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Home , Calcium channel blocker, Catecholaminergic, Digoxin toxicity, Sotalol

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Toxins that affect the cardiovascular system tension should be considered severe when there is clinical or investigative evi- dence of organ hypoperfusion or when systolic pressure has decreased by HK Ruben Thanacoody MD FRCP(Ed), clinical consequences of are Consultant Physician usually most severe in patients with pre- more than 30 mmHg or is consistently lower than 90 mmHg. W Stephen Waring PhD FRCP(Ed), existing cardiovascular disease, who are If severe hypotension occurs despite Consultant Physician less able to compensate for changes in adequate intravenous hydration, the use National Poisons Information Service . Hyperkalaemia may of intravenous pressor agents should be (Edinburgh Unit), Royal Infirmary of occur as a result of impaired renal func- considered. This normally should be Edinburgh, Edinburgh tion and also perhaps as the direct effect of inhibition of ACE or angiotensin undertaken in a critical care environ- ment, with close attention paid to fluid Clin Med 2008;8:92–95 blockade on renal electrolyte transport. status, electrolyte balance and organ per- fusion. Intravenous administration of Introduction angiotensin II, where available, allows Management Cardiotoxic effects account for a large systemic blood pressure to be restored after overdose with an ACE inhibitor, but proportion of the mortality arising from Early management should be directed it is not expected to be very effective after overdose, and many can towards detecting severe hypotension overdose with an ARB. Other pressor cause cardiovascular manifestations, and evidence of organ hypoperfusion. agents, such as (nora- which include effects on rate and Patients should be monitored closely, drenaline), exert a direct pressor effect blood pressure, electrocardiographic with frequent assessment of , on blood vessels and may improve sys- (ECG) abnormalities and systemic blood pressure and cognitive temic blood pressure. High doses may be (Table 1). This article discusses the car- state. Concentrations of electrolytes, urea required, and caution is needed to avoid diovascular management of with and creatinine in serum, urine output, exacerbating organ hypoperfusion. angiotensin-converting enzyme (ACE) fluid balance and electrocardiographs Where pressor agents are used, these are inhibitors and angiotensin receptor should be monitored. normally required only for ≤12 hours. blockers (ARBs), β blockers, The main aim of treatment is to pre- channel blockers, cardiac glycosides and serve adequate systemic blood pressure tricyclic . to allow adequate tissue perfusion and β adrenoceptor blocking drugs oxygenation. Sufficient intravenous crys- Mechanism of toxicity Angiotensin-converting enzyme talloid fluids should be given to correct dehydration and, thereafter, to maintain Stimulation of β receptors on cardiac inhibitors and angiotensin 1 receptor blockers hydration. Severe hypotension must be myocytes results in an increase in the determined on an individual basis, with level of cyclic monophosphate Mechanism of toxicity consideration given to the ‘usual blood (cAMP), which promotes calcium pressure’ before . Hypo- influx via voltage-gated L-type channels. The ACE inhibitors block the conversion of angiotensin I to the potent vasocon- strictor angiotensin II, whereas ARBs Key Points competitively inhibit angiotensin II receptor binding. The major toxic effects After drug overdose, cardiovascular toxicity may manifest as haemodynamic of ACE inhibitors and ARBs are haemo- instability, electrocardiographic changes or rhythm disturbances dynamic, and these are most pronounced when the drugs are taken in combination Patients who ingest drugs with cardiovascular effects should have frequent monitoring of vital signs and continuous cardiac monitoring with other drugs that decrease blood pressure. Glucagon may be helpful in reversing the cardiac effects of β blocker overdose

Insulin and glucose treatment shows promise for calcium overdose Clinical features refractory to conventional treatment

The onset of hypotension is rapid, usually -specific Fab fragments are available to treat hyperkalaemia and within 1–2 hours of ingestion, and may arrhythmias associated with digoxin toxicity persist for more than 24 hours.1 In most 2 Arrhythmias that result from tricyclic are best treated with cases, haemodynamic effects are mild, hypertonic sodium bicarbonate rather than antiarrhythmic agents but severe hypotension occasionally may give rise to acute renal failure, myocardial KEY WORDS: , blocker, hypotension, poisoning, sodium ischaemia and metabolic acidosis. The bicarbonate, tricyclic antidepressants

