IPCS INCHEM HomeProcainamide
1. NAME
1.1 Substance
Procainamide (INN, 1992; BAN, 1994)
Procainamide (USAN, 1994)
hydrochloride
(Fleeger, 1993; WHO, 1992; British Pharmacopoeia Commission,
1994)
1.2 Group
ATC classification index
Cardiac therapy (C01)/Antiarrhythmics, Class 1A
(C01BA).
(WHO, 1992)
1.3 Synonyms
Amidoprocain
Novocamid
Novocainamid
Novocainamide
Novocainamidum
Novocaine amide
Procaine amide
Procaine amide hydrochloride
Procainamidi Chloridum
Procainamidi Hydrochloridum
p-Aminobenzoic diethylaminoethylamide
(Budavari, 1989; Reynolds, 1989; Sax, 1989)
(To be completed by each Centre using local data).
1.4 Identification numbers
1.4.1 CAS number
Procainamide 614-39-1
Procainamide 614-39-1
hydrochloride
1.4.2 Other numbers
RTECS
Procainamide CV2275000
1.5 Brand names, Trade names
Biocoryl (Spain)
Novocamid (Ger.)
Procamide (Belg., Ital., Br.)
Procainamid Duriles (Ger.)
Procainamid Durettes (Neth.)
Procamide
Procan SR (USA)
Procapan (USA)
Procainamide Durules (UK)
Pronestyl (UK., Arg., Austral., Belg., Canad., Den., Fr.,
Ital., Neth., Norw., S. Afr., Swed., Switz., USA)
Procardyl
Promide
(Budavari, 1989; Reynolds, 1989)
(To be completed by each Centre using local data).
1.6 Manufacturers, Importers
Astra (UK)
Squibb (UK)
Parke-Davis
Lederle (USA)
Danbury
Zenith
Elkins-Sinn
Pharmafair
Zambon (Br)
(To be completed by each Centre using local data).
1.7 Presentation, Formulation
Capsules or tablets
250, 375 and 500 mg
Injection
100 mg per mL and 500 mg per mL (in water)
Injection
100 mg per mL and 500 mg per mL (in water containing 0.8% of
benzyl alcohol and the equivalent of 0.1% of sulphur dioxide)
Controlled release tablets
250 and 750 mg
(Reynolds, 1989; Barnhart, 1987; Bigger, 1990)
(To be completed by each Centre using local data).
2. SUMMARY
2.1 Main risks and target organs
The heart is the main target organ. Procainamide is an
antiarrhythmic agent used to suppress ventricular
tachydysrhythmias. It increases the effective refractory
period of the atria, and (to a lesser extent) that of the
bundle of the His-Purkinje system and the ventricles.
Toxic effects result from delay in conduction and depression
of myocardial contractility, leading to cardiac dysrhythmia
and cardiogenic shock. Its oral use is limited immunological
adverse effects such as systemic lupus erythematosus in
patients on chronic oral therapy.
2.2 Summary of clinical effects
Cardiovascular System
Sinus or atrial tachycardia, atrioventricular and
intraventricular block, hypotension, cardiogenic shock,
torsades de pointes, ventricular fibrillation.
Central Nervous System
Lethargy, coma, respiratory arrest
Gastrointestinal Tract
Nausea, vomiting, diarrhoea, abdominal pain
Others
Anticholinergic effects, hypokalemia, metabolic acidosis,
pulmonary edema.
2.3 Diagnosis
Diagnosis of an antiarrhythmic agent must be suspected in
patients presenting with arrhythmias of unknown origin.
Electrocardiogram (ECG) is the most useful investigation as
the QRS-complex and QT-intervals are typically prolonged.
Determination of plasma levels of procainamide and its
metabolite N-acetylprocainamide is performed in many hospital
laboratories but is not necessary for clinical management.
2.4 First aid measures and management principles
Emesis or gastric lavage and oral activated charcoal should
be considered, preferably within one or two hours of
ingestion.
Monitor blood pressure, ECG, serum electrolytes. Insert an
intravenous line for central venous pressure measurement.
Treatment of cardiovascular disturbances may include:
Administration of isoprenaline (avoid all other Class 1
antiarrhythmics) and/or ventricular pacemaker for
atrioventricular block or for severe bradycardia. In torsades
de pointes arrhythmias overdrive pacing is indicated.
Administration of isoprenaline and/or molar sodium
bicarbonate for intraventricular block.
Administration of dobutamine, dopamine and/or epinephrine to
correct hypotension and cardiogenic shock.
Correct hypokalaemia if present.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Synthetic chemical
3.2 Chemical structure
Structural formula
Molecular formula
Procainamide C13H22ClN3O
Procainamide C13H22ClN30,HCl
hydrochloride
Molecular weight:
Procainamide 325.5
Procainamide 271.8
hydrochloride
Chemical names
4-Amno-N-(2-diethylaminoethyl)benzamide hydrochloride.
4-Amino-N-[2-(diethylamino)ethyl]benzamide
monohydrochloride.
