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Quinidine

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
      4.1.1 Indications
      4.1.2 Description
   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
       Quinidine
     1.2 Group
       Class 1a antiarhythmic drug
     1.3 Synonyms
       2-quinaclidinemethanol
       6'-mehoxycinchonan-9-ol
       alpha-(6-methoxy-4-quinolyl)-5-vinyl-2-quinuclidin-2-yl 
       alpha-6-methoxy-4-quinolyl)-5-vinyl-galacturonate
       Anhydrous: 6' methoxy-alpha (5-vinyl-2-quinuclidinyl)-4-quinoline methanol
       beta-guinine
       Cardioquin
       chinidin
       Cin-quin
       Conquinine
       Dihydrate: 6'-methoxycinchonan-9-ol dihydrate
       Dihydroquinidine
       Naticardina
       pitayine
       Quinaglute
       quinicardine
       quinidex
       Quinidine bisulphate
       Quinidine gluconate
       Quinidine phenyl-5-ethyl-5-barbiturate
       Quinidine polygalacturonate
       Quinidine salts:
       Quinidine sulphate
       quinidine-D-gluconate
       quinitex
       quinora
     1.4 Identification numbers
       1.4.1 CAS number
             56-54-2
       1.4.2 Other numbers
             1435-55-8
             27555-34-6
             50-54-4
             63717-04-4
             65484-56-2
             6591-63-5
             7054-25-3
             747-45-5
             7901
             7906
             7908
             7911
             LW 5950000
             LZ 5250000
             VA 4725000
             VA 5250000
             VA 5300000
             VA 5950000

     1.5 Brand names, Trade names
       Quinidine
       
       Quinidine bisulphate: Biquin Durules (Astra), Chinidin-Duriles 
       (Germany), Kiditard (Belgium, Netherlands, Delandale, UK), 
       Kiditard (Delandale, UK), Kinelentin (Denmark), Kinitard (Star,
        SF), Kinichron (Switzerland), Kinidin Duretter (Denmark, 
       Hässle, Sweden), Kinidin Durettes (Belgium; Netherlands), 
       Kinidin Duriles (Switzerland), Kinidin Durules (Australia; 
       Astra, UK), Kiniduron (Orion, SF), Kinilentin (Leo, SF), 
       Quiniduran (Teva, Israel), Quinidurile (France), Quinidurule 
       (Hässle, Sweden) Quini Durules(Argentina).
       
       Quinidine gluconate: Duraquin (Parke, Davis, USA), Gluquine 
       (South Africa), Quinaglute (Canada, South Africa; Berlex, USA),
        Quinate (Rougier, Canada), Quinidine Gluconate (Lilly).
       
       Quinidine polygalacturonate: Cardioquin (Purdue-Frederick; ACF,
        Netherlands; Ferring, Sweden; Sarget, France; Mundipharma, 
       Switzerland), Cardioquine (Belgium; Berenguer-Beneyto, Spain; 
       Switzerland), Galactoquin (Mundipharma, Germany; Mundipharma, 
       Austria), Galatturil-Chinidina (Francia, Italy), Naticardina 
       (Chinoin, Italy), Neochinidin (Brocchieri, Italy), Ritmocor
       (Malesci, Italy).
       
       Quinidine sulphate: Cin-Quin (Rowell, USA), Kinichron (Eurand, 
       Italy), Kinidine (Canada), Novoquinidin (Novopharm, Canada), 
       Optochinidin (Boehringer, Germany), Quincardina (Italy), 
       Quincardine (Fawns & McAllan, Australia), Quinicardine 
       (Nativelle, France; Lewis, UK; Spain, Switzerland), Quinidine 
       Extentabs (Robins, USA), Quinidex LA (Australia), Quinidex 
       (Canada; Robins, USA), Quinitex (Brenner, Germany), Quinidoxin 
       (Wellcome), Quinora (Key, USA), SK-Quinidine Sulfate (Smith 
       Kline & French, USA), Systodin (Germany; Norw.), Systodin (AFI,
        Norw.), Vanquin (Vangard, USA).
       
       Phenylethylbarbiturate of quinine: Natilina (Pan Quimica 
       Farmaceutica, Spain), Natisedina (Italy), Natisedine 
       (Nativelle, France; Lewis, UK; Germany; Netherlands; 
       Switzerland), Prosedyl (Canada), Quidinal forte (Sapos, 
       Switzerland), Quinobarb (Rougier, Canada) Sedoquin (Belgium).
       
       Quinidine arabogalactanesulphate: Longachin (Italy), Longacor 
       (Nativelle, France; Italy; Switzerland).
       
       Quinidine resourcine bichlorhydrate:
       
       Quinidine carmsylate: Canfochind (Bouty, Italy).
       
