Table of Contents
Link to Problems for Discussion
DRUGS INCLUDED IN THIS CATEGORY
- Hydroxychloroquine *
- Primaquine *
- Mefloquine *
* There is little information on these drugs. These are structurally related to chloroquine and until further data are available should be managed in the same manner.
Chloroquine is a potentially fatal poisoning often characterised by a rapid deterioration in an apparently “well” patient. Features of toxicity may develop within 30 minutes, death may occur within 3-4 hours, generally from myocardial depression and arrhythmia. A potentially fatal dose is approximately 50 mg/kg although there is wide variation in the response.
MECHANISM OF TOXIC EFFECTS
The presumed mechanism for the cardiac and neurological effects of chloroquine is blockade of voltage-gated ion channels. The exact type of block(s) has not been determined but the ECG changes in humans and animals suggest Ca++, Na+ and K+ channels may be involved as there is progressive prolongation of PR, QRS and QT intervals. Chloroquine is also a direct vasodilator.
KINETICS IN OVERDOSE
Chloroquine is rapidly absorbed from the small intestine. Peak concentrations occur within 1 hour in therapeutic use.
Chloroquine has a very large volume of distribution and kinetics which fit a two compartment model. The central compartment has a Vd of about 2 L/kg. The major acute toxic syndrome is due to high blood concentrations within this compartment. The fall in chloroquine concentrations (half-life 2-6 days) within this compartment is primarily due to distribution. Chloroquine is a weak base and is slowly concentrated within cells by partitioning resulting in intracellular concentrations 60 fold higher than blood concentrations. The peripheral compartment has a Vd of about 200 L/kg and the terminal elimination half-life is 30-60 days.
The drug crosses the placenta and is associated with foetal abnormalities.
Metabolism - Elimination
Chloroquine is metabolised in the liver to inactive metabolites. It displays dose dependent kinetics giving an even longer half-life in overdose.
The major effects are progressive prolongation of PR, QRS, and QT intervals and brady- and tachyarrhythmias. Arrhythmias are an indication that death is imminent.
Hypotension may be due to a number of causes. Chloroquine causes direct myocardial depression, arrhythmias and vasodilatation. Hypotension may be contributed to by relative volume depletion, which should respond rapidly to intravenous fluids.
The use of alpha agonists (e.g. noradrenaline or phenylephrine) is not advisable. These prolong the effective refractory period (Tisdale et al, 1995), as does chloroquine, and thus may be proarrhythmic. Phenylephrine has been shown to induce VT and shorten survival in a rat model of chloroquine poisoning (Buckley et al, 1996).
Central nervous system effects
Those with significant ingestions of chloroquine who develop cardiac complications may also develop seizures or have a significantly impaired level of consciousness. Patients will often have a rapid onset of decreasing level of consciousness and coma because of a very rapid absorption of the drug. Seizures themselves are likely to be associated with an increased mortality. The acidosis produced by the seizures may then lead to cardiac arrhythmias.
Low potassium is an independent marker for severity in chloroquine overdose. Hypokalaemia occurs rapidly and is likely to relate to an intracellular shift in potassium, perhaps secondary to catecholamine excess or blockade of voltage-gated potassium channels. However, correction of the potassium should be carried out cautiously and there are no data to indicate that this is of benefit (Clemessy et al 1995).
Correction of acidosis and even mild alkalinisation may have a small benefit (Curry et al, 1996)
Conversion factor chloroquine
- mg/L x 3.13 = micromol/L
- micromol/L x 0.320 = mg/L
Conversion factor hydroxychloroquine
- mg/L x 2.98 = micromol/L
- micromol/L x 0.336 = mg/L
These are unhelpful in aiding management but do correlate with severity (Clemessy et al 1996).
Chloroquine should be considered (along with other drugs with membrane blocking effects) in patients with seizures, QRS prolongation and/or ventricular arrhythmias. In contrast with many of these drugs, chloroquine is less sedating and has no anticholinergic effects. It is also not prescribed for psychiatric conditions. A history of travel to an area with endemic malaria by a member of the family may help to make the diagnosis. (Prescriptions for chloroquine usually provide a large surfeit of tablets.)
