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Quinine

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Main brand names, main trade names
   1.6 Main manufacturers,main importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
4. USES
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
7. PHARMACOLOGY AND TOXICOLOGY
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central Nervous System (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive system
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic/specific treatment
   10.3 Decontamination
   10.4 Enhanced elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES) COMPLETE ADDRESS(ES)
    QUININE

    International Programme on Chemical Safety
    Poisons Information Monograph 464
    Pharmaceutical

    This monograph is not complete, and the following sections are
    included: 1,2,7,9,10,13 and 14.

    1.  NAME

        1.1  Substance

             Quinine

        1.2  Group

             ATC code: P01BC01 (Anti-protozoals, quinine alkaloids,
             Other drugs for disorders of the musculoskeletal
             system)

        1.3  Synonyms

             Chinina; Chininum; Quinina;
             (8S,9R)-6'-methoxycinchonan-9-ol trihydrate;
             (R)--(6-methoxy-4-quinolyl)-[(2S,4S,5R)-(5-vinylquinuclidin-
             2-yl)methanol trihydrate

        1.4  Identification numbers

             1.4.1  CAS number

                    130-95-0 (anhydrous)

             1.4.2  Other numbers

                    Other CAS numbers:
                    Quinine bisulphate: 549-56-4
                    Quinine dihydrochloride: 60-93-5
                    Quinine ethyl carbonate: 83-75-0
                    Quinine hydrobromide: 549-49-5
                    Quinine hydrochloride: 130-89-2 (anhydrous)
                    Quinine hydrochloride: 6119-47-7 (dihydrate)
                    Quinine sulphate: 804-63-7 (anhydrous)
                    Quinine sulphate: 6119-70-6 (dihydrate)

                    ATC Code: M09AA72 (quinine combination with
                    psycholeptics)

        1.5  Main brand names, main trade names

             Adaquin; Bi-Chinine; Biquinate; Biquin (Australia);
             Kinin (Sweden); Formula Q (USA)

        1.6  Main manufacturers,main importers

             To be completed by centre using monograph.

    2.  SUMMARY

        2.1  Main risks and target organs

             Cardiotoxicity is usually the cause of death in
             overdose.
             Central nervous toxicity includes stupor, delirium, coma, and
             seizures.
             Loss of vision and tinnitus or partial/complete deafness.

        2.2  Summary of clinical effects

             Nausea, vomiting, tinnitus and deafness, headache and
             dizziness are early signs of toxicity. Additional toxicity
             includes vision disturbances and partial or complete
             blindness.
             Vertigo and ataxia may occur.
             In severe poisoning: hypotension, delirium, coma,
             dysrhythmias, and convulsions are possible.
             The most significant toxicity is cardiovascular and includes
             sinus tachycardia, high-degree atrioventricular heart block,
             prolongation of the PR interval, sinoatrial block and arrest,
             ventricular fibrillation, torsade de pointes. Hypotension may
             be caused by vasodilation.
             Therapeutic doses may give rise to cinchonism, characterized
             by tinnitus, headache, nausea, abdominal pain, pruritus, skin
             rashes, disturbed vision, and temporary blindness. Acute
             renal failure, haemolysis, and thrombocytopenia.

        2.3  Diagnosis

             Primarily by history of ingestion and the presence of
             typical clinical symptoms: early deafness, tinnitus, vision
             disturbances, and cardiac dysrhythmias.

        2.4  First aid measures and management principles

             Evaluation and support of airway, breathing, and
             circulation. Activated charcoal and intensive monitoring of
             cardiovascular function is necessary. Induction of emesis is
             contra-indicated.

    4.  USES

        4.1  Indications

             4.1.1  Indications

             4.1.2  Description

                    Chemotherapy of malaria, especially in
                    chloroquine-resistant malaria and cerebral malaria
                    (White & Warrel, 1983; Hall & Peters, 1985).
                    For nocturnal leg cramps.
                    In patients with myotonia.
                    Heroin may be diluted with quinine (Lupovich et al.,
                    1970).
                    Quinine has often been used as an abortifacient. It
                    has also been used has antipyretic and analgesic.
                    Tonic water contains approximately 80 mg/L quinine
                    sulphate as a flavouring agent.