(Budavari, 1989; Reynolds, 1993)
3.3 Physical properties
3.3.1 Properties of the substance
3.3.1.1 Colour
Procainamide hydrochloride
White to tan-coloured
3.3.1.2 State/Form
Hygroscopic, crystalline powder.
3.3.1.3 Description
Odourless
Melting point 165 to 169 ーC
Solubility is 1 in 0.25 of water, 1 in 2 of
alcohol, 1 in 140 of chloroform, practically
insoluble in ether and benzene
A 10% solution in water has a pH of 5 to 6.5
A 5.08% solution is iso-osmotic with serum
UV max 278 nm
When heated to decomposition it emits toxic
fumes of NOx.
(Reynolds, 1989; Budavari, 1989; Sax, 1989)
3.3.2 Properties of the locally available formulation(s)
To be completed by each Centre using local data.
3.4 Other characteristics
3.4.1 Shelf-life of the substance
Five years.
3.4.2 Shelf-life of the locally available formulation(s)
To be completed by each Centre using local data.
3.4.3 Storage conditions
Commercially available aqueous solutions are preserved
with 0.9% benzyl alcohol and 0.09% sodium bisulfite.
Solutions darker than light amber or otherwise
discoloured should not be used (Budavari, 1989;
Barnhart, 1987).
Store in airtight containers.
Store tablets and capsules at room temperature.
Avoid excessive heat.
Protect from moisture.
All preparations should be protected from light
(Reynolds, 1989; Barnhart, 1987).
3.4.4 Bioavailability
To be completed by each Centre using local data.
3.4.5 Specific properties and composition
To be completed by each Centre using local data.
4. USES
4.1 Indications
4.1.1 Indications
Suppression of ventricular arrhythmias.
Treatment of automatic and reentrant supraventricular
tachycardia.
Supraventricular arrhythmias: Like quinidine,
procainamide is only moderately effective in converting
atrial flutter or chronic atrial fibrillation to sinus
rhythm. The drug can be used to prevent recurrences of
atrial flutter or atrial fibrillation after
cardioversion (Bigger, 1990).
Procainamide is indicated in the treatment of
ventricular premature contractions, and in preventing
recurrence of ventricular tachycardia after conversion
to sinus rhythm by intravenous drugs or by electrical
cardioversion or by other antiarrhythmic therapy; also
in preventing recurrence of paroxysmal supraventricular
tachycardia, atrial fibrillation or flutter following
conversion to sinus rhythm by initial vagotonic
manoeuvres, digitalis preparations, other
pharmaceutical antiarrhythmic agents, or electrical
cardioversion (Barnhart, 1987).
The drug is useful in patients with severe ventricular
arrhythmias who do not respond to lidocaine.
Procainamide is useful for acute terminations of
arrhythmias associated with the Wolff-Parkinson-White
Syndrome (American Medical Association, 1988).
Procainamide is used in the treatment of cardiac
arrhythmias occurring in patients during general
anaesthesia (Osol & Pratt, 1980).
The drug has been used in conjunction with
hexamethonium bromide to produce controlled hypotension
and, consequently, ischaemia of sufficient degree for
relatively "bloodless field" surgery.
The injection of procainamide into painful soft tissues
in fibrosis and radiculitis and into the periarticular
tissues in degenerative arthritis provided relief for
considerable periods (Ozol & Pratt, 1980).
4.1.2 Description
Not relevant
4.2 Therapeutic dosage
4.2.1 Adults
Oral
Up to 50 mg/kg of body weight in divided doses, every
three hours (Reynolds, 1993).
Up to 1.0 g every 2 hours for some arrhythmias
(Reynolds, 1993)
Sustained-release dosage forms are given every 6 to 8
hours. For ventricular tachycardia and premature
ventricular contractions, the suggested maintenance
dosage is 50 mg/kg of body weight daily given in
divided doses at six hours intervals; for atrial
fibrillation and paroxysmal atrial tachycardia, it is 1
g every six hours (Barnhart, 1987; Ozol & Pratt,
1980).
Parenteral
Intramuscular
100 to 500 mg.
Intravenous
Arrhythmia control, direct injection
100 mg every 5 minutes not exceeding 50 mg/minute up to
a maximum dose of 1 g.
Arrhythmia control, continuous infusion
500 to 600 mg over 25 to 30 minutes.
(Reynolds, 1993)
4.2.2 Children
Safety and effectiveness in children have not been
established.
4.3 Contraindications
Complete heart block: because of its effects in suppressing
nodal or ventricular pacemakers.
Torsades de Pointes: administration of procainamide in such
case may aggravate this special type of ventricular
extrasystole or tachycardia instead of suppressing it.
Idiosyncratic hypersensitivity: in patients sensitive to
procaine or other ester-type local anaesthetics, cross
sensitivity to procainamide is unlikely. However, previous
allergic reactions to procainamide is a contraindication.
Lupus erythematosus: aggravation of symptoms is highly
likely (Barnhart, 1987).
Precautions
Preferably, procainamide should not be used in patients with
bronchial asthma or myasthenia gravis.
Accumulation of the drug may occur in patients with heart,
renal or liver failure (Reynolds, 1989; Osol & Pratt, 1980).
