Netherlands Journal of Critical Care

Copyright © 2011, Nederlandse Vereniging voor Intensive Care. All Rights Reserved. Received July 2010; accepted September 2010

Case Report

Use of terlipressin in amitriptylin overdose

DLJ Moolenaar1, BM van der Oord2, A Manten2

1 Department of Internal Medicine, Meander Medical Centre, Amersfoort, The Netherlands 2 Department of Intensive Care, Meander Medical Centre, Amersfoort, The Netherlands

Abstract - This case report describes a patient with severe hypotension due to amitriptyline intoxication not responding to volume suppletion, sodium bicarbonate administration and high dose vasopressive therapy. A very good response was elicited by administering 2 mg of terlipressin which resulted in a quick and uneventful recovery within a few hours.

Keywords - Tricyclic poisoning, hypotension/chemically induced, terlipressin

Introduction loading dose of 100 mmol (100 ml of 8.4% solution). Shortly after Amitriptyline is an important member of the group of tricyclic admission, the patient developed deep hypotension with warm antidepressants and has been used to treat depression since extremities and a central venous pressure of 10 mmHg. The the 1950s. Unfortunately, it is also a commonly used drug in hypotension was refractory to our volume expansion, additional intentional overdose. In a retrospective Dutch analysis, up to bicarbonate administration of 200 mmol (200 ml of 8.4% solution) 25% of intoxication-related ICU admissions were found to be due and high dose norepinephrine therapy (up to 1.5 microgram/ to tricyclic overdose, even though other antidepressant drugs kg/min), and eventually dropped to 60/30 mmHg. During this (mostly SSRIs) where prescribed more often [1]. deep hypotension, the patient had multiple severe generalized tonic-clonic seizures, for which we successfully administered Case report clonazepam and midazolam. A 49-year old man was brought to the emergency department after having ingested 190 tablets of amitriptyline 75 mg and approximately 1 litre of whiskey. He had been found unconscious Table 1. Laboratory results. by the paramedics, alerted by his wife after she had received a text message from him. His medical history stated that he had been under psychiatric treatment since 2007 for major 1 2 3 4 5 6 7 depression. pH 7.31 7.39 7.11 7.23 7.52 7.59 7.56 On admission he was comatose with a Glasgow Coma Score pCO2 (kPa) 6.3 5.4 11.1 7.5 4.4 3.8 4.7 of E1M1V1. His blood pressure was within normal range, his Bicarbonate 23 24 26 23 27 26 31 pulse was rapid and regular, his breathing was deep and slow (mmol/l) and his body temperature was 35°C. The rest of his physical pO2 (kPa) 24.9 16.6 23 31.1 12.6 12 12.8 examination was unremarkable. Saturation 99% 98% 99% 99% 98% 98% 98% Initial laboratory results showed a respiratory acidosis, with Base excess -3 -1 -6 -5 4 6 9 preserved oxygenation (table 1). His ethanol level was 0.6‰. The Lactate 11.1 8.7 4.5 initial ECG showed an accelerated idioventricular rhythm at 130 (mmol/l) beats per minute, a prolonged QRS-interval of 162 milliseconds Amitriptyline 1350 and some repolarisation abnormalities (figure 1). (ug/L) The diagnosis of severe combined amitriptyline- and alcohol Nortriptyline 210 intoxication was made and the patient was admitted to our (ug/L) intensive care unit where he was intubated and mechanically 1. Hospital admission. ventilated. 2. After mechanical ventilation was started and treatment with sodium We initiated general supportive care and administered bicarbonate initiated. activated charcoal and sodium bicarbonate 12 mmol/hr after a 3. during seizure and deep hypotension, three hours after admission. 4. directly after the seizure was terminated. Correspondence 5. An extra dose of 200 mmol (200ml of NaHCO3 8,4%) was given in 30 min.

