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Hydrochlorothiazide

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other number(s)
   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
8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS
   8.1 Material
      8.1.1 Sampling
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gases
         8.1.1.4 Haematological investigations
      8.1.2 Storage
      8.1.3 Transport
   8.2 Toxicological analyses and their interpretation
      8.2.1 Tests for toxic ingredient
         8.2.1.1 Simple qualitative test (s)
         8.2.1.2 Advanced qualitative confirmation test (s)
         8.2.1.3 Simple quantitative method (s)
         8.2.1.4 Advanced quantitative method (s)
      8.2.2 Tests for biological samples
         8.2.2.1 Simple qualitative test (s)
         8.2.2.2 Advanced qualitative confirmation test (s)
         8.2.2.3 Simple quantitative method (s)
         8.2.2.4 Advanced quantitative method (s)
         8.2.2.5 Other dedicated method (s)
      8.2.3 Interpretation
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood
         8.3.1.2 Urine
         8.3.1.3 Other
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation
   8.4 Other relevant biomedical investigations and their interpretation
   8.5 Overall interpretation
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 

           Hydrochlorothiazide   (INN)
           
           (WHO, 1992)

       1.2 Group

           ATC classification index
           
           Diuretics (C03)/Low-ceiling diuretics(C03A)/
           Thiadiazides, plain (C03AA)
           
           (WHO, 1992)

       1.3 Synonyms

           Hidroclorotiazida
           Hydrochlorothiazidum
           Chlorsulfonamidodihydrobenzothiadiazine dioxide
           Chlorosulthiadil
           3,4-dihydrochlorothiazide
          
           (Budavari, 1989; Reynolds 1989)

       1.4 Identification numbers

           1.4.1 CAS number

                 58-93-5

           1.4.2 Other number(s)

                 RTECS

                 DK 9100000

       1.5 Brand Names, Trade names

           Monocomponent preparations
           
           Apo-Hydro (Apotex, Canada); Atenadon (Italy); Catiazida 
           (Spain); Chlorzide (Foy, USA); Clothia (Japan); Clorana 
           (Brazil); Cloredema (Spain); Delco-Retic (USA); Di-Chlotride 
           (Germany); Dichlotride (Australia; Belgium; Norway); 
           Diclotride (Italy); Diidrotiazide (Italy); Direma (UK); 
           Diucem-H (USA); Diuchlor-H (Canada); Diurex (Argentina); 
           Diursana-H (Australia; Belgium; Canada; Denmark; France; 
           Italy; Norway; Spain; Sweden; Switzerland; UK); Esidrix 
           (Germany; USA); Hidrenox (Argentina); Hidrosaluretil (Spain); 
           Hydro-Alquil (Canada); Hydro-Diuril (Canada; USA); 
           HydroSaluric (UK); Hydro-Z (USA); Hydrozide (USA); Hygroton 
           (Brazil); Idrofluin (Italy); Idrolisin (Italy); Jen-Diril 

           (USA): Loqua (USA); Masquitt (Japan); Mictrin (USA); Natrimax 
           (Canada); Neo Minzil (Italy); Neo-Codema (Canada); Neo-Flumen 
           (Australia); Neoflumen (Spain); Newtolide (Japan); 
           Novohydrazide (Canada); Oretic (USA); Ridaq (South Africa); 
           Ro-Hydrazide (USA); SK-Hydrochlorothiazide (USA); Tandiur 
           (Argentina); Thiuretic (USA); Uriex (South Africa); Urozide 
           (Canada).
           
           Combination products
           
           Acezide (UK); Aldactazide (Canada; USA); Aldoril (Canada; 
           USA); Amilco (UK); Amizide (Australia); Apo-Methazide 
           (Canada); Apo-Triazide (Canada); Apresazide (USA); 
           Apresoline-Esidrix (USA); Capozide (UK; USA); Co-Betaloc 
           (Canada; UK); Dopazide (Canada); Dyazide (Australia; Canada; 
           UK; USA); Esidrex-K (UK); Esimil (USA); H-H-R (USA); Hydral 
           (USA); Hydra-Ziode (USA); Hydromet (UK); Hydropres (Canada; 
           USA); HydroSaluric-K (UK); Hydrosine (USA); Hypertane (UK); 
           Hyserp (USA); Inderide (Canada; USA); Kalten (UK); Lopressor 
           HCT (USA); Maxzide (USA); Moducren (UK); Moduret (Canada; 
           UK); Australia; UK; USA); Normetic (UK); Normozide (USA); 
           Novodoparil (Canada); Novospirozine (Canada); Novotriamzide 
           (Canada); Oreticyl (USA); Rezide (USA); Salupres (UK); 
           Secadrex (UK); Seragen (USA); Ser-Ap-Es (Canada; USA); 
           Serpasil-Esidrex (UK); Spironazide (USA); Synuretic (UK); 
           Timolide (Canada; USA) Tolerzide (UK); Trandate HCT (USA); 
           Triamco (UK); Unipres (USA); Vaseretic (USA); Viskazide 
           (Canada) (Reynolds, 1989).
           