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All β adrenoceptor blocking drugs antagonise these effects Table 1. Some drugs characteristically associated with and can cause serious cardiotoxicity in overdose, particu- significant cardiovascular toxicity. larly in elderly people and those with underlying ischaemic heart disease. Non-selective β adrenoceptor antagonists and those with membrane-stabilising properties (for example, Amphetamines ) are particularly toxic. also blocks the β adrenoceptor antagonists delayed rectifier current and delays ventricular β Calcium channel blockers 2 receptor repolarisation. Cholinesterase inhibitors Caffeine Clinical features Digoxin Ecstasy (MDMA) The main cardiac effects are bradycardia and hypotension, GHB Monoamine oxidase inhibitors which may lead to syncope, pulmonary oedema and cardio- genic shock. Conduction abnormalities – for example, sinoa- SSRIs Sympathomimetic agents trial block and – may occur. Sotalol Theophylline may cause QTc prolongation and torsade de pointes after Tricyclic antidepressants overdose. Seizures, delirium and coma may occur after over- Venlafaxine dose with lipid-soluble β blockers. Respiratory depression, and hypoglycaemia have also been reported. Hypotension

Angiotensin-converting Amphetamines Management enzyme inhibitors Cocaine Administration of (up to 3 mg intravenously) may drugs Ecstasy (MDMA) be used for the initial management of bradycardia and Antihistamines Monoamine oxidase inhibitors hypotension. infusion or temporary cardiac drugs pacing may be used for resistant bradycardia or atrioven- β adrenoceptor antagonists tricular block. Unless the patient has pulmonary oedema, hypotension should be corrected initially with intravenous Calcium channel blockers fluids, preferably with central venous pressure monitoring. SSRIs Glucagon acts on glucagon receptors to activate adenyl Tricyclic antidepressants cyclase, which leads to an increase in cAMP, which, in turn, causes an increase in myocardial intracellular concentra- Venlafaxine tions of calcium, thereby enhancing myocardial contrac- QRS prolongation QTc* prolongation tility. Glucagon has been used successfully to treat and should be administered as an intra- drugs Amiodarone 3 venous bolus of 5–10 mg. Further boluses or an infusion of Antihistamines glucagon should be used only if there is a good clinical Antipsychotic drugs response. Adverse effects of glucagon include vomiting, Azole agents hyperglycaemia, hypokalaemia and hypocalcaemia. Macrolide In patients with refractory hypotension, other (, and phosphodiesterase inhibitors) SSRIs Sotalol and the use of intra-aortic balloon counterpulsation may help maintain an adequate cardiac output. Atrioventricular block Tachyarrhythmia

β blockers Antihistamines Calcium channel blocking drugs and Antipsychotic drugs Mechanism of toxicity Digoxin Digoxin Lithium Flecainide Calcium channel blockers (CCBs) are direct inhibitors of Zopiclone SSRIs calcium influx through voltage-gated L-type calcium chan- nels. Dihydropyridine-based CCBs (for example, Tricyclic antidepressants and ) act mainly on vascular and Venlafaxine cause peripheral vasodilatation, while diltiazem and vera- pamil act on myocardial and conducting tissue and reduce *Heart rate-corrected QT interval. GHB = gamma-hydroxybutyric acid; myocardial contractility and conduction. Calcium channel MDMA = 3,4-methylenedioxymethamphetamine; SSRI = selective serotonin reuptake inhibitor. blockers also reduce pancreatic secretion of .

