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Clinical Toxicology

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Angiotensin axis antagonists increase theincidence of haemodynamic instability indihydropyridine calcium channel blockerpoisoning

Jessica Huang , Nicholas A. Buckley , Katherine Z. Isoardi , Angela L. Chiew ,Geoffrey K. Isbister , Rose Cairns , Jared A. Brown & Betty S. Chan

To cite this article: Jessica Huang , Nicholas A. Buckley , Katherine Z. Isoardi , Angela L. Chiew ,Geoffrey K. Isbister , Rose Cairns , Jared A. Brown & Betty S. Chan (2020): Angiotensin axisantagonists increase the incidence of haemodynamic instability in dihydropyridine calcium channelblocker poisoning, Clinical Toxicology, DOI: 10.1080/15563650.2020.1826504

To link to this article: https://doi.org/10.1080/15563650.2020.1826504

Published online: 06 Oct 2020.

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CLINICAL RESEARCH

Angiotensin axis antagonists increase the incidence of haemodynamic instabilityin dihydropyridine calcium channel blocker poisoning

Jessica Huanga, Nicholas A. Buckleyb,c , Katherine Z. Isoardid , Angela L. Chiewa,e , Geoffrey K. Isbisterf ,Rose Cairnsb,c, Jared A. Brownc and Betty S. Chana,e

aFaculty of Medicine, University of New South Wales, Sydney, Australia; bFaculty of Medicine and Health, University of Sydney, Sydney,Australia; cNew South Wales Poisons Information Centre, The Children’s Hospital at Westmead, Westmead, Australia; dClinical ToxicologyUnit, Princess Alexandra Hospital, Woolloongabba, Australia; eClinical Toxicology Unit, Prince of Wales Hospital, Randwick, Australia;fDepartment of Clinical Toxicology and Pharmacology, Calvary Mater Hospital, Waratah, Australia

ABSTRACTContext: Amlodipine, a dihydropyridine calcium channel blocker (CCB), is the leading cause of cardio-vascular drug-related overdose deaths in the USA. In contrast, angiotensin-II receptor blockers (ARBs)and angiotensin converting enzyme inhibitors (ACEIs) cause minimal toxicity in overdose. ACEIs/ARBsare often combined with dihydropyridines in hypertension treatment. Co-ingested ARBs/ACEIs may sig-nificantly contribute to the toxicity of dihydropyridine, but this has not been investigated.Objective: To investigate the clinical outcomes from dihydropyridine overdoses with ARBs/ACEIs ver-sus dihydropyridine overdoses alone.Methods: This was a retrospective study of patients reported to the New South Wales PoisonsInformation Centre (NSW PIC) and 3 toxicology units (Jan 2016 to Jun 2019) in Australia. Patients>14 years who took an overdose of dihydropyridines (amlodipine, felodipine, lercanidipine, nifedipine)were included. Concurrent overdoses with non-dihydropyridine CCBs, alpha-blockers and beta-blockerswere excluded. Patient demographics, drugs exposure details, serial vital signs, treatments and out-come were collected.Results: There were 100 patients. 68 took mixed overdoses of dihydropyridines with ARBs/ACEIs and32 took single overdoses of dihydropyridines without ARBs/ACEIs. The mixed group had lower mediannadir mean arterial pressures (62 vs 75mmHg, p< 0.001), more frequently had hypotension (OR 4.5,95%CI: 1.7–11.9) or bradycardia (OR 8.8, 95%CI: 1.1–70). Multivariable analysis indicated the mixedoverdoses had an 11.5mmHg (95%CI: 4.9–18.1) lower minimum systolic blood pressure (SBP) com-pared with the single group; other factors associated with a lower minimum SBP were higher doses[2.3mmHg (95%CI: 1.1–3.5) lower per 10 defined daily doses] and younger age [2.2mmHg (95%CI:0.3–4.2) higher per decade]. A larger proportion of the mixed ingestion group received intravenousfluids (OR 5.7, 95%CI: 1.8–18.6) and antidotes and/or vasopressors (OR 2.9, 95%CI: 1.004–8.6).Conclusion: Combined overdoses of dihydropyridines with ARBs/ACEIs caused more significant hypo-tension and required more haemodynamic support than overdoses of dihydropyridines alone.

