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Chloroquine

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 Brand names, Trade names
   1.6 Manufacturers, 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
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Properties of the substance
      3.3.2 Properties of the locally available formulation
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Shelf-life of the locally available formulation
      3.4.3 Storage conditions
      3.4.4 Bioavailability
      3.4.5 Specific properties and composition
4. USES
   4.1 Indications
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall Interpretation of all toxicological analyses and toxicological investigations
   8.6 References
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 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 systems
      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
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Relevant laboratory analyses
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures and symptomatic/specific treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. Additional information
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)


    PHARMACEUTICALS
    1. NAME
     1.1 Substance
       Chloroquine
     1.2 Group
       Amino-4-quinoline (quinoline derivative)
     1.3 Synonyms
       7-Chloro-4-(4-diethylamino-1-methylbutylamino)quinoline
       Chingamin
       Chingamin phosphate
       Chlorochin
       Chloroquin diphosphate
       Chloroquina
       Chloroquine diphosphate
       Chloroquine hydrochloride
       Chloroquine phosphate
       Chloroquine sulfate
       Chloroquine sulphate
       Chloroquinum
       Cholarquine
       Choroquin sulfate
       Quinagamin
       RP 3377
       SN 6718
       SN 7618
       W 7618
       WIN 244
     1.4 Identification numbers
       1.4.1 CAS number
             54-05-7
       1.4.2 Other numbers
             Chloroquine dihydrochloride: 3545-67-3 
             Chloroquine diphospate: 50-63-5
             Chloroquine phosphate: 1446-17-9
             Chloroquine sulfate: 132-73-0
             VB2360000 Chloroquine
             VB2450000 Chloroquine diphosphate
             VB2625000 Chloroquine phosphate
             VB2630000 Chloroquine sulfate
             VB9642000 Chloroquine dihydrochloride
     1.5 Brand names, Trade names
     1.6 Manufacturers, Importers
    2. SUMMARY
     2.1 Main risks and target organs
       The main toxic effects of chloroquine are related to its 
       quinidine-like (membrane stabilizing) actions on the heart.  
       Other acute effects are respiratory depression and severe 
       gastro-intestinal irritation.
     2.2 Summary of clinical effects
       Toxic manifestations appear rapidly within one to three hours 
       after  ingestion and include:
       
       Cardiac disturbances: circulatory arrest, shock, conduction 
       disturbances,  ventricular arrhythmias.
       
       Neurological symptoms: drowsiness, coma and sometimes 

       convulsions.  Visual  disturbances not uncommon.
       
       Respiratory symptoms: apnoea.
       
       Gastrointestinal symptoms: severe gastrointestinal irritation; 
       nausea,  vomiting, cramps, diarrhoea.
       
       Children are specially sensitive to toxic effects.
     2.3 Diagnosis
       Dizziness, nausea, vomiting, diarrhoea, headache, drowsiness, 
       blurred vision, diplopia, blindness, convulsions, coma, 
       hypotension, cardiogenic  shock, cardiac arrest and impaired 
       respiration are the characteristic  features of chloroquine 
       poisoning.
       
       Electrocardiography (ECG) may show decrease of T wave, 
       widening of QRS,  ventricular tachycardia and fibrillation.
       
       Hypokalaemia (potassium < 3 mmol/L) is associated with severe 
       poisoning.
       
       High serum chloroquine levels confirm the diagnosis. 
       Concentrations higher than 5 mg/L are usually observed in 
       severe intoxication.
     2.4 First aid measures and management principles
       Patients with acute chloroquine overdose should always be 
       admitted in  an intensive care unit.
       
       Monitor vital signs (ECG, blood pressure, respiration) and 
       measure serum  electrolytes, especially, potassium.
       
       Treatment includes:
       
       - supportive treatment: artificial ventilation, cardiac 
       resuscitation, and
       
       - inotropic and vasopressor drugs: adrenaline, isoproterenol, 
       dopamine, and hypertonic sodium solutions,
       
       - diazepam IV to prevent or reduce cardiotoxicity,
       
       - gastric emptying and activated charcoal.
    3. PHYSICO-CHEMICAL PROPERTIES
     3.1 Origin of the substance
       Chloroquine was originally synthesized in 1934 by Bayer in 
       Germany  (Resochin).
       
       Chloroquine is prepared by the condensation of 4-7-
       dichloroquinoline with  1-diethylamino-4-aminopentane.
     3.2 Chemical structure
       7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline, or N4-
       (7-chloro-4-quinolinyl)-N1-N1-diethyl-1,4-pentanediamine.
       
       Chemical structure:
       
       C18H26CIN3               Molecular weight: 319.92

       
       Derivatives:
       
       Chloroquine diphosphate:
       
       C18H29ClN3.2H3PO4        MW = 515.92
       
       Chloroquine phosphate:
       
       C18H29ClN3.H3PO4         MW = 417.92
       
       Chloroquine sulfate:
       
       C18H26ClN3. H2SO4        MW = 418.00
       
       Chloroquine dihydrochloride:
       
       C18H26ClN3.2HCl          MW = 392.84
     3.3 Physical properties
       3.3.1 Properties of the substance
             Chloroquine is a white or slightly yellow, odourless 
             crystalline powder  with a bitter taste.  Melting point: 
             87 to 92°C.  Very slightly soluble in water, soluble in 
             chloroform, ether and dilute acids.
             
             Chloroquine diphosphate is a white, bitter, crystalline 
             powder that exists in two polymorphic forms, one melting 
             between 193°C and  195°C, and the other  between 210°C and 
             215°C (mixture of the forms melt between 193°C and 215°C.   
             Readily soluble in water at acidic pH.  Practically insoluble 
             in alcohol,  methanol, ether, chloroform.
             
             Chloroquine sulfate is a white, odourless, bitter, 
             crystalline powder.   Melting point: 205°C to 210°C.  
             Readily soluble in water and methanol.   Hydroxychloride 
             chloroquine is a colourless liquid, pH between 5.5 and 6.5.
             