Procainamide may enhance the effects of antihypertensive
agents, propranolol, and some skeletal muscle relaxants.
Grave hypotension may follow intravenous administration of
procainamide; it should be injected slowly under monitoring
of blood pressure and ECG.
Although procainamide has been used effectively in the
treatment of ventricular dysrhythmias caused by digitalis
intoxication, its effects are unpredictable and fatalities
have occurred.
Procainamide should not be administered in nursing mothers.
5. ROUTES OF ENTRY
5.1 Oral
Oral route is a common route of entry in cases of poisoning.
5.2 Inhalation
No data available.
5.3 Dermal
No data available.
5.4 Eye
No data available.
5.5 Parenteral
Toxicity reactions can occur after intravenous injections.
5.6 Other
No data available.
6. KINETICS
6.1 Absorption by route of exposure
Oral
Procainamide is almost completely and rapidly absorbed from
the gastrointestinal tract.
Peak levels are reached within 1 hour after ingestion of
capsules, but somewhat later after administration of tablets.
The bioavailability is approximately 85%. An overdose may
significantly delay intestinal procainamide absorption and
prolong poisoning symptoms.
With the sustained-release formulations, bioavailability is
decreased and the absorption is delayed. The duration of
action exceeds 8 hours (Osol & Pratt, 1980; Bigger, 1990).
Intramuscular
Plasma concentrations showed very large variations.
Procainamide appears in the plasma within 2 minutes and peak
concentrations are reached within 25 minutes (Reynolds,
1989).
Intravenous
Procainamide acts almost immediately, the plasma level
declines 10 to 15% hourly (Osol & Pratt, 1980).
6.2 Distribution by route of exposure
About 20% of the procainamide in plasma is bound to proteins.
Procainamide is rapidly distributed into most body tissues
except the brain (Bigger, 1990).
The apparent volume of distribution (VD) is approximately
2 L/kg, but a small VD of 0.76 L/kg appeared following an
overdose in which renal dysfunction and hypotension occurred.
In an overdose, a smaller VD of 0.76 L/kg has been reported
(Atkinson et al. 1976).
The apparent VD of the active N-acetylated metabolite was
reduced in overdose from 1.4 L/kg to 0.63 L/kg (Atkinson et
al. 1976).
In patients with cardiac failure or shock the volume of
distribution may decrease to 1.5 L/kg.
Procainamide crosses the placental barrier and has been
reported to accumulate in the foetus (Reynolds, 1989).
6.3 Biological half-life by route of exposure
Peak plasma levels
Oral
1 to 2 hours
Intramuscular
80 minutes
Intravenous
Within several minutes (Noji, 1989)
The plasma half-life after therapeutic doses is 3 to 4 hours.
However, in one patient the overdose plasma half-life was 8.8
hours (Atkinson et al., 1976). Congestive heart failure
increases the plasma procainamide half-life to 5 to 8 hours
(Ellenhorn & Barceloux, 1988).
The half-life is reduced in children and is prolonged in
patients with renal insufficiency.
Its major active metabolite, N-acetylprocainamide (NAPA), has
a longer half-life than procainamide, from 6 hours up to 36
hours in overdoses.
6.4 Metabolism
The major metabolic pathway of procainamide is hepatic N-
acetylation. The rate of acetylation is determined
genetically and shows a bimodal distribution into slow and
fast acetylators. The major active metabolite, NAPA, has
antiarrhythmic properties.
Other urinary metabolites include desethyl-NAPA and desethyl-
procainamide, which account for 8 to 15% of a dose of
procainamide.
The exact relationship between antiarrhythmic activity and
plasma levels of NAPA has not been established. Up to 15% of
the intravenous procainamide therapeutic dose is metabolized
to NAPA, and 81% of the NAPA dose is excreted unchanged in
urine.
In fast acetylators or in renal insufficiency, 40% or more of
a dose of procainamide may be excreted as NAPA, and its
concentrations in plasma may equal or exceed those of the
parent drug (American Medical Association, 1988; Ellenhorn&
Barceloux, 1988; Bigger, 1990).
Procainamide hydrochloride is only slightly hydrolysed by
plasma enzymes (to p-aminobenzoic acid and
diethylaminoethylamine) (Osol & Pratt, 1980).
6.5 Elimination by route of exposure
Procainamide is excreted in the urine with about 50% as
unchanged procainamide, and up to about 30% as NAPA (less in
slow acetylators)(Reynolds, 1989). Clearance is 11 mL/min/kg
(American Medical Association,1988).
Since the elimination of both the parent drug and metabolites
is almost entirely by renal excretion, they can accumulate to
dangerous levels when renal failure or congestive heart
failure are present.
After an overdose, hepatic biotransformation probably is a
more important elimination pathway than renal excretion.
Following a 7 g overdose, the elimination half-life (in the
presence of a serum creatinine of 5.8 mg/dL) of NAPA
increased from 6 to 35.9 hours while the procainamide
elimination increased from 3 to 10.5 hours (Ellenhorn &
Barceloux, 1988).