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Clinical features ther doses at 15-minute intervals up to a Digoxin maximum of four doses. Concentrations Myocardial depression and peripheral of calcium in serum should be monitored. Mechanism of toxicity vasodilatation lead to profound hypo- Increasing evidence suggests that ‘hyper- Cardiac glycosides inhibit the Na+/K+ tension. Bradyarrhythmias may occur, insulinaemic euglycaemia’ (HIE) treat- ATPase pump in myocardial and con- including junctional escape rhythms, ment is beneficial for hypotension after ducting tissue. The increase in intracel- second-degree and complete overdose with CCBs by reversing the state lular sodium leads to reduced calcium and asystole. of relative insulin deficiency and resistance efflux by the Na+/Ca2+ exchange mecha- Other non-cardiovascular features and improving myocardial carbohydrate nism, which results in increased intra- include , vomiting, dizziness, agi- uptake, thereby switching the main sub- cellular concentrations of calcium. tation, and occasionally coma strate of from free fatty acid in cases of severe poisoning. Metabolic to carbohydrates.3 Insulin is administered Clinical features acidosis, hyperkalaemia, hypocalcaemia as a bolus dose followed by a glucose and and hyperglycaemia may be present. insulin infusion (Box 1).4 Anecdotal evi- Acute overdosage usually causes marked Seizures have been reported. dence supports the use of a 10 mg intra- bradycardia with PR and QRS prolonga- venous bolus of glucagon, which is tion. Sinus arrest and varying degrees of Management followed by an infusion (3–6 mg/hour) in atrioventricular block with dissociation responders. agents or escape rhythms may occur and cause Unless the patient has pulmonary such as epinephrine, dopamine and haemodynamic instability, but more oedema, hypotension should be corrected may be needed to maintain serious ventricular dysrhythmias are initially with intravenous fluids, prefer- an adequate cardiac output; isoprenaline uncommon. ably with central venous pressure moni- infusion may worsen hypotension. toring. In patients with significant Temporary cardiac pacing should be Management hypotension or bradycardia, calcium chlo- considered for resistant bradycardia or ride should be administered (0.2 ml/kg of atrioventricular block. A 12-lead ECG should be obtained, and 10% solution over five minutes), with fur- cardiac rhythm should be monitored continuously. Serum electrolytes should be measured urgently, and any elec- Box 1. Overview of hyperinsulinaemic euglycaemia protocol for management trolyte disturbances (hypokalaemia or of β blocker and toxicity. Adapted from Reference 4. hypomagnesaemia) and acidosis should be corrected. Concentrations of digoxin Check concentrations of glucose in serum: should be measured at least six hours • If <10 mmol/l, give 50 ml of 50% dextrose after ingestion. Atropine (1.2 mg intra- Check concentrations of potassium in serum: venously) may be given for marked • If <2.5 mmol/l, give 20 mmol KCL intravenously over at least 30 minutes bradycardia and atrioventricular block. Give 1 unit/kg bolus of insulin followed by insulin infusion of 0.5–1.0 unit/kg/hour Digoxin-specific neutralising Fab anti- titrated to clinical response body fragments (Digibind) are indicated Administer 10% dextrose intravenously during insulin infusion if hyperkalaemia is present, bradyarrhyth- Check capillary blood glucose every 20 minutes for one hour and then hourly mias are unresponsive to atropine or a Check concentrations of potassium in serum hourly patient has life-threatening ventricular arrhythmias. Doses sufficient for com- Target systolic blood pressure >100 mmHg and heart rate >50 beats per minute plete neutralisation of total body digoxin KCL = potassium chloride. burden should be used in patients who take an acute overdose while on treatment with digoxin (Table 2), although lower Table 2. Method for estimating dose of Digibind needed for doses may be effective for overdose in complete neutralisation. digoxin-naive patients and those with 5 Known value Equation to estimate dose of Digibind chronic digoxin intoxication. If digoxin-specific are not Dose of digoxin Number of vials = available, bradycardia or atrioventricular ingested amount of digoxin ingested (mg) × 1.6 block unresponsive to atropine may be Serum digoxin Number of vials = managed by temporary cardiac pacing, × concentration serum digoxin concentration (ng/ml) weight (kg) and ventricular arrhythmias may respond 100 to intravenous (8 mmol

Note: dose of ingested digoxin is in milligrams not micrograms. intravenous bolus) despite a normal serum magnesium concentration.6 The

94 Clinical Medicine Vol 8 No 1 February 2008 CardiacInhibitionVascularcontributeHistamine-receptor delayedsodium α of toadrenergicnorepinephrine cardiovascular channelrectifier blockade blockade blockadepotassium reuptake toxicity. (membrane-stabilising channel at nerve (I )terminals blockade or ‘-like’ activity) Anticholinergic1 activity at autonomic nerve endingskr and in the brain