        4.2  Therapeutic dosage

             4.2.1  Adults

                    Antimalarial:
                    Oral treatment: 600 to 650 mg three times daily for at
                    least 3 days (USP; Reynolds, 1996), usually as the
                    sulphate, hydrochloride, or dihydrochloride. These 3
                    salts contain approximately the same amount of quinine
                    and any of them can be used when the dose is cited in
                    terms of "quinine salts" (Reynolds, 1996).
                    The usual dosage of totaquine for malaria is 600 mg
                    three times daily after meals (Webster, 1990).
                    Intravenous: initial loading dose of 7 mg/kg of
                    quinine dihydrochloride given over 30 minutes followed
                    immediately by maintenance infusions, or an initial
                    dose of 20 mg/kg (up to a maximum of 1.4 g) given over
                    4 hours with maintenance infusions being started 8 to
                    12 hours later. Maintenance infusions: 10 mg/kg (up to
                    a maximum of 700 mg) given over 4 hours every 8 to 12
                    hours. If parenteral therapy is required for more than
                    48 hours the dose should be reduced by one-third or
                    one-half. Monitor carefully for signs of
                    cardiotoxicity. Therapy should be changed to oral
                    administration as soon as possible to complete the
                    course.
                    If intravenous infusion is not possible, quinine
                    dihydrochloride may be given intramuscularly where
                    doses, including the loading dose are the same as
                    those used for intravenous administration (Reynolds,
                    1996).
    

                    Nocturnal leg cramps:
                    Recumbency leg muscle cramps (night cramps) are
                    reportedly relieved by quinine. The usual quinine
                    sulphate dose is 200 to 300 mg, which may be repeated
                    once before retiring. In some individuals, only a
                    brief period of quinine therapy is required to provide
                    relief; while even large doses of the drug are
                    ineffective in others (Webster, 1990).

             4.2.2  Children

                    Oral treatment: 10 mg of quinine salt per kg
                    body-weight 3 times a day (Reynolds, 1996).

        4.3  Contraindications

             Quinine is contraindicated in patients with a history of
             hypersensitivity and in the presence of haemoglobinuria
             during malaria and in patients with optic neuritis, or
             tinnitus (Reynolds, 1996).
             It should be used with caution in patients with atrial
             fibrillation and other myocardial conduction
             abnormalities.
             Quinine may enhance the effects of anticoagulants.
             In patients with myasthenia, quinine may cause severe
             respiratory distress and dysphagia.
             In patients with glucose-6-phosphate deficiency, blackwater
             fever may be observed when quinine is used (Reynolds,
             1996).

    7.  PHARMACOLOGY AND TOXICOLOGY

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             Toxicity is observed after overdoses
                             of 2.5 to 4 g (Murray & Jay, 1983).
                             Adverse effects are not dose-related.

                    7.2.1.2  Children

                             Toxicity is described above 25 mg/kg
                             in children. Fatalities have occured at the
                             900 mg dose in children aged 1 to 2 years
                             (Winek et al., 1974; Grattan-Smith et al.,
                             1987).

    9. CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    In a series of overdoses with quinine in
                    adults, 75% of patients were symptomatic, 17% had
                    visual symptoms, and 50% had adverse cardiovascular
                    effects (Dyson et al., 1985)
                    In a review of 16 quinine overdose patients, 9
                    patients had reversible or irreversible visual damage,
                    3 had cardiac arrhythmias and one death was reported
                    (Bateman et al., 1985).
                    The patient may present with stupor, coma, confusion,
                    delirium or have extensive muscle weakness.
                    Convulsions can occur (Wolf et al., 1992).

             9.1.2  Inhalation

                    Not applicable.

             9.1.3  Skin exposure

                    No data.

             9.1.4  Eye contact

                    No data.

             9.1.5  Parenteral exposure

                    When administered intravenously it may produce
                    venous thrombosis. Intramuscular and subcutaneous
                    injection can result in tissue necrosis.
                    The clinical toxicity is the same as in oral
                    administration, and the onset is more rapid.

             9.1.6  Other

                    No data

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    Toxicity includes central nervous system (CNS),
                    cardiovascular, gastrointestinal (GI), dermatologic,
                    hematologic and renal toxicity. Cinchonism may occur
                    with therapeutic doses (Reynolds, 1996). Progressive
                    visual loss following ingestion of excessive amounts
                    of Indian tonic water has been reported (Horgan &
                    Williams, 1995).

             9.2.2  Inhalation

                    Not applicable

             9.2.3  Skin exposure

                    No data available.

             9.2.4  Eye contact

                    No data available.

             9.2.5  Parenteral exposure

                    No data avilable.

             9.2.6  Other

                    Not data.