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
7.1.1 Toxicodynamics
Toxic effects result from quinidine-like effect with
delay of conduction and depression of myocardial
contractility (Ellenhorn & Barceloux, 1988).
Contractility of the undamaged heart is usually not
affected by therapeutic concentrations, although slight
reduction of cardiac output may occur, and may be
significant in the presence of myocardial damage.
High toxic concentrations may prolong atrioventricular
conduction time or induce atrioventricular block or
even cause abnormal automaticity and spontaneous
firing, by unknown mechanisms (Barnhart, 1987).
The toxic mechanism of the drug is dose dependent and
is related to depression of contractility, decreased
vascular resistance secondary to direct vasodilation
and some alpha adrenergic blocking.
Besides the cardiovascular effects, procainamide
produces CNS depression ad has anticholinergic effects
(Noji, 1989).
7.1.2 Pharmacodynamics
Procainamide is an antiarrhythmic agent with
electrophysiological properties similar to that of
quinidine.
Procainamide increases the effective refractory period
of the atria, of the bundle of His-Purkinje system and
of the ventricles. It reduces impulse conduction
velocity in atria, His-Purkinje fibres, and ventricular
muscle. But it has also variable effects on the
atrioventricular node, a direct slowing action and a
weaker vagolytic effect which may speed atrio-
ventricular conduction slightly. Myocardial
excitability is reduced in the atria, Purkinje fibres,
papillary muscles, and ventricles by an increase in the
threshold for excitation.
NAPA is less potent than procainamide, and some of its
cardiac actions are qualitatively different.
Procainamide does not produce alpha-adrenergic
blockade, but, in the dog, it can block autonomic
ganglia weakly and cause a measurable impairment of
cardiovascular reflexes (Bigger, 1990).
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
A single oral dose of 2 g may produce symptoms
of toxicity. Ingestion of 3 g may be
dangerous, especially if patient is slow
acetylator or has renal impairment or
underlying heart disease.
Death was reported from intravenous
administration of 200 mg. The postulated
mechanism of death was either hypersensitivity
reaction or too rapid injection (Noji, 1989).
Plasma levels above 10 ug/mL are increasingly
associated with toxic findings, which are seen
occasionally in the 10 to 12 ug/mL range, more
often in the 12 to 15 ug/mL range, and commonly
in patients with plasma levels greater than
15 ug/mL (Barnhart, 1987).
The lowest reported oral lethal dose for humans
(LDLo) is 2280 mg/kg (Sax, 1989).
7.2.1.2 Children
No data available.
7.2.2 Relevant animal data
LD50 (intravenous) rat 95 mg/kg
LD50 (oral) mouse 312 mg/kg
LD50 (intravenous) mouse 103 mg/kg
LDLo (oral) dog 2210 mg/kg
LD50 (intravenous) rabbit 250 mg/kg
LD50 (intravenous) 280 mg/kg
guinea pig
(Niosh, 1978)
7.2.3 Relevant in vitro data
No data available.
7.3 Carcinogenicity
No data available.
7.4 Teratogenicity
Animal reproduction studies have not been conducted, but
procainamide should be given to a pregnant woman only if
clearly needed.
7.5 Mutagenicity
No data available.
7.6 Interactions
If other antiarrhythmic drugs are being used, additive
effects on the heart may occur with procainamide
administration, and dosage reduction may be necessary.
Anticholinergic drugs administered concurrently with
procainamide may produce additive antivagal effects on A-V
nodal conduction.
Patients taking procainamide who require neuromuscular
blocking agents such as succinylcholine may require less than
usual doses of the latter, due to procainamide effect on
reducing acetylcholine release (Barnhart, 1987).
Procainamide enhanced suxamethonium-induced neuromuscular
blockade in cats (Reynolds, 1989).
The neuromuscular blocking activity of an antibiotic having
such action may be accentuated by procainamide.
The hypotensive action of antihypertensive agents, including
thiazide diuretics, may be potentiated by procainamide (Osol
& Pratt, 1980).
Cimetidine therapy given to older male patients taking
procainamide may increase steady-state concentrations of
procainamide (Bauer, 1990).
7.7 Main adverse effects
The side-effects most frequently reported after high dosage
of procainamide include anorexia, diarrhoea, nausea, and
vomiting.
Intravenous administration may cause hypotension, ventricular
fibrillation or asystole if the injection is too rapid.
Following chronic administration, systemic lupus
erythematosus-like syndrome may develop.
Other side-effects which have been reported include mental
depression, dizziness, psychosis with hallucinations, joint
and muscle pain, muscular weakness, a bitter taste, flushing,
skin rashes, pruritus, angioneurotic edema and
hypersensitivity leading to chills, fever and urticaria.
Leucopenia and agranulocytosis have followed repeated use of
procainamide.
Neutropenia, thrombocytopenia, or haemolytic anaemia may
rarely be encountered (Barnhart, 1987).
High concentrations of procainamide in plasma can produce
ventricular premature depolarization, ventricular
tachycardia, or ventricular fibrillation.
Hepatomegaly with increased serum aminotransferase level has
been reported after a single oral dose (Barnhart, 1987).
