- Email: [email protected]
Calcium Channel Blockers
POISONOUS SUBSTANCES
and moderate CNS penetration. The free fraction of verapamil may increase in overdose. All are metabolized in the liver to less active or inactive metabolites. The half-life of nifedipine, verapamil and diltiazem in therapeutic use is short (3–8 hours). Newer dihydropyridine drugs have considerably longer half-lives. The apparent half-life of many CCBs appears to be longer following overdose but is generally thought to reflect rate-limited absorption. There may be significant enterohepatic circulation, particularly with verapamil. Verapamil has two enantiomers with different kinetics and activity. The S isomer is more active but has a shorter half-life and lower bioavailability than the R isomer. The greater proportion of available S isomer is the major reason why intravenous verapamil has more cardiac effects for a given serum concentration than oral verapamil. Controlled-release preparations – because of their short halflives, the older CCBs (verapamil, diltiazem and nifedipine) are often sold as controlled-release preparations. The pharmacokinetics of these preparations are different from the above, particularly in overdose. Peak levels of verapamil were seen at 22 hours following ingestion of 2.3 g of a sustained-release preparation, and onset of toxic effects was delayed for 16 hours. Further delays in absorption can occur with the formation of pharmacobezoars of sustainedrelease preparations. This delays presentation and affects use of the preferred method of gastrointestinal decontamination.
Calcium Channel Blockers Ian Whyte Nick Buckley Andrew Dawson
There are three types of calcium channel blockers (CCBs) in common use, of three distinct chemical classes: • phenylalkylamines (e.g. verapamil) • benzothiazepines (e.g. diltiazem) • dihydropyridines (e.g. amlodipine, felodipine, lercanidipine, nicardipine, nifedipine, nimodipine). Self-poisoning with CCBs is a common cause of in-hospital death from self-poisoning. Morbidity and mortality generally result from cardiovascular collapse caused by a combination of extreme peripheral vasodilatation, myocardial depression and impaired myocardial conduction. Extracardiac toxicity (e.g. hyperglycaemia, lactic acidosis, seizures, non-cardiogenic pulmonary oedema) is less common and implies a poorer prognosis. Sustained-release preparations are available and produce both delayed and prolonged toxicity. Individuals vary considerably in their response to CCBs independent of underlying disease and other medication. Doses of only two to three times the therapeutic dose may cause profound toxicity in susceptible individuals.
Clinical features Cardiac – hypotension results from a combination of vasodilatation (with relative volume depletion), heart block and myocardial depression. It develops over the first few hours following ingestion of a standard preparation, but may be delayed for up to 18–24 hours with controlled-release preparations. Both cardiac and non-cardiogenic pulmonary oedema are reported. Non-cardiogenic pulmonary oedema can occur relatively late, when other cardiac parameters are improving. Increasing heart block typically occurs in a sequence, from sinus bradycardia through first-degree heart block, junctional bradycardia (with absent p-waves) and slow idioventricular rhythm, to asystole. This may occur with any CCB, but higher degrees of block are more common with verapamil and diltiazem. Intractable hypotension and/or asystole is the usual mode of death. Gastrointestinal – nausea and vomiting are common. The effects of CCBs on the gut can lead to ileus formation, which may significantly interfere with gastrointestinal decontamination of controlled-release preparations. Other effects are seldom life-threatening and include hyperglycaemia, lactic acidosis and seizures. These do not appear to occur in the absence of significant cardiac effects. Late presentation is most likely with sustained-release preparations. The clinical features are similar to the above. If the patient is asymptomatic and more than 24 hours has elapsed since ingestion of the CCB, no treatment is indicated. In all other situations, treatment (including consideration of gastrointestinal decontamination) should be undertaken as usual.
Mechanism of toxicity CCBs act by preventing the opening of voltage-gated calcium channels (L-type). Their major actions are vasodilatation (by inhibition of contraction of vascular smooth muscle) and inhibition of cardiac conduction, particularly in the sinoatrial and atrioventricular (AV) nodes, where there are no sodiumgated channels and conduction is totally dependent on calcium flux. Binding of CCBs to these calcium channels may be both use-dependent and voltage-dependent. At therapeutic doses, nifedipine and other dihydropyridine CCBs are predominantly peripheral vasodilators with little direct cardiac effect. Verapamil and, to a lesser extent, diltiazem have direct cardiac effects (including reduced sinus node activity, AV conduction and myocardial contractility) in addition to peripheral vasodilatation. In overdose, all of the drugs have both cardiac and vasodilating actions. However, the cardiac effects of verapamil and diltiazem appear to be generally more significant, and few deaths have been reported from dihydropyridine overdose alone.