       Quinidine desoxyribonucleate: Nuclinid (Bouty, Italy)
       
       Generic products are also available.
     1.6 Manufacturers, Importers
       See section 1.5.
    2. SUMMARY

     2.1 Main risks and target organs
       Cardiotoxicity is the main risk of quinidine poisoning.  
       Quinidine may induce central nervous system symptoms.
     2.2 Summary of clinical effects
       Toxic effects appear within 2 - 4 hours after ingestion but 
       the delay may vary according to the quinidine salt and to the 
       preparation forms.  Symptoms may include disturbances of 
       cardiac rhythm (especially in patients with underlying 
       cardiovascular disease), neurotoxicity and respiratory 
       depression.
     2.3 Diagnosis
       Cardiac disturbances: circulatory arrest, shock, conduction 
       disturbances, ventricular arrhythmias, ECG changes, 
       Neurological symptoms: tinnitus, drowsiness, syncope, coma, 
       convulsions, delirium.  Respiratory depression.
       
       Quinidine concentrations may be helpful in diagnosis but are 
       not useful for clinical management.  Quinidine plasma 
       concentrations higher than 10 to 15 mg/l are mostly associated 
       with severe intoxication.  Therapeutic range of quinidine 
       plasma concentration is 1.5 to 3.5 mg/l. Monitor 
       cardiotoxicity by ECG (see section 10.2.2).
     2.4 First aid measures and management principles
       Patients with acute quinidine overdose should always be 
       admitted to an intensive care unit.  Monitor vital signs: ECG, 
       blood pressure, respiration.
                 
       Treatment may include:   
       
            supportive treatment: artificial ventilation, cardiac 
       resuscitation.
            inotropic and vasopressor drugs: isoprenaline, dopamine, 
       adrenaline.
            hypertonic sodium solutions (lactate or bicarbonate).
            gastric lavage, oral activated charcoal.
    3. PHYSICO-CHEMICAL PROPERTIES
     3.1 Origin of the substance
       Quinidine is the d- isomer of quinine.  Quinidine is an 
       alkaloid that may be derived from various species of cinchona. 
        Cinchona barks contain 0.25 to 3.0% quinidine.  Quinidine is 
       also prepared from quinine.  Quinidine was first described in 
       1848 by Van Heymingen and it was prepared and given its 
       present name by Pasteur in 1853.
     3.2 Chemical structure
                      Molecular weight         Molecular formula
       
       Quinidine                360.5          C20H24N202, 2(H20)
       Quinidine bisulphate     422.5          C20H24N202, H2SO4
       Quinidine gluconate      520.6          C20H24N2021C6H1207
       Quinidine
       polygalacturonate        782.9          C20H24N202, (C6H1007)x,
       
                                               (H20)x 2(C20H24N202),
       Quinidine sulphate                      H2S04,2(H20)           
              
     3.3 Physical properties

       3.3.1 Properties of the substance
                              State       Colour       Odour      Taste    Melting
                                                                           point °C
             
                              Powder or 
             Quinidine        crystals    white        odourless  bitter
             
             Quinidine
              bisulfate       crystals    colourless   odourless  bitter
             
             Quinidine
              gluconate       powder      white        odourless  bitter
             
             Quinidine poly-
              galacturonate   powder    
             
             Quinidine        powder or
              sulphate        crystals    white        odourless  bitter   207
       3.3.2 Properties of the locally available formulation
     3.4 Other characteristics
       3.4.1 Shelf-life of the substance
             No data available
       3.4.2 Shelf-life of the locally available formulation
             No data available
       3.4.3 Storage conditions
             Store in airtight conditions, protect from light.
       3.4.4 Bioavailability
             Absorption is virtually complete after oral 
             administration
       3.4.5 Specific properties and composition
    4. USES
     4.1 Indications
       4.1.1 Indications
       4.1.2 Description
             Premature ventricular extrasystoles and ventricular 
             tachycardia; supraventricular arrhythmia; maintenance of 
             sinus rhythm after cardioversion of atrial flutter or 
             fibrillation.
     4.2 Therapeutic dosage
       4.2.1 Adults
             The usual doses of oral quinidine range from 200 to 600 
             mg three to four times a day.  Maximum total daily dose 
             should not exceed 3 to 4 grams and should be accompanied 
             by ECG and plasma level monitoring.
       4.2.2 Children
             In neonates, the suggested dosage regimen is 4 to 10 
             mg/kg every 6 hours.  In infants the dosage is 6 mg/kg 
             every 4 to 6 hours.
     4.3 Contraindications
       Allergy or idiosyncrasy to cinchona alkaloids
       Atrioventricular or complete heart block
       Intraventricular conduction defects
       Absence of atrial activity
       Digitalis intoxication
       Myaesthenia gravis
       Ventricular dysrhythmia of the torsades de pointes type

       
       Precautions: 
       
       Congestive heart failure, hypotension, renal disease, hepatic 
       failure; concurrent use of other antiarhythmic drugs; old age; 
       breast-feeding (potential for intoxication in the infant).
    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 IV administration is rare but has been 
       reported in patients treated with IV quinidine for cardiac 
       dysrhythmia.
     5.6 Other
       Not relevant
    6. KINETICS
     6.1 Absorption by route of exposure
       Oral
       
       Quinidine is almost completely absorbed from the 
       gastrointestinal tract. However, because of hepatic first-pass 
       effect, the absolute bioavailability is about 70 to 80% of the 
       ingested dose and may vary between patients and preparations.  
       The time to plasma peak concentration is 1 to 3 hours for 
       quinidine sulfate, 3 to 6 hours for quinidine gluconate and 
       about 6 hours for quinidine polygalacturonate.  Sustained-
       release quinidine is absorbed continuously over 8 to 12 hours.
       