             Solutions of chloroquine phosphate and hydroxychloroquine 
             sulfate have a pH = 4.5.
       3.3.2 Properties of the locally available formulation
             No data available.
     3.4 Other characteristics
       3.4.1 Shelf-life of the substance
             At least five years.
       3.4.2 Shelf-life of the locally available formulation
             To be completed.
       3.4.3 Storage conditions
             Chloroquine diphosphate is stable to heat in solution of 
             pH 4.0 to 6.5. Chloroquine phosphate and chloroquine 
             sulfate are sensitive to light.
       3.4.4 Bioavailability
             To be added by the local poisons centre.
       3.4.5 Specific properties and composition
             No data available.
    4. USES
     4.1 Indications

       Malaria - Chloroquine is the drug of choice for the prophylaxis 
       and treatment of malaria caused by Plasmodium vivax. P. ovale, 
       P. malariae and sensitive P. falciparum.

       Amoebiasis - Chloroquine is used for the treatment of 
       extraintestinal amebiasis (usually in combination with amebicides).

       Discoid lupus erythematosus and rheumatoid arthritis (acute and 
       chronic).  Chloroquine may be used for the treatment of these 
       conditions.

       Other less common indications are: amebic liver abscess,  
       polymorphus light eruption, prophyria cutanea tarda, solar 
       urticaria, chronic cutaneous vasculitis.

     4.2 Therapeutic dosage
       4.2.1 Adults
             Malaria treatment
             
             Oral: 600 to 900 mg the lst day, then 300 mg daily
             I.M.: 200 to 300 mg/day for three to five days.
             
             Malaria prophylaxis
             
             Oral: 100 mg/day or one dose of 300 mg weekly for six 
             weeks.
             
             Hepatic amebiasis
             
             Oral: 600 mg/day for three days then 300 mg/day.
             
             Discoid lupus erythematosus and rheumatoid arthritis
             
             Oral: 300 mg/day.
       4.2.2 Children
             Malaria treatment
             
                  Oral: 10 mg/kg as loading dose, then 5 mg/kg/day 
             for four days.
                  IM: is not recommended in children.
             
             Malaria prophylaxis
             
                  Oral: age below 1 year: 25 mg every two days
                        age over 1 year: 25 to 50 mg per day
                        or: 5 mg/kg one dose weekly.
     4.3 Contraindications
       Hepatic and renal function impairment, blood disorders, 
       gastrointestinal illnesses, glucose-6-phosphate dehydrogenase 
       (G-6-PD) deficiency, severe neurological disorders, retinal or 
       visual field changes.
       
       Chloroquine should not be used in association with gold salts 
       or phenylbutazone.
       
       Chloroquine in doses used for malaria prophylaxis is safe in 

       pregnancy and breast feeding (Kasilo et al. 1988).
    5. ROUTES OF ENTRY
     5.1 Oral
       Oral absorption is the most frequent cause of intoxication.
     5.2 Inhalation
       Not relevant.
     5.3 Dermal
       Not relevant.
     5.4 Eye
       Not relevant.
     5.5 Parenteral
       Intoxication after parenteral administration is rare.  Abu 
       Aisha et al. (1979) reported a fatal outcome after 250 mg IV 
       chloroquine in a 42-year-old man.
     5.6 Other
       Not relevant.
    6. KINETICS
     6.1 Absorption by route of exposure
       Readily and almost completely absorbed from the 
       gastrointestinal tract.
       
       Bioavailability is 89% for tablets (Gustafsson et al., 1983).
       
       Half time of absorption is 0.56 h (Adelusi et al., 1982).
       
       Peak plasma concentration is reached 1.5 to 3 hours after 
       ingestion.
     6.2 Distribution by route of exposure
       Protein binding: 5O to 65% (Walker et al. 1983).
       
       Apparent volume of distribution is very high: 116 to 285 L/kg 
       (Gustafsson et al., 1983).
       
       Chloroquine accumulates in high concentrations in kidney, 
       liver, lung and spleen, and is strongly bound in melanin-
       containing cells (eye and skin).
       
       Red cell concentration is five to ten times the plasma 
       concentration.
       
       Very low concentrations in intestinal wall.
       
       Crosses the placenta.
     6.3 Biological half-life by route of exposure
       Plasma terminal half-life is mean 278 hours (Gustafsson et al. 
       1983) or 70 to 120 hours (USP, 1988).
       
       Shorter plasma elimination half-lives have been reported in 
       children: 75 to 136 hours.
     6.4 Metabolism
       Chloroquine undergoes partly hepatic metabolism.
       
       The main active metabolite is desethylchloroquine.  Plasma 
       half-life of desethylchloroquine is similar to chloroquine 
       (Walker et al., 1983).
     6.5 Elimination by route of exposure

       Chloroquine is eliminated very slowly.  About 55% is excreted 
       in urine and 19% in faeces within 77 days following therapy 
       with 310 mg for 14 days (McChesnay et al. 1967).
       
       Kidney: in urine about 70% is unchanged chloroquine and 23% is 
       desethylchloroquine (Gustafsson et al., 1983).
       
       Renal clearance is mean 410 ml/min (Gustafsson et al., 1983).
       
       Total body clearance: mean 722 ml/min (Gustafsson et al., 
       1983).
       
       It is excreted in breast milk (USP, 1988).
    7. PHARMACOLOGY AND TOXICOLOGY
     7.1 Mode of action
       7.1.1 Toxicodynamics
             The cardiotoxicity of chloroquine is related to it 
             quinidine-like (membrane/stabilizing) effects.  
             Chloroquine has a negative inotropic  ction, inhibits 
             spontaneous diastolic depolarization, slows conduction, 
             lengthens the effective refractory period and raises the 
             electrical threshold (Jaeger et al., 1987).  This 
             results in depression of contractility, impairment of 
             conductivity, decrease of excitability, but with 
             possible abnormal stimulus re-entry mechanism.  The 
             following progression of ECG changes was observed in 
             dogs with experimental overdosage (Don Michael and 
             Aiwazzadey, 1970): severe tachycardia preceded by loss 
             of voltage and widening of QRS, followed by sinus 
             bradycardia, ventricular tachycardia, ventricular 
             fibrillation and finally asystole.
             
             Hypokalaemia: Acute hypokalaemia may occur in acute 
             poisoning (Lofaso et al., 1986; Jaeger et al., 1987).  
             It is probably related to intracellular transport of 
             potassium by a direct effect on cellular membrane  
             permeability.
             
             Neurological symptoms:  Neurological symptoms in acute 
             overdose may be related to a direct toxic effect on CNS 
             or to cerebral ischaemia due to circulatory failure or 
             respiratory insufficiency.
       7.1.2 Pharmacodynamics
             Chloroquine and its 4 amino-quinoline congeners block 
             the enzymatic synthesis of DNA and RNA.  Chloroquine is 
             an excellent blood schizonticide but has no effect on 
             secondary tissue schizonts and on sporozoites.  It 
             inhibits the erythrocytic stage of development of 
             plasmodia. Thus relapses may occur after cessation of 
             the treatment.
             