Box 2. Pharmacological properties of tricyclic antidepressants thought to

CME Poisons

Box 2. Pharmacological properties of tricyclic antidepressants thought to euglycaemia) therapy in acute calcium contribute to cardiovascular toxicity. channel antagonist and beta-blocker poisoning. Toxicol Rev 2004;23:215–22. 4 Salhanick SD, Shannon MW. Management Anticholinergic activity at autonomic nerve endings and in the brain of calcium channel antagonist overdose. Inhibition of norepinephrine reuptake at nerve terminals Drug Saf 2003;26:65–79. α Vascular 1 blockade 5 Bateman DN. Digoxin-specific antibody Cardiac blockade (membrane-stabilising or ‘quinidine-like’ activity) fragments. How much and when? Toxicol Rev 2004;23:135–43. Cardiac delayed rectifier (I ) blockade kr 6 Chen JY, Liu PY, Chen JH, Lin LJ. Safety of Histamine-receptor blockade transvenous temporary cardiac pacing in patients with accidental digoxin overdose and symptomatic bradycardia. Cardiology 2004;102:152–5. use of class 1a and 1c antiarrhythmic ECG pattern (downsloping ST segment 7 Thanacoody HK, Thomas SH. Tricyclic drugs (for example, quinidine, flecainide elevation in leads V1–V3 in association antidepressant poisoning: cardiovascular and ) should be avoided, as with right bundle branch block) was seen toxicity. Toxicol Rev 2005;24:205–14. they may worsen atrioventricular nodal in about 15% of cases of tricyclic anti- 8 Goldgran-Toledano D, Sideris G, conduction. overdose.8 Kevorkian JP. Overdose of cyclic antidepressants and the Brugada syndrome. N Engl J Med 2002;346:1591–2. Tricyclic antidepressants Management 9 Hoffman JR, Votey SR, M et al. Effect of hypertonic sodium bicarbonate in the Mechanism of toxicity Cardiac rhythm should be monitored treatment of moderate-to-severe cyclic continuously, and a 12-lead ECG should antidepressant overdose. Am J Emerg Med Tricyclic antidepressants have complex 1993;11:336–41. be performed to determine the QRS pharmacological properties that con- duration. Hypotension should be man- tribute to their cardiotoxicity (Box 2). aged initially by administration of intra- venous fluids. Seizures should be Clinical features managed aggressively to minimise the risk of hypoxia. Anticholinergic effects include sinus Alkalinisation with intravenous tachycardia, hot dry skin, dry mouth and boluses (50 ml) of hypertonic 8.4% tongue, dilated pupils, sodium bicarbonate is the treatment of and ileus. Central fea- choice for arrhythmias and hypotension tures include nystagmus, divergent unresponsive to fluid administration. It squint, drowsiness and convulsions, should also be administered in patients which may progress to respiratory who have metabolic acidosis or a QRS depression and deep coma. Increased duration >120 ms. Further doses of tone and hyperreflexia may be present sodium bicarbonate may be given cau- with extensor plantar reflexes, but all tiously until the ECG normalises or to reflexes may be absent in deep coma. achieve an arterial pH of 7.45–7.55.9 Seizures may occur, and the associated Antiarrhythmic agents (especially class hypoxia may precipitate arrhythmias. Ia and Ic drugs) are best avoided if Delayed propagation of depolarisation arrhythmias occur. After , in the atrioventricular node, His- prolonged resuscitation may be suc- Purkinje fibres and ventricular myo- cessful and should be continued for at cardium leads to prolongation of the PR least one hour if appropriate. and QRS interval and may give rise to ECG changes that mimic myocardial infarction (ST segment elevation and References T wave inversion). The QTc interval may 1 Lucas C, Christie GA, Waring WS. Rapid be prolonged because of delayed repolar- onset of haemodynamic effects after isation. The most specific electrocardio- angiotensin converting enzyme-inhibitor graphic sign of toxicity from tricyclic overdose: implications for initial patient antidepressants is right axis deviation of triage. Emerg Med J 2006;23:854–7. the terminal 40-ms vector of the QRS 2 Forrester MB. Adult ingestions reported to Texas control centers, complex in the frontal plane (T 40-ms 1998–2005. Hum Exp Toxicol 2007;26:483–9. axis), as indicated by an R wave in aVR, 3 Mégarbane B, Karyo S, Baud FJ. The role of with an S wave in lead I.7 The Brugada insulin and glucose (hyperinsulinaemia/

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