       Parenteral
       
       Absorption of quinidine after intramuscular injection may be 
       erratic and unpredictable with incomplete absorption of the 
       administered dose, probably due to precipitation of drug at 
       the site of injection (Greenblatt et al, 1977).  However, 
       Mason et al (1976) observed no difference between the rate of 
       quinidine absorption when given by intramuscular injection or 
       oral absorption.
     6.2 Distribution by route of exposure
       Oral
       
       Protein binding:  About 70 to 80% of the drug is bound to 
       plasma protein.  Plasma protein binding is decreased in 
       patients with chronic liver disease.
       
       Volume of distribution:  The apparent volume of distribution 
       is 2.7 to 3.0 l/kg (Ueda et al, 1978).  This is decreased to 
       about 1.8 l/kg in patients with congestive heart failure and 
       is increased in patients with chronic liver disease or 
       nephrotic syndrome to about 3.8 l/kg.  The apparent volume of 
       distribution may change with the formulation used: Mahon et al 

       (1976) reported a volume of distribution of 2.6 l/kg for 
       quinidine sulfate and of 4.4 l/kg with quinidine sulfate slow 
       release.
       
       Tissue:  Quinidine concentrations in liver are 10 to 30 times 
       higher than those in plasma.  Skeletal and cardiac muscle, 
       brain and other tissues contain intermediate amounts (Sokolow 
       and Perloff, 1961).  The red cell plasma partition ratio is 
       0.82 (Highes et al, 1975).
     6.3 Biological half-life by route of exposure
       Elimination half-life:  The half-life is about 6 to 7 hours.  
       It is increased in chronic liver disease and in the elderly.  
       It does not appear to be altered in congestive heart failure 
       or renal failure.
                 
       Total body clearance:  The average total clearance is about 
       4.7 ml/min/kg (or 20 l/hr/70 kg).  The total clearance is 
       decreased in congestive heart failure and in liver disease.
     6.4 Metabolism
       50 to 90% of quinidine is metabolized in the liver to 
       hydroxylated products.  Metabolites include 3-hydroxyquinidine,
        2 oxoquinidinone, 0-desmethylquinidine, quinidine-N-oxide.  
       The principal metabolite is 3 hydroxyquinidine which exerts 
       similar effects to quinidine and may account for part of the 
       observed antiarrhythmic effects (Vozeh et al, 1985).  The 
       elimination kinetics of hydroxyquinidine appear to be similar 
       to those of quinidine (Lesne et al, 1981).
     6.5 Elimination by route of exposure
       Kidney
       
       The amount excreted unchanged in urine is variable but is 
       about 17% of an administered dose (Ueda et al, 1976).  Up to 
       50% of a dose of quinidine (unchanged + metabolites) is 
       excreted in urine within 24 hours after administration.  Renal 
       excretion is dependent upon the pH of the urine.  Excretion 
       varies inversely with urine pH (Gerhardt et al, 1969).  
       Excretion is reduced in renal insufficiency and in congestive 
       heart failure.
       
       Liver
       
       50 to 90% of a dose of quinidine is metabolized in the liver 
       (see 6.4).
       
       Bile
       
       Approximately 1 to 3% is excreted in the faeces via the bile 
       (Sokolow and Perloff, l961).
       
       Breast milk
       
       Quinidine is excreted in breast milk.  Hill and Malkasian 
       (1979) reported a breast milk concentration of 6.4 mg/l in a 
       24-year-old woman, 3 hours after taking 600 mg quinidine.  At 
       the same time plasma level was 9.0 mg/l.
    7. PHARMACOLOGY AND TOXICOLOGY

     7.1 Mode of action
       7.1.1 Toxicodynamics
             Quinidine reduces the permeability of heart muscle to 
             electrolytes (membrane stabilizer) and is a general 
             cardiac depressant (Brandfonbrener et al, 1966).  It has 
             a negative inotropic effect; inhibits the spontaneous 
             diastolic depolarization; slow conduction; lengthens the 
             effective refractory period; and raises the electrical 
             threshold.  This results in depression of contractility, 
             impaired conductivity (atrioventricular and 
             intraventricular) and decreased excitability but with 
             possible abnormal stimulus re-entry mechanism.  
             Quinidine has an anticholinergic effect and peripheral 
             vasodilator properties.  In experimental studies the 
             following progression changes was observed: (Vellet et 
             al, 1959, Wasserman et al, 1959): 
             
             ECG: bradycardia, prolongation of the PR interval, 
             lengthening of the QT interval, widening of the QRS with 
             development of an idioventricular rhythm and then in 
             ventricular standstill.  Sometimes the terminal event 
             was ventricular fibrillation.
             
             Blood pressure decreases progressively.  A significant 
             decrease of blood pressure was noted with the appearance 
             of QRS widening and blood pressure was close to zero 
             when slow idioventricular rhythm appeared.
             