Pharmacokinetics in overdose CCBs are rapidly absorbed from the small intestine. With standard formulations in therapeutic use, peak levels occur within 1–2 hours. There is a significant first-pass effect; bioavailability is as low as 10–40% for verapamil and diltiazem. Increased bioavailability has been shown for some CCBs in overdose, suggesting that the firstpass effect is saturable. CCBs have large volumes of distribution
MEDICINE
Investigations Blood concentrations of CCBs are unhelpful in the management of poisoning. The most useful investigation is repeated ECG, with
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continuing monitoring if available; this is a measure of severity and is the best guide to the need for specific treatment. Arterial blood gases should be determined and venous blood taken for electrolytes, renal function, calcium and blood glucose. Renal impairment may be associated with accumulation of active metabolites of verapamil and diltiazem. Assessment of severity – prognosis in CCB poisoning correlates best with the degree of heart block. Hypotension from vasodilatation without heart block usually responds to fluid loading and is seldom life-threatening. Other factors that increase the severity of overdose are: • underlying heart disease • late presentation and/or ineffective gastrointestinal decontamination • co-ingestion or regular treatment with β-blockers or digoxin (antidotes to these drugs may also be considered in these situations) • elderly patient.
Management of serious calcium channel blocker overdose in adults • Normal saline bolus (10–20 ml/kg) • 10% calcium chloride, 5–10 ml, or 10% calcium gluconate, 10–20 ml, over 5 minutes Repeat every 3–5 minutes, up to three to five doses If response, institute calcium infusion (10% calcium chloride, 1–10 ml/hour) Monitor serum calcium after 30 ml of calcium chloride or equivalent • Glucagon, 0.075–0.15 mg/kg i.v. (use water for injection as diluent) Repeat every 5–10 minutes as needed If response, consider infusion of 0.075–0.15 mg/kg/hour • Atropine, isoprenaline (isoproterenol) and/or pacing may be tried if associated symptomatic bradycardia • Dopamine infusion if persistent hypotension • If no response to the above, begin insulin euglycaemia therapy Insulin bolus, 1 unit/kg with glucose, 50% dextrose, 25 ml i.v. followed by Insulin infusion, 0.5 units/kg/hour with 50% dextrose infusion, 0.5 g/hour, adjusted according to hourly glucose checks • As a last resort, extracorporeal blood pressure support (e.g. cardiopulmonary bypass) may be considered
Management Management of CCB poisoning is shown in Figure 1. Supportive care: intravenous access with fluid resuscitation using normal saline should be instituted as soon as possible. Most patients with hypotension with no evidence of a conduction defect respond to volume expansion and should be given a bolus of normal saline (10–20 ml/kg). Patients whose blood pressure does not respond to such a fluid challenge should undergo central venous pressure monitoring. ECG monitoring in an ICU is indicated in all but the most trivial poisonings.
1
Acidosis should be corrected. Atropine, inotropes, insulin–dextrose euglycaemia and glucagon are probably the best adjunctive treatments. Bicarbonate – acidosis should be corrected to a pH within the normal range (L-type calcium channel function is impaired when pH is outside this). Acidosis enhances the effect of verapamil and reduces that of calcium. In a swine model of verapamil poisoning, sodium bicarbonate significantly improved myocardial contractility and cardiac output. Calcium loading is the most logical and appears to be the most effective treatment in CCB poisoning. It is primarily indicated in patients with heart block (who have usually taken verapamil or diltiazem). The initial dose for treatment of CCB toxicity in adults is 10% calcium chloride, 5–10 ml, or calcium gluconate solution, 10–20 ml. The dose in children is 10% calcium chloride, 0.2 ml/kg, or 10% calcium gluconate, 0.7 ml/kg. Calcium chloride should be infused at a rate no faster than 1–2 ml/minute, with the patient on a monitor. The initial dose can be followed by further doses every 3–5 minutes if there is no response in blood pressure or pulse rate. Large doses may be required (up to 10 g as initial treatment and 30 g in total have been used successfully without evidence of calcium toxicity). If there is an initial response to calcium, a continuous infusion may be warranted; this may be given as 10% calcium chloride, 1–10 ml/hour. Serum calcium should be measured, but note that hypercalcaemia is the aim of treatment. Doubling of serum calcium was associated with significant haemodynamic improvement in animals and in humans. An ionized serum calcium concentration
Gastrointestinal decontamination: gastric lavage should be considered in patients who present within 1 hour of ingestion of sustained-release verapamil or diltiazem. Atropine should be given before lavage, and in any patient who is vomiting because of the risk of vagal stimulation causing increased heart block. Oral activated charcoal should be given to patients who have ingested an overdose of a CCB and be followed by repeat doses, particularly in verapamil poisoning (though controlled clinical trial data supporting this approach are lacking). Those who have taken a sustained-release preparation should undergo whole-bowel irrigation with polyethylene glycol. Generous fluid replacement to counteract the volume depletion associated with gastrointestinal decontamination is important in vasodilating drug overdoses. Specific treatment: many treatments have been claimed as antidotes to CCB poisoning: • correction of acidosis • calcium loading • glucagon • insulin–dextrose euglycaemia • atropine • inotropic agents • cardiac pacing • Bay K 8644 (calcium channel agonist). However, many of these are supported only by occasional case reports. Critical reviews support calcium as first-line treatment.