DIFFERENCES IN TOXICITY WITHIN THIS DRUG CLASS
It is not known whether the other antimalarial quinolines have similar severity and type of toxicity in overdose to chloroquine (or quinine). On the basis of a few case reports and a small series, hydroxychloroquine toxicity is similar to chloroquine. Further data are required.
DETERMINATION OF SEVERITY
Patients with any of the following have a poor prognosis in the absence of aggressive intervention (Riou et al, 1988, Clemessy et al , 1995) and specific treatment should be given to all patients who have any of these features:
- systolic BP less than 90 mmHg
- QRS duration greater than 110 milliseconds
- ingestion of greater than 5 grams of chloroquine
- hypokalaemia (K+ less than 3.0)
The usual - maintenance of airway, ventilation, IV access and fluids.
Oral activated charcoal should be given within 1-2 hours to all adult patients ingesting more than 1 gram of chloroquine. Patients with any history, signs or investigation indicating severe poisoning should have elective intubation, consideration of gastric lavage and activated charcoal as well as the specific treatment outlined below (Clemessy et al, 1996; Riou et al, 1988).
This is a very controversial area. Combined treatment with thiopentone induction, elective intubation, gastric lavage and activated charcoal, high dose diazepam (2-3 mg/kg) and adrenaline was claimed to dramatically improve the outcome compared with historical controls (Riou et al, 1988). The historical controls were selected on the basis of their poor outcome and a study of the effect of diazepam using unselected controls demonstrated no significant improvement in outcome with the routine use of diazepam (Demaziere et al, 1992). A randomised controlled trial of diazepam in poisonings of moderate severity also demonstrated no significant benefit (Clemessy et al, 1996). The effect of the diazepam in animal models is small and reflects actions on GABA receptors in the central nervous system since IV clonazepam and intracerebral diazepam are more effective than IV diazepam (Gnassounou 1988a & b).
Diazepam and clonazepam have no beneficial effects in a rat model of chloroquine poisoning where the rats were anaesthetised with barbiturates. Furthermore, a recent case series suggests that barbiturates themselves may be harmful (Clemessy et al, 1996). This was also suggested in our animal work (Buckley et al, 1996).
Adrenaline, as well as increasing blood pressure, may act as a pharmacological overdrive pacer and thus suppress early after depolarisations and triggered arrhythmias. In a rat model of chloroquine poisoning, isoprenaline provided more protection against the cardiovascular effects of chloroquine than adrenaline (Buckley et al, 1996). Alpha agonist activity appeared to be harmful.
In summary, our recommended treatment for significant poisonings would be
- high dose clonazepam (0.1 mg/kg IV STAT)
- elective intubation without barbiturate anaesthesia (maintaining sedation with benzodiazepines)
- activated charcoal
- adrenaline or isoprenaline (titrated to maintain blood pressure and heart rate).
Treatment of specific complications
Initially, diazepam 10-20 mg IV followed by clonazepam 0.1 mg/kg IV and elective intubation and ventilation. This should be followed by adrenaline or isoprenaline and other specific treatment outlined above.
Barbiturates should not be used.
Isoprenaline and/or overdrive pacing (rate 120-140 bpm) is indicated for torsade de pointes and should be considered for all tachyarrhythmias. Any acidosis should be corrected.
Beta blockers (including sotalol) are contraindicated (Sofola 1983).
Class 1A antiarrhythmic drugs are contraindicated
Magnesium is normally the drug of choice for treating torsade de pointes but its calcium channel blocking activity may aggravate the hypotension and heart block that can complicate chloroquine poisoning.
Not useful due to the high volume of distribution.
LATE COMPLICATIONS, PROGNOSIS - FOLLOW UP
Long term sequelae in survivors have not been reported and no follow up is required after resolution of the initial clinical signs and ECG findings.
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