             Electrolytes abnormalities: decrease in plasma 
             concentrations of potassium, sodium and magnesium with 
             the development of acidosis.
             
             Electrolytes:  Hypokalaemia may occur and is probably 
             related to an intracellular transport of potassium by a 
             direct effect on cellular membrane permeability (Kerr et 
             al, 1971, Reimold et al, 1973).
             
             Neurologic symptoms:  Syncope and convulsions may 
             represent a direct toxic effect on CNS or may be related 
             to cerebral ischaemia due to circulatory or respiratory 
             failure (Gosselin et al, 1984).
       7.1.2 Pharmacodynamics
             Quinidine slows the rate of firing of the normal and of 
             ectopic rhythmic foci; it raises the threshold for 
             electrically induced arrhythmias; it protects against 
             ventricular arrhythmias; and it prevents or terminates 
             circus movement flutter (Goodman and Gillman, 1985).
     7.2 Toxicity
       7.2.1 Human data
             7.2.1.1 Adults
                     The toxic dose of quinidine is estimated about 3 
                     to 4 g (40 to 50 mg/kg) for an adult.  However, 
                     doses over l gram may cause symptoms in adults, 
                     especially those with chronic heart failure.  
                     Concurrent use of other class Ia antiarrhythmic 
                     drugs of class I, (beta-blockers, tricyclic 

                     antidepressants) may precipitate quinidine 
                     toxicity.
             7.2.1.2 Children
                     The toxic dose is 50 to 100 mg/kg.
       7.2.2 Relevant animal data
                       Species   Route          LD50      LDLO
                                                mg/kg     mg/kg
             
                         rat     oral           263  
             Quinidine   rat     intraven.       23
                        mouse    intraperit.    173
             
             
             Dihydro     rat     oral           369
             guinidine   rat     intraven.       32
             
             
             Quinidine  mouse    intraperit.               150
             gluconate
                         rat     oral           456
             Quinidine   rat     intraperit.               140
             sulphate   mouse    oral           594
                        mouse    intraperit.     69
       7.2.3 Relevant in vitro data
             No data available
     7.3 Carcinogenicity
       No data available
     7.4 Teratogenicity
       Quinidine has been implicated as a cause of light cranial 
       nerve damage to the fetus at doses much larger than those 
       needed to treat arrhythmias (Mendelson, 1956).
     7.5 Mutagenicity
       No data available
     7.6 Interactions
       Several interactions have been reported.  Quinidine has a 
       synergistic action with warfarin (decrease of prothrombin 
       level).  Quinidine potentiates both non-depolarizing and 
       depolarizing neuromuscular blocking agents. The 
       cardiodepressant effects of other antiarrhythmic agents are 
       increased by concurrent use of quinidine; amiodarone increases 
       quinidine concentrations in the blood. 
       
       Quinidine concentrations are reduced by: rifampicin, 
       anticonvulsants, nifedipine and acetazolamide.
       
       Quinidine concentrations are increased by antacids, cimetidine,
        verapamil and amiodarone; the risk of quinidine toxicity is 
       increased by terfenadine, astemizole, and thiazide and loop 
       diuretics.
       
       Quinidine increases the plasma concentrations of propafenone 
       and digoxin. 
     7.7 Main adverse effects
       Numerous adverse effects during quinidine therapy have been 
       reported (Drugdex, Reynolds, Goodman and Gillman, 1985; Dukes, 
       1975; Meyers et al, 1974).

       
       Cardiovascular 
                 
       Hypotension after IV administration
                 
       Syncope
                 
       Proarrhythmic effect: "torsades de pointes"
                 
       ECG: widening of QRS interval; prolongation of PR and QT 
       intervals.
       
       
       CNS
                 
       Cinchonism:  headache, fever, visual disturbances, mydriasis, 
       tinnitus, nausea, vomiting, rashes.
       
       Gastrointestinal
       
       Nausea, vomiting, diarrhoea, colic
       
       Hepatic
       
       Granulomatous hepatitis or hepatitis with centrilobular 
       necrosis
       
       Skin
       
       Skin rashes with drug fever, photosensitivity
       
       Haematologic:
       
       Thrombocytopenia (immunologic reaction)
       
       Other rare side effects include: haemolytic anemia, 
       agranulocytosis, vasculitis, periarteritis nodosum, dementia, 
       lupus nephritis, nephrotic syndrome, toxic amblyopia, lichen 
       planus, lupus erythematous.
    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
             The antiarrhythmic effects of quinidine are achieved 
             within a relatively narrow range of drug concentrations 
             (Ueda, 1981).  The therapeutic concentrations may vary 
             with the analytical method used:
             
                  Fluorimetric method with single extraction: 2.3 to 
             5 mg/l.
                  High performance liquid chromatography: 1 to 3.5 
             mg/l.
             
             
             Toxic concentrations:  Toxic symptoms appear usually 
             with plasma concentrations over 8 mg/l. Severe 
             cardiotoxicity is mainly observed with levels above 12 
             to 14 mg/l (fluorimetric method with single extraction). 
              Sokolow et al (1956) showed that the incidence of 
             important myocardial toxicity was closely related to 
             plasma concentrations.
             
