Sum of the parts: a cascade of adverse effects

Case

Presentation and history

A 58-year-old man presented to the emergency department in 2023 following 3 days of vomiting and reduced oral intake, on the background of a 4-month history of nausea refractory to multiple antiemetics. He reported losing 10 kg in the past year and now weighed 65 kg. He reported no other symptoms, including fever, coryza, urinary symptoms or diarrhoea, and could not recall when his bowels last opened.

Significant medical history included bipolar affective disorder, type 2 diabetes with microvascular complications, moderate cervical canal stenosis, spinal osteoarthritis, drug-induced parkinsonism and chronic hepatitis B (Table 1). The patient was an ex-smoker.

Table 1 Patient’s medical history and medications at presentation

Medical condition	Current medications	Prescriber	When started
chronic nausea	metoclopramide 10 mg orally in the morning prochlorperazine 5 mg orally up to 3 times daily ondansetron 4 mg orally up to 3 times daily	general practitioner	metoclopramide since 2022; prochlorperazine and ondansetron since 2023
pre-exposure prophylaxis for HIV	tenofovir+emtricitabine 300+200 mg in the morning	general practitioner	2023 (7 months before current presentation)
constipation	lactulose 10 mL orally twice daily as required	general practitioner	2022
chronic hepatitis B	entecavir 0.5 mg orally in the evening	hepatologist	2022
insomnia	temazepam 10 mg at night and 10 mg as required	general practitioner	2022
drug-induced parkinsonism	levodopa+benserazide 100+25 mg orally 3 times daily	neurologist	2021
bipolar affective disorder	quetiapine (modified release) 50 mg orally at night vortioxetine 30 mg orally in the morning	psychiatrist	quetiapine long term (since at least 2018); vortioxetine since 2021
type 2 diabetes	linagliptin+metformin 2.5 mg+1 g orally twice daily dapagliflozin 10 mg orally in the morning insulin glargine 30 units subcutaneously in the evening	general practitioner	long term (since at least 2018)
chronic pain secondary to moderate cervical canal stenosis and spinal osteoarthritis	paracetamol (modified release) 1.33 g orally twice daily as required	pain specialist/general practitioner	long term (since at least 2018)
anxiety symptoms	diazepam 5 mg orally at night	general practitioner	long term (since at least 2018)
chronic obstructive pulmonary disease	tiotropium 2.5 micrograms by inhalation in the morning budesonide+formoterol 400+12 micrograms inhaled twice daily salbutamol 200 micrograms inhaled up to 4 times daily as required	general practitioner	long term (since at least 2018)
hypertension	telmisartan 40 mg orally in the morning	general practitioner	long term (since at least 2018)
hypercholesterolaemia	atorvastatin 80 mg orally at night fenofibrate 145 mg orally in the morning	general practitioner	long term (since at least 2018)
thyroid replacement	levothyroxine 100 micrograms daily Monday to Friday, and 150 micrograms daily Saturday and Sunday	general practitioner	long term (since at least 2018)

On examination, he appeared to be dehydrated with a heart rate of 64 beats per minute and blood pressure of 145/80 mmHg, but no postural hypotension or tachycardia was detected. There were no abnormalities found on abdominal examination. He had a stooped posture and short-stepping gait, but no rigidity, bradykinesia or resting tremor.

The patient’s pathology results on presentation are listed in Table 2. A computed tomography (CT) scan of his abdomen and pelvis was performed as part of the workup for chronic nausea and loss of weight. It showed faecal loading distal to the descending colon.

