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
13. REFERENCES
Abrams J (1973). Quinidine toxicity. A Review. Rocky Mtn Med J
70: 31.

Aviado DM, Salem H (1975). Drug action, reaction and
interaction. Quinidine for cardiac arrhythmias. J Clin Pharmacol
447-485.

Baumann JL, Bauerfeind RA, Hoff JV et al (1984). Torsade de

pointes due to quinidine: observation in 31 patients. Am Heart J
107: 425-430.

Bailey DJ Jr (1960). Cardiotoxic effects of quinidine and their
treatment. AMA Arch Intern Med 105: 37/13-46/22.

Bellet S, Wasserman F (1957). The effect of molar sodium lactate
in the treatment of hyperpotassemia. Arch Int Med 100: 565.

Bellet S, Hamdan G, Somlyo A, Lara R (1959). The reversal of
cardiotoxic effects of quinidine by molar sodium lactate: an
experimental study. Am J Med Sci 237: 165-176.

Bowers LD, Nelson KM, Connor R, Lais CJ, Krauss E (1985).
Evidence supporting 3(S)-3-hydroxyquinidine associated
cardiotoxicity. Ther Drug Mon 7: 308-312.

Brandfonbrener M, Kronholm J, Jones HR (1966). The effect of
serum potassium concentration on quinidine toxicity. J Pharmacol
Exp Ther 154: 250-254.

Carroll FI, Smith D, Wall ME, Moreland CG (1974). Carbon-13
magnetic resonance study. Structure of the metabolites of orally
administered quinidine in humans. J Med Chem 17: 985-987.

Drugdex (1989) February issue.

Dukes MNG, (1975-1987). Side effects of drugs. Excerpta Medica.

Ellenhorn MJ Barceloux DG, (1988). Medical toxicology -
Diagnosis and treatment of human poisoning. 1 ed. New York
Elsevier.

Evans WE, Schentag JJ, Jusko WJ et al (1981). Applied
Pharmacokinetics. 2nd ed. Inc Spokane WA.

Gerhardt RE, Knouss RF, Thyrum PT et al (1969). Quinidine
excretion in aciduria and alkaluria. Ann Intern Med 71: 927-933.

Goodman LS, Gilman AG, Rall TW, Murad F (1985). Goodman and
Gilman's Pharmacological Basis of Therapeutics. 7th ed. New York,
Macmillan.

Gosselin RE, Hodge HC, Smith RP, Gleason MN (1976). Clinical
toxicology of commercial products. 4th ed. Williams & Wilkins
Company.

Gottsegen G, Ostör E (1963). Prevention of the cardiotoxic
effect of quinidine by isoproterenol. Am Heart J 65: 102-109.

Greenblatt DJ, Pfeifer HJ, Ochs HR et al (1977).
Pharmacokinetics of quinidine in humans after intravenous,
intramuscular and oral administration. J Pharmacol Exp Ther 202:
365-378.

Haapanen EJ, Pellinen TJ (1981). Hemoperfusion in quinidine

intoxication. Acta Med Scand 210: 515-516.

Hall K, Meatherall B, Krahn J et al (1982). Clearance of
quinidine during peritoneal dialysis. Am Heart J 646-647.

Hill LM, Malkasian GD Jr (1979). The use of quinidine sulfate
throughout pregnancy. Obstet Gynecol Sep 54: 366-368.

Hughes IE, Elett KF, Jellett LB (1975). The distribution of
quinidine in human blood. Br J Clin Pharmacol 2: 521-525.

Index Nominum (1984).

Kerr F, Kenoyer G, Bilitch M (1971). Quinidine overdose:
Neurological and cardiovascular toxicity in a normal person. Br
Heart J 33: 629-631.

Lesne M, Devos DM (1981). Enterogastric cycle and intoxication
with hydroquinidine: a case report. Clin Toxicol 18: 659-662.