Mild hypovolaemia, hypokalemia, metabolic acidosis may occur
(Noji, 1989).
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
8.1.2.1 Blood should be placed in heparinised tubes, be
protected from light and frozen at -20.
True in vivo plasma procainamide levels may
differ from measured levels when freshly drawn
and separated blood samples are not used for
analyses. In storage procainamide continues to
diffuse into red blood cells and undergoes
metabolism to both active (NAPA) and inactive
metabolites (Ellenhorn, 1988).
8.1.3.1 Blood samples should be frozen and protected
from light.
8.2 Toxicological Analytical Methods
Blood.
8.2.1 Tests for active ingredient
8.2.1.3 Simple quantitative method(s):
Colorimetric assay: Plasma is made alkaline
with a sodium hydroxide-sodium chloride mixture
and extracted with dichloromethane. The
organic layer is removed and evaporated to
dryness. The residue is dissolved in
hydrochloric acid and reacted with sodium
nitrite at 0 C, as the diazotization step and
then with N-(1-naphtyl)-ethylenediamine reagent
to form the complex which absorbs at 550 nm.
The method is suitable for assay of
procainamide in plasma over the range 0.5 to 25
ul/ml. The diazotization step at 0 C prevent
acid hydrolysis of NAPA and subsequent
overestimation (Chamberlain, 1987).
8.2.1.4 Advanced quantitative method(s)
- High Pressure Liquid Chromatography (HPLC)
- Fluorescense immunoassay
- Enzyme Multiplied Immunoassay Technique,
commercially marketed by Syva Corporation as
EMIT kit (Chamberlain, 1987).
8.2.2 Tests for biological sample
8.2.3 Interpretation
Plasma levels > 10 ug/ml are increasingly associated
with toxic findings.
Levels of procainamide and NAPA > 60 ug/ml were
observed in a severe intoxication with junictional
tachycardia and conduction deffects (Noji, 1989).
Occasionally procainamide levels up to 16 ug/ml are
required to suppress ventricular dysrhythmias. Mild
toxicity may appear in the 12-to-15 ug/ml range, and
serious toxicity occurs when procainamide levels exceed
15 ug/ml. The presence of the active metabolite (NAPA)
complicates interpretation of a true therapeutic and
toxic procainamide level; therefore both levels are
necessary to predict accurate therapeutic
concentrations. NAPA production depends on the rate of
acetylation, which is genetically determinated and
variable between races. Total procainamide and NAPA
therapeutic levels range from 5 to 25-30 ug/ml
(Ellenhorn, 1988).
Plasma levels of NAPA may rise disproportionately in
patients with renal impairment, because it is more
dependent than procainamide on renal excretion for
elimination (Drug Evaluations, 1980).
8.3 Other laboratory analyses
Therapeutic, toxic and lethal concentrations
8.3.1 Biochemical analysis
8.3.1.1 Blood
- Electrolytes, BUN, creatinine (fluid and
electrolyte status if severe vomiting,
diarrhoea)
8.3.1.2 Urine
Not relevant.
8.3.2 Arterial blood gas analyses
Blood.
8.3.3 Haematological or Haemostasiological investigations
Blood.
8.3.2 Arterial blood gas analyses
Determination of arterial gases should be preformed in
acute poisoning.
8.3.3 Haematological analyses
Not relevant.
8.3.4 Interpretation
Potassium disturbances may aggrevate procainamide
cardiotoxicity.
Frequent blood examinations should be made during
prolonged use of procainamide to detect
agranulocytosis, leucopenia and granulocytopenia.
8.4 Other relevant biomedical investigations and their
interpretation
Monitoring of ECG is the most useful investigation in
procainamide overdose. ECG may show:
1. Widened QRS complex (characteristic in overdose)
2. Prolongation of QT interval (characteristic in overdose)
3. U waves
4. Bundle branch block
5. Sinoatrial block
6. Atrioventricular block
7. Sinus arrest
8. Junctional or ventricular bradycardia
9. Asystole
10. Ventricular tachycardia
11. Torsade de pointes
12. Ventricular fibrillation (Noji, 1989)
Increased QT interval and prolonged QRS together with
hypotension are sensitive indexes of serious poisoning
(Ellenhorn,1988).
Parenteral administration of procainamide should be monitored
electrocardiographically to give evidence of impending heart
block.
Chest radiograph may reveal pulmonary edema.
8.5 References (in section 13)
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
Serious toxic effects include conduction disturbances
(QRS, QT prolongations), ventricular arrhythmias and
cardiogenic shock.
Increased ventricular extrasystoles, ventricular
tachycardia (especially of the "torsades de pointes"
type) or fibrillation may occur.
The threshold of cardiac pacing is increased and the
heart may even be nonresponsive.
Lethargy, confusion and coma may occur.
Other toxic manifestations are pulmonary edema,
respiratory depression, urticaria, pruritus, nausea,
vomiting, diarrhoea and abdominal pain.
Psychosis with hallucinations have been reported
occasionally (Ellenhorn & Barceloux, 1988; Noji, 1989;
Barnhart, 1987).
