Chloroquine and Amodiaquine
Chloroquine and amodiaquine are 4-aminoquinolines which were products of American research during World War II, though there are reliable indications that chloroquine had been synthesised by the Germans several years earlier as Resochin, which is incidentally a very popular brand name for chloroquine even today. Other members of the group of 4-aminoquinolones include broxyquinoline, cycloquine, di-iodohydroxyquine, hydroxychloroquine, mepacrine, pamaquine, pentaquine, and plasmocid.
Amodiaquine is actually a congener of chloroquine and is no longer used abroad owing to its propensity for causing hepatic damage and agranulocytosis. Another related compound, hydroxychloroquine is preferred in the treatment of rheumatoid arthritis and SLE in place of chloroquine since it is less oculotoxic in the long run.
Chloroquine is well absorbed orally and parenterally (intra-muscular and subcutaneous injection). It has a large volume of distribution, and is moderately protein-bound (50%). Peak plasma levels are achieved in 2 to 3 hours. There is a large amount of tissue storage with chloroquine. Chloroquine accu-mulates especially in heart, kidney, liver, pancreas, lung and spleen, and is strongly bound in melanin-containing cells (eye and skin). Excretion occurs in the urine, upto 20% of the drug being unchanged. The main metabolite is monodesethyl chloro-quine. Renal excretion of chloroquine and its major metabolite is enhanced by acidification of the urine.
· Long-term effects of prolonged chloroquine therapy include malaise, anorexia, pruritus, urticaria, haemolytic anaemia, methaemoglobinaemia, retinopathy, psychosis, seizures, convulsions, vertigo, headache, and convulsions. Sudden respiratory apnoea can occur. CVS manifesta-tions comprise hypotension, atrioventricular conduction defects, and cardiac arrhythmias. Hypokalaemia is often present. Cardiomyopathy has also been reported in several cases.
· In a retrospective chart review, chronic therapy with hydroxychloroquine was found to be less toxic to the retina than chloroquine therapy. Effects of chloroquine retinopathy include pigmentary stippling, mottling, a “bull’s eye” pattern of macular hyperpigmentation, attenuation of the retinal arteries, pale optic discs, disturbance of colour vision, loss of central vision scotoma and visual field defects.
· Psychosis as the sole adverse effect has been reported often with therapeutic use of chloroquine, especially in children. Capgras’ syndrome (the misguided belief that a familiar person has been replaced by an imposter), was reported in the case of an 8-year-old girl who was treated with therapeutic chloroquine for three days. Psychiatric disturbances may appear as early as within 24 hours of the first dose, or as late as several days after the final dose. A retrospective review of chloroquine-induced psychiatric complications (organic psychoses, schizophrenia, depres-sion, and anxiety) found that symptoms appeared after intake of 2.4 to 6 grams of chloroquine between 4 and 40 days after onset of therapy. The exact mechanism remains unknown.
· Acute overdose with chloroquine can cause nausea, vomiting, diarrhoea, haemorrhagic gastritis, hyperexcit-ability, agitation, convulsions, coma, QRS widening, ventricular arrhythmias, hypotension, shock, cardiac arrest, respiratory arrest and death.
o The following are indications of severe toxicity: systolic BP < 90 mmHg, QRS duration >110 milliseconds, and hypokalaemia (K+< 3.0 mEq).
o Chloroquine overdose has resulted in life-threatening cardiotoxic effects. The primary effects include hypo-tension, vasodilation, ECG abnormalities (prolonged PR, QRS, and QT interval), ventricular arrhythmias and cardiovascular collapse. Cardiac arrest may occur rapidly, within 1 to 2 hours following ingestion. Hypotension is frequent and may progress rapidly to cardiogenic shock with increased central venous pres-sure following chloroquine or hydroxychloroquine overdose. Severe hypokalaemia (1 to 2 mmol/L) is frequent in severe intoxication.
· Amodiaquine toxicity results in spasticity, seizures, convul-sions, dysarthria, syncope, hepatitis and agranulocytosis.
· Hydroxychloroquine poisoning produces vomiting, seizures, arrhythmias (less common), myocarditis and myopathy and hepatic failure.
· Chloroquine is wrongly believed to be an effective aborti-facient by the lay public. It is true that stillbirths and spon-taneous abortions have occurred after taking chloroquine or hydroxychloroquine, but these drugs are by no means reliable abortifacients.
■■ Chloroquine: 3 to 6 grams. As little as 2.25 to 3 grams of chloroquine may be fatal in an adult. About 2 to 3 times the therapeutic dose may be fatal in children. Estimated fatal dose is 30 to 50 mg chloroquine base/kg.