             The mechanism of the anti-inflammatory effect is not 
             known.
             
             Chloroquine has a quinidine-like (membrane stabilizing) 
             effect on the cardiovascular system.

     7.2 Toxicity
       7.2.1 Human data
             7.2.1.1 Adults
                     Oral
                     
                     Chloroquine has a low margin of safety; the 
                     therapeutic, toxic and lethal doses are very 
                     close.
                     
                     In adults fatalities have been reported after 
                     ingestion of 2.25 to 3 g chloroquine (Britton & 
                     Kevau, 1978). Without treatment, a dose of 4 g 
                     is usually lethal.
                     
                     So 20 mg/Kg is a toxic dose, 30 mg/Kg may be 
                     lethal and 40 mg/Kg is usually lethal without 
                     early intensive therapy (Jaeger et al., 1987).
                     
                     Vitris and Aubert (1983) distinguished three 
                     types of overdose:
                     
                     _________________________________________________
                     Dose      Severity  Symptoms       Plasma(g)
                     absorbed            of poisoning   chloroquine
                                                        concentration
                                                        (mg/l)
                     _________________________________________________
                     
                     > 4       severe    neurological   > 5
                                         symptoms
                                         circulatory
                                         failure
                                         ECG disturbance
                     
                     2 to 4    moderate  neurologic     2.5 to 5
                                         symptoms
                                         ECG disturbance
                     
                     < 2       mild      ./.            < 2.5
                     _________________________________________________
                     
                     -    Intravenous
                     
                     Abu Aisha et al. (1979) reported fatal outcome 
                     after an intravenous administration of 250 mg in 
                     a 42-year-old man.
             7.2.1.2 Children
                     20 mg/kg (i.e., twice the maximal therapeutic 
                     dose) is a toxic  dose.
                     
                     Fatalities have been reported in children after 
                     chloroquine overdoses; in a three-year-old boy 

                     after 300 mg (Clyde, 1966); in a three-year-old 
                     child after 1 gram, a 14-month-old child after 1 
                     to 2 grams (Markowitz & McGinley, 1964) and in a 
                     three-year-old child after 0.75 to 1 gram (Cann 
                     & Verhulst, 1961).
       7.2.2 Relevant animal data
             DSO L (mg/kg)
             
             _______________________________________________________
                       IV   Intraperi-     Subcutaneous   Oral
                            toneal
             _______________________________________________________
             Mouse     40     250             150         200-400
             Rat        -     102              -          1050
             Rabbit     8      -               -            75 
             Dogs      100     -               -             -
             _______________________________________________________
       7.2.3 Relevant in vitro data
     7.3 Carcinogenicity
       No data available.
     7.4 Teratogenicity
       No teratogenic effects reported in therapeutic doses but in 
       high doses see 9.4.15 B.
     7.5 Mutagenicity
       No data available.
     7.6 Interactions
       Chloroquine toxicity may be increased by all drugs with 
       quinidine-like effects.
       
       Combination with hepatotoxic or dermatitis-causing medication 
       should be avoided, as well as with heparin (risk of 
       haemorrhage) and penicillamine (USP, 1988).
       
       May interfere with rabies vaccination (Kasilo, 1988).
     7.7 Main adverse effects
       Chloroquine is generally well tolerated when given in 
       antimalarial doses and when side effects occur they are 
       rapidly reversible on withdrawal of the drug.  Higher doses 
       used for prolonged periods are more likely to produce adverse 
       effects (Reynolds, 1982).
       
       The following adverse effects have been reported during 
       chloroquine treatments:
       
       - Cardiovascular: ECG changes, flattening and inversion of T 
       waves, prolongation of QT interval.
       
       - Neurological: toxic psychosis with hallucinations and 
       agitation, peripheral neuropathy, myopathy, convulsions.
       
       - Gastrointestinal: nausea, vomiting, diarrhoea, abdominal 
       cramps.
       
       - Dermatological: pruritus, maculopapular eruption, 
       exfoliative   dermatitis, purpuric skin reactions, 
       photosensitivity,   hyperpigmentation, alopecia, greying of 

       the hair.
       
       - Eye: Keratopathy and retinopathy may occur when large doses 
       of chloroquine are used for long periods.  Changes occurring 
       in the cornea are usually completely reversible on 
       discontinuing treatment; changes in the retina, pigmentary 
       degeneration of the retina, loss of vision, scotomas, optic 
       nerve atrophy, field defects and blindness are irreversible.  
       Retinopathy is considered to occur when the total cumulative 
       dose ingested exceeds 100 g.  Blurring of vision, diplopia may 
       occur with short-term chloroquine therapy and are reversible.
       
       - Ear: tinnitus and deafness are rare.
       
       - Haematological: leucopenia, methaemoglobinaemia.
       
       - Other: pronounced porphyrinuria after chloroquine treatment 
       in patients with cutaneous porphyria has been reported.
    8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
     8.1 Material sampling plan
       8.1.1 Sampling and specimen collection
             8.1.1.1 Toxicological analyses
             8.1.1.2 Biomedical analyses
             8.1.1.3 Arterial blood gas analysis
             8.1.1.4 Haematological analyses
             8.1.1.5 Other (unspecified) analyses
       8.1.2 Storage of laboratory samples and specimens
             8.1.2.1 Toxicological analyses
             8.1.2.2 Biomedical analyses
             8.1.2.3 Arterial blood gas analysis
             8.1.2.4 Haematological analyses
             8.1.2.5 Other (unspecified) analyses
       8.1.3 Transport of laboratory samples and specimens
             8.1.3.1 Toxicological analyses
             8.1.3.2 Biomedical analyses
             8.1.3.3 Arterial blood gas analysis
             8.1.3.4 Haematological analyses
             8.1.3.5 Other (unspecified) analyses
     8.2 Toxicological Analyses and Their Interpretation
       8.2.1 Tests on toxic ingredient(s) of material
             8.2.1.1 Simple Qualitative Test(s)
             8.2.1.2 Advanced Qualitative Confirmation Test(s)
             8.2.1.3 Simple Quantitative Method(s)
             8.2.1.4 Advanced Quantitative Method(s)
       8.2.2 Tests for biological specimens
             8.2.2.1 Simple Qualitative Test(s)
             8.2.2.2 Advanced Qualitative Confirmation Test(s)
             8.2.2.3 Simple Quantitative Method(s)
             8.2.2.4 Advanced Quantitative Method(s)
             8.2.2.5 Other Dedicated Method(s)
       8.2.3 Interpretation of toxicological analyses
     8.3 Biomedical investigations and their interpretation
       8.3.1 Biochemical analysis
             8.3.1.1 Blood, plasma or serum
             8.3.1.2 Urine
             8.3.1.3 Other fluids