             Plasma concentration               Incidence of cardiac
                  mg/l                          toxicity %
             
                  < 3                              0
                  3-6                              1.6
                  6-8                             12
                  8-10                            30
                  12-13                           45
                  > 14                            65
     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 quinidine poisoning is related to the 
             cardiotoxic effects.  Symptoms appear usually within 2 
             to 4 hours and may include:
             
                cardiovascular symptoms: hypotension, cardiogenic 
             shock, cardiac
                arrest.  ECG may show: decrease of T wave; 
             prolongation of QT and QRS
                intervals; atrioventricular block; ventricular 
             dysrhythmia (torsade de
                pointes).
             
                neurological symptoms: tinnitus, drowsiness, syncope, 
             coma,
                convulsion, blurred vision, diplopia.
             
                respiratory symptoms: hypoventilation, apnoea.
             
             Cardiotoxicity may be enhanced if other cardiotoxic 
             drugs have been ingested (antiarrhythmic drugs, 
             tricyclic antidepressants).
       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
             After IV administration symptoms appear more rapidly.  
             For symptoms see section 9.1.1.
       9.1.6 Other
             No data available
     9.2 Chronic poisoning
       9.2.1 Ingestion
             The most relevant symptoms of chronic poisoning are:
             
                  ECG disturbances
                  syncope due to ventricular dysrhythmia, (torsade de 
             pointes)
                  cinchonism (see section 7.7)
                  gastrointestinal disturbances
       9.2.2 Inhalation
             No data available
       9.2.3 Skin exposure
             No data available
       9.2.4 Eye contact
             No data available
       9.2.5 Parenteral exposure
             See section 9.2.1
       9.2.6 Other
     9.3 Course, prognosis, cause of death
       The usual course of quinidine poisoning is dominated by the 

       cardiovascular disturbances which usually occur within 2 to 4 
       first hours but may first appear as late as 12 hours after 
       exposure (and perhaps even later after ingestion of a slow-
       release preparation).  Symptoms may last for 24 to 36 hours.  
       Patients who survive 48 hours after acute poisoning are likely 
       to recover.
       
       Death may result from cardiac arrest by asystole or 
       electromechanical dissociation and, rarely, by ventricular 
       fibrillation.
     9.4 Systematic description of clinical effects
       9.4.1 Cardiovascular
             Acute:  Cardiovascular symptoms are the major features 
             of quinidine toxicity. 
             
             Tachycardia due to anticholinergic effects is usually 
             observed initially or in moderate intoxication.  In 
             severe intoxication, bradycardia due to
             atrioventricular block may occur.
             
             Hypotension and shock:  hypotension due to peripheral 
             vasodilation is common. In severe intoxication, 
             cardiogenic shock with increased central venous pressure 
             is usually observed and is related to decreased cardiac 
             contractility.
             
             Cardiac arrest may occur, which may be related to 
             electromechanical dissociation, ventricular dysrhythmia 
             or asystole.
             
             Cardiac dysrhythmias are common and may include:  
             atrioventricular block, idioventricular rhythm, 
             ventricular tachycardia and fibrillation, torsades de 
             pointes.
             
             ECG changes are always present in symptomatic 
             intoxication:  repolarization abnormalities, decreased T 
             wave, increase of U wave, prolongation of QT and PR 
             intervals, widening of QRS complexes (> 0.08 sec), 
             atrioventricular block.  
             
             Syncope due to torsade de pointes may occur.
             
             Chronic:  ECG changes with repolarization abnormalities, 
             decreased T wave and increase of QT interval are a 
             common feature during quinidine therapy.  Syncope is 
             related to transient torsade de pointes and occurs in 1 
             to 8% of patients receiving quinidine.  The occurrence 
             of torsade de pointes is not correlated with plasma 
             quinidine levels but is favored by an increase in the QT 
             interval (Baumann et al, 1984).
       9.4.2 Respiratory
             Acute:  Respiratory depression or apnoea is mostly 
             associated with severe cardiac disturbances such as 
             shock or ventricular dysrhythmia.  Shub et al (1978) 
             reported pulmonary oedema with normal pulmonary 

             capillary wedge pressure following attempted suicide by 
             ingestion of 8 g of quinidine.
             
             Chronic:  No data available
       9.4.3 Neurological
             9.4.3.1 CNS
                     Acute 
                     
                     Drowsiness, delirium, coma and convulsions may 
                     appear without cardiac symptoms.  However, 
                     cardiac failure should always be considered when 
                     CNS symptoms appear.  Cinchonism may sometimes 
                     appear (see section 9.4.9).
                     