ARTICLE HISTORYReceived 4 May 2020Revised 24 August 2020Accepted 11 September 2020

KEYWORDSAngiotensin II receptorblockers; angiotensinconverting enzymeinhibitors; amlodipine;overdose; toxicity

Introduction

Dihydropyridine calcium channel blockers (CCBs) such asamlodipine, felodipine, lercanidipine and nifedipine are usedas first-line treatment for essential hypertension [1]. In 2015,amlodipine was the fourth most commonly dispensed medi-cation in Australia and the second most commonly pre-scribed antihypertensive medication by defined daily doseper day [2]. Dihydropyridine CCBs are perceived to be saferat therapeutic doses than non-dihydropyridine CCBs, such asverapamil and diltiazem, as they have more vascular selectiv-ity and less negative chronotropy and inotropy [3]. Despitethis, amlodipine is the leading contributor to cardiovasculardrug related poisoning deaths (31.5%) in the USA [4].Dihydropyridine overdose involves a loss of vascular selectiv-ity [5,6] and a decrease in systemic vascular resistance to

cause haemodynamic instability with hypotension and reflextachycardia [7]. This may lead to vasodilatory shock [8,9].

Dihydropyridines are often prescribed in combinationwith angiotensin-converting enzyme inhibitors (ACEIs) orangiotensin-II receptor blockers (ARBs). Combined therapyof dihydropyridines and ACEI/ARB may be superior toother first-line combinations such as beta-blockers withdiuretics or ACEIs with diuretics in some patients [10,11].In the renin-angiotensin-aldosterone system, ARBs blockthe Angiotensin (AT)-1 receptor of angiotensin-II andinhibit vasoconstriction [12] whilst ACEIs block angioten-sin-converting enzyme (ACE) to inhibit the conversion ofangiotensin I to angiotensin II, similarly leading to lessvasoconstriction [13]. Overdoses of ARBs/ACEIs alone arerelatively benign [14–17] and are rarely listed as the pri-mary cause of poisoning deaths [4].

CONTACT Betty S. Chan betty.chan1@health.nsw.gov.au Clinical Toxicology Unit, Prince of Wales Hospital, Barker Street, Randwick, NSW, 2031, Australia� 2020 Informa UK Limited, trading as Taylor & Francis Group

CLINICAL TOXICOLOGYhttps://doi.org/10.1080/15563650.2020.1826504

There is a paucity of evidence pertaining to the severityof a mixed dihydropyridine and ARB/ACEI overdose, with cur-rent literature predominately limited to case reports. A smallnumber of case reports detail concurrent overdoses of dihy-dropyridines and an ARB/ACEI that have resulted in a pro-longed and severe hypotension refractory to standardtreatment with intravenous fluids, antidotes and vasopressors[8,9,18–24]. Therefore, this study aims to determine the clin-ical course of this poisoning in a larger cohort of patients, bycomparing patients who had an overdose of a dihydropyri-dine with an ARB/ACEI, with patients who had an overdoseof a dihydropyridine without an ARB/ACEI, in terms ofhaemodynamic stability, treatment requirements andpatient outcomes.

Methods

Study design and setting

This was a multi-centre, retrospective study, with data col-lected from January 2016 to June 2019. Patients were retro-spectively identified through the New South Wales PoisonsInformation Centre (NSW PIC), the South Eastern AreaToxicology Service (SEATS), the Princess AlexandraToxicology Service (PATS) and the Hunter Area ToxicologyService (HATS) databases. These services collect data on drugexposures and doses prospectively from telephone consulta-tions Australia-wide and admissions in local hospitals andthe three toxicology units. In particular, the NSW PIC receivesapproximately half of Australia’s 200,000 poisons-related callsfrom the public and medical professionals [25]. This studyreceived ethics approval provided by local Human ResearchEthics Committees for NSW PIC (HREC/16/SCHN/71), HATS(LNR15/HNE/18), PATS (HREC/14/QPAH/308) and the SEATS(LNR/12/POWH/355).

Case identification

Patients >14 years who had orally ingested a dihydropyridineCCB over the maximum daily dose (amlodipine >10mg; felo-dipine >20mg; lercanidipine >20mg; nifedipine immediaterelease >80mg; nifedipine controlled release >120mg) wereincluded. Patients were excluded if they had concurrentlyoverdosed on a beta-blocker, an alpha blocker, verapamil ordiltiazem, or if their medical records were sent with incom-plete fluid, observation or treatment charts.