       8.3.2 Arterial blood gas analyses
       8.3.3 Haematological analyses
       8.3.4 Interpretation of biomedical investigations
     8.4 Other biomedical (diagnostic) investigations and their 
       interpretation
     8.5 Overall Interpretation of all toxicological analyses and 
       toxicological investigations
     8.6 References
    9. CLINICAL EFFECTS
     9.1 Acute poisoning
       9.1.1 Ingestion
             Severity of chloroquine poisoning is related to the 
             cardiotoxic effects. Symptoms appear rapidly after 
             ingestion and may include: dizziness,  nausea, vomiting, 
             diarrhoea and headache.
             
             Neurological symptoms: drowsiness, blurred vision, 
             diplopia, blindness, convulsions and coma.
             
             Respiratory symptoms: polypnoea, apnoea.
             
             Cardiovascular symptoms: hypotension, cardiogenic shock, 
             cardiac arrest.  ECG - decrease of T wave, widening of 
             QRS, ventricular tachycardia and fibrillation.
             
             Hypokalaemia (K < 3 mmol/L) is associated with severe 
             poisoning.
       9.1.2 Inhalation
             Not relevant.
       9.1.3 Skin exposure
             Not relevant.
       9.1.4 Eye contact
             Not relevant.
       9.1.5 Parenteral exposure
             Clinical effects are similar to those observed after 
             ingestion. See Section 9.1.1.
       9.1.6 Other
             No data available.
     9.2 Chronic poisoning
       9.2.1 Ingestion
             The most relevant features of chronic poisoning are 
             keratopathy, retinopathy and neurological symptoms (see 
             Section 7.7, main side effects).
       9.2.2 Inhalation
             Not relevant.
       9.2.3 Skin exposure
             Not relevant.
       9.2.4 Eye contact
             Not relevant.
       9.2.5 Parenteral exposure
             No data available.
       9.2.6 Other
             No data available.
     9.3 Course, prognosis, cause of death
       Course
       

       The most important feature of acute chloroquine intoxication 
       is the rapid onset (within one to three hours) of severe toxic 
       manifestations.
       
       Drowsiness appears early within 10 to 30 minutes of ingestion. 
        Severe cardiovascular symptoms appear within one to three 
       hours of ingestion.  Fatal outcome usually occur within two to 
       three hours.  Cardiovascular symptoms may last for 48 hours.  
       After the 48th hour patients usually recover.
       
       Prognosis
       
       Criteria of severe intoxications are: dose ingested higher 
       than 3 to 4 g, hypotension, cardiogenic shock, QRS widening, 
       ventricular arrhythmias, hypokalaemia.  Severity of the 
       intoxication is closely related to the serum potassium 
       concentration (Lofaso et al., 1987; Jaeger et al., 1987).
       
       Cause of death
       
       The cause of death is circulatory arrest which occurs 
       predominantly during the first few hours of the intoxication 
       and is related to cardiac insufficiency or ventricular 
       arrhythmia.
     9.4 Systematic description of clinical effects
       9.4.1 Cardiovascular
             Acute
             
             Cardiovascular symptoms are present in 50 to 60% of the 
             cases (Jaeger et al., 1987).
             
             Cardiac arrest: may occur within one to two hours 
             following ingestion.  It is related to cardiac 
             insufficiency, ventricular dysrhythmia or asystole.  
             After the eighth hour, cardiac arrest is mostly related 
             to ventricular dysrhythmia and especially "torsade de 
             pointes".
             
             Shock: Hypotension is frequent and may rapidly progress 
             to a cardiogenic shock with increased venous pressure.  
             Haemodynamic studies showed a decrease of cardiac output 
             and a peripheral vasodilatation (Bavoux et al., 1987).
             
             Ventricular dysrhythmia: Ventricular tachycardia and 
             fibrillation may occur up to 24 to 28 hours after 
             ingestion.
             
             Ventricular extrasystoles and torsade de pointes mainly 
             occur after the eighth hour post-ingestion.
             ECG changes:  Repolarization abnormalities: flattening 
             of T wave increase of QT interval, increase of U wave, 
             depression of ST segment.  Conduction abnormalities: 
             increase of QRS duration (QRS > 0.08 sec).   
             Atrioventricular block.  Ventricular dysrhythmias: 
             fibrillation, extrasystoles, torsades de pointes.
             

             Chronic
             
             ECG changes are not uncommon during high dosage 
             treatments: T wave abnormalities, prolongation of the QT 
             interval.  Cardiomyopathy and heart block have rarely 
             been reported.
       9.4.2 Respiratory
             Acute
             
             Hyperpnoea is frequent.  Apnoea may occur, especially at 
             the onset of convulsions or cardiac failure.
             
             Chronic
             
             No data available.
       9.4.3 Neurological
             9.4.3.1 CNS
                     Acute
                     
                     Drowsiness appears early within 10 to 30 minutes 
                     post-ingestion.  Coma is less common and is in 
                     most cases associated with circulatory failure.  
                     A concomitant ingestion of psychotropic drugs 
                     should be suspected in the case of deep coma 
                     without circulatory failure.  CNS 
                     hyperexcitability with agitation and convulsions 
                     usually precedes circulatory arrest.
                     
                     Chronic
                     
                     Several cases of acute psychosis ascribed to 
                     chloroquine have been reported.  Symptoms 
                     included confusion, agitation, aggressiveness, 
                     personality changes, psychotic symptoms and 
                     depression.  Seizures preceded by blurring of 
                     vision have also occurred in a few patients at 
                     therapeutic dosages.
             9.4.3.2 Peripheral nervous system
                     Acute
                     
                     Quadriplegia concomitant with severe 
                     hypokalaemia has been reported (Lofaso et al., 
                     1987).
                     