MEDICINE
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© 2003 The Medicine Publishing Company Ltd
POISONOUS SUBSTANCES
Insulin euglycaemia therapy Insulin, 1 U/kg
and
Insulin, 0.5 U/kg/hour
50% glucose, 25 ml (12.5 g)
50% glucose, 0.5 g/hour
Systolic blood pressure < 90 mm Hg after 1 hour
Blood sugar < 5.5 mmol/litre
Blood sugar > 11 mmol/litre
Insulin, 1 U/kg/hour
↑Glucose
↓Glucose
Systolic blood pressure > 100 mm Hg for 6 hours
Off insulin, eating, blood sugar > 5.5 mmol/litre
Stop insulin
Stop glucose
2
of 2 mmol/litre was effective in severe nifedipine toxicity and has been suggested as a target concentration. Hypotension with no evidence of cardiac conduction problems does not usually require calcium or any cardioactive medication. Calcium may be cardiotoxic in this situation (particularly in patients who have ingested a dihydropyridine such as nifedipine) and may induce ventricular arrhythmias. Hypotension alone should initially be treated with volume expansion, followed by pressor agents if required. Glucagon is a well-accepted antidote for β-blocker poisoning. The rationale for its use in CCB poisoning is that it activates myosin kinase independent of calcium flux. Clinical experience suggests that it is less effective in this setting than in β-blocker poisoning. Typically, a 5–10 mg intravenous bolus followed by the same amount as an hourly infusion may reverse hypotension and bradycardia in some CCB overdoses. The solvent provided in some glucagon injection kits should not be used when reconstituting glucagon for use at these doses, because it may be toxic; use water for injection instead. Insulin–dextrose euglycaemia (Figure 2) is a promising technique that has been more effective in animal models than calcium, adrenaline (epinephrine) or glucagon. Its efficacy has been demonstrated in a case series of clinically serious poisonings. Insulin infusions should be used to treat hyperglycaemia or hyperkalaemia. Patients with hypotension refractory to volume loading, correction of acidosis and calcium salts should be treated using insulin–dextrose euglycaemia. Atropine should be given to all patients with bradycardia to reverse enhanced vagal tone associated with nausea and gastro-
MEDICINE
intestinal decontamination. A response may occur only after calcium loading. Sympathomimetic amines – dopamine is the initial pressor agent of choice for diltiazem overdose (75% response). It should be given in high doses (10–20 µg/kg/minute). Isoproterenol produces a therapeutic response in 50% of patients. These agents are often ineffective as chronotropic agents in patients with a high degree of conduction block, because they act predominantly by increasing the frequency of impulses originating in the sinoatrial node. Cardiac pacing can be undertaken to increase heart rate, provided ventricular rather than atrial pacing is performed. In severe poisoning, the heart may fail to capture and pharmacological therapy is required. Experimental therapies – calcium channel agonists (e.g. Bay K 8644) appear to be a logical antidote, but animal studies have not been promising. Elimination enhancement – high biliary concentrations of verapamil have been found following overdose. Multiple-dose activated charcoal is theoretically attractive, but has not been shown to enhance elimination.
Late complications Late complications/deterioration have been reported following ingestion of controlled-release verapamil or diltiazem. They may occur as late as 24 hours in asymptomatic patients. Life-threatening cardiovascular collapse and death can occur 2–3 days after ingestion (in patients who were symptomatic within 24 hours). Long-term sequelae have not been reported, and no follow-up is
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© 2003 The Medicine Publishing Company Ltd
POISONOUS SUBSTANCES
required after resolution of the clinical signs and ECG findings unless the patient has been profoundly hypotensive.
