Publikation: Survival of severe amlodipine intoxication due to medical intensive care

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Survival of severe amlodipine intoxication due to medical intensive care

Susanne Vogt

^a

, Annekathrin Mehlig

^b

, Patrick Hunziker

^c

, Andre´ Scholer

^d

, Julia Jung

^a

, Ana Baranda Gonza´lez

^a

, Wolfgang Weinmann

^a,

* , Stephan Marsch

^c

aInstitute of Forensic Medicine, University Hospital, Albertstrasse 9, D79104 Freiburg, Germany

bDepartment Internal Medicine, University Hospital Basel, Switzerland

cMedical Intensive Care Unit, University Hospital Basel, Switzerland

dDepartment Laboratory Medicine, University Hospital Basel, Switzerland

Received 27 November 2005; received in revised form 3 February 2006; accepted 3 February 2006

Abstract

We report the case of attempted suicide with amlodipine, chlorthalidone and mefenamic acid and subsequent medical intensive care measures which resulted in total recovery of a 42-year-old male. After admission to the medical intensive care unit the intoxicated patient was deeply hypotensive and needed fluid replacement, dobutamine and norepinephrine. Additionally insulin and calcium gluconate were given. Since hypotension persisted and the patient developed oliguria, terlipressin was applied and finally showed an effect on blood pressure and on urinary output. A volume overload of 7 L in the first 24 h resulted in a pulmonary edema. The patient was started on non-invasive ventilation with continuous positive airway pressure (CPAP) and frusemide was added to the therapy with good success. Quantitative determination of amlodipine in plasma samples was performed by liquid chromatography–tandem mass spectrometry (LC–MS/MS). The highest amlodipine concentrations was measured in the plasma sample collected approximately 8 h after ingestion of the drug, and was 393mg/L. Four days later, it was possible to stop the treatment with catecholamines, at that time the amlodipine plasma concentration had declined to 132mg/L, still tenfold higher than therapeutic (5–18mg/L). Elimination half-life of amlodipine is approximately 55 h. After 6 days in the intensive care unit the patient was transferred to psychiatric treatment. Intensive care management and plasma levels in this intoxication case are compared to data from literature on other cases.

Keywords: Amlodipine; Dihydropyridine (DHP); Calcium channel blocker (CCB); Intoxication; Overdose; Terlipressin; Liquid chromatography–tandem mass spectrometry (LC–MS/MS)

1. Introduction

Amlodipine is one of the newer calcium channel blockers of the dihydropyridine group used as an antihypertensive. It is prescribed as the besylate salt in tablets of 2, 5–10 mg. Unlike other calcium channel blockers amlodipine has a very low metabolic clearance with the advantage of using a once-daily- dosage to maintain a near constant plasma concentration[1,2].

The therapeutic plasma level ranges from 5 to 18mg/L [3].

Plasma half-life is reported as 35–65 h[4,5]. There are several cases of amlodipine overdoses reported with several of them having a lethal outcome.

Terlipressin (triglycyl-lysine–vasopressin) is an analogue of vasopressin with a longer duration of action. Vasopressin is used in septic shock with hypotension not responsive to catecholamines[6,7].

2. Case report

A 42-year-old man was admitted to hospital 7.5 h after attempting suicide by ingesting 1000 mg amlodipine, 3000 mg chlorthalidone, 3000 mg of mefenamic acid and 2 L of beer.

Medical history included a mild hypertension and a splenect- omy due to an accident several years previously.

On admission the patient was lethargic but arousable. Blood pressure was 80/49 mmHg, the measured heart rate was 89 bpm. Besides the hypotension the physical examination was unremarkable. The patient had vomited prior to admission and still complained nausea. Laboratory studies showed a mild

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* Corresponding author. Tel.: +49 761 203 6828; fax: +49 761 203 6858.

E-mail address:Wolfgang.Weinmann@uniklinik-freiburg.de (W. Weinmann).

doi:10.1016/j.forsciint.2006.02.051

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leucocytosis with 12.3110⁹/L with left shift in the differential blood count, creatinine was 203mmol/L, potassium 3.1 mmol/L, glucose was slightly elevated with 6.4 mmol/L.