                     Chronic
                     
                     Peripheral neuritis, neuromyopathy and myopathy 
                     have been  described as a complication of long-
                     term chloroquine therapy.  The onset is 
                     insidious with a progressive weakness first 
                     affecting the proximal muscle of the lower 
                     extremities.  Increased serum levels of SGOT and 
                     SGPT may be present.  Reduction in efferent 
                     nerve conduction time and EMG abnormalities of 
                     neuropathy and myopathy can be found.
                     

                     Involuntary movements with protrusion of tongue 
                     and other extrapyramidal symptoms have been 
                     recorded (Reynolds, 1982).
             9.4.3.3 Autonomic nervous system
                     No data available.
             9.4.3.4 Skeletal and smooth muscle
                     No data available.
       9.4.4 Gastrointestinal
             Acute
             
             Nausea, vomiting, abdominal cramps and diarrhoea.  
             Haematemesis gastric and duodenal erosions has been 
             reported after therapeutic doses of chloroquine 
             phosphate (Bhasin & Chhina, 1989)
             
             Chronic
             
             Nausea, vomiting and diarrhoea may occur. Stomatitis has 
             rarely been  reported.
       9.4.5 Hepatic
             Acute:  No direct hepatotoxic effect has been reported.  
             Increase in hepatic enzymes may be observed after 
             circulatory failure.
             
             Chronic:  Chloroquine administered in high doses may 
             elevate serum aspartate-aminotransferase (SGOT) 
             activity.
       9.4.6 Urinary
             9.4.6.1 Renal
                     Acute:  No direct nephrotoxic effect has been 
                     reported.  An acute renal failure related to 
                     cardiogenic shock may occur.
                     
                     Chronic:  No data available.
             9.4.6.2 Other
                     No data available.
       9.4.7 Endocrine and reproductive systems
             No data available.
       9.4.8 Dermatological
             Acute:  No data available.
             
             Chronic:  Skin lesions have been attributed to the use 
             of chloroquine.  Photosensitivity and photoallergic 
             dermatitis have been reported, particularly in patients 
             on long-term therapy with high dosages.  Pronounced 
             porphyrinuria after chloroquine has occurred in patients 
             with porphyria cutanea tarda.
             
             Pigmentation abnormalities may occur and include: blue 
             black pigmentation involving the palate, facial, 
             pretibial and subungual areas, bleaching of the scalp, 
             eyebrows.
       9.4.9 Eye, ear, nose, throat: local effects
             Eye
             
             Acute:  Visual disturbances are frequent (10 to 38% of 

             the cases) and include blurred or impaired colour vision,
              diplopia, photophobia and sometimes blindness.  
             Blindness, however, is always transient and recovers 
             without sequelae.
             
             Chronic:  Keratopathy and retinopathy may occur in a 
             large number of patients when large doses of chloroquine 
             are used for a long period.  Both side effects are dose-
             related.  The incidence of keratopathy is high (30 to 
             70% of treated patients) and corneal changes are usually 
             completely reversible on discontinuing treatment.  
             Changes in the retina are irreversible and may become 
             worse even though the drug is discontinued.  Symptoms 
             are:  difficulty in reading, scotomata, defective colour 
             vision, photophobia, blindness.  The typical retinal 
             picture is an intact foveal area surrounded by a 
             depigmented ring, narrowing of the arteria and optic 
             disk atrophy.  Retinal changes occur very early and may 
             appear as a first symptom.  Electro-oculogram and 
             electro-retinogram show early depression in chloroquine 
             retinopathy.
             
             Ear
             
             Acute:  Tinnitus may occur.  Deafness is observed 
             rarely.
             
             Chronic:  Ototoxicity has been mentioned occasionally.  
             Tinnitus and deafness were described related to high 
             doses.
             
             Throat:  No data available.
       9.4.10 Haematological
              Acute:  No data available.
              
              Chronic:  Leucopenia has been reported after long-term 
              therapy. Haemoglobinuria with acute renal failure has 
              been reported in patients with glucose-6-phosphate 
              dehydrogenase deficiency (G6PD).
       9.4.11 Immunological
              No data available.
       9.4.12 Metabolic
              9.4.12.1 Acid-base disturbances
                       Acute:  Metabolic acidosis may occur in severe 
                       poisoning with circulatory failure.
                       
                       Chronic:  No data available.
              9.4.12.2 Fluid and electrolyte disturbances
                       Acute:  Hypokalaemia is almost always present 
                       in severe intoxications.  The severity of 
                       chloroquine intoxication is closely related to 
                       the serum potassium concentration.  
                       Hypokalaemia appears within three hours of 
                       ingestion (Jaeger et al., 1987).  Severe 
                       hypokalaemia of 0.8 to 1.1 mmol/L have been 
                       reported (Lofaso et al., 1987).  Hypokalaemia 

                       is probably due to an intracellular transport 
                       of potassium by a direct toxic effect of 
                       chloroquine on cellular membrane permeability.
                       
                       Chronic:  No data available.
              9.4.12.3 Others
                       No data available.
       9.4.13 Allergic reactions
       9.4.14 Other clinical effects
              No data available.
       9.4.15 Special risks
              Pregnancy
              
              Chronic:  4-aminoquinolines have been shown to 
              accumulate selectively in melanin structures of fetal 
              eyes.  They may be retained in ocular tissues for up to 
              five months after elimination from the rest of the body 
              (USP, 1988).
              
              Chloroquine in doses used for malaria prophylaxis 
              appears to be safe for use during pregnancy (Anon., 
              1987).  However, chloroquine can cross the placental 
              barrier and bilateral cochleo-vestibular disturbances 
              have been reported in children of mothers treated with 
              high doses of chloroquine during pregnancy.  
              Chloroquine is not contraindicated in pregnancy but 
              high doses or long-term treatment should be avoided.
              
              Breast feeding
              
              Insignificant amounts of chloroquine are found in 
              breast milk (Clyde & Shut, 1976). 
              
              Enzyme deficiencies
              
              G-6-P-D deficiency: chloroquine may induce haemolysis 
              (Reynolds, 1982).
              
              The use of chloroquine in porphyrias is controversial 
              (Reynolds, 1982).
     9.5 Other
       Unknown.
     9.6 Summary
    10. MANAGEMENT
      10.1 General principles
         Patients with chloroquine overdose should always be admitted 
         to an intensive care unit.  Treatment depends on the dose 
         ingested and on the severity of poisoning.  It includes 
         gastric lavage.  IV diazepam to prevent or reduce 
         cardiotoxicity, and supportive treatment with artificial 
         ventilation, inotropic and vasopressor drugs.  Vital signs 
         (ECG, blood pressure, respirations) and serum potassium 
         concentrations should be monitored.
      10.2 Relevant laboratory analyses
         10.2.1 Sample collection
                Blood samples for chloroquine should be drawn into 

                plastic tube with heparin.  Chloroquine may be 
                analyzed in whole blood or plasma.  Chloroquine 
                concentrations in whole blood are five to ten times 
                higher than those in plasma.
                