A. Manten 6. two hours later terlipressin was given. 7. three hours later norepinephrine was almost discontinued E-mail: [email protected]

76 NETH J CRIT CARE - VOLUME 15 - NO 2 - APRIL 2011 Netherlands Journal of Critical Care Use of terlipressin in amitriptylin overdose

An ECG was made immediately following the seizures and showed Tricyclic antidepressant drugs are highly lipid soluble and rapidly a widening of the QRS-complex resembling an almost sinusoid absorbed from the gastro-intestinal tract. Peak levels usually wave, and was classified as an accelerated idioventricular rhythm occur within 2 hours. Because of its high lipid-solubility, it is (figure 2). Amitriptyline- and nortriptyline levels were drawn widely distributed into tissues and therefore has a high volume shortly afterwards, and established as very high – amitriptyline of distribution. 1350 ug/L and nortriptyline 210 ug/L, which is more than three Most of the tricyclic antidepressants are highly protein-bound: times the lower limit of toxicity [2]. less than 10% is unbound to protein (mostly albumine) depending Terlipressin was administered intravenously in a dose of 2 mg, on the pH of plasma. In acidosis, the bound fraction decreases after which the blood pressure returned to almost normal levels whereas in alkalosis it increases. This is especially important with within minutes and required only slight amounts of norepinephrine amitriptyline, as a pH higher than 7.4 can increase the protein- to be maintained. No additional administration of terlipressin was bound fraction by more than 42% [2]. needed. Amitriptyline is metabolized to nortriptyline and 10-hydroxynor­ The patient regained consciousness within 24 hours. He was triptyline by the hepatic cytochrome P-450 oxidative enzyme- extubated and on neurologic examination appeared to have system. This system saturates quickly in overdose, increasing suffered no permanent sequelae from this incident. He was the elimination half-life time by as much as 100% in some cases. discharged to the psychiatric ward the next day. His ECG on Because of the high protein-bound fraction, renal excretion is discharge is shown in figure 3. only 3% to 10% [2]. All tricyclics share their most potent pharmacological effect: Discussion a histamine-antagonism, which accounts for their sedative Amitriptyline is a tricyclic antidepressant and was approved as an properties, and reflect their origin; most if not all neuroleptics and anti-depressant in the USA in the 1950s, and shortly thereafter tricyclics were developed in the 1950s from antihistamines [4]. in the European Union and the Netherlands. Because of its The postsynaptic alpha-adrenergic receptor antagonist effect side-effects and lethality in overdose, it is no longer used as a is responsible for postural hypotension in therapeutic ranges and first-line drug when treating major depressive episodes, but has severe hypotension in overdose. From table 2, it may be deducted been replaced with serotonin reuptake inhibitors (SSRI), which that amitriptyline has the most potent affinity for theα -adrenergic are safer when taken in overdose [3]. However, it is still used receptor, as does its direct metabolite nortriptyline [5]. It also in the treatment of several other psychiatric disorders, such as blocks the GABA-a (gamma-aminobutyric acid) receptor, which obsessive-compulsive disorder, nocturnal enuresis, anxiety and may contribute to the development of seizures. By blocking the sleeping disorders. Furthermore, amitriptylin is used for the muscarine receptor, it has a potent anti-cholinergic effect, which treatment of neuropathic pains. can manifest as mildly as non-responsive wide pupils, or as

Figure 1. ECG on presentation. Note the widened QRS-complex and the tachycardia, both hallmarks of severe amitriptylin intoxication.