Data collection

Patients were separated into two groups; the first with amixed overdose of a dihydropyridine with an ARB/ACEI, andthe second with an overdose of a dihydropyridine withoutan ARB/ACEI. De-identified medical records were requestedfrom hospitals Australia-wide for these patients. A custom-tailored REDCap abstraction form was created to standardisedata collection for consistency and to reduce error.Demographical data and drug exposure details were col-lected. All vital sign observations during the admission

(systolic blood pressure (SBP), diastolic blood pressure (DBP),calculated mean arterial pressure (MAP) and heart rate (HR))were collected serially. Treatment, length of stay and finaloutcomes were also recorded. To standardise the overdoseof different dihydropyridines, the number of defined dailydoses (DDDs) ingested was calculated, as per the WorldHealth Organization Collaborating Centre for Drugs StatisticsMethodology [26]. Ten percent of patient charts were ran-domly selected and cross-checked by a second reviewer toconfirm the accuracy and reliability of the initialdata collection.

Outcomes

The two primary outcomes were the comparison of lowestSBP and the lowest MAP. Hypotension was defined as SBP<90mmHg or DBP <60mmHg or MAP <65mmHg.Secondary outcomes included bradycardia, tachycardia, intra-venous fluid requirement, decontamination, antidote andvasopressor requirements, intensive care unit admission andlength of stay. Bradycardia was defined as a HR <60 bpmand tachycardia defined as HR >100 bpm.

Statistical analysis

The data were imported and analysed in Statistical Packagesfor the Social Sciences (SPSS; SPSS Inc., Chicago, IL, USA) andGraphPad Prism 8.1.2 (GraphPad Software Inc., San Diego,CA, USA). Normality was identified with Shapiro–Wilk test.The Mann–Whitney U test was used to compare non-para-metric data between the two groups. Chi-squared test wasused to compare categorical values, substituting Fisher’sexact test in comparisons when any cell size count was lessthan five. The Kaplan–Meier curves for time-to events (timeto fluids, time to vasopressors and/or antidotes and time todischarge) were compared with the log rank test. Multiplelinear regression was used to determine the correlationbetween co-ingestion of a dihydropyridine CCB and an ARB/ACEI vs. ingestion of a dihydropyridine CCB without an ARB/ACEI, age and DDD with lowest SBP and lowest MAP. A p-value <0.05 was deemed statistically significant.

Odds ratios (OR) are presented with a 95% confidence inter-val as a measure of association between mixed ingestions andbinary outcomes. Multinominal logistic regression analysis wasused to determine the adjusted odds ratio (aOR) to account forthe influence of other covariates and/or factors.

Results

Patient demographics

A total of 223 cases were identified which satisfied the inclu-sion criteria. Forty-three patients were excluded due to aconcurrent overdose of a beta-blocker, an alpha blocker, ver-apamil or diltiazem. Eighty patients were lost to follow up orhad components of their records that were not sent to datacollectors (Figure 1). A total of 100 patients were thereforeincluded, with 68 having ingested a dihydropyridine with an

2 J. HUANG ET AL.

ARB/ACEI (mixed ingestion group), and 32 having ingested adihydropyridine without an ARB/ACEI (single ingestiongroup). In terms of comorbid medical conditions, one patientin the single ingestion group and no patients in the mixedingestion group had congestive cardiac failure. Two patientsin the single ingestion group and five patients in the mixedingestion group had ischaemic heart disease. Patient demo-graphic and ingestion data are summarised in Table 1.

The proportion of amlodipine ingestions were significantlyhigher in the mixed group (p¼ 0.008), whilst the proportion oflercanidipine ingestions were significantly higher in the singleingestion group (p< 0.001). There was no significant differencein the proportion ingesting felodipine and nifedipine IR and ER.Forty-three patients from the mixed ingestion group (63%)ingested combination tablets containing dihydropyridines.

Haemodynamic effects

The mixed ingestion group had significantly lower nadirs forSBP and MAP during admissions (Table 2, Figure 2). The

odds of hypotension were 4.5 times higher (95% CI: 1.7–12)in the mixed ingestion group, and this was statistically sig-nificant (Table 3). This remained significant after adjusting forage and DDD [adjusted odds ratio (aOR) ¼ 3.9 (95%CI: 1.4–11)].