Cannabis
FURTHER READING Achike F I, Dai S. Influence of pH Changes on the Actions of Verapamil on Cardiac Excitation–contraction Coupling. Eur J Pharmacol 1991; 196: 77–83. Achike F I, Dai S. Cardiovascular Responses to Verapamil and Nifedipine in Hypoventilated and Hyperventilated Rats. Br J Pharmacol 1990; 100: 102–6. Buckley C D, Aronson J K. Prolonged Half-life of Verapamil in a Case of Overdose: Implications for Therapy. Br J Clin Pharmacol 1995; 39: 680–3. Buckley N A, Dawson A H, Howarth D M et al. Slow Release Verapamil Poisoning. Use of Polyethylene Glycol Whole-bowel Lavage and High-dose Calcium. Med J Aust 1993; 158: 202–4. Buckley N A, Dawson A H, Whyte I M et al. Self-poisoning in Newcastle: 1987–1992. Med J Aust 1995; 162: 190–3. Doyon S, Roberts J R. The Use of Glucagon in a Case of Calcium Channel Blocker Overdose. Ann Emerg Med 1993; 22: 1229–33. Ferner R E, Monkman S, Riley J et al. Pharmacokinetics and Toxic Effects of Nifedipine in Massive Overdose. Hum Exp Toxicol 1990; 9: 309–11. Hariman R J, Mangiardi L M, McAllister R G Jr et al. Reversal of the Cardiovascular Effects of Verapamil by Calcium and Sodium: Differences between Electrophysiologic and Hemodynamic Responses. Circulation 1979; 59: 797–804. Howarth D M, Dawson A H, Smith A J et al. Calcium Channel Blocking Drugs in Overdose: An Australian Series. Hum Exp Toxicol 1994; 13: 161–6. Jaeger A, Sauder P, Bianchetti G et al. Acute Diltiazem Poisoning: Kinetic and Hemodynamic Study. J Toxicol Clin Exp 1990; 10: 243–8. Kivisto K T, Neuvonen L, Tarssanen P J. Pharmacokinetics of Verapamil in Overdose. Hum Exp Toxicol 1997; 16: 35–7. Lam Y M, Tse H F, Lau C P. Continuous Calcium Chloride Infusion for Massive Nifedipine Overdose. Chest 2001; 119: 1280–2. Pearigen P, Benowitz N. Poisoning due to Calcium Antagonists. Drug Saf 1991; 6: 408–30. Ramoska E A, Spiller H A, Winter M et al. A One-year Evaluation of Calcium Channel Blocker Overdoses: Toxicity and Treatment. Ann Emerg Med 1993; 22: 196–200. Sporer K A, Manning J J. Massive Ingestion of Sustained-release Verapamil with a Concretion and Bowel Infarction. Ann Emerg Med 1993; 22: 603–5. Tanen D A, Ruha A M, Curry S C et al. Hypertonic Sodium Bicarbonate is Effective in the Acute Management of Verapamil Toxicity in a Swine Model. Ann Emerg Med 2000; 36: 547–53. Toffoli G, Robieux I, Fantin D et al. Non-linear Pharmacokinetics of High-dose Intravenous Verapamil. Br J Clin Pharmacol 1997; 44: 255–60. Yuan T H, Kerns W P II, Tomaszewski C A et al. Insulin-glucose as Adjunctive Therapy for Severe Calcium Channel Antagonist Poisoning. J Toxicol Clin Toxicol 1999; 37: 463–74.
Allister Vale
Cannabis (Figure 1) is obtained from the plant Cannabis sativa, which contains many active chemicals including the tetrahydrocannabinols. Delta(9)-tetrahydrocannabinol is responsible for the psychological effects seen with cannabis use. Smoking is the usual route of abuse, but cannabis is occasionally ingested as a ‘cake’, made into a ‘tea’ or injected intravenously. Cannabis abuse is often a group activity. Clinical features Acute intoxication – features include euphoria, distorted and heightened images, colours and sounds, altered tactile sensations, sinus tachycardia, hypotension and ataxia. Visual and auditory hallucinations, depersonalization and acute psychosis are particularly likely to occur after substantial ingestion in naïve cannabis users. Cannabis infusions injected intravenously may cause nausea, vomiting and chills within minutes; after about 1 hour, profuse watery diarrhoea, tachycardia, hypotension and arthralgia may develop. Marked neutrophil leucocytosis is often present, and hypoglycaemia has been reported occasionally. Chronic abuse – whether chronic cannabis abuse causes brain damage remains controversial, though there is increasing evidence that this is the case. Heavy users often become apathetic, and suffer impairment of memory and attention and poor academic performance. There is an increased risk of anxiety and depression. Cannabis smoke is probably carcinogenic. Management: most acutely intoxicated patients require no more than reassurance and supportive care. Sedation with diazepam, 10 mg i.v. repeated as necessary, should be administered to patients who are disruptive or distressed. Chlorpromazine, 50–100 mg i.m., or haloperidol, 2.5–5 mg i.m. repeated as necessary, is occasionally required.
1 Cannabis resin. (By courtesy of Lothian and Borders Police.)
This contribution was adapted with permission from Buckley N A, Dawson A H, Whyte I M. HyperTox 2002 for Windows and PDA: Assessment and Treatment of Poisoning. www.hypertox.com; copyright is retained by the authors.
MEDICINE
FURTHER READING Ameri A. The Effects of Cannabinoids on the Brain. Prog Neurobiol 1999; 58: 315–48. Ashton C H. Pharmacology and Effects of Cannabis: A Brief Review. Br J Psychiatry 2001; 178: 101–6.