        9.3  Course, prognosis, cause of death

             The major causes of morbidity in quinine overdose
             include reversible renal failure, cinchonism, prolonged
             hearing deficits, and blindness; the skin is often hot and
             flushed initially then may become cold and pale (Rollo, 1975;
             Dannenberg et al., 1983; Licciardello & Stanbury, 1984;
             Medical letter, 1984; Marr, 1985; Reynolds, 1993;
             McEvoy,1994). Death generally follows cardiac disturbances,
             renal failure, acute haemolytic anaemia and respiratory
             arrest (Dannenberg et al., 1983; Licciardello & Stanbury,
             1984).

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Quinine has a negative inotropic action, it
                    slows the rate of depolarization and conduction, and
                    increases the action potential duration and the
                    effective refractory period in the myocardium (Bateman
                    & Dyson, 1986; Mack, 1986; Jaeger et al., 1987).
                    Prolongation of the PR, QT, and QRS intervals, ST and
                    T waves changes, and U waves may be observed (Bateman
                    & Dyson, 1986; Smilkstein et al., 1987; Goldfrank &
                    Osborn, 1990,). SA block/arrest, high degree AV block,
                    complete AV dissociation, ventricular tachycardia,
                    ventricular fibrillation, and torsade de pointes are
                    reported (Boland et al., 1985; Bateman & Dyson et al.,
                    1986; Smilkstein et al., 1987; Goldfrank & Osborn,
                    1990).
    

                    Quinine has an alpha-adrenergic blocking effect and
                    hypotension may occur as result of vasodilation,
                    myocardial depression, or dysrhythmias (Bateman &
                    Dyson, 1986; Goldenberg & Wexler, 1988). Bradycardia
                    rarely occurs due to vagolytic activity (Smilksten et
                    al., 1987).
                    Bodenhamer & Smilkstein (1993) reported a quinine
                    overdose resulting in the delayed onset of cardiac
                    ventricular conduction defects, ectopy, and torsade de
                    pointes and subsequent cardiac arrest 25 hours after
                    ingestion.
                    Quinine administered intravenously may produce venous
                    thrombosis.

             9.4.2  Respiratory

                    Initially increased, later shallow and
                    depressed respirations.

             9.4.3  Neurological

                    9.4.3.1  Central Nervous System (CNS)

                             In severe poisonings, headache,
                             fever, vomiting, excitement, confusion,
                             delirium, syncope, lowering of the body
                             temperature.
                             Vertigo and ataxia, with presumed involvement
                             of the vestibular nerve may occur (Bateman &
                             Dyson, 1986).

                    9.4.3.2  Peripheral nervous system

                             No data available.

                    9.4.3.3  Autonomic nervous system

                             No data available.

                    9.4.3.4  Skeletal and smooth muscle

                             Quinine increases the tension
                             response to a single maximal stimulus
                             delivered to the muscle directly or through
                             the nerve, but it also increases the
                             refractory period of the muscle so that the
                             response to tetanic stimulation is
                             diminished. The excitability of the motor
                             end-plate region decreases so that responses
                             to repetitive nerve stimulation and to
                             acetylcholine are reduced. Thus, quinine can
                             antagonize the actions of physostigmine on
                             skeletal muscle as does curare. The same

                             mechanism, however, may provoke alarming
                             respiratory distress in patients with
                             myasthenia gravis (Webster, 1990).
                             On uterine muscle it may be oxytocic to the
                             pregnant uterus (Rollo, 1975).

             9.4.4  Gastrointestinal

                    Nausea, vomiting, abdominal pain, and diarrhea
                    result from the local irritant action of quinine.
                    Nausea and vomiting may also be secondary to a CNS
                    mechanism. (Goodman & Gilman, 1990).

             9.4.5  Hepatic

                    Granulomatous hepatitis has been reported (Katz
                    et al., 1983; Mathur et al., 1990); cholestatic and
                    hepatocellular toxicity, probably secondary to a
                    hypersensitivity reaction, has also been
                    described.

             9.4.6  Urinary

                    9.4.6.1  Renal

                             Tubular obstruction, acute renal
                             failure (Winek et al., 1974; Bateman & Dyson,
                             1986).

                    9.4.6.2  Other

                             No data vailable.