                Collect samples of urine and gastric aspirate. 
                because chloroquine may also be analyzed in them. 
         10.2.2 Biomedical analysis
                A biochemical profile with glucose, BUN, creatinine, 
                electrolytes and blood gases should be obtained on 
                admission.  In severe cases, monitor every four to 
                six hours serum potassium level during the 24 to 48 
                hours post-ingestion.
         10.2.3 Toxicological analysis
                Chloroquine analysis is not usually available.  A 
                serum chloroquine concentration less than 2 mg/L, 
                four to six hours post-ingestion, indicates a mild 
                intoxication.
                
                The blood fraction used for measuring chloroquine 
                concentration is important since different 
                concentrations have been noted when plasma 
                erythrocytes and whole blood were analyzed.  
                Chloroquine concentrations are higher in erythrocytes 
                than in plasma.
                
                Chloroquine may be analyzed by UV spectrometry, 
                fluorometry and high pressure liquid chromatography 
                (HPLC).  HPLC is the preferred method since 
                chloroquine and also desethylchloroquine can be 
                assayed separately.
                
                It is crucial to state whether analyses are done on 
                whole blood, serum or properly separated plasma 
                (Gustafsson et al., 1983).
                
                In a study of patients under chloroquine therapy 
                occurrence of side effects was related to chloroquine 
                serum concentrations (Frisk Holmberg et al., 1979).  
                No side effects occurred in patients with 
                concentrations less than 0.39 mg/L whereas 80% of the 
                patients with levels higher than 0.8 mg/L had side 
                effects.
                
                Vitris and Aubert (1983) distinguished three grades 
                of severity in chloroquine overdose.  Chloroquine 
                serum concentrations were less than 2.5 mg/L in mild 
                concentrations, between 2.5 and 5 mg/L in moderate 
                and higher than 5 mg/L in severe intoxications.
                
                In severe poisoning accompanied by shock or cardiac 
                arrest, serum concentrations are usually higher than 
                5 mg/L (Jaeger et al., 1987).
                
                Post-mortem serum blood concentrations reported range 
                from 1.7 to 132.5 mg/L.

                
                A toxicokinetic study performed in seven cases of 
                chloroquine poisoning showed a mean plasma half-life 
                of 24.5 hours, an absorption half-time of two hours.  
                A mean of 7% chloroquine was removed by gastric 
                lavage and mean 9.2% was excreted in urine over 49 
                hours (Jaeger et al., 1987).
         10.2.4 Other investigations
      10.3 Life supportive procedures and symptomatic/specific 
         treatment
         -    Observation and monitoring
         
              Monitor systematically vital signs, ECG and blood 
         pressure.  Frequent (at least every five minutes during the 
         acute phase) blood pressure monitoring is essential for the 
         detection of circulatory arrest without asystole.
         
              Insert a central venous catheter for monitoring and 
         drug injection.
         
         -    Circulatory arrest
         
              Perform external cardiac massage. Support ventilation 
         using appropriate mechanical device. Administer oxygen (for 
         many hours if necessary).  Administer adrenaline: 1 to 4 mg 
         IV in an adult, 0.25 to 0.5 mg by intratracheal route in a 
         child.  Administer sodium bicarbonate for correction of 
         acidosis.
         
         -    Respiratory depression
         
              Should be treated by artificial ventilation.  
         Artificial ventilation is also indicated when patients 
         present cardiotoxic symptoms or even when the patient is 
         asymptomatic and the dose ingested is higher than 3 to 4 g.
         
         -    Hypotension, cardiogenic shock
         
              Vasopressor drugs are indicated for the treatment of 
         cardiogenic shock.  Adrenaline appears to be the drug of 
         choice but isoproterenol or dopamine may be given.
         
              Adrenaline: Administer adrenaline in continuous 
         infusion.  Begin at a dose of 0.25 µg/kg/minute and progress 
         to 0.1 µg/kg/minute in increments as needed.  Five mg 
         adrenaline diluted in 250 ml of dextrose 5% produces a 
         concentration of 20 µg/ml.
         
              Isoproterenol: Administer isoproterenol in continuous 
         infusion.  Begin at a dose of 0.3 µg/kg/minute and progress 
         in 0.2 µg/kg/minute in increments as needed.  Four mg 
         isoproterenol diluted in 250 ml of dextrose 5% produces a 
         concentration of 16 µg/ml.
         
              Dopamine: Administer dopamine in continuous infusion.  
         Begin at a dose of 10 µg/kg/minute and progress in 5 

         µg/kg/minute inincrements as needed.  600 mg dopamine 
         diluted in 250 ml of dextrose 5% produces a concentration of 
         2400 µg/ml.
         
         -    Conduction disturbances
         
              Isoproterenol: Administer adrenaline or isoproterenol 
         at the same regimens as described above if bradyarrhythmia, 
         cardiac arrest or AV block occur (even in grade I).
         
              Sodium hypertonic solutions: Sodium hypertonic 
         solutions may be effective in conduction disturbances due to 
         quinidine-like membrane stabilizing effects.
         
              (i)  molar sodium lactate: 100 to 250 ml over 15 to 45 
         minutes, or 
              (ii) molar sodium bicarbonate: administer 100 to 250 ml 
         of molar sodium bicarbonate solution (8.4 g per cent) over 
         15 to 45 minutes.
         
              Remark:  Add 2 g KCl per 250 ml of these solutions in 
         order to avoid hypokalaemia.  Repeated monitoring of 
         electrolytes is necessary because hypernatraemia and 
         hypokalaemia may appear.
         
         -    Ventricular dysrhythmias
         
              All antiarrhythmic drugs and especially those with 
         quinidine-like effects are contraindicated.  Electric 
         countershock is indicated for ventricular tachycardia and 
         fibrillation and eventually torsades de pointes. 
         Acceleration of cardiac rhythm by isoproterenol (up to 120 
         minutes) may be useful for preventing further dysrhythmia 
         due to re- entry mechanisms.
         