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© 2003 The Medicine Publishing Company Ltd
and moderate CNS penetration. The free fraction of verapamil may increase in overdose. All are metabolized in the liver to less active or inactive metabolites. The half-life of nifedipine, verapamil and diltiazem in therapeutic use is short (3–8 hours). Newer dihydropyridine drugs have considerably longer half-lives. The apparent half-life of many CCBs appears to be longer following overdose but is generally thought to reflect rate-limited absorption. There may be significant enterohepatic circulation, particularly with verapamil. Verapamil has two enantiomers with different kinetics and activity. The S isomer is more active but has a shorter half-life and lower bioavailability than the R isomer. The greater proportion of available S isomer is the major reason why intravenous verapamil has more cardiac effects for a given serum concentration than oral verapamil. Controlled-release preparations – because of their short halflives, the older CCBs (verapamil, diltiazem and nifedipine) are often sold as controlled-release preparations. The pharmacokinetics of these preparations are different from the above, particularly in overdose. Peak levels of verapamil were seen at 22 hours following ingestion of 2.3 g of a sustained-release preparation, and onset of toxic effects was delayed for 16 hours. Further delays in absorption can occur with the formation of pharmacobezoars of sustainedrelease preparations. This delays presentation and affects use of the preferred method of gastrointestinal decontamination.
Calcium Channel Blockers Ian Whyte Nick Buckley Andrew Dawson
There are three types of calcium channel blockers (CCBs) in common use, of three distinct chemical classes: • phenylalkylamines (e.g. verapamil) • benzothiazepines (e.g. diltiazem) • dihydropyridines (e.g. amlodipine, felodipine, lercanidipine, nicardipine, nifedipine, nimodipine). Self-poisoning with CCBs is a common cause of in-hospital death from self-poisoning. Morbidity and mortality generally result from cardiovascular collapse caused by a combination of extreme peripheral vasodilatation, myocardial depression and impaired myocardial conduction. Extracardiac toxicity (e.g. hyperglycaemia, lactic acidosis, seizures, non-cardiogenic pulmonary oedema) is less common and implies a poorer prognosis. Sustained-release preparations are available and produce both delayed and prolonged toxicity. Individuals vary considerably in their response to CCBs independent of underlying disease and other medication. Doses of only two to three times the therapeutic dose may cause profound toxicity in susceptible individuals.
Clinical features Cardiac – hypotension results from a combination of vasodilatation (with relative volume depletion), heart block and myocardial depression. It develops over the first few hours following ingestion of a standard preparation, but may be delayed for up to 18–24 hours with controlled-release preparations. Both cardiac and non-cardiogenic pulmonary oedema are reported. Non-cardiogenic pulmonary oedema can occur relatively late, when other cardiac parameters are improving. Increasing heart block typically occurs in a sequence, from sinus bradycardia through first-degree heart block, junctional bradycardia (with absent p-waves) and slow idioventricular rhythm, to asystole. This may occur with any CCB, but higher degrees of block are more common with verapamil and diltiazem. Intractable hypotension and/or asystole is the usual mode of death. Gastrointestinal – nausea and vomiting are common. The effects of CCBs on the gut can lead to ileus formation, which may significantly interfere with gastrointestinal decontamination of controlled-release preparations. Other effects are seldom life-threatening and include hyperglycaemia, lactic acidosis and seizures. These do not appear to occur in the absence of significant cardiac effects. Late presentation is most likely with sustained-release preparations. The clinical features are similar to the above. If the patient is asymptomatic and more than 24 hours has elapsed since ingestion of the CCB, no treatment is indicated. In all other situations, treatment (including consideration of gastrointestinal decontamination) should be undertaken as usual.
Mechanism of toxicity CCBs act by preventing the opening of voltage-gated calcium channels (L-type). Their major actions are vasodilatation (by inhibition of contraction of vascular smooth muscle) and inhibition of cardiac conduction, particularly in the sinoatrial and atrioventricular (AV) nodes, where there are no sodiumgated channels and conduction is totally dependent on calcium flux. Binding of CCBs to these calcium channels may be both use-dependent and voltage-dependent. At therapeutic doses, nifedipine and other dihydropyridine CCBs are predominantly peripheral vasodilators with little direct cardiac effect. Verapamil and, to a lesser extent, diltiazem have direct cardiac effects (including reduced sinus node activity, AV conduction and myocardial contractility) in addition to peripheral vasodilatation. In overdose, all of the drugs have both cardiac and vasodilating actions. However, the cardiac effects of verapamil and diltiazem appear to be generally more significant, and few deaths have been reported from dihydropyridine overdose alone.
