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.