             9.4.7  Endocrine and reproductive system

                    Therapeutic doses of quinine may lower blood
                    glucose concentrations by stimulating insulin
                    secretion (Looareesuwan et al., 1985; Okitolonda et
                    al., 1987).
                    Recurrent hyperinsulinemic hypoglycaemia can be
                    particularly serious when quinine is used during
                    pregnancy or when there is severe infection (Webster,
                    1990).
                    Symptomatic hypoglycaemia has been reported (Browne &
                    Coppel, 1984; Limburg et al., 1993).
                    It has been reported to decrease male reproductive
                    capacity.
                    Use of quinine as an abortifacient can produce
                    poisoning in the fetus with frequent infant deafness
                    (Dannenberg et al., 1983).

             9.4.8  Dermatological

                    The skin may be hot, flushed and sweating.
                    Rashes frequently appear.
                    Angioedema, especially of the face, may be observed.
                    The skin becomes cold and cyanotic as the poisoning
                    progresses (Webster, 1990).

             9.4.9  Eye, ear, nose, throat: local effects

                    Ear: Transient hearing loss, usually a first
                    side effect, occurs a few hours after initiating high-
                    dose therapy (up to 2 g in the treatment of malaria).
                    After prolonged daily courses of 200 to 300 mg, up to
                    20% of patients can be expected to suffer from hearing
                    loss (Miller, 1985). The sensorineural hearing loss is
                    typically reversible, bilateral, and symetric,
                    affecting the high frequencies first (4, 6, and 8 kHz)
                    with a characteristic 4-kHz notch (Roche et al.,
                    1990).
                    Discrimination scores have been noted to fall below
                    30% (Koegel, 1985).
                    Ototoxicity of quinine is probably secondary to direct
                    cochlear hair cell damage (Rybak, 1985). Vertigo and
                    ataxia secondary to presumed involvement of the
                    vestibular nerve may occur (Bateman & Dyson,
                    1986).
    
                    Eye: as early as 15 to 30 mn after a quinine
                    overdose the patient may complain of a blurred
                    vision.
                    The mean time of onset of blindness is 6 hours, while
                    usually gradual, can be sudden.
                    It may pass after 14 to 24 hours, however it may last
                    up to 10 weeks or longer.
                    Generally there is full recovery in 1 to 3 weeks,
                    however patient may become permanently blind.
                    Ophtalmic findings during the acute phase are dilated
                    pupils and unresponsiveness to light in proportion to
                    the degree of blindness. The ophthalmoscopic
                    appearances have varied considerably from case to case
                    and this has occasioned much dispute concerning the
                    mechanism by which vision is affected. In some cases
                    the retinal vessels have appeared narrowed early. In
                    another group of cases the retina has appeared
                    oedematous and the papilla hyperaemic. Occasionally a
                    red spot in the macula has been noted with oedema. In
                    yet other cases the fundi have appeared normal at an
                    early stage while the patient was already profoundly
                    blind. It has been reported very frequently that at a
                    later stage, after some days or weeks, the retinal
                    arterioles have become strikingly narrowed, often at a

                    time when central vision had returned, or was
                    returning. Pallor of the optic nerve heads has often
                    been noted, developing gradually, generally
                    proportional to the amount of permanent loss of visual
                    field (Grant, 1986).
                    In the acute stages of loss of vision, the
                    electroretinogram may be normal. Thereafter it becomes
                    abnormal during the phase of visual improvement and
                    parallels the changes of visual acuity on the second
                    or third day.
                    Visual evoked potentials, dark adaptation, and color
                    testing measurements are often abnormal (Ellenhorn et
                    al., 1997).
                    Visual loss was observed in a patient who was drinking
                    4 liters of tonic water each day for 12 months prior
                    to presentation. Retinal vessels were of normal
                    calibre but each macula exhibited fine stippling shown
                    by fluorescein angiography (Horgan & Williams,
                    1995).

             9.4.10 Haematological

                    Quinine-induced agranulocytosis has been
                    reported. It has been confirmed by the inhibition,
                    in vitro, of bone-marrow cell cultures by
                    therapeutic concentrations of quinine (Sutherland et
                    al., 1977).
                    Other abnormalities include: Coombs' positive
                    haemolytic anaemia, neutropenia, dissiminated
                    intravascular coagulation, hypoprothrombinaemia, and
                    thrombocytopenia (Belkin, 1976; Pfueller et al., 1988;
                    Spearing et al., 1990; Hagley et al., 1992; Aster,
                    1993; Maguire et al., 1993).
                    Haemolysis can result when quinine is administered to
                    patients with G6PD deficiency.

             9.4.11 Immunological

                    No data available.

