CME Poisons 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 blood pressure has decreased by HK Ruben Thanacoody MD FRCP(Ed), clinical consequences of hypotension 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 blood pressure. 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 receptor 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 drug overdose, and many drugs can towards detecting severe hypotension overdose with an ARB. Other pressor cause cardiovascular manifestations, and evidence of organ hypoperfusion. agents, such as norepinephrine (nora- which include effects on heart rate and Patients should be monitored closely, drenaline), exert a direct pressor effect blood pressure, electrocardiographic with frequent assessment of heart rate, on blood vessels and may improve sys- (ECG) abnormalities and arrhythmias 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 toxicity 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, calcium The main aim of treatment is to pre- channel blockers, cardiac glycosides and serve adequate systemic blood pressure tricyclic antidepressants. 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 adenosine monophosphate Mechanism of toxicity consideration given to the ‘usual blood (cAMP), which promotes calcium pressure’ before drug overdose. 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 channel blocker overdose Clinical features refractory to conventional treatment The onset of hypotension is rapid, usually Digoxin-specific Fab antibody 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 antidepressant poisoning 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: arrhythmia, calcium channel blocker, hypotension, poisoning, sodium ischaemia and metabolic acidosis. The bicarbonate, tricyclic antidepressants 92 Clinical Medicine Vol 8 No 1 February 2008 CME Poisons 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 Bradycardia Tachycardia heart disease. Non-selective β adrenoceptor antagonists and those with membrane-stabilising properties (for example, Amiodarone Amphetamines propranolol) are particularly toxic. Sotalol also blocks the β adrenoceptor antagonists Antipsychotics delayed rectifier potassium current and delays ventricular β Calcium channel blockers 2 receptor agonists repolarisation. Cholinesterase inhibitors Caffeine Clonidine Cocaine 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- Opiates Nitrates genic shock. Conduction abnormalities – for example, sinoa- SSRIs Sympathomimetic agents trial block and atrioventricular block – 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, bronchospasm and hypoglycaemia have also been reported. Hypotension Hypertension Angiotensin-converting Amphetamines Management enzyme inhibitors Cocaine Administration of atropine (up to 3 mg intravenously) may Anticonvulsant drugs Ecstasy (MDMA) be used for the initial management of bradycardia and Antihistamines Monoamine oxidase inhibitors hypotension. Isoprenaline infusion or temporary cardiac Antipsychotic drugs pacing may be used for resistant bradycardia or atrioven- β adrenoceptor antagonists tricular block. Unless the patient has pulmonary oedema, Benzodiazepines 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 cardiogenic shock and should be administered as an intra- Tricyclic antidepressant drugs Amiodarone 3 venous bolus of 5–10 mg. Further boluses or an infusion of Flecainide Antihistamines glucagon should be used only if there is a good clinical Antipsychotic drugs response. Adverse effects of glucagon include vomiting, Azole antifungal agents hyperglycaemia, hypokalaemia and hypocalcaemia. Macrolide antibiotics In patients with refractory hypotension, other inotropes Methadone (dobutamine, dopamine 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 Diltiazem and verapamil 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- Thyroid hormones nels. Dihydropyridine-based CCBs (for example, nifedipine Tricyclic antidepressants and amlodipine) act mainly on vascular smooth muscle 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 insulin. Clinical Medicine Vol 8 No 1 February 2008 93 CME Poisons 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 heart block overdose with CCBs by reversing the state lular sodium leads to reduced calcium and asystole.