Pharmacokinetics in overdose CCBs are rapidly absorbed from the small intestine. With standard formulations in therapeutic use, peak levels occur within 1–2 hours. There is a significant first-pass effect; bioavailability is as low as 10–40% for verapamil and diltiazem. Increased bioavailability has been shown for some CCBs in overdose, suggesting that the firstpass effect is saturable. CCBs have large volumes of distribution
MEDICINE
Investigations Blood concentrations of CCBs are unhelpful in the management of poisoning. The most useful investigation is repeated ECG, with
37
© 2003 The Medicine Publishing Company Ltd
POISONOUS SUBSTANCES
continuing monitoring if available; this is a measure of severity and is the best guide to the need for specific treatment. Arterial blood gases should be determined and venous blood taken for electrolytes, renal function, calcium and blood glucose. Renal impairment may be associated with accumulation of active metabolites of verapamil and diltiazem. Assessment of severity – prognosis in CCB poisoning correlates best with the degree of heart block. Hypotension from vasodilatation without heart block usually responds to fluid loading and is seldom life-threatening. Other factors that increase the severity of overdose are: • underlying heart disease • late presentation and/or ineffective gastrointestinal decontamination • co-ingestion or regular treatment with β-blockers or digoxin (antidotes to these drugs may also be considered in these situations) • elderly patient.
Management of serious calcium channel blocker overdose in adults • Normal saline bolus (10–20 ml/kg) • 10% calcium chloride, 5–10 ml, or 10% calcium gluconate, 10–20 ml, over 5 minutes Repeat every 3–5 minutes, up to three to five doses If response, institute calcium infusion (10% calcium chloride, 1–10 ml/hour) Monitor serum calcium after 30 ml of calcium chloride or equivalent • Glucagon, 0.075–0.15 mg/kg i.v. (use water for injection as diluent) Repeat every 5–10 minutes as needed If response, consider infusion of 0.075–0.15 mg/kg/hour • Atropine, isoprenaline (isoproterenol) and/or pacing may be tried if associated symptomatic bradycardia • Dopamine infusion if persistent hypotension • If no response to the above, begin insulin euglycaemia therapy Insulin bolus, 1 unit/kg with glucose, 50% dextrose, 25 ml i.v. followed by Insulin infusion, 0.5 units/kg/hour with 50% dextrose infusion, 0.5 g/hour, adjusted according to hourly glucose checks • As a last resort, extracorporeal blood pressure support (e.g. cardiopulmonary bypass) may be considered
Management Management of CCB poisoning is shown in Figure 1. Supportive care: intravenous access with fluid resuscitation using normal saline should be instituted as soon as possible. Most patients with hypotension with no evidence of a conduction defect respond to volume expansion and should be given a bolus of normal saline (10–20 ml/kg). Patients whose blood pressure does not respond to such a fluid challenge should undergo central venous pressure monitoring. ECG monitoring in an ICU is indicated in all but the most trivial poisonings.
1
Acidosis should be corrected. Atropine, inotropes, insulin–dextrose euglycaemia and glucagon are probably the best adjunctive treatments. Bicarbonate – acidosis should be corrected to a pH within the normal range (L-type calcium channel function is impaired when pH is outside this). Acidosis enhances the effect of verapamil and reduces that of calcium. In a swine model of verapamil poisoning, sodium bicarbonate significantly improved myocardial contractility and cardiac output. Calcium loading is the most logical and appears to be the most effective treatment in CCB poisoning. It is primarily indicated in patients with heart block (who have usually taken verapamil or diltiazem). The initial dose for treatment of CCB toxicity in adults is 10% calcium chloride, 5–10 ml, or calcium gluconate solution, 10–20 ml. The dose in children is 10% calcium chloride, 0.2 ml/kg, or 10% calcium gluconate, 0.7 ml/kg. Calcium chloride should be infused at a rate no faster than 1–2 ml/minute, with the patient on a monitor. The initial dose can be followed by further doses every 3–5 minutes if there is no response in blood pressure or pulse rate. Large doses may be required (up to 10 g as initial treatment and 30 g in total have been used successfully without evidence of calcium toxicity). If there is an initial response to calcium, a continuous infusion may be warranted; this may be given as 10% calcium chloride, 1–10 ml/hour. Serum calcium should be measured, but note that hypercalcaemia is the aim of treatment. Doubling of serum calcium was associated with significant haemodynamic improvement in animals and in humans. An ionized serum calcium concentration
Gastrointestinal decontamination: gastric lavage should be considered in patients who present within 1 hour of ingestion of sustained-release verapamil or diltiazem. Atropine should be given before lavage, and in any patient who is vomiting because of the risk of vagal stimulation causing increased heart block. Oral activated charcoal should be given to patients who have ingested an overdose of a CCB and be followed by repeat doses, particularly in verapamil poisoning (though controlled clinical trial data supporting this approach are lacking). Those who have taken a sustained-release preparation should undergo whole-bowel irrigation with polyethylene glycol. Generous fluid replacement to counteract the volume depletion associated with gastrointestinal decontamination is important in vasodilating drug overdoses. Specific treatment: many treatments have been claimed as antidotes to CCB poisoning: • correction of acidosis • calcium loading • glucagon • insulin–dextrose euglycaemia • atropine • inotropic agents • cardiac pacing • Bay K 8644 (calcium channel agonist). However, many of these are supported only by occasional case reports. Critical reviews support calcium as first-line treatment.