           (To be completed by Centre using local data)

       1.6 Manufacturers, Importers

           Abbott (USA): Adcock Ingram (South Africa); Apotex (Canada); 
           Central Pharmaceuticals (USA); Ciba (Australia; Belgium; 
           Canada; Denmark; France; Germany; Italy; Netherlands; Norway; 
           Spain; Sweden; Switzerland; USA; UK); Cronofar (Spain); Dista 
           (UK); Foy (USA); Gayoso Wellcome (Spain); Lennon (South 
           Africa); Mayrand (USA); Medic (Canada); Melusin (Canada); 
           Melusin (Germany); Merck Sharp & Dohme (Australia; Belgium; 
           Canada; Denmark; Germany; Norway; USA; UK); Neolab (Canada); 
           Novopharm (Canada); Parke Davis (USA); Pharmador (South 
           Africa); Smith Kline & French (USA); Trianon (Canada); Valeas 
           (Italy) (Reynolds, 1989).
           
           (To be completed by Centre using local data)

       1.7 Presentation, Formulation

           Hydrochlorothiazide  Tablets 12.5; 25; and 50 mg
           Hydrochlorothiazide  Oral solution  50 mL
           
           (To be completed by Centre using local data)

    2. SUMMARY

       2.1 Main risks and target organs

           Hydrochlorothiazide is generally a very safe diuretic, as the 
           distance between therapeutically effective and frankly toxic 
           doses is large (Gosselin, 1984). Clinical toxicity is 
           relatively infrequent and may result from overdosage, adverse 
           reactions or unexpected hypersensitivity.
           
           Main risks
           
           Electrolytes imbalances that may lead to cardiac arrhythmias 
           and orthostatic hypotension.
           
           Metabolic disturbances, such as hyperglycaemia and 
           hyperuricaemia.
           
           Aggravation of hepatic and/or renal insufficiency
           
           Hypersensitivity reactions.
           
           Blood dyscrasias.
           
           Acute noncardiogenic pulmonary edema.
           
           Gastrointestinal irritability.
           
           Central Nervous System manifestations.
           
           Target organs
           
           Kidneys, heart, central nervous system.

       2.2 Summary of clinical effects

           Haematological
           
           Thrombocytopenia, granulocytopenia, leucopenia, a-plastic 
           anaemia, and haemolytic anaemia.
           
           Hypersensitivity
           
           Purpura, intravascular immunohaemolysis, pneumonitis, skin 
           rashes, urticaria, eczema, lichen planus-like reactions; 
           photosensitivity, similar to subacute cutaneous lupus 
           erythematosus; vasculitis, Stevens Johnson Syndrome.
           
           Cardiovascular
           
           Cardiac arrhythmias, increasing the effect of digitalis on 
           cardiac muscle, orthostatic hypotension. 
           
           Gastrointestinal
           
           Anorexia, gastric irritation, nausea, vomiting, cramping, 
           diarrhoea, constipation, jaundice due to intrahepatic 
           cholestasis, pancreatitis, sialadenitis, dry mouth, hepatic 
           insufficiency, intestinal ulceration.
           
           Central Nervous System
           
           Dizziness, vertigo, paraesthesias, headache, xanthopsia.
           
           Respiratory tract
           
           Acute noncardiogenic pulmonary edema.
           
           Renal tract
           
           Renal insufficiency.
           
           Others
           
           Attacks of gout, hyperuricaemia, hyperglycaemia, glycosuria, 
           thirst, weakness, muscle pain, lethargy, drowsiness, 
           restlessness, increasing in plasma concentrations of 
           cholesterol and triglycerides, impotence.
           
           Oedema after abrupt suspension.