                     Chronic
                     
                     Cinchonism.  Delirium has been reported (see 
                     section 7.7).
             9.4.3.2 Peripheral nervous system
                     Acute: No data available
                     
                     Chronic
                     
                     Quinidine can potentiate the neuromuscular 
                     blocking action of some skeletal muscle 
                     relaxants and may cause the return of 
                     respiratory paralysis if it is given shortly 
                     after recovery from neuromuscular blockade 
                     (Reynolds 1989).
             9.4.3.3 Autonomic nervous system
                     Acute
                     
                     Quinidine has an anticholinergic effect.  
                     However, this effect is usually limited to the 
                     vagal system.
             9.4.3.4 Skeletal and smooth muscle
                     Chronic
                     
                     An increase in serum concentrations of skeletal 
                     muscle enzymes has been reported in a man 
                     treated with quinidine (Reynolds 1989).
       9.4.4 Gastrointestinal
             Acute
             
             Nausea and vomiting may occur.
             
             Chronic
             
             Gastrointestinal toxicity (nausea, vomiting, diarrhoea 
             and colic) is the most frequent side effect of 
             quinidine.
       9.4.5 Hepatic
             Acute: No data available
             
             Chronic
             

             Hepatotoxicity has been reported, with an increase in 
             serum concentrations of transaminases, LDH, alkaline 
             phosphatase, and cholestasis.
       9.4.6 Urinary
             9.4.6.1 Renal
                     Acute
                     
                     No direct nephrotoxic effect has been reported.  
                     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
             Acute: No data available
             
             Chronic: No data available
       9.4.8 Dermatological
             Acute: No data available
             
             Chronic
             
             Skin lesions have been attributed to the use of 
             quinidine and include skin rash, photosensitivity, 
             lichen planus (Dukes 1975, 1987).
       9.4.9 Eye, ear, nose, throat: local effects
             Acute
             
             Cinchonism is rarely observed in acute poisonings.  
             Toxic amblyopia, scotoma and impaired colour perception 
             may occur at toxic doses (Abrams, 1973; personal case).
             
             Chronic
             
             Chronic cumulative overdose may cause cinchonism: 
             headache, tinnitus, vertigo, mydriasis, blurred vision, 
             diplopia, photophobia, deafness, and corneal deposits 
             have been reported in a patient who took quinidine for 2 
             years (Reynolds, 1989).
       9.4.10 Haematological
              Acute: No data available
              
              Chronic
              
              Thrombocytopenia and hemolytic anaemia of immunologic 
              origins have been reported (Dukes 1979-1987).
       9.4.11 Immunological
              Acute: No data available 
              
              Chronic
              
              Quinidine may cause several immunologic mediated 
              reactions: thrombocytopenia, haemolytic anaemia, 
              angioneurotic oedema, skin rash, fever (Dukes 1979-
              1987).

       9.4.12 Metabolic
              9.4.12.1 Acid-base disturbances
                       Acute
                       
                       Metabolic acidosis may occur in severe 
                       intoxication with shock.
                       
                       Chronic: No data available
              9.4.12.2 Fluid and electrolyte disturbances
                       Acute
                       
                       Hypokalaemia is frequently observed
                       
                       Chronic: No data available
              9.4.12.3 Others
                       No data available
       9.4.13 Allergic reactions
              See section 9.4.11.
       9.4.14 Other clinical effects
              Acute: No data available
              
              Chronic: No data available
       9.4.15 Special risks
              Pregnancy
              
              Acute: No data available
              
              Chronic
              
              Quinidine has been implicated as a cause of cranial 
              nerve damage to the fetus at doses much larger than 
              those needed to treat arrhythmia (Mendelson, 1956).
              
              In a neonate born to a woman taking quinidine 
              throughout  pregnancy, serum levels were equal to that 
              of the mother.  The child's ECG was normal and there 
              was no evidence of teratogenicity (Hill and Malkasian, 
              1979) (see section 6.5.4).  However, breast feeding was 
              not advised because of potential quinidine accumulation 
              in the immature newborn liver.
              
              Breast-feeding
              
              Acute: No data available
              
              
              Chronic
              
              Quinidine is present in breast milk at levels slightly 
              lower than serum levels.  The dose of quinidine 
              received by an infant taking 1l of milk would be below 
              therapeutic doses (Hill and Malkasian, 1979) (see 
              section 6.5.4).  However, breast-feeding is not 
              recommended because of potential quinidine accumulation 
              in the immature newborn liver.
              

              Enzyme deficiency: No data available
     9.5 Other
       Unknown
     9.6 Summary
    10. MANAGEMENT
      10.1 General principles
         Patients with quinidine overdose should always be admitted 
         to an intensive care unit.  Because cardiovascular shock may 
         occur rapidly, intravenous access lines, oxygen and 
         monitoring of ECG and vital signs are the first priorities.  
         Treatment depends on the dose ingested and on the severity.  
         It includes gastric lavage and supportive treatment with 
         artificial ventilation, inotropic and vasopressor drugs and 
         hypertonic sodium solutions.
      10.2 Relevant laboratory analyses
         10.2.1 Sample collection
                No data available   
         10.2.2 Biomedical analysis
                ECG is the relevant investigation to detect 
                cardiotoxicity.  A biochemical profile with glucose, 
                BUN, creatinine, electrolytes and blood gases should 
                be obtained on admission.  Monitor particularly serum 
                potassium levels and calcium and magnesium levels if 
                refractory arrhythmia occurs.
         10.2.3 Toxicological analysis
                Measurement of serum quinidine concentrations may be 
                helpful in diagnosis but is not useful for clinical 
                management.  Levels over 8 mg/l may be associated 
                with toxic symptoms and levels over 12 to 14 mg/l are 
                usually seen in patients with severe cardiotoxicity 
                (fluorimetric method).
         10.2.4 Other investigations
      10.3 Life supportive procedures and symptomatic/specific 
         treatment
         Observation and monitoring:  Systematically monitor vital 
         signs, ECG, blood pressure and central venous pressure.  
         Repeated non-invasive blood pressure monitoring is essential 
         for the detection of circulatory arrest due to 
         electromechanical dissociation.  
         