The mixed ingestion group had a significantly lower nadirfor HR (Table 2). Bradycardia was more common in themixed ingestion group [OR: 8.8 (95% CI: 1.1–70)], but whenadjusted for age and DDD this difference was no longer stat-istically significant (Table 3). There was no difference in pro-portion of patients who experienced tachycardia.

In multivariable analysis, mixed ingestion, dose and age,but not gender, were associated with a lower nadir for SBP.With all other predictors kept constant, mixed overdoses hadan 11.5mmHg (95% CI: 4.9–18.1) lower minimum systolicblood pressure (SBP) compared with the single group; alower minimum SBP was seen with higher doses [2.3mmHg(95% CI: 1.1–3.5) lower per 10 daily defined doses] andyounger age [SBP was 2.2mmHg (95% CI: 0.3–4.2) higherper decade].

Patients meeting the inclusion criteria from databases

(n=223)

All included patients

(n=100)

Mixed overdose of dihydropyridine CCBs with ARBs or ACEIs

(n=68)

Overdose of dihydropyridine CCBs without ARBs or ACEIs

(n=32)

Patients excluded (n=123):* Patients concurrently exposed to a non-

dihydropyridine CCB or an alpha- and/or a beta-blocker (n=43)

* Patients lost to follow up or missing files (n=80)

Figure 1. Recruitment Flow Chart.

Table 1. Patient characteristics and drug doses.

ParameterDihydropyridine CCB

with ARB/ACEI (n¼ 68)Dihydropyridine CCB

without ARB/ACEI (n¼ 32) p Value

Median age (years) 54 (IQR 45–61) 52 (IQR 35–67) 0.68Number of females (n) 39 (57%) 18 (56%) 0.92Defined daily dose of dihydropyridine CCB (n) 22 (IQR 10–40) 13 (IQR 7–30) 0.058Dihydropyridine ingested (n)� Amlodipine 57 (84%) 19 (59%) 0.008� Felodipine 3 (4%) 0 (0%) 0.55� Lercanidipine 3 (4%) 10 (31%) <0.001� Nifedipine IR 2 (3%) 3 (9%) 0.32� Nifedipine ER 3 (4%) 0 (0%) 0.55

Bold values represent statistically significant values.

CLINICAL TOXICOLOGY 3

Treatment

A significantly larger proportion of the mixed ingestiongroup received intravenous fluids (aOR 4.9; Table 3). The vol-ume of intravenous fluids received was also higher in themixed ingestion group (4.0 L (IQR 2.4–5.6) vs. 3.5 L (IQR1.9–5.0), p¼ 0.04). A significantly higher proportion of themixed ingestion group received antidotes and/or vasopres-sors (OR 2.9, 95% CI: 1.004–8.6). However, this effect was notobserved after adjustment for age, ingestion group and DDD(aOR 2.3, 95% CI: 0.73–7.4). The antidote and vasopressoragents received are detailed in Table 4. Log rank test of theKaplan–Meier curve for time-to-fluids shows a significant dif-ference between the two groups (p¼ 0.001). Log rank test of

the Kaplan–Meier curve for time-to-vasopressors and/or anti-dotes just failed to show a significant difference between thetwo groups (p¼ 0.052; Figure 3).

A larger proportion of the single ingestion group receivedactivated charcoal (p¼ 0.4) or was intubated (p¼ 0.7), butthis was not statistically significant (Table 3). There was ahigher proportion of intensive care unit admissions in themixed ingestion group, though this was not statistically sig-nificant (p¼ 0.4; Table 3). There were no cardiac arrests, seiz-ures or strokes. There was no significant difference inmedian highest serum creatinine levels between the mixedand single ingestion groups (81 lmol/L (IQR 69–112.5) vs.78 lmol/L (IQR 65–110), p¼ 0.78). There were no significant

Table 2. Haemodynamic outcomes.

ParameterDihydropyridine CCBwith ARB/ACEI (n¼ 68)

Dihydropyridine CCBwithout ARB/ACEI (n¼ 32) p Value

Lowest SBP (mmHg) 87 (IQR 79–95) 102 (IQR 94–112) <0.001SBPhjghest – SBPlowest (mmHg) 50 (IQR 39–62) 43 (IQR 29–50) 0.024Lowest MAP (mmHg) 62 (IQR 56–68) 75 (IQR 69–82) <0.001MAPhighest – MAPlowest (mmHg) 37 (IQR 28–45) 34 (IQR 22–41) 0.16Lowest heart rate (bpm) 70 (IQR 60–78) 80 (IQR 71–83) 0.001Highest heart rate (bpm) 100 (IQR 90–114) 106 (IQR 95–122) 0.063

Bold values represent statistically significant values.