       2.3 Diagnosis

           Clinical
           
           There are no key clinical features to the diagnosis.
           
           Diagnostic tests
           
            Blood
           
           Complete blood count.
           Determination of creatinine, urea, transaminases, amylase, 
           calcium, glucose, Triglycerides, uric acid, lipoproteins, 
           electrolytes (chloride, magnesium, potassium, and sodium), 
           blood gases and pH.
           
            Urine
           
           Urinalysis.
           
            Other
           
           ECG, Chest radiograph. 
           
       2.4 First aid measures and management principles

           Stabilization
           
           Make a proper assessment of airway, breathing, circulation, 
           and neurological status of the patient.
           
           Maintain a clear airway.
           
           Open and maintain at least one intravenous route and maintain 
           blood pressure by intravenous fluids or pressor agents.
           
           Monitor fluid and electrolyte balance and acid-base balance.
           
           Control cardiac dysrhythmias.
           
           Decontamination
           
           Ipecac syrup or gastric lavage may be useful if treatment is 
           instituted within the first 1 or 2  hours after ingestion.
           
           Activated charcoal.
           There are no antidotes.
           
           Elimination enhancement: No satisfactory measures
           
           Supportive care
           
           In diuretic overdosage: hospitalization for continuous 
           cardiac, electrolyte, and renal control. Correct 
           hyponatraemia and hypokalaemia. Monitor the haematocrit and 
           complete blood count. Daily control of body weight.

    3. PHYSICO-CHEMICAL PROPERTIES

       3.1 Origin of the substance
          
           Synthetic. Thiazide diuretics are sulphonamide-derived drugs.

       3.2 Chemical structure

           Structural formula
           
           Molecular formula
           
           C7H8ClN3O4S2
           
           Molecular weight
           
           297.72
           
           Chemical names
           
           6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 
           1,1-dioxide.
           
           6-Chloro-3,4-dihydro-7-sulfamoyl-2H-1,2,4-benzothiadiazine 
           1,1-dioxide
           
           6-Chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine 1,1-
           dioxide
           
           (Budavari, 1989; Reynolds, 1989)
                     
       3.3 Physical properties

           3.3.1 Properties of the substance

                 3.3.1.1 Colour

                         White or almost white

                 3.3.1.2 State/Form
                         
                         Crystalline powder.

                 3.3.1.3 Description

                         Odourless or almost odourless.
                         
                         Slightly or very slightly soluble in water; 
                         sparingly soluble in alcohol; soluble in 
                         acetone; freely soluble in dimethylformamide; 
                         n-butylamine; and solutions of alkali 
                         hydroxides; insoluble in ether, chloroform, and 
                         dilute mineral acids.
                         
                         (Reynolds, 1989; Budavari, 1989).
                         
                         When heated decomposes in toxic fumes (SO2, C1,
                         NO2) (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

                 Expiry dates of the commercially available preparations 
                 vary between 5 to 6 years.

           3.4.2 Shelf-life of the locally available formulation(s) 

                 Expiry dates of the commercially products vary between 
                 5 to 6 years.
                 
                 (To be completed by eachCentre using local data).

           3.4.3 Storage conditions

                 Store in well-closed containers. All preparations 
                 should be protected from light.
                 
                 (To be completed by Centre using local data)

           3.4.4 Bioavailability

                 To be completed by Centre using local data.

           3.4.5 Specific properties and composition

                 To be completed by Centre using local data.

    4. USES

       4.1 Indications

           4.1.1 Indications

                 Hydrochlorothiazide is a diuretic which reduces the 
                 reabsorption of electrolytes from the renal tubules.
                 
                 Used to treat hypertensive disease and to manage the 
                 oedema due to mild-to-moderate congestive heart 
                 failure. Oedema due to chronic hepatic or renal disease 
                 may also respond favourably (Weiner, 1990; Reynolds, 
                 1989).
                 
                 It may also be used in patients with diabetes 
                 insipidus, due to a paradoxical effect.
                 
                 May be used in the treatment of hypercalciuria in 
                 patients who have recurrent urinary calculi composed of 
                 calcium salts (Weiner, 1990).
                 
                 The use of hydrochlorothiazide has been indicated for 
                 the oedema of the premenstrual tension, if there is 
                 evidence of fluid retention (Reynolds, 1989).