         Insert a central venous catheter.
         
         Circulatory arrest:  Perform external cardiac massage and 
         mechanical ventilation with oxygen.  Adrenaline is 
         indicated: 1 to 4 mg IV or IM in an adult, 0.25 to 0.5 mg by 
         intratracheal route in a child.  Administer sodium 
         bicarbonate to correct acidosis. (consult the relevant 
         treatment protocol)
         
         Respiratory depression:  Should be treated by artificial 
         ventilation.  Artificial ventilation is also indicated when 
         patients present cardiotoxic symptoms like hypotension or 
         cardiogenic shock. (consult the relevant treatment protocol)
         
         Hypotension, cardiogenic shock:  Vasopressor drugs are 
         indicated for the treatment of hypotension or cardiogenic 

         shock. (consult the relevant treatment protocol)
         
         a)   Dopamine: Is indicated in hypotension due to peripheral 
         vasodilatation.  Administer dopamine as a continuous 
         infusion, beginning at a dose of 10 microg/kg/min and 
         progress in 5 microg/kg/min in increments as needed to a 
         maximum of 20 - 50 microgram/kg/min.
         
         b)   Isoprenaline: is the drug of choice in quinidine-
         induced cardiogenic shock (Gottsegen an Öster, 1963).  
         Administer isoprenaline in continuous infusion.  Begin at a 
         dose of 0.3 microg(kg/min and progress in 0.2 microg/kg/min 
         in increments as needed.  Adrenaline may also be used 
         (similarity with chloroquine poisoning).
         
         Conduction disturbances
         
         a)   Isoprenaline:  Administer isoprenaline in the same 
         regimens as described above.
         
         b)   Hypertonic sodium solutions have been shown to be 
         effective in conduction disturbances due to quinidine 
         (Bellet et al, 1959; Bailey, 1960; Wasserman et al, 1959).
         
         l. Molar sodium lactate:  Administer 100 to 250 ml over 15 
         to 45 minutes.
         
         2. Molar Sodium bicarbonate:  Administer 100 to 250 ml of 
         molar sodium bicarbonate    solution (8.4 g per cent) over 
         15 to 45 minutes.
         
              Add 2 g potassium chloride 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, 
         especially those with quinidine-like effects, are 
         contraindicated.  Electric countershock is indicated for 
         ventricular fibrillation, sustained ventricular tachycardia 
         or torsade de pointes.  Acceleration of cardiac rhythm (up 
         to 120/min) by isoprenaline or temporary pacemaker may be 
         useful for preventing further dysrhythmia due to re-entry 
         mechanisms (torsade de pointes).  However, a temporary 
         pacemaker may be inefficient because of an increase in the 
         stimulating threshold (Kerr et al, 1979).
         
         Convulsions
         
         May be treated by intravenous diazepam. 
         
         Hypokalaemia
         
         Initially, hypokalaemia may be protective because potassium 
         and quinidine have a synergistic cardiotoxic effect (Bellet 

         et Wasserman, 1957).  Initial hypokalaemia should therefore 
         be corrected cautiously.  Hypokalaemia persisting beyond 8 
         hours after the ingestion may promote ventricular 
         dysrhythmia and should be corrected.  
         
         Administer potassium continuously with frequent monitoring 
         of plasma potassium levels (every 4 hours).  Add 5 g KCl to 
         500 ml of dextrose 5% and do not exceed infusion of more 
         than 1 to 1.5 g KCl per hour.
      10.4 Decontamination
         Gastric lavage:  Gastric lavage is indicated within the 
         first 12 hours.  If cardiac symptoms are present, it should 
         be preceded by symptomatic treatment and artificial 
         ventilation in order to avoid sudden cardiac arrest.
         
         Emesis:  Because cardiotoxicity may occur suddenly, inducing 
         emesis with ipecac is not recommended.
         
         Oral activated charcoal:  Quinidine absorption is very 
         effectively inhibited by activated charcoal (Neuvonen and 
         Olkkola, 1986).  Charcoal 50 g given 5 minutes after 
         quinidine (200 mg) reduced its absorption by 99%.  Repeated 
         doses (25 g every 2 hours) may enhance the elimination of 
         quinidine.
         
         Cathartics:  The value of cathartics has not been 
         established but they may be useful when a sustained-release 
         preparation has been taken.
      10.5 Elimination
         Forced acid diuresis is extremely difficult and hazardous in 
         acute intoxication and cannot be recommended.
         