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Tabel 2. Receptor profile, Ki (nmol/l), of TCAs and comparator drugs: severely as a full-blown anti-cholinergic syndrome with delirium, uptake inhibition and receptor antagonism (HCR data) urine retention, dry skin, tachycardia and paralytic ileus. Cardiac toxicity stems primarily from the blockade of sodium channels, thereby prolonging the QRS-complex and promoting Drug Reuptake Post-synaptic receptor arrhythmias. This association is so strong that a correlation exists inhibition antagonism between free TCA-drug concentration and QRS-prolongation, so that a wider QRS should be interpreted as an increased free TCA 5-HT NA H1 a1 Musc 5-HT2A concentration. A prolonged QT-interval is the result of blockade Mirtazapine* >10000 4600 0.14 500 670 16 of the potassium channels responsible for repolarisation, giving Mianserin* >4000 71 0.40 34 820 7 rise to dysrythmia generation (e.g. ventricular tachycardia). Doxepin 68 29.5 0.24 24 83 25 The most important therapeutic modalities in TCA poisoning Amitriptyline 20 50 1 27 18 29 are gastrointestinal adsorption via activated charcoal and the Imipramine 7 60 40 32 46 80 administration of sodium bicarbonate to promote the binding of Clomipramine 0.14 54 15 32 25 35 TCA to protein. Because it has such a high protein-bound fraction Nortriptyline 100 10 6.3 55 37 44 and volume of distribution, haemodialysis or haemofiltration are Dothiepin 78 70 4 400 38 260 not effective. Recently, several case reports have been published Desipramine* 18 0.83 110 100 100 280 documenting successful treatment with plasmapheresis [6,7]. Reboxetine* 58 7.2 310 >1000 >1000 >1000 Activated charcoal adsorbs tricyclic drugs, thereby preventing absorption and promoting removal. Its use is limited, however, Abbreviations: HCR, human cloned receptor. because of the quick absorption of TCAs from the gastro- Smaller Ki values represent greater potency. Note: where values are available from different laboratories and different experiments, affinities intestinal tract, decreasing usefulness 2-4 hours after ingestion. can vary by about one order of magnitude; mid-range values are given Also, several severe pulmonary complications have been repor­ (Table 2a and b gives ranges). ted, of which aspiration of stomach content or activated char­coal Receptors: H1, Histamine type 1; Musc, acetylcholine muscarinic; a” a, is the most important [8]. adrenoceptor. Note that no HCR data are known for lofepramine. Sodium bicarbonate alkalinizes plasma, increasing the protein- All data have been extracted from PDSP Kj database, http://pdsp.med. bound fraction of TCAs and decreasing sodium-channel binding, unc.edu/pdsp.php (except *Richelson, 2001). thereby alleviating cardiac toxicitiy. It also creates hypertonicity, which has a similar effect on cardiac sodium channels. The risks

Figure 2. ECG directly after clonic-tonic seizures and during deep refractory hypotension. Increased widening of the QRS-complex signifying increased TCA-levels

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of this treatment are primarily hypernatraemia and pulmonary it has a half-life of about 1 hour, necessitating a 6-hour dosing oedema respectively. Because of these side-effects, sodium scheme. It is currently licensed for the management of acute bicarbonate should only be given when cardiac toxicity is variceal bleeding. Inherent to its pharmacological profile, the suspected (widened QRS-interval or frank dysrythmias), or to main drawback of terlipressin is its ability to cause severe arterial reverse hypotension and acidosis. When hypotension develops, constriction, causing end organ ischaemia [10,11]. several guidelines advise giving generous volume expansion Terlipressin specifically and vasopressin in general have been and to use norepinephrine cautiously, as it can worsen cardiac implicated in treating severe septic shock [12,13], hypotension arrhythmias. in calcium channel blocker overdose [14], vasodilatory and/or Vasopressin is a peptide hormone, common to most cardiogenic shock [11], and in treating hepatorenal syndrome mammals. It is produced in the hypothalamus and secreted [11,15], Terlipressin has successfully been used in tricyclic by the posterior part of the pituitary gland. Under physiologic overdose in two other cases in the literature [16,17]. Theoretically, circumstances it is secreted in response to hyperosmolality, there is a strong rationale for its use in treating hypotension in hypotension or hypovolaemia. It exerts its action via 3 receptor tricyclic intoxication instead of norepinephrine, since TCAs types, called V(asopressin) 1, V2 and V3. The V1 receptor is compete with catecholamines to bind to alpha-adrenergic mostly involved with vasoconstriction, V2 with water retention receptors while terlipressin accomplish vasoconstriction by and V3 with ACTH (adrenocorticotropin hormone) release. stimulation of V1 receptors. In our patient, terlipressin was given The V1 receptor is expressed on smooth muscle cells of the successfully and without complications. vessels. After binding and activation of the V1 receptor by vasopressin, phospholipase-C is activated which, by promoting Conclusion. the formation of inositol triphosphate (IP3), releases calcium from We report a case of acute tricyclic intoxication, complicated the sarcoplasmatic reticulum which causes contraction and thus by severe vasodilatory hypotension refractory to volume and vasoconstriction. This pathway is called the phosphatidylinositol vasopressive therapy, that was successfully and safely treated pathway and is the final common pathway for α1-agonists, with terlipressin. There is a strong pathophysiological rationale angiotensin and vasopressin, all acting through their respective for its use in these circumstances. receptors (figure 4) [9]. Terlipressin, triglycyl-lysine-vasopressin, is a synthetic vaso­ pressin analogue, and a relative selective agonist for the V1 receptor (V1-V2 ratio of 2:1, as compared to vasopressin). After injection, it is metabolized to lypressine by the enzymatical removal of the triglycyl group. Elimination is via the urine, and