           4.1.2 Description

                 Not relevant

       4.2 Therapeutic dosage

           4.2.1 Adults

                  Hypertension
                 
                 25 to 50 mg daily. Doses of up to 200 mg have been 
                 recommended but are rarely necessary.
                 
                 (Ellenhorn & Barceloux, 1988; Reynolds, 1989).
                 
                  Oedema
                 
                 50 to 100 mg daily (initial dose), reduced to a dose of 
                 25 to 50 mg daily or intermittently. 200 mg daily have 
                 been recommended.
                 
                 (Reynolds, 1989).
                 
                  Renal disorders
                 
                 50 mg twice daily appeared to be effective in 
                 preventing the formation of calcium stones in the 
                 urinary tract in a study of 67 patients.
                 
                 (Reynolds, 1989).
                 
                  Diabetes insipidus
                 
                 50 mg twice a day. (Randall, 1987).
                 
                  Premenstrual tension
                 
                 50 to 100 mg daily.
                 
           4.2.2 Children

                 2.5 mg/kg body-weight daily in two divided doses. 
                 Infants under 6 months may need doses of up to 
                 3.5 mg/kg body-weight daily (Reynolds, 1989).

       4.3 Contraindications

           Anuria and hypersensitivity to sulfonamide-derived drugs.
           
           Precautions
           
           Hydrochlorothiazide should be used with caution in:
           
           .     patients with impaired hepatic function since it may 
           increase the risk of hepatic encephalopathy;
           
           .     patients with renal impairment since it can further 
           reduce renal function, and precipitate azotemia. Cumulative 
           effects of the drug may develop in patients with impaired 
           renal function (Barnhart, 1987).
           
           .     patients with gout since it can precipitate attacks of 
           the disease.
           
           The patients should be carefully observed for signs of fluids 
           and electrolyte imbalance.
           
           Hydrochlorothiazide may enhance the toxicity of digitalis 
           glycosides by depleting serum-potassium concentrations.  The 

           possibility of exacerbation or precipitation of systemic 
           lupus erythematosus has been reported (Barnhart, 1987).
           
           Thiazides cross the placental barrier and appear in umbilical 
           cord blood.  Thiazides appear in breast milk (Ellenhorn & 
           Barceloux, 1988; Barnhart, 1987).

    5. ROUTES OF ENTRY

       5.1 Oral

           Oral route is the common route of administration. Accidental 
           or deliberate ingestion of large doses may occur. 
       
       5.2 Inhalation

           No data available.

       5.3 Dermal

           No data available.

       5.4 Eye

           No data available.

       5.5 Parenteral

           No data available.

       5.6 Other

           No data available.

    6. KINETICS

       6.1 Absorption by route of exposure

           Hydrochlorothiazide is variably but fairly rapidly absorbed 
           from the gastrointestinal tract. Bio-availability of 
           hydrochlorothiazide after oral administration is 
           approximately 60 to 80 per cent. Peak plasma level occurs 
           after 1 to 2 hours (Ellenhorn & Barceloux, 1988).

       6.2 Distribution by route of exposure

           Hydrochlorothiazide is widely distributed in body tissue and 
           its volume of distribution following oral administration 
           corresponds to 0.83 L/Kg (Ellenhorn & Barceloux, 1988; Gilman 
           et al., 1990).
           
           Protein binding in the plasma is estimated at 58% (Gilman et 
           al., 1990).

       6.3 Biological half-life by route of exposure

           A plasma half-life of about 9.5 hours has been estimated.  
           The red blood cells half-life is 2.7 to 7 hours (Ellenhorn & 
           Barceloux, 1988).
           
       6.4 Metabolism

           Hydrochlorothiazide is not modified by organic biochemical 
           processes.

       6.5 Elimination by route of exposure

           Elimination of hydrochlorothiazide is mainly due to renal 
           clearance that occurs in about 320 mg/min (Ellenhorn, 1988). 
           It is excreted unchanged in the urine. Hydrochlorothiazide 
           crosses the placental barrier and appears in breast milk 
           (Ellenhorn & Barceloux, 1988; Reynolds, 1989).
           
           Total systemic clearance of drug from the plasma is 
           4.9 mL/min/kg , decreasing in patients with uremia or 
           congestive heart failure. (Gilman et al., 1990)

    7. PHARMACOLOGY AND TOXICOLOGY

       7.1 Mode of action

           7.1.1 Toxicodynamics

                 Most of the toxicodynamic manifestations are due to 
                 electrolyte imbalances including hypochloraemic 
                 alkalosis, hyponatraemia, hypokalaemia and 
                 hypomagnesaemia.
                 