Mahon WA et al (1976). Disposition kinetics of two oral forms of
quinidine. Clin Pharm Ther 19: 566.

Mason JW (1980) Cardiotoxicity of quinidine and other Type I
antiarrhythmic agents. Drug-induced heart disease. Ed Bristow
MR. p 261-277

Mason WD, Covinsky JO, Valentine JL, Kelly KL, Weddle OH, Martz
BL (1976). Comparative plasma concentrations of quinidine
following administration of one intramuscular and three oral
formulations of 13 human subjects. J Pharm Sci 65: 1325-1329

Mendelson CL (1956) Disorders of the heartbeat during pregnancy.
Am J Obstet Gynecol 72: 1901-1904

Merck Index (1983). 10th ed p. 238. New Jersey, Merck & Co Inc

Meyers FH, Jawetz E, Goldfien A (1976) Review of medical
pharmacology. 5th ed. Lange Medical Publications

Neuvonen PJ, Olkkola KT (1988). Oral activated charcoal in the
treatment of intoxications. Med Toxicol 3: 33-58

Podrid PJ (1985). Aggravation of ventricular arrhythmia: a drug-
induced complication. Drugs 29: 33-44

Poisindex (1988). February issue

Registry of toxic effects of chemical substances volume one
(1979). US Department of Health and Human Services. Ed Lewis RJ,
Tatken RL.

Reynolds JEF (1989). Martindale, The Extra Pharmacopoeia
Pharmaceutical Press, 29th ed. p 351. London.

Quenzer CF, Hardy DR (1980). A death investigation involving

quinidine and propranolol. J Analyt Toxicol 4: 54-57

Rainer-Pope CR, Schrire V, Beck W, Barnard CN (1962). The
treatment of quinidine-induced ventricular fribrilation by closed-
chest resuscitation and external defibrillation. Am Heart J 63:
582-590

Reimold EW, Reynolds WJ, Fixler DE et al (1973). Use of
hemodialysis in the treatment of quinidine poisoning. Pediatrics
52: 95-99.

Selzer A, Wray HW (1964). Quinidine syncope: paroxysmal
ventricular fibrillation occurring during treatment of chronic
atrial arrhythmias. Circulation 30: 17-26

Shub C, Gau GT, Sidell PM et al (1978). The management of acute
quinidine intoxication. Chest 2: 173-178

Sokolow M, Ball RE (1956). Factors influencing conversion of
chronic atrial fibrillation with special reference to serum
quinidine concentration. Circulation 14: 568-583

Sokolow M, Perloff DB (1961). The clinical pharmacology and use
of quinidine in heart disease. Prog Cardiovas Dis 3: 316

Ueda CT et al (1976). Disposition kinetics of quinidine. Clin
Pharmacol Ther 19: 30

Ueda CT, Dzindzio BS (1978). Quinidine kinetics in congestive
failure. Clin Pharmacol Ther 23: 158

Ueda CT (1981). Quinidine. Applied Pharmacokinetics 2nd ed, p.
436-463

Valebit V, Podrid Ph, Lown B, Cohen BH, Graboys TD (1982).
Aggravation and provocation of ventricular arrhythmias by
antiarrhythmic drugs. Circulation 65: 886-894

Vozeh S et al (1985). Kinetics and electrocardiographic changes
after oral 3-OH-quinidine in healthy subjects. Clin Pharmacol
Ther 37: 575-581

Wasserman F, Brodsky L, Dick MM et al (1958). Successful
treatment of quinidine and procainamide intoxication. Report of
3 cases. New Engl J Med 259: 797-802

Wasserman F, Brodsky L, Kathe JH, Rodensky PL, Dick MM, Denton PS
(1959). The effect of molar sodium lactate in quinidine
intoxication. Am J Cardiol 294-299

Woie L, Oyri A (1974). Quinidine intoxication treated with
hemodialysis. Acta Med Scand 195: 237-239
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