Summary for UKPID QUININE Kathryn Pughe, BSc (Hons) MRPharmS National Poisons Information Service (Newcastle Centre) Regional Drug & Therapeutics Centre Wolfson Building Claremont Place Newcastle upon Tyne NE1 4LP UK This monograph has been produced by staff of a National Poisons Information Service Centre in the United Kingdom. The work was commissioned and funded by the UK Departments of Health, and was designed as a source of detailed information for use by poisons information centres. Peer review group: Directors of the UK National Poisons Information Service. Summary Name quinine sulphate quinine bisulphate quinine hydrochloride quinine dihydrochloride Chemical group/family Antimalarials BNF 5.4.1 Reference number (CAS) 130-95-0 (anhydrous quinine) Manufacturer/supplier (generic) Cox Arthur H & Co Ltd Whiddon Valley Barnstable North Devon EX32 8NS Tel: 01271 311200 Fax: 01271 46106 Presentation quinine sulphate 125 mg, 200 mg, 300 mg quinine bisulphate 200 mg, 300 mg quinine hydrochloride 300 mg quinine dihydrochloride 300 mg produced in various pack sizes e.g. 100,1000 injection 300 mg/ml also available from Martindale Pharmaceuticals Physico-chemical properties (Dollery) 6-methoxy-alpha-(5-vinyl-2-quinuclidinyl)-4-quinolone-methanol Molecular Weight 378.5 pKa quinuclidinyl group 4.1 quinolone group 8.5 Solubility in water very low in alcohol 1 in 1 USES Indications prophylaxis and treatment of malaria prevention of nocturnal muscle cramps Therapeutic Dosage (BNF) Adults malaria 300 mg - 600 mg daily muscle cramps 200 mg - 300 mg daily Children malaria 30 mg/kg daily Contraindications Hypersensitivity to quinine and other cinchona alkaloids. Concurrent use with cimetidine, amiodarone, digoxin and other digitalis glycosides. Therapeutic administration of mefloquine within the preceding 14 days. Haemoglobinuria Optic neuritis Precautions Caution should be used in patients with history of asthma, serious heart disease or tinnitus. Quinine may stimulate pancreatic insulin release and should be used cautiously in hypoglycaemic persons. Quinine may cause thrombocytopenia purpura and should be used cautiously in patients with a history of this reaction, or in highly sensitive patients. Pharmacokinetics Oral absorption >80% Presystemic metabolism >10% Volume of distribution (healthy subjects) 1.5 Lkg-1 (severe malaria) 1.2 Lkg-1 Plasma half life range (healthy subjects) 7 - 11 hr (severe malaria) 6 - 47 hr mean (healthy subjects) 8.7 hr mean (severe malaria) 18.2 hr Toxicokinetics (Bateman DN et al, 1985) At toxic levels elimination half life is reported to be 26.5 +/- 5.8 hrs. Adverse effects Cinchonism, including tinnitus, headache, hot and flushed skin, nausea, abdominal pain, rashes, visual disturbances (including temporary blindness), confusion. Hypersensitivity reactions including angioedema, blood disorders (including thrombocytopenia and intravascular coagulation) and acute renal failure. Hypoglycaemia (especially after parenteral administration). Pregnancy Quinine is used mainly in the treatment of chloroquine resistant malaria. There have been a large number of case reports of malformations following quinine ingestion in human pregnancy. Many of these pregnancies involved large doses of quinine used as an abortifacient. The most frequently reported abnormality following quinine exposure during early pregnancy is hypoplasia of the auditory nerve with resultant deafness. Other major malformations involving most organ systems have been reported also. However, the Perinatal Collaborative Study reported no association between first trimester exposure to quinine and birth defects. In general, there has been no proven association between quinine at doses used for malarial prophylaxis and an increased risk of malformations. Third trimester exposure to quinine does not appear to adversely effect uterine contractility. However, an increase in insulin secretion associated with hypoglycaemia has been reported. Therefore, monitoring of blood or serum glucose levels during quinine therapy is advisable. Breast milk Quinine is excreted into breast milk. Following 300 and 640 mg oral doses