                 The mechanism of hypercalcaemia and hypophosphataemia 
                 are unknown.
                 
                 Clinical studies indicate that depletion of potassium 
                 has a role in glucose intolerance, probably by 
                 inhibition of insulin secretion (Weiner, 1990).
                 
                 For reasons that are unexplained thiazides increase the 
                 concentrations of cholesterol and triglycerides in 
                 plasma (Weiner, 1990).
                 
                 Other toxic effects produced by hydrochlorothiazide are 
                 due to hypersensitivity reactions.

           7.1.2 Pharmacodynamics 

                 Hydrochlorothiazide acts directly on the kidney, 
                 increasing the excretion of sodium chloride an 
                 potassium and consequently water, mainly in the distal 
                 tubule (Ellenhorn & Barceloux, 1988; Weiner, 1990; 
                 Reynolds, 1989).

       7.2 Toxicity 

           7.2.1 Human data 

                 7.2.1.1 Adults 

                         No data available.

                 7.2.1.2 Children 

                         No data available.

           7.2.2 Relevant animal data 

                 LD50 (Intravenous) mouse     590 mg/Kg
                      (Oral) mouse            up to 8,000 mg/Kg 
                 (Budavari, 1989)
                 
                 TDLo (Oral) rat              582 g/kg
                 LD50 (Intraperitoneal)rat    234 mg/kg
                 LD50 (Subcutaneous) rat      1270 mg/kg
                 LD50 (Intravenous) rat       990 mg/kg
                 LD50 (Oral) mouse            2380 mg/kg
                 LD50 (Intraperitoneal)mouse  578 mg/kg
                 LD50 (Subcutaneous) mouse    1470 mg/kg
                 LD50 (Intravenous) mouse     590 mg/kg
                 LD50 (Intravenous) dog       250 mg/kg
                 LD50 (Intravenous) rabbit    461 mg/kg
                 
                 (Sax, 1989)

           7.2.3 Relevant in vitro data

                 No data available.

       7.3 Carcinogenicity

           There is inadequate evidence for the carcinogenicity of 
           hydrochlorothiazide in humans (IARC, 1990).
           
           There is inadequate evidence for the carcinogenicity of 
           hydrochlorothiazide in experimental animals (IARC, 1990).

       7.4 Teratogenicity 

           In general the exposure to diuretics was not associated with 
           teratogenicity. A slight association with respiratory 
           malformation was suggested (Reynolds, 1989).
           
           Other risks include foetal or neonatal jaundice, 
           thrombocytopenia, and possible other adverse reactions which 
           have occurred in the adult (Barnhart, 1987).
           
           In rats, no teratogenic, embryotoxic or foetotoxic effect was 
           observed (IARC, 1990).

       7.5 Mutagenicity 

           Hydrochlorothiazide induced gene mutations in mouse lymphoma 
           cells and sister chromatid exchange in Chinese hamster cells.
           
           It did not induce chromosomal aberrations in Chinese hamster 
           cells in vitro or sex-linked recessive lethal mutations in 
           Drosophila.
           
           Hydrochlorothiazide induced mitotic recombination and non-
           disjunction in Aspergillus.
           
           It was not mutagenic to Salmonella typhimurium or Escherichia 
           coli. 
           
           (IARC, 1990).

       7.6 Interactions 

           Hydrochlorothiazide may increase the toxicity of digitalis 
           glycosides by depleting serum-potassium concentrations.  Due 
           to the potassium depletion it may enhance the neuromuscular 
           blocking action of competitive muscle relaxants such as 
           tubocurarine or gallamine triethiodide (Ellenhorn & 
           Barceloux, 1988).
           
           It may increase the effect of anti-hypertensive agents such 
           as guanethidine sulfate, methyldopa, or a ganglionic blocking 
           agent (Ellenhorn & Barceloux, 1988; Reynolds, 1989).
           
           The postural hypotension due to thiazide diuretic therapy may 
           be increased by concomitant ingestion of alcohol, 
           barbiturates, or opiates (Reynolds, 1989; Barnhart, 1987). 
           The potassium-depleting effect of thiazide diuretic may be 
           enhanced by corticosteroids, corticotrophin, carbenoxolone, 
           and amphotericin (Ellenhorn & Barceloux, 1988).
           