9.1.2 Inhalation
No data available.
9.1.3 Skin exposure
No data available.
9.1.4 Eye contact
No data available.
9.1.5 Parenteral exposure
Intravenous administration may cause hypotension,
ventricular fibrillation or asystole if the injection
is too rapid (Reynolds, 1989).
See also section 9.1.1
9.1.6 Other
Not relevant.
9.2 Chronic poisoning
9.2.1 Ingestion
A lupus erythematosus-like syndrome of arthralgia,
pleural or abdominal pain, and sometimes arthritis,
pleural effusion, pericarditis, fever, chills, myalgia,
and possibly related haematologic or skin lesions is
fairly common after prolonged procainamide
administration.
Neutropenia, thrombocytopenia, or haemolytic anaemia
may rarely be encountered. Agranulocytosis has
occurred after repeated use of procainamide (Barnhart,
1987).
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
No data available.
9.3 Course, prognosis, cause of death
Presence of PVCs and runs of ventricular tachycardia that are
almost always successfully treated.
Prognosis is usually good if there is not progress to
ventricular fibrillation or asystole.
Death is due to ventricular fibrillation or asystole.
Long-term effects are agranulocytosis from hypersensitivity
reaction, that is associated with 90% recovery rate (Noji,
1989).
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
Acute
Sinus or atrial tachycardia due to the vagolytic
effects.
Conduction disturbances such as atrioventricular block,
intraventricular block.
Ventricular arrhythmias, including torsades de pointes,
ventricular tachycardia, fibrillation.
Hypotension and cardiogenic shock.
ECG may show widening QRS, atrioventricular block,
prolongation of QT interval, ventricular arrhythmia
(see section 8.4)
Chronic
Chronic exposure may also produce arrhythmias.
Cardiac "tamponade" due to pericarditis has been
reported in a case of procainamide-induced systemic
lupus syndrome.
9.4.2 Respiratory
Acute
Respiratory arrest and pulmonary oedema (Noji, 1989).
Chronic
No data available.
9.4.3 Neurological
9.4.3.1 Central nervous system (CNS)
Acute
Dizziness or giddiness, weakness, mental
depression, and psychosis with hallucinations
have been reported occasionally (Barnhart,
1987).
Lethargy may progress to coma (Noji, 1987).
Chronic
Same as acute.
9.4.3.2 Peripheral nervous system
No data available.
9.4.3.3 Autonomic nervous system
No data available.
9.4.3.4 Skeletal and smooth muscle
Acute
No data available.
Chronic
Skeletal muscular weakness and diaphragmatic
paralysis has been reported in a case.
9.4.4 Gastrointestinal
Acute
Anorexia, nausea, vomiting, abdominal pain, bitter
taste, or diarrhoea may occur in 3 to 4% of patients
taking oral procainamide (Barnhart, 1987).
Chronic
Nausea, vomiting may be seen.
9.4.5 Hepatic
Acute
Hepatomegaly with increased serum aminotransferase
level has been reported after a single oral dose
(Barnhart, 1987).
Chronic
No data available.
9.4.6 Urinary
9.4.6.1 Renal
No data available.
9.4.6.2 Other
No data available.
9.4.7 Endocrine and reproductive systems
No data available.
9.4.8 Dermatological
Acute
No data available.
Chronic
Angioneurotic edema, urticaria, pruritus, flushing,
and maculopapular rashes (Barnhart, 1987).
9.4.9 Eye, ear, nose, throat: local effects
Acute
Blurred vision has been reported.
Chronic
No data available.
9.4.10 Haematological
Acute
No data available.
Chronic
Neutropenia, thrombocytopenia, or haemolytic anaemia
and agranulocytosis may rarely be encountered
(Barnhart, 1987).
9.4.11 Immunological
Acute
No data available.
Chronic
systemic lupus erythematosus-like syndrome (Barnhart,
1987).
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
Acute
Metabolic acidosis has been reported (Noji,
1989).
Chronic
No data available.
9.4.12.2 Fluid and electrolyte disturbances
Acute
Hypokalemia may occur (Noji, 1989).
Chronic
No data available.
9.4.12.3 Others
No data available.
9.4.13 Allergic reactions
Acute
No data available.
Chronic
Angioneurotic edema, maculopapular rashes (Barnhart,
1987).
9.4.14 Other clinical effects
No data available.
9.4.15 Special risks
Pregnancy
It is not known whether procainamide cause fetal harm
when administered to a pregnant woman. Procainamide
should be given to a pregnant woman only if clearly
needed.
Breast feeding
Both procainamide and NAPA are excreted in human milk.
Therefore, procainamide should be given to a nursing
mother only if clearly needed.
Paediatric use
Safety and effectiveness in children have not been
established.
9.5 Other
No data available.
9.6 Summary
Not relevant.
10. MANAGEMENT
10.1 General principles
Monitor vital signs, blood pressure, ECG and serum
electrolytes.
Insert an intravenous line for central venous pressure
Treatment of cardiovascular disturbances may include the
following:
Isoprenaline and/or ventricular pacing for atrio
ventricular block.
