 mm Hg, her heart rate is 102 beats per minute, and her temperature is 101ºF. She is diaphoretic and hyperreflexive and has myoclonus. 

Which medication or medication class did AB likely take too much of?

The patient is hypertensive, hyperthermic, and tachycardic. These symptoms, in combination with agitation, clonus, confusion, diaphoresis, hyperreflexia, and restlessness suggest serotonin syndrome. Several medications to suspect include selective norepinephrine reuptake inhibitors (eg, duloxetine and venlafaxine), selective serotonin reuptake inhibitors (eg, citalopram and sertraline), and tricyclic antidepressants (eg, amitriptyline and nortriptyline). The pharmacist should review the discharge summary or obtain the medication records from the patient's hospitalization to confirm this suspicion.

TJ is a 75-year-old woman with a history of osteoporosis and at the hospital for preop testing. She is scheduled for right hip replacement surgery. TJ's surgical history includes a left hip replacement 2 years earlier. The pharmacist on duty is processing TJ's medications for the procedure, and a system-generated alert pops up stating that TJ requires an alternative for heparin because she experienced heparin-induced thrombocytopenia type 2 reaction (HIT-II) during her last hip replacement. 

Should the pharmacist contact the prescriber for an alternative anticoagulant?

HIT-II is not considered a true allergy. It is an adverse effect of and an immune-mediated reaction to heparin that occurs in about 0.2% of patients who have received therapeutic doses. Because antibodies form during the initial HIT episode and last only 2 to 3 months, TJ could be rechallenged with heparin, despite the availability of other options. Investigators of a recent small study found that just 1 in 20 patients experienced HIT again after reexposure to heparin.

 The pharmacist, therefore, does not necessarily have to request an alternative anticoagulant but should order a heparin-platelet factor 4 assay to detect whether the antibodies are still present prior to approving the order.

 is a PharmD candidate at Massachusetts College of Pharmacy and Health Sciences in Boston.

Warkentin TE, Sheppard JA. Serological investigation of patients with a previous history of heparin-induced thrombocytopenia who are reexposed to heparin. 

. 2014;123(16):2485-2493. doi: 10.1182/blood-2013-10-533083.

Can you figure out this medical mysteries?

Case Studies (November 2019)

YM is a 47-year-old woman who wants to fill a new prescription for dulaglutide (Trulicity). While completing a prospective drug utilization review, you identify a potential drug-related problem. YM’s medication profile shows that she takes insulin degludec (Tresiba), metformin ER, and sitagliptin (Januvia). You speak to her, and she informs you that her most recent hemoglo- bin A1c (HbA1c) was 8.4%. YM was advised by her primary-care provider (PCP) to continue her regimen and add the dulaglutide weekly to help improve her glycemic control.

What drug-related problem did the pharmacist identify?

The pharmacist identified a potential duplication in therapy involving dulaglutide, a glucagon-like peptide-1 receptor (GLP-1) agonist, and sitagliptin, a dipeptidyl-peptidase inhibitor (DPP-4). Both medications involve incretins and stimulate insulin release in a glucose-dependent manner.

“DPP-4 inhibitors and GLP-1 agonists should not be prescribed in combination,” according to the American Diabetes Association.

The pharmacist should contact YM’s PCP and explain that there is a paucity of efficacy data regarding the combination. In a small crossover study, the addition of sitagliptin to liraglutide and metformin resulted in a marginal but nonsignificant effect on glycemic control.2 Similarly, the results of another study concluded that the addition of twice-daily exenatide in combination with met- formin and sitagliptin resulted in a further 0.3% reduction in HbA1c.3 Although the safety of the combination has not been established, it is costly and unlikely to help YM achieve her goal of <7%.

Dicker D. DRP-4 inhibitors. American Diabetes Association website. 

care.diabetesjournals.org/content/34/Supplement_2/S276

Nauck MA, Kahle M, Baranov O, Deacon CF, Holst JJ. Addition of a dipeptidyl peptidase-4 inhibitor, sitagliptin, to ongoing therapy with the glucagon-like peptide-1 receptor agonist liraglutide: a randomized controlled trial in patients with type 2 diabetes. 

 2017;19(2):200-207. doi: 10.1111/dom.12802.

Violante R, Oliveira JH, Yoon KH, et al. A randomized non-inferiority study comparing the addition of exenatide twice daily to sitagliptin or switching from sitagliptin to exenatide twice daily in patients with type 2 diabetes experiencing inadequate glycaemic control on metformin and sitagliptin. 

 2012;29(11):e417-424. doi: 10.1111/j.1464-5491.2012.03624.x.

You are the on-call pharmacist at your hospital and receive a page that patient TJ is being moved to the intensive care unit (ICU). He presents to the ICU confused and has a depressed respiratory rate. Upon obtaining vital signs, TJ’s heart rate is 45 beats per minute and his blood pressure is 80/60 mm Hg. While examining his chart, you notice that he takes lisinopril 10 mg daily, oxycodone 5 mg as needed for pain, propranolol 80 mg twice daily, and zolpidem 10 mg as needed for sleep. TJ’s wife tells the medical team that he has been extremely depressed lately and that she found a suicide note on his desk. The medical team suspects a drug overdose. The team starts fluids and gives a dose of epinephrine, with no response on vitals.

What medication has TJ likely overdosed on, and how can his care be managed?

TJ most likely overdosed on propranolol. Beta-blocker toxicity can present in much the same way as an opioid overdose. Shortness of breath or wheezing accompanied by a decrease in the respiratory rate can be signs of respiratory depression, and confusion and dizziness indicate central nervous system depression. TJ’s vitals did not respond to epinephrine because it is a selective beta-agonist that cannot overcome the toxicity in beta-blocker overdose. The preferred agent to treat beta-blocker toxicity is glucagon. Glucagon increases cyclic adenosine monophosphate, which stimulates myocardial contraction and increases the heart rate independent of the adrenergic pathway. TJ should receive a loading dose followed by a continuous infusion titrated to response. He must then be monitored for hyperglycemia, hypokalemia, and nausea and vomiting.

 Boyd R. Ghosh A. Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Glucagon for the treatment of symptomatic beta-blocker overdose. 

 2003;20(3):266-267. doi:10.1136/emj.20.3.266.

Lucchesi BR. Cardiac actions of glucagon. 

This month's case studies include a potential drug-related problem and a possible overdose.