             Initial hypokalaemia may be protective because potassium 
         and quinidine- like drugs have a synergistic cardiotoxic 
         effect (Bellet & Wasserman, 1987).  Initial hypokalaemia 
         should be corrected cautiously because intensive potassium 
         administration may lead to a sudden hyperkalaemia (Lofaso et 
         al., 1987; Jaeger et al. 1987).  Persistent hypokalaemia 
         beyond eight hours after the ingestion may favour 
         ventricular dysrhythmia and should be corrected.
         
              Administer potassium continuously with frequent control 
         of plasma potassium levels (every four hours).  Add 5 g KCl 
         to 500 ml of dextrose 5% and do not exceed infusion of more 
         than 1 g to 1.5 g KCl per hour.
      10.4 Decontamination
         -    Gastric lavage
         
              Early gastric lavage is indicated but should be 
         preceded by symptomatic treatment and intubation with 
         artificial ventilation in order to avoid sudden cardiac 
         arrest and lung aspiration.  The efficacy of gastric lavage 
         varies greatly but up to 22% of the dose ingested may be 

         removed (Jaeger et al., 1987).
         
              If convulsions or cardiovascular disturbances occur, 
         they  should be controlled before attempting gastric lavage.
         
         -    Emesis
         
              Because coma, cardiac and respiratory arrests may occur 
         one to two hours post-ingestion, emesis is contraindicated 
         unless done immediately after ingestion.
         
         -    Oral activated charcoal
         
              Chloroquine is well absorbed by charcoal although its 
         efficacy has not yet been established.  However, oral 
         activated charcoal is recommended at the end of gastric 
         lavage and repeated every four hours for 24 hours.
         
         -    Cathartics
         
              The usefulness of cathartics has not been established.  
         Cathartics should be used with caution in this situation 
         because shock and hypokalaemia are frequent.
      10.5 Elimination
         -    Forced diuresis
         
              The low elimination of chloroquine in urine does not 
         justify forced diuresis (Jaeger et al. 1987).  Urine 
         chloroquine elimination is more dependent on the 
         haemodynamic status than on infusion of osmotic solutions or 
         acidification of urine.
         
         -    Dialysis
         
              Peritoneal dialysis and haemodialysis are of little 
         value in removing chloroquine from the body.  Experimental 
         studies in dogs showed that haemodialysis removed less than 
         5% of the administered dose (Van Stone, 1976).  In human 
         poisonings, haemodialysis (Jaeger et al. 1987) and 
         peritoneal dialysis (Lareng et al. 1980; McCann et al. 1975) 
         proved to be ineffective.
         
         -    Haemoperfusion
         
              Haemoperfusion is not recommended.
         
              The following clearances have been reported: clearance 
         with resin haemoperfusion = 135 ml/min (Heath et al. 1982), 
         clearance with charcoal haemoperfusion = 45 to 60 ml/minute 
         (Maier & Benkert, 1984).  However, chloroquine has a large 
         volume of distribution.  The amount removed by 
         haemoperfusion is not significant; only 5% in a case treated 
         by Heath et al. (1982).
      10.6 Antidote treatment
         10.6.1 Adults
                -    Diazepam

                
                Experimental and clinical studies show that diazepam 
                may exert a protective effect against chloroquine 
                cardiotoxicity (Bondurand et al. 1980; Bouvier et al. 
                1986; Charbonneau et al. 1986; Hoang et al. 1981; 
                Riou et al. 1986; Riou et al. 1987).  Thus, diazepam 
                should be systematically administered in chloroquine 
                intoxication when the dose ingested is higher than 2 
                g (in adults) (Jaeger et al. 1987; Wattel et al. 
                1988).
                
                a)   Loading dose
                
                A loading dose of 1 mg/kg is recommended.  If 
                cardiotoxic abnormalities do not improve, higher 
                doses may be administered.
                Diazepam administration should always be associated 
                with intubation and mechanical ventilation in order 
                to avoid respiratory depression and with inotropic 
                vasopressor drugs when cardiotoxic symptoms are 
                present.
                
                A loading dose of 0.5 mg/kg is recommended if 
                intubation facilities are not available.
                
                b)   Continuous infusion
                
                Further administration of diazepam depends on the 
                clinical features and on the amount ingested.  If 
                cardiotoxic symptoms are present or if the dose 
                ingested is higher than 3 g in adult or 30 mg/kg in 
                child, a continuous infusion of diazepam may be given 
                at a dose of 5 to 10 mg/hour in adults or 0.25 to 0.4 
                mg/kg/hour in children over a period of 24/48 hours.  
                Recurrence of cardiotoxic signs may need additional 
                direct IV injection of diazepam.
                
                Given that chloroquine cardiotoxicity is rarely 
                observed later than 48 hours after ingestion, 
                diazepam administration after the 48th hour appears 
                not to be justified.
         10.6.2 Children
                See Section 10.6.1.
      10.7 Management discussion
         - Outside of intensive care unit (ICU):
         
         (i)   Monitor vital signs
         
         (ii)  Treatment
         
           a) No treatment: if dose ingested is less than 2 g in 
         adult(or less than 20 mg/kg in child) and if these patients 
         do not present cardiotoxic symptoms.
         
           b) Diazepam 0.5 mg/kg: if dose ingested is higher than 2 g 
         in adult (or higher than 20 mg/kg in child) or if 

         cardiotoxic symptoms are present with a lower dose ingested.
         
           c) Adrenaline or isoproterenol (see section 10.3) if 
         cardiotoxic symptoms are present.
         
         (iii) Transfer the patient as soon as possible to an ICU 
         
         - Inside the ICU:
         
           (i)  Monitor vital signs and biochemical parameters
         
           (ii) Treatment
         
             a) Dose ingested < 2 g in adults (< 20 mg/kg in child) 
         and no cardiotoxic symptoms: perform gastric lavage.
         
             b) Dose ingested > 2 g in adult (> 20 mg/kg in child) 
         or patients with cardiotoxic symptoms
         
                 - diazepam in a loading dose of 1 mg/kg and then 
         continuous infusion (see Section 10.6)
         
                 - intubation and artificial ventilation
         
                 - gastric lavage
         
                 - adrenaline or isoproterenol (see Section 10.3)
    11. ILLUSTRATIVE CASES
      11.1 Case reports from literature
         Jaeger et al. (1987) in a review analyzed the frequency of 
         clinical features observed in 5 series of chloroquine 
         intoxications (170 cases in total) reported in literature 
         (Frija, 1975; Britton et al. 1978; Vitris & Aubert, 1983; 
         Jaeger et al. 1987).  Frequency of different signs was: 
         drowsiness 30 to 45%; coma 9 to 23%; convulsion 4 to 11%; 
         visual symptoms 12-38%; apnoea 5to 19%; cardiovascular 
         symptoms 50 to 61%; shock 23%; cardiac arrest 3 to 23%; 
         widening of QRS 3 to 35%; ventricular tachycardia 11.5%; 
         ventricular fibrillation 4%; hypokalaemia 23%.  Fatalities 
         occurred in 3 to 19% of the cases.
         