Figure 2. Violin Plot showing the probability density of (a) lowest SBP in dihydropyridine with ACEI/ARB (mixed) and dihydropyridine only (single) groups; (b) low-est MAP in mixed and single groups. The solid line represents the median and dotted lines represent the 25th and 75th percentile.

Table 3. Treatment and dichotomous haemodynamic outcomes.

ParameterDHP CCB with ARB/

ACEI (n¼ 68)DHP CCB without ARB/

ACEI (n¼ 32) p Value Odds ratio (95% CI)Adjusted Odds ratio

(95% CI)a

Hypotensionb 58 (85%) 18 (56%) 0.002 4.5 (1.7–12) 3.9 (1.4–11)Bradycardiac 15 (22%) 1 (3%) 0.018 8.8 (1.1–70) 7.8 (0.97–63)Tachycardiad 33 (49%) 18 (56%) 0.47 0.73 (0.32–1.7) 0.73 (0.30–1.8)Number received

activated charcoal7 (10%) 5 (16%) 0.44 0.62 (0.18–2.1) 0.78 (0.20–3.0)

Number receivedintravenous fluids

63 (93%) 22 (69%) 0.002 5.7 (1.8–19) 4.9 (1.5–16)

Number receivedantidote or inotropes

24 (35%) 5 (16%) 0.043 2.9 (1.004–8.6) 2.3 (0.7–7.4)

Number intubated 4 (6%) 3 (9%) 0.68 0.60 (0.13–2.9) 0.51 (0.094–2.7)Number of

ICU admissions18 (26%) 6 (19%) 0.40 1.6 (0.55–4.4) 1.3 (0.42–4.1)

Length of stay (days) 1.3 (IQR 0.7–2.2) 0.9 (IQR 0.5–1.6) 0.10 – –Deaths 0 0 – – –

DHP: dihydropyridine.aAdjusted for age, group and DDD.bHypotension defined if SBP < 90mmHg or DBP < 50mmHg.cBradycardia defined for heart rate < 60 bpm.dTachycardia defined for heart rate > 100 bpm.Bold values represent statistically significant values.

4 J. HUANG ET AL.

differences in incidence of systemic symptoms between thetwo groups (Table 5). The three patients who developed pul-monary oedema in the mixed ingestion group, received 3 L,6 L and 9 L of intravenous fluids respectively.

All patients survived and were discharged. There was nosignificant difference in length of stay between the twogroups (p¼ 0.1; Table 3). Log rank test of the Kaplan–Meiercurves for time-to-discharge (Figure 4) showed no significantdifference between the two groups (p¼ 0.3).

Discussion

Our results indicate that patients with a combined overdoseof dihydropyridines and ACEIs/ARBs had significantly lowermedian nadirs of SBP and MAP; and a significantly higherproportion experienced hypotension, bradycardia, receivedintravenous fluids treatment and vasopressors and/or anti-dotes. The rate of receiving intravenous fluids was alsohigher in the mixed ingestion group. A target MAP of atleast 65mmHg is recommended for sufficient organ perfu-sion [27], and a larger proportion of patients in the mixedingestion group did not meet this target on admission.These associations were minimally changed after adjustmentfor other factors associated with these outcomes (doseand age).

Overdoses of ARBs/ACEIs are mostly benign and rarelycause serious adverse effects requiring vasopressors [15,17].Though there have been a few cases of hypotension thatwere responsive to fluid and vasopressor therapy [28,29],most case reports of ARB/ACEI overdose do not report sig-nificant hypotension [16,29–31]. There was a single case of

Table 4. Distribution of antidotes and vasopressors.

Parameter

DihydropyridineCCB with

ARB/ACEI (n¼ 68)

DihydropyridineCCB without

ARB/ACEI (n¼ 32)

Number received antidotea 20 4� Calcium chloride 17 3� Calcium gluconate 6 3Number received vasopressora 15 4� Adrenaline 2 0� HIET 4 0� Noradrenaline 11 4� Metaraminol 11 3� Methylene blue 1 0� Vasopressin 7 2

HIET: high-dose insulin euglycaemic therapy.aPatients could receive more than one antidote or vasopressor.