Table 2 Patient’s pathology results at presentation

Investigation	Result	Reference range [NB1]
serum pH	7.31	7.32 to 7.43
serum bicarbonate concentration	19 mmol/L	22 to 33 mmol/L
anion gap [NB2]	13 mmol/L	4 to 13 mmol/L
capillary blood ketone concentration	1.6 mmol/L	less than 0.6 mmol/L
blood glucose concentration	3.5 mmol/L	3.0 to 7.8 mmol/L
HbA1c	48 mmol/mol (6.5%) (most recent result 12 months prior)	target less than 54 mmol/mol (7.1%)1
serum creatinine concentration	159 micromol/L (previously 115 micromol/L)	60 to 110 micromol/L
eGFR	41 mL/min (previously 60 mL/min)	more than 90 mL/min
serum phosphate concentration	0.60 mmol/L	0.75 to 1.50 mmol/L
urinary white cell count	10 x 106 cells/L	less than 10 x 106 cells/L
urinary red cell count	less than 10 x 106 cells/L	less than 10 x 106 cells/L
TSH	0.67 mIU/L (most recent result 10 weeks prior)	0.50 to 4.00 mIU/L
eGFR = estimated glomerular filtration rate; HbA1c = glycated haemoglobin; TSH = thyroid stimulating hormone NB1: Apart from HbA1c, reference ranges are taken from the health service’s laboratory reports. NB2: The anion gap is a calculated parameter; anion gap = (serum sodium + serum potassium concentrations) – (serum chloride + bicarbonate concentrations). Some laboratories do not include serum potassium concentration in the equation.2

At the time of admission his current medication list, compiled from multiple sources, included 20 regular medications and several ‘as needed’ medications (Table 1). It was challenging to determine the timeline by which the patient came to be on his current medications, but the following events were determined.

Five years prior (in 2018), the patient had been hospitalised by his psychiatrist for psychotropic medication rationalisation, with concerns about drug-induced parkinsonism. Multiple medication changes occurred between 2018 and 2022 until he was stabilised on his current psychotropic regimen of vortioxetine and quetiapine (prescribed by the psychiatrist), and diazepam and temazepam (prescribed by the patient’s general practitioner).

Between 2018 and 2020 the patient was reviewed at a neurology outpatient clinic. The neurology team felt that drug-induced parkinsonism was a more likely diagnosis than Parkinson disease, because dopaminergic uptake in the basal ganglia appeared to be relatively well preserved in a fluorodopa positron emission tomography (F-DOPA PET) scan. Nonetheless, levodopa+benserazide was started in 2020. There was a plan to reduce and cease treatment once the patient’s mood was more stable; however, treatment was ongoing at the time of the patient’s current presentation.

Around 2020 the patient was referred to a rehabilitation physician for review of reduced mobility and increasing falls. He started to use a 4-wheeled walker.

The patient’s general practitioner managed his other comorbidities, including his sexual and preventative health. Pre-exposure prophylaxis (PrEP) against HIV with tenofovir+emtricitabine was started 7 months before his current presentation as the patient was a man who had sex with men (MSM). Treatment was ongoing; however, the patient now stated he was no longer sexually active.

Diagnoses and management

The patient was managed in the first instance for mixed starvation and euglycaemic ketoacidosis, and a mild acute kidney injury. Other acute issues requiring management were nausea, constipation and dehydration. Treatment included intravenous glucose-containing fluids, glycaemic monitoring, aperients and antiemetics.

A joint medical and pharmacist review identified a cascade of prescriptions, from multiple prescribers, which were contributing to his current presentation:

• nausea may have been caused or worsened by PrEP (tenofovir+emtricitabine), levodopa, constipation and ketoacidosis
• constipation may have been associated with ondansetron, prochlorperazine and nausea-related dehydration
• ketoacidosis may have been associated with dapagliflozin and nausea-related starvation
• acute kidney injury may have been associated with telmisartan, PrEP and nausea-related dehydration.

It was also noted that metoclopramide and prochlorperazine could worsen parkinsonism, and that his use of 2 benzodiazepines could be contributing to poor mobility and falls risk.

The opportunity was taken to rationalise some of the patient’s medications in hospital (Table 3).

A subsequent outpatient barium swallow excluded gastroparesis. Other investigations for acute kidney injury, gastrointestinal pathology and weight loss found no abnormalities present.

At 1-month follow-up, the patient’s nausea had improved and antiemetic therapy (which had been switched to domperidone in hospital) was stopped. His kidney function had returned to baseline.