MEDICINE
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© 2003 The Medicine Publishing Company Ltd
POISONOUS SUBSTANCES
Insulin euglycaemia therapy Insulin, 1 U/kg
and
Insulin, 0.5 U/kg/hour
50% glucose, 25 ml (12.5 g)
50% glucose, 0.5 g/hour
Systolic blood pressure < 90 mm Hg after 1 hour
Blood sugar < 5.5 mmol/litre
Blood sugar > 11 mmol/litre
Insulin, 1 U/kg/hour
↑Glucose
↓Glucose
Systolic blood pressure > 100 mm Hg for 6 hours
Off insulin, eating, blood sugar > 5.5 mmol/litre
Stop insulin
Stop glucose
2
of 2 mmol/litre was effective in severe nifedipine toxicity and has been suggested as a target concentration. Hypotension with no evidence of cardiac conduction problems does not usually require calcium or any cardioactive medication. Calcium may be cardiotoxic in this situation (particularly in patients who have ingested a dihydropyridine such as nifedipine) and may induce ventricular arrhythmias. Hypotension alone should initially be treated with volume expansion, followed by pressor agents if required. Glucagon is a well-accepted antidote for β-blocker poisoning. The rationale for its use in CCB poisoning is that it activates myosin kinase independent of calcium flux. Clinical experience suggests that it is less effective in this setting than in β-blocker poisoning. Typically, a 5–10 mg intravenous bolus followed by the same amount as an hourly infusion may reverse hypotension and bradycardia in some CCB overdoses. The solvent provided in some glucagon injection kits should not be used when reconstituting glucagon for use at these doses, because it may be toxic; use water for injection instead. Insulin–dextrose euglycaemia (Figure 2) is a promising technique that has been more effective in animal models than calcium, adrenaline (epinephrine) or glucagon. Its efficacy has been demonstrated in a case series of clinically serious poisonings. Insulin infusions should be used to treat hyperglycaemia or hyperkalaemia. Patients with hypotension refractory to volume loading, correction of acidosis and calcium salts should be treated using insulin–dextrose euglycaemia. Atropine should be given to all patients with bradycardia to reverse enhanced vagal tone associated with nausea and gastro-
MEDICINE
intestinal decontamination. A response may occur only after calcium loading. Sympathomimetic amines – dopamine is the initial pressor agent of choice for diltiazem overdose (75% response). It should be given in high doses (10–20 µg/kg/minute). Isoproterenol produces a therapeutic response in 50% of patients. These agents are often ineffective as chronotropic agents in patients with a high degree of conduction block, because they act predominantly by increasing the frequency of impulses originating in the sinoatrial node. Cardiac pacing can be undertaken to increase heart rate, provided ventricular rather than atrial pacing is performed. In severe poisoning, the heart may fail to capture and pharmacological therapy is required. Experimental therapies – calcium channel agonists (e.g. Bay K 8644) appear to be a logical antidote, but animal studies have not been promising. Elimination enhancement – high biliary concentrations of verapamil have been found following overdose. Multiple-dose activated charcoal is theoretically attractive, but has not been shown to enhance elimination.
Late complications Late complications/deterioration have been reported following ingestion of controlled-release verapamil or diltiazem. They may occur as late as 24 hours in asymptomatic patients. Life-threatening cardiovascular collapse and death can occur 2–3 days after ingestion (in patients who were symptomatic within 24 hours). Long-term sequelae have not been reported, and no follow-up is
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POISONOUS SUBSTANCES
required after resolution of the clinical signs and ECG findings unless the patient has been profoundly hypotensive.