           Hydrochlorothiazide has been reported to reduce the response 
           to pressor amines, such as noradrenaline, but the clinical 
           significance of this effect is uncertain.
           
           Concomitant administration of thiazide diuretic and lithium 
           salts is not recommended since the association may lead to 
           toxic blood concentration of lithium (Reynolds, 1989).
           
           The pharmacological effects of oral hypoglycaemic agents may 
           be reduced (Ellenhorn & Barceloux, 1988; Weiner, 1990).
           
           The urinary excretion of chloramphenicol in healthy subjects 
           was decreased by thiazide diuretics (Reynolds, 1989).  
           Cholestyramine may produce a decrease of 30 to 35% in the 
           absorption of hydrochlorothiazide. Hydrochlorothiazide may 
           reduce the tubular secretion of amantadine.  The non-
           steroidal anti-inflammatory drugs may antagonise the diuretic 
           actions of thiazides (Reynolds, 1989).
           
           The hyperglycaemic, hypotensive and hyperuricaemic effects of 
           diazoxide can be potentiated by thiazides (Ellenhorn & 
           Barceloux, 1988).
           
           Probenecid enhances excretion of calcium, magnesium and 
           citrate during thiazide therapy, but does not affect 
           excretion of sodium, potassium, ammonium chloride, 
           bicarbonate and phosphate and titratable acid (Ellenhorn & 
           Barceloux, 1988).
           
           Thiazides increase urinary pH and may decrease urinary 
           excretion of amphetamines and quinidine (Ellenhorn & 
           Barceloux, 1988).

       7.7 Main adverse effects 

           The thiazide diuretic may cause a number of metabolic 
           disturbances.  Hydrochlorothiazide may induce hyperglycaemia 
           and may aggravate pre-existing diabetes mellitus.  It may 
           cause hyperuricaemia and precipitate attacks of gout in some 
           patients. Thiazide diuretics increase the concentrations of 
           cholesterol and triglycerides in plasma by unknown mechanisms 
           (Weiner, 1990).
           
           The use of hydrochlorothiazide may be associated with 
           electrolyte imbalance including hypochloraemic alkalosis, 
           hyponatraemia, and hypokalaemia.  Hypokalaemia increases the 
           effect of digitalis on cardiac muscle.  Patients with severe 
           coronary artery disease and cirrhosis of the liver are 
           particularly at risk from hypokalaemia (Reynolds, 1989).  
           There is some evidence that the increase of cardiac 
           arrhythmias that appears in long-term treatment with 
           hydrochlorothiazide is due to electrolyte imbalances.
           
           Severe hypokalaemia has the potential to increase the 
           developing of ventricular arrhythmias.  In a detailed review, 
           it was noted that hypokalaemia increases resting membrane 
           potential (the duration of both the action potential and the 
           refractory period), thus predisposing the reentrant 
           arrhythmias.  In addition, hypokalaemia may also increase the 
           threshold potential, leading to greater automaticity (Myers, 
           1990).
           
           Hyponatraemia may be observed in patients with severe 
           congestive heart failure who are very oedematous, 
           particularly with large doses and with restricted salt in the 
           diet.
           
           Prolonged therapy with hydrochlorothiazide on some occasions 
           gives rise to hypercalcaemia and hypophosphataemia that 
           simulate hyperparathyroidism (Weiner, 1990).  Hypomagnesaemia 
           has also occurred. Signs due to electrolyte imbalance include 
           dry mouth, thirst, weakness, lethargy, drowsiness, 
           restlessness, muscle pain and cramps, and gastro-intestinal 

           disturbances. Borderline renal and/or hepatic insufficiency 
           may be aggravated by hydrochlorothiazide.
           
           In patients with hypertensive disease and decreased renal 
           reserve, the manifestations of renal insufficiency may be 
           aggravated after intensive or prolonged therapy. Increased 
           concentrations of ammonia in the blood have been reported 
           (Weiner, 1990).
           
           Other side-effects include anorexia, gastric irritation, 
           nausea, vomiting, constipation, diarrhoea, headache, 
           dizziness, postural hypotension, paraesthesia, impotence, and 
           yellow vision (Reynolds, 1989).
           
           Hypersensitivity reactions may occur and are represented by 
           skin rashes, eczema, lichen planus-like reactions, Stevens-
           Johnson Syndrome, photosensitivity, similar to subacute 
           cutaneous lupus erythematosus, and pneumonitis.
           