in six patients, milk concentrations varied up to 2.2 mcg/ml, with an average level of 1 mcg/ml at 3 hours. No adverse effects in breast fed babies were reported. Quinine is thought to be compatible with breast feeding (Bennet PN, 1988). Interactions (BNF) Anti-arrhythmic plasma concentration of flecainide increased Antihistamines increased risk of ventricular arrythmias with astemizole and terfenadine Cardiac glycosides plasma concentration of digoxin increased - halve digoxin maintenance dose (includes use of quinine for cramps) Ulcer-healing drugs cimetidine inhibits quinine metabolism (increased plasma quinine concentration) Other antimalarials Increased risk of arryhthmias with halofantrine and mefloquine SUMMARY Quinine Type of product: For treatment of malaria and leg cramps. Quinine salt Tablet size (mg) Quinine base content (mg) Sulphate 125 103 200 165 300 248 Dihydrochloride 300 246 Hydrochloride 300 246 Toxicity Highly toxic. There is a higher risk of visual loss and cardiac complications when plasma concentrations of quinine exceed 15 mg/l at any stage of overdosage. The average fatal dose for an adult is about 8 g although deaths have been reported from as little as 1.5 g in an adult and 900 mg in a child. General features Quinine causes nausea, vomiting, tremor, tinnitus and deafness. Visual features Blurred vision may proceed to complete blindness within a few hours. As vision is lost the pupils become dilated and unresponsive to light. Initially only narrowing of the retinal arterioles may be seen on fundoscopy but after 3 days retinal oedema may appear. Cardiac features Tachycardia, dysrhythmias, hypotension and ECG conduction abnormalities may precede cardiac arrest. Other features Oliguria and acute renal failure from intravascular haemolysis. Coma and convulsions (especially in children) Management 1. Monitor cardiac conduction and rhythm. 2. Supportive measures from coma and convulsions. 3. Empty the stomach if within 4 hours of ingestion. 4. Repeated dose oral activated charcoal has been shown to increase quinine elimination in volunteers, and should therefore be used in patients. 5. Severe impairment of vision cannot be treated. The evidence that stellate ganglion block, retro-bulbar injections or vasodilators are effective is poor and based on wrong assumptions about the mode of toxicity of quinine. Discuss with the doctor on call. Some recovery of vision can be expected but permanent, severe restriction of the visual fields may occur. Optic atrophy may appear later. 6. Methods to enhance elimination of quinine from the body (other than oral activated charcoal) are of doubtful value. This is particularly true of forced acid diuresis, exchange transfusion, haemodialysis and charcoal haemoperfusion. The value or otherwise of resin haemoperfusion is yet to be demonstrated. Serious poisoning should be discussed with the doctor on call. References Wolf LR et al. Cinchonism: two case reports and review of acute quinine toxicity and treatment. J Emerg Med 1992;10:295-301. Schonwald and Shannon M. Unsuspected quinine intoxication presenting as acute deafness and mutism. Am J Emerg Med 1991;9:318-320. Canning CR, Hague S. Ocular quinine toxicity. Br J Opthalmol 1988;72:23-26. Bateman DN. Quinine toxicity. Adv Drug React Ac Pois Rev 1986;4:215- 233. Dyson EH, et al. Quinine amblopia: is current management appropriate ? Clin Toxicol 1985-86;23:571-578. Bateman DN et al. Pharmacokinetics and clinical toxicity of quinine overdosage: lack of efficacy of techniques intended to enhance elimination. Q J Med 1985;ns54,no214:125-131. Murray SB, Jay JL. Loss of sight after self-poisoning with quinine. Br Med J 1983;287:1700. EPIDEMIOLOGY OF POISONING MECHANISM OF ACTION/TOXICITY Quinine has class 1A antiarrhythmic effects, but is less potent than its stereoenantiomer quinidine. These effects include sodium channel blockade, slowed phase o depolarisation, conduction delay and prolonged repolarisation. Quinine also has alpha agonist action and may have oxytocic actions. Range of toxicity (Poisindex) The adult toxic dose may be as little as 2g, although usually greater than 3 to 