Isoprenaline and/or molar sodium bicarbonate for
intraventricular block.
Dobutamine, dopamine and/or epinephrine to correct
hypotension and cardiogenic shock.
Correct hypokalaemia if present.
Although absorption may be slow, emesis or lavage is rarely
indicated later than 1 to 2 hours after ingestion.
Activated charcoal should given.
10.2 Relevant laboratory analyses
10.2.1 Sample collection
Blood and urine.
10.2.2 Biomedical analysis
Determination of arterial blood gases, electrolytes,
BUN and creatinine.
10.2.3 Toxicological analysis
Determination of plasma levels of procainamide and
NAPA may be useful in patients with impaired hepatic
or renal function.
10.2.4 Other investigations
ECG is the most useful biomedical investigation.
10.3 Life supportive procedures and symptomatic/specific
treatment
Intravenous lines, oxygen and cardiac monitoring should be
rapidly initiated.
Support respiratory and cardiac function.
Avoid quinidine, disopyramide and other antiarrhythmic
drugs.
Severe bradycardia or atrioventricular block should be
treated with isoprenaline or cardiac pacing. Higher
energies to stimulate refractory myocardium may be needed.
Intraventricular block should be treated with isoprenaline
and molar sodium bicarbonate.
Hypotension and cardiogenic shock may be treated with
inotropic agents such as dobutamine, dopamine and in severe
cases, epinephrine (adrenaline).
Ventricular dysrhythmia, such as torsades de pointes, may
be treated with isoprenaline or cardiac overdrive pacing.
Correct hypokalaemia if present.
10.4 Decontamination
The usual measures of emesis/lavage, within 1 to 2 hours
post-ingestion are indicated unless contraindications for
their use exist. Charcoal should also be given. These
measures should be undertaken very carefully in patients
with severe cardiovascular disturbances (Ellenhorn &
Barceloux, 1988).
10.5 Elimination
Renal elimination of procainamide appears not to be
affected by urinary pH or by urinary flow rate (Galeazzi et
al., 1976). However, because procainamide and NAPA are
substantially eliminated by the kidney, it is important to
maintain adequate renal functions.
Haemodialysis and haemoperfusion remove relatively little
procainamide because of extensive tissue distribution of
the drug. But when the usual routes of drug elimination
are depressed or absent, haemodialysis or haemoperfusion
could be considered, because, even though not highly
effective, they may offer the only route of drug
elimination (Benowitz, 1990).
A case report suggests that haemodialysis may remove the
active metabolite NAPA (NAPA plasma levels decreased from
43 to 20 ug/mL). But the absence of the pharmacokinetic
documentation of the total amount of drug removed means
that its efficacy remains to be proven (Ellenhorn &
Barceloux, 1988).
10.6 Antidote treatment
10.6.1 Adults
There are no antidotes.
10.6.2 Children
There are no antidotes.
10.7 Management discussion
A case report suggests that haemodialysis may remove the
active metabolite NAPA (NAPA plasma levels decreased from
43 to 20 ug/mL). But the absence of the pharmacokinetic
documentation of the total amount of drug removed means
that its efficacy remains to be proven (Ellenhorn &
Barceloux, 1988).
Haemoperfusion and haemodialysis may only be considered in
patients with impaired renal, and/or hepatic function.
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
Acute toxicity
Braden et al. (1986) reported a poisoning in a 60-year-old
man treated by intravenous procainamide for ventricular
tachycardia. The patient was treated with resin
haemoperfusion for 4 hours followed by haemodialysis for 4
hours. N-acetyl procainamide levels decreased by 19 mcg/mL
with haemoperfusion and by 2 mcg/mL with haemodialysis.
Plasma clearance with haemoperfusion was 3.5 times greater
than with haemodialysis.
Chronic toxicity
A 66-year-old male patient was evaluated for bilateral
vaso-occlusive retinopathy of uncertain etiology. He had a
3-week history of progressive painless visual loss with
marked worsening over the last 4 days. Past ocular history
was unremarkable, although past medical history was
significant for essential hypertension, coronary artery
disease, cardiac arrhythmia, chronic obstructive pulmonary
disease, and pneumonectomy for lung carcinoma several years
ago. He had been taking sustained release procainamide
hydrochloride (750 to 1000 mg 4 times daily for the past 10
months), in addition to furosemide, dipyridamole,
theophylline, albuterol, and aspirin. Associated clinical,
laboratory, and pathologic findings suggest the diagnosis
of drug-induced lupus. This represents the first
documented case of retinal disease attributed to
procainamide-induced lupus (Nichols & Mieler, 1989).
In 1989, a 47-year-old man experienced acute loss of
consciousness. He was found to be in ventricular
fibrillation and was resuscitated successfully. Cardiac
catheterization revealed minimal diffuse coronary
arteriosclerosis. Electrophysiological testing was
declined, and procainamide was empirically selected as the
initial antiarrhythmic agent. Approximately three months
later, he developed a dull pain in his left shoulder and
left hand that intensified with exposure to cold weather.