Table 3 Rationalisation of patient’s medication regimen during hospitalisation

Drug change	Rationale
Ceased
dapagliflozin	euglycaemic ketoacidosis
insulin glargine	no longer required (glycaemic control satisfactory)
metoclopramide	risk of drug-induced parkinsonism
ondansetron	constipation
prochlorperazine	risk of drug-induced parkinsonism; constipation
telmisartan	acute kidney injury
temazepam	falls risk
tenofovir+emtricitabine	nausea; possible nephrotoxicity; no longer required (altered risk of acquiring HIV)
Dose-adjusted
lactulose dose increased	constipation
levodopa+benserazide dose halved	nausea; no significant parkinsonism observed in hospital
Started
docusate+senna	constipation
domperidone [NB1]	nausea
macrogol 3350 with electrolytes	constipation
NB1: Domperidone is associated with lower risk of parkinsonism compared with metoclopramide and prochlorperazine.

 

Comment

This case highlights how a cascade of diagnoses and prescriptions from multiple prescribers can lead to extreme polypharmacy, multiple compounding adverse effects and serious sequelae.^3,4

It was proposed that this patient’s presentation may have been provoked by ‘start-up syndrome’ associated with PrEP. The syndrome is a constellation of headache, nausea, flatulence and kidney injury.⁵ The syndrome usually resolves within the first 3 months of taking PrEP; however, this patient had been taking PrEP for 7 months. His presentation could have been compounded by euglycaemic ketoacidosis from continued use of a sodium glucose transporter-2 inhibitor (dapagliflozin) while in an intermittent state of unplanned fasting and dehydration.⁶ Of note, nephrotoxicity from PrEP is uncommon in patients with a baseline estimated glomerular filtration rate (eGFR) of more than 60 mL/min, in younger MSM, and in patients without comorbidities of hypertension and diabetes.⁷ Prescription of ondansetron and prochlorperazine may have contributed to his constipation, which further compounded his symptoms.

While most of the adverse effects this patient experienced are well described, they can be overlooked when there are multiple comorbidities, multiple prescribers, and often multiple pharmacies involved; and they may be more severe when multiple implicated drugs are used in combination.

In this case, it was not clear whether changes and adverse effects had been communicated between the patient’s various prescribers.

 

Conclusion and recommendations

Rationalisation of medication lists relies on a clinician approach that reconciles the complexity of a patient’s medication timeline, pre-empts complications from comorbidities, and addresses competing subspecialty priorities. Multiple prescribers create a logistical challenge that can lead to prescribing cascades. This case illustrates the importance of ensuring access to a shared medication history by all clinicians, including the timelines and the rationale for starting, changing and ceasing a patient’s medications, and communication between patients, specialists and the patient’s primary care providers. It also highlights the importance of regular interprofessional medication review.

Patient consent for publication of this case study was obtained by the authors.

Acknowledgements: The authors thank Dr C Denaro and Dr S Craven for their contribution to the clinical management of this case.

Conflicts of interest: Ian and Fiona Coombes are immediate family members of Judith Coombes, who is a member of the Australian Prescriber Editorial Advisory Committee. Judith was excluded from editorial decision-making related to the acceptance and publication of this article.

This article is peer reviewed.

 

References

1. Cheung NW, Conn JJ, d'Emden MC, Gunton JE, Jenkins AJ, Ross GP, et al. Position statement of the Australian Diabetes Society: individualisation of glycated haemoglobin targets for adults with diabetes mellitus. Med J Aust 2009;191:339-44.
2. Royal College of Pathologists of Australasia. Manual of use and interpretation of pathology tests. Version 6.0. 2023. [cited 2024 Jun 18]
3. Kalisch L, Caughey G, Roughead E, Gilbert A. The prescribing cascade. Aust Prescr 2011;34:162-6.
4. Rochon PA, Gurwitz JH. The prescribing cascade revisited. Lancet 2017;389:1778-80.
5. Glidden DV, Amico KR, Liu AY, Hosek SG, Anderson PL, Buchbinder SP, et al. Symptoms, Side Effects and Adherence in the iPrEx Open-Label Extension. Clin Infect Dis 2016;62:1172-7.
6. Hamblin PS, Wong R, Ekinci EI, Fourlanos S, Shah S, Jones AR, et al. SGLT2 Inhibitors Increase the Risk of Diabetic Ketoacidosis Developing in the Community and During Hospital Admission. J Clin Endocrinol Metab 2019;104:3077-87.
7. Australasian Society for HIV Viral Hepatitis and Sexual Health Medicine. Assessment of renal function at baseline. National PrEP Guidelines. 2021. [cited 2024 Jun 18]