4g. Toxic Levels Plasma concentrations over 5 mcg/ml causes cinchonism Plasma concentrations above 10 mcg/ml are associated with visual impairment. Plasma concentrations above 15 mcg/ml are associated with cardiac arrhythmias. Fatal Level Death was reported in a patient with an initial quinine level of 22.2 mcg/ml. A peak level of 17.8 mcg/ml was reported in a fatal case (Wenstone et al 1989). FEATURES OF POISONING Summary Quinine overdose either intentionally or accidentally has been reported to result in signs and signs and symptoms including headache, deafness, tachycardia, depression of atrial, atrioventricular and ventricular conduction arrhythmias, hypotension, heart failure syncope, respiratory arrest, paraesthesia, coma and death. EYES Visual field constriction may progress to sudden blindness with non-reactive dilated pupils. Fixed dilated pupils are seen frequently in children following quinine overdosage (Grattan-Smith et al,1987). In addition to cinchonism quinine is thought to have a direct toxic effect on the retina, causing constricted fields that can progress to blindness with dilated non reactive pupils (Dyson et al,1985). Central vision usually recovers first. Complete recovery of vision may take several months; pupils may remain dilated after recovery of vision. Blindness following quinine overdosage is typically delayed in onset usually for more than 12 hours (Smilkstein et al, 1987). Plasma concentrations associated with the visual deficits usually exceed 15mg/l in less than 10 hours post-ingestion and greater than 10 mg/l after 10 hours. However, plasma concentrations appear to be inadequate to predict the extent of visual deficit. Ears Transient tinnitus and eighth bilateral nerve damage have been observed after overdose. Deafness and mutism occurred in a 14 year old who ingested approximately 6.5 to 7.8 g of quinine sulphate. Symptoms lasted for approximately 3 days (Schonwald & Shannon, 1991). Cardiovascular Cardiotoxicity typically appears within 8 hours following ingestion of quinine, but delayed cardiotoxicity up to 25 hours after ingestion have been reported (Bodenhamer & Smilkstein, 1993). Sinoatrial, atrioventricular and His-ventricular depression of conduction may occur along with ventricular tachycardia and ventricular fibrillation. Syncope is usually related to transient torsade de pointes ventricular tachycardia (Bauman et al, 1984). Hypotension occurs frequently. Heart failure may result. Toxic ECG abnormalities include prolongation of the PR, QRS and QT intervals. ST depression and T wave inversion may also occur. Respiratory Respiratory depression may occur. Adult respiratory distress syndrome has been reported in one fatal case (Wenston et al, 1989). Neurological Ataxia, paresthesias. Convulsions may follow an overdose. Central nervous system toxicity seems to be more marked in children than adults. Children frequently present with seizures following and overdose (Grattan-Smith et al, 1987). Gastrointestinal Nausea and vomiting are common side effects of quinine. Hepatic Hepatic granulomas have been reported with quinidine as well as reversible hypersensitivity-related hepatitis. Fluid-Electrolyte Hypokalaemia may occur secondary to quinine induced electrolyte fluxes. Aggressive treatment is not recommended. Haematological Haemolytic anaemia may occur in patients with G6PD deficiency. Thrombocytopenia (immune mechanism) Endocrine Therapeutic use of quinine and overdosage has resulted in severe hypoglycaemia (Wenstone et al, 1989). Dermatologic Photosensitivity reactions may occur Chronic toxicity No information MANAGEMENT Decontamination Repeated doses of oral activated charcoal should be started as soon as possible since their is some evidence that this shortens the half life which is otherwise about 26 hours after over dosage. 50 - 100g (25g in children) should be given initially followed by 25 g 2 hourly or 50 g 4 hourly (12g in children). 