■■Hydroxychloroquine: 10 to 20 grams. Adults have developed hypotension and ventricular arrhythmias after ingesting 12 to 22 grams.
■■ Chloroquine toxicity is dose dependant. The following has been observed in adults:
o Dose ingested greater than 4 grams - neurological, cardiovascular and ECG disturbances; serum chloro-quine level greater than 5 mg/L at the 4th hour.
o Dose ingested 2 to 4 grams - neurological symptoms and ECG abnormalities, serum chloroquine level of 2.5 to 5 mg/L.
o Dose ingested less than 2 grams - no clinical symptoms, serum chloroquine level less than 2.5 mg/L.
o The occurrence of side effects in patients under chlo- roquine therapy is related to chloroquine serum levels. No side effects occurred in patients with serum levels less than 0.4 mg/L, whereas 80% of the patients with a level higher than 0.8 mg/L had side effects.
· Serum level estimation by high pressure liquid chroma-tography. Chloroquine levels higher than 5 mcg/ml are associated with serious toxicity.
· Like quinine, chloroquine fluoresces under UV light (254 nm and 366 nm), and this property can be used to identify the substance in urine. For this purpose, first add 0.1 ml of dilute HCl to 1 ml of urine and then vortex-mix for 10 seconds. If there is fluorescence, add 1 gram of sodium chloride, vortex-mix for 10 seconds and examine under UV light again. The urine will not fluoresce any more.
· Patients with suspected chloroquine overdose should receive gastric decontamination, have an ECG performed and continuous cardiac monitoring for a minimum of 6 hours after ingestion. Patients who are asymptomatic during this period may be discharged after psychiatric evaluation (if indicated). Monitor serum electrolytes and arterial blood gases in symptomatic patients.
· Stabilisation: The patient should be treated in an intensivecare unit and continuous cardiac monitoring must be done. Preparations should be made for airway protection (endotra-cheal intubation) and mechanical ventilation. Defibrillator and cardiac pacemaker may be required.
· Correct anoxia by administering 100% oxygen.
· Give diazepam (upto 10 mg IV slowly in adults; 0.1 to 0.3 mg/kg IV slowly in children).
· If convulsions do not respond to diazepam, administer phenytoin (15 mg/kg IV at 0.25 to 0.5 mg/kg/min). In severe cases, neuromuscular paralysis may be required to avoid hyperthermia, severe acidosis, and rhabdo-myolysis; continuous EEG monitoring is mandatory if neuromuscular paralysis is used.
· Correct hypotension by IV fluids, Trendelenberg posi-tion, and dopamine or noradrenaline.
· Adrenaline (1: 10,000) at a dose of 0.25 mcg/kg/min, until systolic pressure is at least 100 mmHg.
· Diazepam 2 mg/kg over 30 minutes (preferably through motor-driven syringe type pump). The role of diazepam in chloroquine poisoning has long been under study. It is believed that diazepam apparently competes for cardiac chloroquine fixation sites.
· Indications for noradrenaline therapy include massive ingestion (> 5 gm chloroquine), very low systolic pres-sure (< 80 mmHg), and prolonged QRS interval (> 120 milliseconds). Diazepam is indicated in patients with convulsions, arrhythmias, QRS widening, hypotension, or circulatory collapse.
Decontamination: Gastric lavage may be done if the patientis seen within 2 hours of ingestion. Activated charcoal (1 gm/kg) is highly recommended.
Elimination: Acid diuresis though advocated by some inves-tigators is best avoided. Exchange transfusion may be useful. Peritoneal dialysis and haemodialysis are of little value in removing chloroquine from the body. Chloroquine is well adsorbed by charcoal. However it has a large volume of distribution and is rapidly distributed intracellularly; there-fore the amount removed by haemoperfusion is not large.
· Correct hypokalaemia with potassium (0.25 mEq/kg/ hr, upto a maximum of 10 mEq/hr in 2 hours). Initial hypokalaemia should be corrected cautiously because potassium and quinidine-like drugs have a synergistic cardiotoxic effect, and intensive administration of potassium may lead to a sudden hyperkalaemia.
· Arrhythmias may require lignocaine. Ventricular tachy-cardia/fibrillation can be corrected by direct current cardioversion. Recurrence can be prevented by rapid pacemaker stimulation. Avoid class Ia antiarrhythmics (quinidine, disopyramide, procainamide, aprindine), and most class III antiarrhythmics (N- acetylprocaina-mide, sotalol).
· Monitor liver and renal function.
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