Figure 3. Kaplan–Meier curves for (a) Time to Intravenous Fluids for the first24 h; (b) Time to Vasopressors/Antidotes for the first 48 h. Both curves werecensored at 18 h as all events had occurred by this time.

Table 5. Systemic signs and symptoms.

Signs and symptomsDihydropyridine CCBwith ARB/ACEI (n¼ 68)

Dihydropyridine CCBwithout ARB/ACEI (n¼ 32) p Value

Nausea 25 (35%) 10 (31%) 0.59Vomiting 16 (24%) 9 (28%) 0.62Headache 7 (10%) 2 (6%) 0.72Abdominal pain 9 (13%) 3 (9%) 0.75Metabolic acidosis 15 (22%) 5 (16%) 0.45Hyperglycaemia 14 (21%) 4 (13%) 0.41Pulmonary oedema 3 (4%) 0 (0%) 0.55

Figure 4. Kaplan–Meier Curves for Time to Discharge.

CLINICAL TOXICOLOGY 5

hypotension in a case series of 19 paediatric overdoses ofARBs or ACEIs and the patient required no treatment [14]. Ina case series of 206 ARB overdoses, only one paediatricpatient required treatment with intravenous fluids [17]. Inanother case series of 33 ACEI overdoses, only one patientrequired vasopressors, but it was unclear whether theybelonged to the 13 cases who had concurrent ingestionswith other antihypertensives [32]. Furthermore, ARBs/ACEIswere not the primary cause of any deaths in the 2017Annual Report of the American Association of Poison ControlCentres [4]. Despite this exceptionally low toxicity, our resultsshow that severity appears to be significantly worse when anARB/ACEI is added to a dihydropyridine in overdose.

This potential synergism can be explained mechanistically.Theoretically, a dihydropyridine overdose will cause wide-spread peripheral vasodilation, triggering homeostatic coun-ter-regulatory mechanisms through the activation of therenin-angiotensin-aldosterone system (RAAS; Figure 5).However, the RAAS homeostatic response is inhibited withconcurrent overdose of ARB/ACEI [33]. Furthermore, thiscombination may also reduce sympathetic outflow [34]. Withthese mechanisms compromised, dihydropyridines and ARBs/ACEIs are predicted to act synergistically, blunting thehomeostatic vasoconstrictive response to endogenous andexogenous catecholamines [8,9,21]. Indeed, mixed ingestionpatients in our study required more haemodynamic supportas well as less conventional therapies such as methyleneblue and high-dose insulin euglycaemic therapy (HIET), likelydue to developing a more catecholamine-resistant shock[35]. Furthermore, while a typical dihydropyridine overdosepresents with hypotension and reflex tachycardia [7], inhib-ition of catecholamine release with AT1 blockade mayexplain the clinically higher rate of bradycardia and lowermedian lowest HR in the mixed ingestion group.

In addition, amlodipine and various ARBs and ACEIs havebeen shown to increase nitric oxide (NO) mediated

vasodilation, which may contribute to the prolonged, refrac-tory hypotension experienced with combination overdoses.Amlodipine strongly inhibits ACE to a similar extent to theACEI enalapril at equal concentrations in vitro [36], causingan increase in bradykinin and potential activation of bradyki-nin 2 receptors to produce vasodilatory NO from endothelialcells in animal models [36–38]. Zhang et al. [39] determinedthat of the two enantiomers of amlodipine, theRþ enantiomer was responsible for NO production inde-pendent of calcium channel blockade, whilst the S-enantio-mer caused calcium channel antagonism only. It is notedthat NO production is not demonstrated in nifedipine [36],and there is a lack of evidence regarding this mechanism inlercanidipine or felodipine. Furthermore, the ARB olmesartanwas also shown to increase NO release at an amountdependent on the type of endothelial nitric oxide synthase(eNOS) variant [40]. Imanishi et al. [41] also demonstrated ina rabbit model that acetylcholine-induced NO release wassignificantly higher in groups treated with the ACEI enalapriland/or the ARB losartan, when compared with controls.