20ml of lactulose should be given with each dose of charcoal. Supportive care There is no evidence that stellete ganglion block, retro-bulbar injections or vasodilators are effective. Evidence is based on wrong assumptions about the mode of toxicity of quinine. They are not recommended. Fluid and electrolyte monitoring and repeated evaluations of renal function should be performed Monitoring Monitor vital signs - pulse, blood pressure, respiration Careful monitoring of ECG and ventilation should be instituted. Blood for evaluation of plasma quinine level may useful to asses prognosis Renal function Blood gases if patient is unconscious Blood sugar Antidotes There are no effective antidotes Elimination techniques Measures to enhance the elimination of quinine have been generally ineffective (Bateman et al, 1985). The natural history of quinine amblyopia is such that elimination procedures may not critically alter its course (Heath,1985). Forced diuresis has not been found not to produce a sufficiently rapid reduction in plasma concentration or to have a substantial effect on visual disturbances. (Bateman DN at al 1985). Peritoneal dialysis is less effective than normal renal excretion, but has been used occasionally in patients with renal failure (Markham et al, 1967). Haemodialysis, charcoal haemoperfusion and exchange transfusion have similarly been found to be ineffective in increasing quinine elimination (Bateman DN et al 1985). Haemodialysis combined with resin haemoperfusion may be effective in the treatment of quinine blindness refractory to the usual therapy (Gibbs JL,1985). However these data have yet to be corroborated (Bateman DN, 1985). Investigations On admission blood should be drawn for a full blood count, blood sugar, prothrombin time, renal function tests, urinalysis and electrolytes. Periodic eye examinations should include visual acuity. Other techniques that may be used in the longer term assessment of patients with quinine ambylopia include electroretinography, electrooculogram, visual evoked potentials, dark adaptations, and colour testing. Periodic ECGs as indicated. Management controversies Most recent evidence has shown that enhancement of elimination of quinine by forced acid diuresis, peritoneal dialysis, haemodialysis, charcoal haemoperfusion are ineffective (Bateman DN et al 1985). The evidence that stellate ganglion block, retro-bulbar injections or vasodilators are effective is poor and based on wrong assumptions about the mode of toxicity of quinine. This technique should, therefore, not be used. CASE DATA 1. Bodenhamer & Smilkstein (1993) reported delayed cardiotoxicity following ingestion of 16.25g of quinine in a 49 year old female. Symptoms appeared 11.5 hours following ingestion, with conduction abnormalities, ectopy and torsades de pointes occurring 25 hours after ingestion. 2. Notelovitz et al (1970) report a case of a 21 year old female who ingested 90g of quinine during her 8th week of pregnancy to induce abortion. The patient subsequently became drowsy with dark red urine which was positive for blood and albumin. The patient became oliguric and her blood urea rose to 2080 g/l. The patient was treated with diuretics, blood transfusion and haemodialysis with improvement and discharge within 72 hours. 3.Visual damage occurred following overdose of quinine in 2 patients ( a 38 year old male who ingested 2g of quinine and a 60 year old woman who ingested 4g of quinine). The vision loss was only partially reversible (Murray & Jay 83). A 26 year old male developed bilateral loss of vision after ingesting 20 quinine tablets and an unknown quantity of alcohol (Drake & Hiorns 1994). 4. A 17 year old man ingested 5 g of quinine and developed deafness within several hours. Upon presentation he was noted to have broad complex tachycardia, which normalised over 8 hours. The case was complicated with hypokalaemia (2.2 mmol/l) and hypoglycaemia (2.7 mmol/l). Later chest x-ray revealed non-cardiogenic pulmonary oedema. He was treated with antibiotics and inotropic agents. Renal dysfunction developed on the ninth day and the patient died from hypoxic cardiac arrest on the twelfth day. Necropsy revealed ARDS. The peak quinine level was 17.8 mg/l (Wenston et al 1989). 