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Procainamide

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
   1.7 Presentation, Formulation
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
         3.3.1.1 Colour
         3.3.1.2 State/Form
         3.3.1.3 Description
      3.3.2 Properties of the locally available formulation(s)
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Shelf-life of the locally available formulation(s)
      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
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central nervous system (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive 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)
    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 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
          


    See Also:
       Toxicological Abbreviations