Figure 3. ECG on discharge

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Figure 4. The phosphatidylinositol pathway. [18] References

1. Bosch TM, van der Werf TS, Uges DR et al. Antidepressants self-poisoning and ICU admissions in a university hospital in The Netherlands. Pharm World Sci 2000;22:92-95. 2. Dawson AH. Cyclic Antidepressant Drugs. In: Dart RC, editor. Medical Toxicology. 3rd ed ed. Philadelphia: Lippincott, Williams & Wilkins; 2004:834-843. 3. Farmacie in Cijfers. Pharm Weekblad 2002;137:245. 4. Fangmann P, Assion HJ, Juckel G, Gonzalez CA, Lopez-Munoz F. Half a century of antidepressant drugs: on the clinical introduction of monoamine oxidase inhibitors, tricyclics, and tetracyclics. Part II: tricyclics and tetracyclics. J Clin Psychopharmacol 2008;28:1-4. 5. Gillman PK. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J Pharmacol 2007;151:737-748. 6. Kolsal E, Tekin IO, Piskin E et al. Treatment of severe amitriptyline intoxication with plasmapheresis. J Clin Apher 2009;24:21-24. 7. Nenov VD, Marinov P, Sabeva J, Nenov DS. Current applications of plasmapheresis in clinical toxicology. Nephrol Dial Transplant 2003;18 Suppl 5:v56-v58. 8. Dart RC. Gastrointestinal Decontamination. In: Dart RC, editor. Medical Toxicology. 3rd ed ed. Philadelphia: Lippincott, Williams & Wilkins; 2004:32-39. 9. Klabunde RE. Vascular Function. In: Klabunde RE, editor. Cardiovascular physiology concepts. Philadelphia: Lippincott Williams & Wilkins; 2005:91-116. 10. den Ouden DT, Meinders AE. Vasopressin: physiology and clinical use in patients with vasodilatory shock: a review. Neth J Med 2005;63:4-13. 11. Treschan TA, Peters J. The vasopressin system: physiology and clinical strategies. Anesthesiology 2006;105:599-612. 12. Dellinger RP, Levy MM, Carlet JM et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008;36:296-327. 13. O’Brien A, Clapp L, Singer M. Terlipressin for norepinephrine-resistant septic shock. Lancet 2002;359:1209-1210. 14. Kanagarajan K, Marraffa JM, Bouchard NC, Krishnan P, Hoffman RS, Stork CM. Various vasoactive mediators each activate phospholipase C (PL-C) The use of vasopressin in the setting of recalcitrant hypotension due to calcium channel through their own respective receptor causing the formation of inositol blocker overdose. Clin Toxicol (Phila) 2007;45:56-59. triphosphate (IP3) from phosphatidylinositol (PIP2), which in turn stimu- 15. Gines P, Schrier RW. Renal failure in cirrhosis. N Engl J Med 2009;361:1279-1290. lates the sarcoplasmic reticulum (SR), causing contraction through the 16. Barry JD, Durkovich DW, Williams SR. Vasopressin treatment for cyclic antidepres- release of calcium. sant overdose. J Emerg Med 2006;31:65-68. 17. Zuidema X, Dunser MW, Wenzel V, Rozendaal FW, de Jager CP. Terlipressin as an adjunct vasopressor in refractory hypotension after tricyclic antidepressant intoxication. Resuscitation 2007;72:319-323. 18. CV Physiology: Vascular Signal Transduction Mechanisms (G-Protein, IP3 and cGMP Linked). http://www cvphysiology com/Blood%20Pressure/BP011b htm, 2008 (Accessed July 22, 2010) .

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