Further clinical chemistry results including calcium, sodium, potassium and pH determination and venous blood gas analysis were in the normal range.

The patient was started on i.v.-fluids and transferred to the intensive care unit. The blood pressure decreased and dobutamine and norepinephrine were started as well as calcium gluconate and insulin infusion. A cardiac echograph was performed which showed a left ventricular ejection fraction of 40%. In the following hours the hypotension remained intractable with a lowest blood pressure of 53/30 mmHg.

Fifteen hours after ingestion the patient was oliguric to anuric despite catecholamines and an aggressive volume therapy. The patient was started on terlipressin every 6 h. Two hours after the first dose the blood pressure could be stabilized at 80/40 mmHg and the urine production started again, but there was still a volume overload of 7 L in the first 24 h.

The next day the patient’s blood pressure remained stable at low level with support of norepinephrine, dobutamine and terlipressin, insulin and calcium gluconate were still continued.

The patient started to complain about difficulties in breathing.

On physical examination he showed orthopnea, bilateral crackles and had distended jugular veins. Chest X-ray showed signs of cardiomegaly and pulmonary edema. The patient was started on non-invasive ventilation with CPAP, and furosemide was added to the therapy with good success. The patient was weaned from catecholamines 85 h after he had ingested the amlodipine. A cardiac echograph on day 4 showed a normal left ventricular ejection fraction. The patient was transferred to a psychiatric hospital 7 days after he had attempted suicide and finally he was discharged a few days later in good condition.

3. Methods

The analysis of amlodipine was performed using LC–MS/

MS with a method that had recently been validated [8,9].

Within-day and inter-day precision and accuracy showed relative standard deviations (R.S.D.) below 15%. Limit of detection (LOD) was 0.2 ng/mL, limit of quantitation (LOQ) was 1 ng/mL, range of linearity was 1–100 ng/mL.

The chromatographic system consisted of an HTC PAL autosampler (Chromtech GmbH, Idstein, Germany) fitted with a 100mL syringe (Hamilton Microliter Syringes, Chromtech) and two high pressure gradient pumps LC10AD (Shimadzu, Duisburg, Germany). The chromatographic separation was performed using a Luna RP-C18 (2) analytical column (150 mm2 mm i.d., 3.0mm, Phenomenex, Aschaffenburg), heated to 408C. The mobile phase consisted of solvent A (0.1%

formic acid with 1 mM ammonium formate, pH 2.7) and solvent B (acetonitrile/0.1% formic acid with 1 mM ammonium formate, 95:5, v/v). The following gradient was used for quantitative analysis of the compounds: 0–1 min, 20% B; 1–3 min, 20–40%

B (linear); 3–11 min, 40–70% B (linear); 11–12 min, 70–95% B (linear); 12–12.5 min, 95% B; 12.5–13.5 min, 95–20% B (linear); 13.5–15.5 min, 20% B.

For detection a triple–quadrupole MS/MS system (API 365, Applied Biosystems/Darmstadt, Germany) with turbo-ionspray source (ESI) and Analyst 3.1 Software was used. Quantitation was performed using a multiple reaction monitoring (MRM) method with the following transitions (precursor ion!product ion): m/z 409!294 and 409!238 for amlodipine, 480!315 for the internal standard nicardipine (Fig. 1).

Extraction of the samples was prepared by automated solid phase extraction. The extraction columns Bond Elut C18 (endcapped) 200 mg/3 mL (Varian, Darmstadt, Germany) were preconditioned with 2 mL methanol followed by 2 mL 0.05 M acetate buffer (pH 5). A 200mL of plasma, spiked with 50 ng of internal standard (10mL of a 5mg/mL methanolic solution) was diluted with 800mL blank human plasma and 1 mL acetate buffer and passed through the column which was then washed with 1 mL of the same acetate buffer to remove endogenous material of the samples. After drying the columns for 1 min with compressed nitrogen the compounds were finally eluted using 2 mL of a mixture of acetonitrile and 25% ammonium

S. Vogt et al. / Forensic Science International 161 (2006) 216–220 217

Fig. 1. Multiple reaction monitoring (MRM) chromatogram of a plasma sample (taken on day 1 at 16:02 h; amlodipine concentration: 248mg/L) showing two transitions for amlodipine (m/z409!294 and 409!238) and one transition for the internal standard (ISTD) nicardipine (m/z480!315).