5. Goldenberg AM & Wexler LF (1988) report a case of a 24 year old man who ingested 8 g of quinine sulphate in a suicide attempt. The patient presented within 2 hours and was given a stomach washout. Despite haemoperfusion which was started 10 hours after ingestion, the patient suffered a fatal asystolic cardiac arrest. 6. A case of unsuspected quinine overdose is reported in a 14 year old girl who presented with symptoms including deafness and mutism (Schonwald S & Shannon M, 1991). Diagnosis was delayed for approximately 4 hours because of the absence of an accurate history. The patient took upto 7.8g of quinine, and the serum level 6-8 hours postingestion was 4.5mg/L. Hearing gradually returned on the third day after admission and later that day the patients mutism resolved spontaneously. 7. Two cases of acute quinine toxicity are reported by Wolf LR et al (1992). Both patients presented with acute bilateral blindness. They also experienced the classic symptoms of sinchinism, including nausea, vomiting, and tinnitus. Prolongation of the Q-T interval developed in both patients. Serum quinine levels were 5.3 mg/l and 13 mg/l. Although their visual acuity improved, both patients has some residual deficit at follow up. ANALYSIS Plasma quinine levels can be performed with a modification of the test used to measure quinidine levels using high performance liquid chromatography. (Dyson EH et al 1985 BMJ1985) Author Kathryn Pughe, BSc (Hons) MRPharmS National Poisons Information Service (Newcastle Centre) Regional Drug & Therapeutics Centre Wolfson Building Claremont Place Newcastle upon Tyne NE1 4LP UK This monograph was produced by the staff of the Newcastle Centre of the National Poisons Information Service in the United Kingdom. The work was commissioned and funded by the UK Departments of Health, and was designed as a source of detailed information for use by poisons information centres. Peer review was undertaken by the Directors of the UK National Poisons Information Service. Last updated March 1996 REFERENCES Bateman DN, Blain PG, Woodhouse KW, Rawlins MD, Dyson H, Heyworth R, Prescott LF, Proudfoot AT. Q J Med N Ser. 1985;54:125-131. Bauman JL, Baurenfiend RA, Strasberg B. Torsades de pointes due to quinidine; observation in 31 patients. Am Heart J 1984;107:4125-4230. Bennett PN and the WHO Group, Drugs and Human Lactation, Elsevier 1988. Bodenhamer JE & Smilkstein MJ. Delayed cardiotoxicity following quinine overdosage: A case report. J Emerg Med. 1993;11:279-285. British National Formulary. Number 30 (September 1995). British Medical Association and Royal Pharmaceutical Society. Drake WM and Hiorns MP. Quinine overdose: review of toxicity and treatment. Clin Cardiol. 1988;11:726-718. Dollery C. Therapeutic Drugs. Churchill Livingstone. 1991. Dyson EH, Proudfoot AT, Prescott LF, Heyworth R. Death and blindness due to overdose of quinine. Br Med J 1985;291:31-33. Gibbs JL, Trafford A, Sharpstone P. Quinine amblyopia treated by combined haemodialysis and activated resin haemoperfusion. Lancet 1985;1:752-753. Goldenberg AM & Wexler LF. Quinine overdose: review of toxicity and treatment. Clin Cardiol. 1988;11:716-718. Grattan-Smith TM, Gillis J, Killham H. Quinine poisoning in children. Med J Aust. 1987;147:93-95. Heath A. Resin haemoperfusion for quinine poisoning. Lancet 1985;1:1244. Markhan TN, Dodson VN, Eckberg DL. Peritoneal dialysis in quinine sulphate intoxication. JAMA 1967;202:1102-1103. Murray SB and Jay JL. Loss of sight after self poisoning with quinine. Br Med J 1983;287:1700. Notelovitz M. Acute renal failure following quinine poisoning. So Afr Med J 1970;44:649. Poisindex System(R), Micromedex, inc, Denver Colorado, Edition Expires 31/3/96. Schonwald S & Shannon M. Unsuspected quinine intoxication presenting as acute deafness and mutism. Am J Emerg Med. 1991;9:318-320. Smilkstein MJ, Kulig KW, Rumack BH. Acute toxic blindness: Unrecognised quinine poisoning. Ann Emerg Med. 1987;16:98-101. Wenstone R, Bell ME, Mostafa SM. Fatal adult respiratory distress syndrome after quinine overdose (letter). Lancet 1989;1:1143-1144 Wolf LR, Otten EJ, Spadafora MP. Cinchonism: Two case reports and review of acute quinine toxicity and treatment. J Emerg Med. 1992;10:295-301.