He denied chest pain, orthopnea, paroxysmal nocturnal
dyspnea, fever or cough. The physical examination revealed
an anxious, afebrile patient with normal blood pressure.
Respiratory examination showed no paradoxical pulse or
jugular venous distention. A pericardial friction rub was
present. An acneiform rash was noted across his trunk.
There was not evidence of active synovitis. The WBC count
was 12,800/cubic mm with a normal differential, the
haematocrit was 44%, and the platelet count was
310,000/cubic mm; electrolytes and creatinine were normal,
and antinuclear antibody was negative. Chest X-ray was
free of infiltrates or effusions. The pericardial friction
rub, arthralgia, and rash resolved with discontinuation of
procainamide (Ebaugh, 1990).
11.2 Internally extracted data on cases
No data available.
11.3 Internal cases
To be completed by each Centre using local data.
12. ADDITIONAL INFORMATION
12.1 Availability of antidotes
There are no available antidotes.
12.2 Specific preventive measures
Not relevant
12.3 Other
No data available.
13. REFERENCES
American Medical Association (1988) Drug Evaluations, 6th
edition-Philadelphia, WB Saunders Co.
Atkinson AJ, Krumlovsky FA, Huang GM, & del Greco F (1976)
Hemodialysis for severe procainamide toxicity. Clinical and
pharmacokinetic observation. Clin Pharmacol Ther, 20(5): 585-
592.
Barnhart ER (publ) (1987) Physicians' Desk Reference. 41th ed.
New Jersey, Medical Economics Co. Inc.
Bauer L, Black D, & Gensler A (1990) Procainamide-cimetidine
drug interaction in elderly male patients. Journal American
Geriatrics Society, 38: 467-169.
Benowitz NL (1990) Quinidine, Procainamide, and Disopyramide.
In: Haddad LM & Winchester JF eds. Clinical management of
poisoning and drug overdose. Philadelphia, W. Saunders Co.
Bigger JR (1990) Antiarrythmic drugs. In: Gilman AG, Rall TW,
Nies AS, & Taylor P eds. Goodman and Gilman's. The
pharmacological basis of therapeutics. 8th ed. New York,
Pergamon Press.
Braden GL, Fitzgibbons JL, Germain MJ, & Ledewitz HM
(1986)Hemoperfusion for treatment of N-acetylprocainamide
intoxication. Ann Intern Med, 105(1): 64-65.
British Pharmacopoeia Commission (1994) British approved names
1994. London, HMSO.
Budavari S, ed. (1989) The Merck index, an encyclopedia of
chemicals, drugs, and biologicals, 11th ed. Rahway, New Jersey,
Merck and Co. Inc.
Chamberlain J (1987) Analysis of drugs in biological fluids. 4th
ed. Florida, CRC Press.
Ebaugh L, Fleet W, & Morgan H (1990) Pericarditis following
antiarrhythmic therapy. Vanderbilt Morning Report. Journal
Tennessee Medical Association. April: 190.
Ellenhorn MJ & Barceloux DG (1988) Medical Toxicology. Diagnosis
and treatment of human poisoning. New York, Elsevier.
Fleeger CA ed. (1993) USAN 1994: USAN and the USP dictionary of
drug names. Rockville, MD, United States Pharmacopeial
Convention, Inc., p 547.
Galeazzi R, Sheiner L, Lockwood B, & Benet L (1976) The renal
elimination of procainamide. Clinical Pharmacology and
Therapeutics, 19(1): 55-62.
Nichols C & Mieler W (1989) Severe retinal vaso-occlusive
disease secondary to procainamide-induced lupus. Ophthalmology
96(10): 1535-1540.
NIOSH - National Institute of Occupational Safety Health (1978)
Register of Toxic Effects of Chemical Substances. Cincinnati,
NIOSH.
Noji EK & Kelen GD (1989) Manual of toxicologic emergencies
Chicago, Year Book Medical Publishers, Inc.
Osol A & Pratt R (1980) The United States Dispensatory 27th ed.
Philadelphia, J.B. Lippincott Company.
Reynolds JEF ed. (1989) Martindale, the extra pharmacopoeia 29th
ed. London, The Pharmaceutical Press, pp 82-84.
Reynolds JEF ed. (1993) Martindale, the extra pharmacopoeia 30th
ed. London, The Pharmaceutical Press, pp 69-71.
Sax NI & Lewis RJ (1989) Dangerous properties of industrial
materials, 7th ed. New York, Van Nostrand Reinhold.
WHO (1992) International nonproprietary names (INN) for
pharmaceutical substances. Geneva, World Health Organisation,
p 432.
WHO (1992) Anatomical Therapeutic Chemical (ATC) classification
index. Oslo, WHO Collaborating Centre for Drug Statistics
Methodology, p 23.
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
ADDRESS(ES)
Author Flavia Valladao Thiesen Applied Toxicology
Centre/PUCRS Carlos Huber, 412 91330 Porto
Alegre Brazil
Fax: 55 51 224 65 63
Reviewer Dr A Jaeger
Peer Review Drs Hanafy, Rahde, Myrenfors, Murray, Group
Ruggerone, & Jaeger. September 1992