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hydroxide solution (97:3, v/v). The eluates were evaporated to dryness under a stream of nitrogen. The residues were redissolved in LC-mobile phase (A:B, 70:30, v/v), vortex- mixed and transferred into brown glass autosampler vials. A 20mL aliquots were injected into the LC–MS/MS system.

Dilution of the plasma samples has been necessary to yield results in the linear range of the validated method. Urine was treated in the same way.

To make sure that nicardipine, a rarely prescribed dihydropyridine calcium antagonist, could be used as internal standard, the first three plasma samples and the first urine sample were tested for nicardipine and were found to be negative.

4. Results

The suspected amlodipine intoxication was confirmed.

Amlodipine was detected in toxic concentration in all plasma samples and in the two urine samples (Table 1). The maximum plasma concentration of amlodipine was 393mg/L measured on the day of hospitalization. After 8 days the amlodipine concentration (47mg/L) was still above therapeutic level (5–

18mg/L[3]). Unfortunately, plasma samples of the following days (day 9 until release) were not available.

With the marked values ofTable 1an elimination curve was drawn and the plasma half-life for this case was determined as approximately 55 h (Fig. 2). Plasma half-life is usually listed as 35–50 h but can increase in elderly subjects (65 h) [4] or in patients with hepatic impairment (54 h)[5].

5. Discussion

In 2003 there were 57 fatalities due to overdoses of calcium channel blockers reported to the American Association of Poison Control Centres, eight of them including overdoses of amlodipine[10]. In the literature there are several reports about lethal and survived amlodipine intoxications, some are listed in Table 2. Cases A, B and C present fatal cases. In case A drug interaction may be involved because of a toxic level of oxazepam, while the plasma concentration of amlodipine (185mg/L) was lower than in our case. Cases B and C both show very high blood concentrations but these are not directly comparable to the plasma concentrations, since the plasma/

whole blood ratio for amlodipine is unknown.

Patients of cases E, F and G (Table 2) survived amlodipine intoxication. The oral ingestions of amlodipine ranged from 50 to 600 mg—compared to a daily-recommended dose of 5–

10 mg. The peak plasma concentration (88mg/L) of case E with an intake of 50–100 mg amlodipine was much lower than in our case (393mg/L). Unfortunately, plasma concentrations of cases F and G have not been reported. Ingestion of 600 mg of amlodipine has been the highest reported dose in a survival so far[11]. Our case describes a suicide attempt with an overdose of 1000 mg amlodipine and a maximum plasma level of 393mg/L. However, the patient had vomited prior to admission.

Thus not all of the amlodipine was hemodynamically relevant but the measured plasma concentration (393mg/L) was still very high compared to the other reported cases.

Current concepts for the management of calcium channel blocker intoxication include intravenous calcium salts, glucagons and insulin-dextrose infusion for hyperinsulinemia- euglycemia [12–15]. In cases of severe intoxications fluid resuscitation and the use of catecholamines such as norepinephrine, epinephrine, dobutamine and dopamine can be necessary[11,16]. In the presented case, the usual management with calcium salts, insulin-dextrose infusion, glucagon, fluid resuscitation and epinephrine/norepinephrine was not sufficient to achieve hemodynamic stabilization. The initially started volume therapy was followed by a pulmonary edema so the patient had to be put on non-invasive CPAP ventilation. We assume that the pulmonary edema was caused by the reduced cardiac ejection fraction, the impaired renal function due to the hypotension and additionally by the volume overload of 7 L.

The main problem of the amlodipine intoxication is the prolonged hypotension due to the sustained-release formulation and the low metabolic clearance of amlodipine with a plasma half-life in a range from 35 to 65 h [4,12]. Terlipressin is an analogue of vasopressin with the advantage of a longer duration of action and it is used in vasodilatory shock states resistant to catecholamines[6,17]. In the presented case the hypotension and especially the reduced renal function could finally be

Table 1

Concentrations of amlodipine determined in plasma and urine samples Days after

hospitalization

Time of sampling (h)

Amlodipine concentration (mg/L)

Sample type

0^a 6:22 393 Plasma

0 8:02 390 Plasma

0 10:31 240 Plasma

0 11:24 3385 Urine

0 12:09 353 Plasma

0 16:03 379 Plasma

0 20:10 62125 Urine

1^a 6:12 269 Plasma

1 12:43 256 Plasma

1 16:02 248 Plasma

2^a 6:20 218 Plasma

3^a 6:08 131 Plasma

4^a 6:00 132 Plasma

5^a 6:00 90 Plasma

6^a 6:00 62 Plasma

7^a 8:00 50 Plasma

8^a 8:00 47 Plasma

a These data have been used for the elimination curve shown inFig. 2.