         Lofoso et al. (1981) reported two cases of chloroquine 
         poisoning with severe hypokalaemia.
         
         Case 1: A 28-year-old man developed cardiac arrest after 
         ingestion of 10 g chloroquine.  Cardiac arrest was 
         reversible with symptomatic treatment; external cardiac 
         massage, artificial ventilation, sodium bicarbonate and 
         adrenaline 21 mg.  On admission, patient was comatose, blood 
         pressure was 80/30 mmHg.  ECG showed QRS duration of 0.12 
         sec.  Serum potassium concentration was 1.4 mmol/l, fell to 
         1.1 mmol/l and was accompanied by a quadriplegia.  Potassium 
         administration (41 g KCl over 33 hours) led to a sudden 
         hyperkalaemia (8.5 mmol/l) with cardiac arrest on the 38th 
         hour post-ingestion.  The patient died on the third day from 

         septic shock.
         
         Case 2:  A 26-year-old man developed cardiac arrest after 
         ingestion of 10 g chloroquine.  Cardiac arrest was 
         reversible with symptomatic treatment.  But was followed by 
         shock, widening of QRS and anoxic coma.  Serum potassium 
         concentration was 1.1 mmol/l on admission.  Serum potassium 
         was 2.2 mmol/l on the 12th hour (after 230 mmol potassium 
         IV) and 4.2 mmol/l on the 26th hour (after a total dose of 
         365 mmol potassium IV).  The patient died on the 8th day 
         post-ingestion from infections complications. Severe 
         chloroquine intoxication may induce hypokalaemia, probably 
         by an intracellular transport of potassium.  Intensive 
         administration of potassium may lead to a subsequent severe 
         hyperkalaemia.
         
         Riou et al. (1988) reported a comparative study of two 
         groups of patients with severe chloroquine poisoning.  The 
         second group of patients was treated early by diazepam (2 
         mg/kg over 30 min), intubation with artificial ventilation, 
         and adrenaline (0.25 µg/kg/min with 0.25 µg/kg/min 
         increments as needed).  Mortality in the group without this 
         treatment was 91% (11 patients, dose ingested 7.5 ± 0.5 g), 
         whereas the mortality in the group with this early treatment 
         was only 9% (11 patients, dose ingested 8.5 ± 0.2 g). Early 
         treatment with diazepam, artificial ventilation and 
         adrenaline improved the prognosis of severe chloroquine 
         poisoning.
         
         A 39-year-old patient was found to be unconscious after 
         having taken 2.5 g of chloroquine. Treatment consisted 
         mainly of gastric lavage and diazepam.  Experimental and 
         clinical evidence is presented to show that diazepam in 
         varying doses significantly decreases the mortality rate 
         (Rajah, 1990).
         
         A 29-year-old patient ingested 6 g of chloroquine in a 
         suicide attempt. After initial ventricular fibrillation, she 
         rapidly developed a pulmonary oedema with cardiogenic shock. 
         She was successfully treated with diazepam, epinephrine, 
         dobutamine and mechanical ventilation. Plasma chloroquine 
         levels showed and initial peak of 36 µg/ ml. The patient 
         discharged fully recovered after 19 days (Bauer et al, 
         1991).
     11.2 Internally extracted data on cases
         Jaeger et al. (1987) studied the relationship between 
         symptoms, dose absorbed and plasma potassium concentration.  
         The severity of the intoxication was closely related to the 
         serum potassium concentration.
         
         Severity                      Dose absorbed       Kalaemia
                                       (g)                 (mmol/L)
         -------------------------------------------------------------
         
         Mild poisoning (7 cases)      1.3 ± 0.35          4.06 ± 
         0.47

         
         Moderate poisoning (5 cases)  4.4 ± 3.14          3.38 ± 0.3
         
         Severe poisoning (6 cases)    9.75 ± 7.15         0.95 ± 
         0.46
         -------------------------------------------------------------
         
      11.3 Internal cases
         To be added by the centre using the monograph.
    12. Additional information
      12.1 Availability of antidotes
         Use of diazepam is under research.
      12.2 Specific preventive measures
         No data available.
      12.3 Other
         No data available.
    13. REFERENCES
    Abu-Aisha H, Abu-Sabaa HMA, Nur T (1979).  Cardiac arrest after 
    intravenous chloroquine injection.  Journal of Tropical Medicine 
    Hygiene, 82: 36-37.
    
    Adelusi SA, Dawodu AH, Salako LA (1982)  Kinetics of the uptake 
    and elimination of chloroquine in children with malaria.  British 
    Journal of Pharmacology, 14: 483-487.
    
    Barriot P, Riou B (1988)  Intoxications sévères par la 
    chloroquine.  Amélioration du pronostic par un traitement 
    associant diazépam, adrenaline et ventilation mécanique précoce.  
    Réanimation, Soins Intensifs, Médecine d'Urgence, 4: 55.
    
    Baud FJ (1988).  Intoxication aiguë par la chloroquine.  Aspects 
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    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)
    Author:   A. Jaeger, F. Flesch 
              Pavillon Pasteur
              Hospices Civils de Strasbourg
              Service de Réanimation Médicale et Centre Anti-poisons
              BP 426
              67091 Strasbourg Cédex
              France
    
              Telephone:33-88 16 11 44
              Telefax:  33-88 16 13 30
    
    Reviewer: R. Fernando
              National Poison Information Centre
              Faculty of Medicine
              Kynsey Road
              Colombo 8
              Sri Lanka
    
              Telephone:94-1-94016
              Telefax:  94-1-599231
    

    Peer Review:   Hamilton, Canada, May 1989
                   London, United Kingdom, March 1990
    
    Review:   IPCS, May 1994




See Also:
        Chloroquine (IARC Summary & Evaluation, Volume 13, 1977)