This is the first large case series of dihydropyridine over-doses with or without an ARB/ACEI that provided statisticalanalysis. There are only nine case reports available in the lit-erature detailing mixed overdoses with dihydropyridine CCBsand ARBs/ACEIs [8,9,18–24]. Of these, all cases developedprofound hypotension and received intravenous fluids. Whilethere could be publication bias reporting severe cases, thisobservation is in keeping with our results. The lowest MAPduring admission within these case reports ranged from39mmHg [23] to 54mmHg [9], well below targets foradequate tissue perfusion. Most cases were refractory to con-ventional therapies, requiring extra corporeal membrane oxy-genation [20,23], methylene blue [19,23], continuous veno-venous haemofiltration [8,18], intravenous lipid emulsion[8,20,21] and molecular adsorbent recirculating system [8] tofacilitate recovery from toxicity. Our results also reflect the

Figure 5. Synergistic Actions of ARB/ACEI and CCBs. Red indicates elements contributing to decreased BP and green indicates elements contributing to increasedBP. CCBs cause vasodilation, thereby decreasing peripheral resistance and blood pressure. The green dotted line represents the subsequent activation of the RAASby increased renin release to raise peripheral resistance. ACEIs and ARBs antagonise steps within the RAAS, disrupting homeostatic responses and causing a syner-gistic decrease in peripheral resistance and blood pressure.

6 J. HUANG ET AL.

need for more aggressive therapies for patients with a mixedingestion, where HIET and methylene blue were used withinthe mixed ingestion group but not in the single inges-tion group.

With increasing rates of hypertension and cardiovasculardisease, there will be an inevitable increase in the prescrip-tion and overdose of combination therapies of dihydropyri-dine CCBs and ARBs/ACEIs. Given the worsenedhaemodynamic and treatment requirement with a mixedingestion overdose found in this study, physicians should becautious in prescribing these combination products inpatients with a history of deliberate self-poisoning.

Limitations

In this study, our recruitment through poison centre callsmay have been biased towards more severe cases. The doseinformation may also not be accurately recorded [42], andthis may therefore affect the dose–outcome relationship inour results. Drug levels were not available to confirm orquantify dihydropyridine ingestions as they were not rou-tinely performed. However, other Australian data havereported a high correlation between plasma levels andpatient-reported doses [43]. Furthermore, eighty cases (72from PIC, 8 from toxicology units) could not be included inthe study as their medical records could not be retrieved bythe authors. This reflects the greater difficulties in usingPoison Centre databases for patient recruitment as medicalrecords must then be requested from individual hospi-tals nationwide.

Our study was not sufficiently large enough to explorethe differences between individual drugs within the dihydro-pyridines class. This study was conducted under the assump-tion that all dihydropyridines have the same mechanism ofaction. However, the literature suggests that amlodipine, butnot nifedipine, enhances NO release from endothelial cells[36]. Furthermore, NO-dependent dilatory mechanisms havenot been well-studied in felodipine and lercanidipine. Thisraises the possibility that each drug within the dihydropyri-dine class could act with unique mechanisms that may ormay not be increased by the coingestion of ARBs/ACEIs inoverdose. Although most of our patients ingested amlodi-pine (84% in the mixed group and 59% in the single inges-tion group), the mixed ingestion group had a significantlyhigher proportion of amlodipine ingestions which couldhave contributed to the observed differences between eachgroup. Further mechanistic information and larger clinicalstudies would be needed to explore whether such differen-ces are important in overdose.

Conclusions

Mixed overdose of dihydropyridine CCBs with an ARB/ACEIwere associated with more hypotension, bradycardia and asignificantly lower median lowest SBP/MAP than single over-dose and required more haemodynamic support.Hypotension is more common in patients following a mixedoverdose of dihydropyridines with ARBs/ACEIs, increased

dosage of dihydropyridines and decreased age. These resultscould be attributed to synergistic interaction between dihy-dropyridine CCBs and ARB/ACEI in overdoses.

Acknowledgments

The authors sincerely thank the staff at the NSW Poisons InformationCentre and the Princess Alexandra Hospital Toxicology Service for theirassistance in recruiting patients.

Disclosure statement

No potential conflict of interest was reported by the author(s).

ORCID

Nicholas A. Buckley http://orcid.org/0000-0002-6326-4711Katherine Z. Isoardi http://orcid.org/0000-0002-1176-7923Angela L. Chiew http://orcid.org/0000-0002-0079-5056Geoffrey K. Isbister http://orcid.org/0000-0003-1519-7419Betty S. Chan http://orcid.org/0000-0003-0083-282X

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