Fig. 2. Elimination curve drawn with the results of the plasma samples marked inTable 1. The plasma half-life was determined as approximately 55 h.

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stabilized by application of terlipressin. In our patient there were no adverse effects.

There are two case reports where vasopressin analogues have been used in hypotension due to sustained released calcium antagonists. Weisgerber et al. [7] (Table 2, case D) reported a patient who ingested 430 mg amlodipine in addition to 2 g isosorbide mononitrate, 250 mg benazepril and 600 mg of the antidepressant mirtazapine. It was possible to achieve hemodynamic stabilization by the vasopressin analog argipressin while the primary efforts with intravenous fluid resuscitation, calcium gluconate, glucagons, naloxone and norepinephrine failed. The patient developed a mesenteric ischemia 10 h after discontinuing argipressin and finally died.

Leone et al. [17] reported about a patient with an intoxication of 140 mg felodipine, another sustained-release calcium channel blocker. The patient remained hypotensive and developed an oliguric renal failure despite the initiated therapy with fluids, calcium gluconate, insulin, epinephrine and norepinephrine. By using terlipressin a hemodynamic stabilization could be achieved and the patient survived.

In another severe amlodipine poisoning unresponsive to conventional therapy metaraminol, a potent sympathomimetic amine that increases both systolic and diastolic blood pressure, has been used for treatment of amlodipine intoxication.

Following a loading bolus of 2 mg and intravenous infusion (83mg/min) of metaraminol there was improvement in the patient’s blood pressure, cardiac output and urine output[18].

6. Conclusions

Intoxications with calcium channel blockers are still difficult to treat and the usual management can fail in serious cases with high medication levels. Terlipressin or other vasopressin analogs can be an option to treat the hypotension in addition to the usual management. With terlipressin it might be possible to reduce the needed volume in patients with a reduced cardiac ejection fraction to prevent complications like pulmonary edema.

Although therapeutic drug monitoring for amlodipine does not exist, quantitation in cases of intoxication can be useful.

The overdose of 1000 mg amlodipine, which were not totally absorbed due to vomiting a few hours after uptake, survived, despite the highly toxic plasma concentration of 393mg/L.

The determined elimination half-life of 55 h was slightly higher than reported for healthy persons receiving therapeutic doses of amlodipine[4]. The fast recovery of the patient, who needed no more treatment with catecholamines 85 h after ingestion, is noteworthy because the amlodipine concentration (132mg/L) at that time was still above the assumed toxic level of 88mg/L[19].

References

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Table 2

Comparison of cases involving amlodipine overdoses

Case A[20] Case B[21] Case C[22] Case D[7] Case E[19] Case F[13] Case G[11] This case

Age (years) 63 50 15 78 42 20 23 42

Male/female F M F F F M F M

Dose of amlodipine

70 mg Unknown 140 mg 430 mg 50–100 mg 400 mg 600 mg 1000 mg

Plasma concentration of amlodipine

0.185 mg/L, 11 h after ingestion

2.2 mg/L post-mortem, blood

2.7 mg/L post-mortem, blood

Not reported 0.088 mg/L, 2.5 h after ingestion

Not reported

0.393 mg/L, 8.5 h after ingestion Other drugs

involved

Oxazepam:

5.5 mg/L (toxic level)

Traces of alcohol: 0.008%

Mefenamic acid:

2.0 mg/L (therapeutic level)

Mirtazapine:

0.2 mg/L, benazepril, isosorbide

mononitrate

Alcohol:

0.12%

– – Mefenamic acid,

chlorthalidone

Outcome Fatal Fatal Fatal Fatal Survived Survived Survived Survived

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