Cannabis
FURTHER READING Achike F I, Dai S. Influence of pH Changes on the Actions of Verapamil on Cardiac Excitation–contraction Coupling. Eur J Pharmacol 1991; 196: 77–83. Achike F I, Dai S. Cardiovascular Responses to Verapamil and Nifedipine in Hypoventilated and Hyperventilated Rats. Br J Pharmacol 1990; 100: 102–6. Buckley C D, Aronson J K. Prolonged Half-life of Verapamil in a Case of Overdose: Implications for Therapy. Br J Clin Pharmacol 1995; 39: 680–3. Buckley N A, Dawson A H, Howarth D M et al. Slow Release Verapamil Poisoning. Use of Polyethylene Glycol Whole-bowel Lavage and High-dose Calcium. Med J Aust 1993; 158: 202–4. Buckley N A, Dawson A H, Whyte I M et al. Self-poisoning in Newcastle: 1987–1992. Med J Aust 1995; 162: 190–3. Doyon S, Roberts J R. The Use of Glucagon in a Case of Calcium Channel Blocker Overdose. Ann Emerg Med 1993; 22: 1229–33. Ferner R E, Monkman S, Riley J et al. Pharmacokinetics and Toxic Effects of Nifedipine in Massive Overdose. Hum Exp Toxicol 1990; 9: 309–11. Hariman R J, Mangiardi L M, McAllister R G Jr et al. Reversal of the Cardiovascular Effects of Verapamil by Calcium and Sodium: Differences between Electrophysiologic and Hemodynamic Responses. Circulation 1979; 59: 797–804. Howarth D M, Dawson A H, Smith A J et al. Calcium Channel Blocking Drugs in Overdose: An Australian Series. Hum Exp Toxicol 1994; 13: 161–6. Jaeger A, Sauder P, Bianchetti G et al. Acute Diltiazem Poisoning: Kinetic and Hemodynamic Study. J Toxicol Clin Exp 1990; 10: 243–8. Kivisto K T, Neuvonen L, Tarssanen P J. Pharmacokinetics of Verapamil in Overdose. Hum Exp Toxicol 1997; 16: 35–7. Lam Y M, Tse H F, Lau C P. Continuous Calcium Chloride Infusion for Massive Nifedipine Overdose. Chest 2001; 119: 1280–2. Pearigen P, Benowitz N. Poisoning due to Calcium Antagonists. Drug Saf 1991; 6: 408–30. Ramoska E A, Spiller H A, Winter M et al. A One-year Evaluation of Calcium Channel Blocker Overdoses: Toxicity and Treatment. Ann Emerg Med 1993; 22: 196–200. Sporer K A, Manning J J. Massive Ingestion of Sustained-release Verapamil with a Concretion and Bowel Infarction. Ann Emerg Med 1993; 22: 603–5. Tanen D A, Ruha A M, Curry S C et al. Hypertonic Sodium Bicarbonate is Effective in the Acute Management of Verapamil Toxicity in a Swine Model. Ann Emerg Med 2000; 36: 547–53. Toffoli G, Robieux I, Fantin D et al. Non-linear Pharmacokinetics of High-dose Intravenous Verapamil. Br J Clin Pharmacol 1997; 44: 255–60. Yuan T H, Kerns W P II, Tomaszewski C A et al. Insulin-glucose as Adjunctive Therapy for Severe Calcium Channel Antagonist Poisoning. J Toxicol Clin Toxicol 1999; 37: 463–74.
Allister Vale
Cannabis (Figure 1) is obtained from the plant Cannabis sativa, which contains many active chemicals including the tetrahydrocannabinols. Delta(9)-tetrahydrocannabinol is responsible for the psychological effects seen with cannabis use. Smoking is the usual route of abuse, but cannabis is occasionally ingested as a ‘cake’, made into a ‘tea’ or injected intravenously. Cannabis abuse is often a group activity. Clinical features Acute intoxication – features include euphoria, distorted and heightened images, colours and sounds, altered tactile sensations, sinus tachycardia, hypotension and ataxia. Visual and auditory hallucinations, depersonalization and acute psychosis are particularly likely to occur after substantial ingestion in naïve cannabis users. Cannabis infusions injected intravenously may cause nausea, vomiting and chills within minutes; after about 1 hour, profuse watery diarrhoea, tachycardia, hypotension and arthralgia may develop. Marked neutrophil leucocytosis is often present, and hypoglycaemia has been reported occasionally. Chronic abuse – whether chronic cannabis abuse causes brain damage remains controversial, though there is increasing evidence that this is the case. Heavy users often become apathetic, and suffer impairment of memory and attention and poor academic performance. There is an increased risk of anxiety and depression. Cannabis smoke is probably carcinogenic. Management: most acutely intoxicated patients require no more than reassurance and supportive care. Sedation with diazepam, 10 mg i.v. repeated as necessary, should be administered to patients who are disruptive or distressed. Chlorpromazine, 50–100 mg i.m., or haloperidol, 2.5–5 mg i.m. repeated as necessary, is occasionally required.
1 Cannabis resin. (By courtesy of Lothian and Borders Police.)
This contribution was adapted with permission from Buckley N A, Dawson A H, Whyte I M. HyperTox 2002 for Windows and PDA: Assessment and Treatment of Poisoning. www.hypertox.com; copyright is retained by the authors.
MEDICINE
FURTHER READING Ameri A. The Effects of Cannabinoids on the Brain. Prog Neurobiol 1999; 58: 315–48. Ashton C H. Pharmacology and Effects of Cannabis: A Brief Review. Br J Psychiatry 2001; 178: 101–6.
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