         Dialysis - haemoperfusion
         
         Peritoneal dialysis, haemodialysis and haemoperfusion are of 
         little value in removing quinidine and are not recommended.  
         In comparison to the total body clearance of quinidine 
         (about 280 ml/min), the clearances are low: 
         
              peritoneal dialysis 1.2 ml/mn (Hall et al, 1982)
              haemodialysis       11.3 to 17.6 ml/min (Reimold et al, 
         1973)
              haemoperfusion      24 ml/min (Haapanen and Pellinen,  
         1981).
      10.6 Antidote treatment
         10.6.1 Adults
                No antidote for quinidine is available.
         10.6.2 Children
                No antidote for quinidine is available.
      10.7 Management discussion
         Outside of Intensive Care Unit (ICU)
         
         a)   Recent ingestion and no cardiotoxic symptoms
         
              gastric lavage and oral activated charcoal
         

         b)   Cardiotoxic symptoms with hypotension, shock 
                        
              Dopamine and isoprenaline
         
              Transfer to ICU  
         
         In ICU
         
         a)   Monitor vital signs and biochemical parameters
         b)   Gastric lavage and activated oral charcoal
         c)   Hypotension or shock
                   
              intubation and artificial ventilation
              dopamine and isoprenaline
         
         d)   Conduction disturbances
                   
              isoprenaline
              molar sodium lactate or bicarbonate
                   
         e)   Ventricular dysrhythmia
                        
              electric countershock
              acceleration of cardiac rhythm by isoprenaline or 
         temporary pacemaker.
         
         
         f)   For other treatments, see section 10.3
                   
              Keep the patient in ICU until symptoms of 
         cardiotoxicity have
              disappeared or plasma quinidine levels are within the 
         therapeutic
              range.
         
         Controversies
         
              Although antiarrhythmic drugs have been used in some 
         cases for the
              treatment of ventricular dysrhythmias due to quinidine, 
         antiarrhythmic
              drugs should be avoided because they may exert a 
         synergistic
              cardiotoxic effect.
                   
              Adrenaline may be used because it has been proven to be 
         efficient in
              quinidine-like intoxication by chloroquine.
    11. ILLUSTRATIVE CASES
      11.1 Case reports from literature
         Kerr et al (1971) reported severe intoxication after 
         ingestion of 4 g quinidine sulfate by a 57-year-old woman.  
         Three hours after ingestion, she presented with convulsions 
         and shock.  Treatment consisted of 1/6 molar lactate 
         infusion, metaraminol, intravenous sodium bicarbonate and 
         potassium chloride and furosemide 20 mg IV.  The ECG showed 

         prolonged PR, QRS and QT intervals.  Temporary 
         intraventricular pacemaker was unable to achieve pacing at a 
         level of 22 mA.  Serum quinidine levels were 9.7 and 0.35 
         mg/l at 6 and 80 hours after ingestion.  The patient 
         recovered within 24 hours.
         
         Haapenen and Pellinen (1981) reported a 22-year-old woman 
         who had ingested 8.1 g quinidine.  Blood pressure was 85/60 
         mmHg and ECG showed idioventricular tachycardia.  Serum 
         concentration was 8.5 mg/l on admission and 7 mg/l at the 
         beginning of a 6-hour charcoal haemoperfusion.  The mean 
         clearance by haemoperfusion was 24 ml/min.
         
         Reimold et al (1973) treated a patient with quinidine 
         intoxication by haemodialysis.  Quinidine clearance ranged 
         from 11.3 to 17.6 ml/min.
         
         Hall et al (1982) reported treatment of quinidine poisoning 
         by peritoneal dialysis. Clearances for quinidine were: 
         
              peritoneal     1.2 ml/min
              renal          8.4 ml/min
              total body     277 ml/min 
         
         For total quinidine compounds:
         
              peritoneal     8.6 ml/min 
              renal          4.9 ml/min
         
         Bailey (1960) reported 2 cases of quinidine overdose in 
         which cardiotoxic symptoms were reversed by molar sodium 
         lactate.
         
         Bauman et al (1984) reported 31 patients who developed 
         torsades de pointes under quinidine therapy.  Torsades de 
         pointes was associated in 70 per cent of the cases with 
         increased QT interval but this was not correlated with serum 
         quinidine levels.
      11.2 Internally extracted data on cases
      11.3 Internal cases
    12. Additional information
      12.1 Availability of antidotes
         No data available
      12.2 Specific preventive measures
         No data available
      12.3 Other
         No data available
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    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 
    ADDRESS(ES)
    Author(s):     Jaeger A, Flesch F, Ph Sauder J, Kipferschmitt
                   Service de Réanimation Médical et Centre Anti-Poisons

                   Pavillon Pasteur
                   Hospice Civil de Strasbourg
                   BP 426
                   67091 Strasbourg Cédex
                   France
    
    Date:          May 1989
    
    Peer review:   London, United Kingdom, March 1990 



    See Also:
       Toxicological Abbreviations