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             Secondary to respiratory
                             insufficiency and renal disturbances,
                             seizures and cardiovascular
                             collapse.

                    9.4.12.2 Fluid and electrolyte disturbances

                             Secondary to renal dysfunction.

                    9.4.12.3 Others

                             No data available.

             9.4.13 Allergic reactions

                    Some patients are hypersensitive to quinine
                    and even small doses may give rise to symptoms of
                    cinchonism, together with angioneurotic oedema, asthma
                    and other allergic phenomena (Barr et al., 1990).
                    Haemolytic anaemia and thrombocytopenia have been
                    reported. As a test for quinine idiosyncrasy a scratch
                    test may be made with a 1 to 10% solution of a quinine
                    salt in physiological saline: redness, oedema, and
                    itching occur within 5 to 15 minutes if the patient is
                    hypersensitive (Reynolds, 1982).
                    Photosensitivity reactions following systemic
                    administration (Reynolds, 1996).

             9.4.14 Other clinical effects

                    No data available.

        9.5  Other

             No data available.

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             Admission in an intensive care department is indicated.
             Monitoring the airway, breathing, and circulation.
             Gastrointestinal decontamination with activated charcoal
             should be undertaken.

        10.2 Life supportive procedures and symptomatic/specific treatment

             After basic support of airway, breathing, and
             circulation, vasopressors and specific treatment of
             conduction disorders may be required. Antiarrhythmics that
             depress conduction (Class IA) should be avoided, ie
             quinidine, procainamide. Sodium bicarbonate may be used,
             fluids and electrolyte administration may be required.

        10.3 Decontamination

             Early gastric decontamination should be used. The use
             of ipecac should be avoided, and gastric lavage used only for
             recent/large ingestion. Activated charcoal is very effective
             and should be the primary method of gastric
             decontamination.

        10.4 Enhanced elimination

             Efficacy of elimination procedures is limited by the
             extensive protein binding and volume of distribution (Maher,
             1983). Acidification of urine is not recommended, as it does
             increase cardiotoxicity. Forced diuresis is not effective.
             Early resin haemoperfusion may be effective in severe
             poisoning. In later phases of poisoning, haemoperfusion,
             haemodialysis or peritoneal dialysis are not effective.
             Exchange transfusion has not been successful (Bateman et al.,
             1985).

        10.5 Antidote treatment

             10.5.1 Adults

                    Not available.

             10.5.2 Children

                    Not available.

        10.6 Management discussion

             The treatment of cardiac dysrhythmias with bicarbonate
             or lactate counteracts the elimination of quinine. The
             elimination of quinine in acidic urine is two times higher
             than in alkaline urine, but not clinically important.
             The treatment of quinine amblyopia is controversial. Because
             the etiology was originally thought to be retinal ischaemia,
             multiple methods have been used to cause retinal
             vasodilation. Stellate ganglion block, retrobulbar injection
             of vasodilators, and anterior chamber paracentesis have all
             generally been found to be ineffective in the treatment of
             quinine-induced blindness (Gangitano & Keltner, 1980; Dyson
             et al., 1985; Smilkstein et al., 1987; Canning & Hague,
             1988). Stellate ganglion block has been associated with
             serious complications, including death (Adriani et al.,
             1952).
             Hyperbaric oxygen, hemodialysis, and resin hemoperfusion have
             been suggested to be effective in the treatment of blindness
             refractory to other therapy.

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    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES)
        COMPLETE ADDRESS(ES)

        Author: Prof. Dr. A.N.P. van Heijst
        Baarnseweg 42 A
        3735 MJ Bosch en Duin
        The Netherlands
        Tel: (31) (30) 228 71 78
        Fax (31) (30) 225 13 68
        E-Mail: 106072.2411@compuserve.com
    
        Date: January 1997
    
        Reviewer: MO Rambourg Schepens
        Centre Anti-Poisons de Champagne Ardenne
        Centre Hospitalier Universitaire
        F-51092 Reims Cedex
        E-mail: marie-odile.rambourg@wanadoo.fr
    
        Date: August 1997
    

        Peer review: INTOX-10 Meeting, Rio, Brazil September, 3rd, 1997
        (Drs M Kowalczyk, L Lubomirov, R Mc Keown, P Rosen, W Watson)
    
        Finalization: MO Rambourg Schepens/M Ruse
        October 1997
    



    See Also:
       Toxicological Abbreviations
       Quinine (WHO Food Additives Series 30)
       Quinine (UKPID)