           Cases of cholestatic jaundice, dermatitis, necrotising 
           vasculitis have been reported.
           
           Blood dyscrasias include thrombocytopenia, and, more rarely, 
           granulocytopenia, leucopenia, and aplastic and haemolytic 
           anaemia (Weiner, 1990; Reynolds, 1989).
           
           Acute non-cardiogenic pulmonary oedema associated with 
           hydrochlorothiazide use has been described (Weiner, 1990; 
           Grace, 1989; Kavaru, 1990; Reynold, 1989).
           
           Pancreatitis has been reported.
           
           Intestinal ulceration has occurred following the 
           administration of tablets containing thiazides with an 
           enteric-coated core of potassium chloride.
           
           Thiazide diuretics can produce acute renal failure by 
           producing saline depletion and hypovolaemia and also by a 
           hypersensitivity reaction. They can cause the formation of 
           non-opaque urate calculi.
           
           After two weeks of abrupt suspension of hydrochlorothiazide, 
           8 patients developed an intense oedema (Reynolds, 1989).

    8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS 

       The evaluation of hydrochlorothiazide levels in blood is not 
       useful in guiding therapy. However, analyses of electrolytes, 
       glycaemia, blood cells and renal function are important. 

       8.1 Material 

           8.1.1 Sampling 

                 8.1.1.1 Toxicological analyses 

                 8.1.1.2 Biomedical analyses
    
                         Blood is preferably collected by venipuncture, 
                         at any time.

                 8.1.1.3 Arterial blood gases

                 8.1.1.4 Haematological investigations

           8.1.2 Storage

                 Blood should be placed in heparinised tubes, be 
                 protected from light and frozen at -20°C.

           8.1.3 Transport

                 Blood samples should be frozen and protected from 
                 light.

       8.2 Toxicological analyses and their interpretation

           The evaluation of Hydrochlorothiazide levels in blood is not 
           useful to guiding therapy.

           8.2.1 Tests for toxic ingredient

                 8.2.1.1 Simple qualitative test (s)

                 8.2.1.2 Advanced qualitative confirmation test (s)

                 8.2.1.3 Simple quantitative method (s)
                 
                 8.2.1.4 Advanced quantitative method (s)

           8.2.2 Tests for biological samples

                 8.2.2.1 Simple qualitative test (s)

                 8.2.2.2 Advanced qualitative confirmation test (s)

                 8.2.2.3 Simple quantitative method (s)

                 8.2.2.4 Advanced quantitative method (s)

                 8.2.2.5 Other dedicated method (s)

           8.2.3 Interpretation

       8.3 Biomedical investigations and their interpretation

           8.3.1 Biochemical analysis

                 8.3.1.1 Blood

                         Venous blood: Glucose, Tryglicerides, Uric 
                         acid, Chloride, Magnesium, Potassium, Sodium, 
                         Creatinine, Calcium, Amylase, Transaminases.
 
                 8.3.1.2 Urine

                         Urinalysis

                 8.3.1.3 Other
                  
           8.3.2 Arterial blood gas analyses

                 Determination of arterial gases.

           8.3.3 Haematological analyses

                 Complete blood count.
                 
           8.3.4 Interpretation

                 Main consequences of overdosage or identification of 
                 adverse hypersensitivity reactions are best detected 
                 through laboratory analysis, such as:
                 
                 - Blood dyscrasias
                 - Disturbs on renal and hepatic functions.
                 - Rise in blood amylase suggesting pancreatitis.
                 - Increase in blood levels of calcium, glucose,
                 triglycerides, uric acid, and very low density
                 lipoproteins.
                 - Decreased blood levels of chloride, magnesium,
                 potassium and sodium.
                 - Detection of hypochloremic alkalosis.

       8.4 Other relevant biomedical investigations and their interpretation

           Electrocardiogram is useful to recognize arrhytmias, 
           digitalis toxicity and hypokalemia characteristic changes.
           
           Chest radiograph is useful to identify pulmonary edema.

       8.5 Overall interpretation

           The identification of electrolyte imbalances, specially 
           hyperkalemia and hypovolemia, are the most important features 
           that biomedical investigations can offer to the diagnosis and 
           management of thiazide toxicity
    
    9. CLINICAL EFFECTS 

       9.1 Acute poisoning 

           9.1.1 Ingestion 

                 Overdosage with hydrochlorothiazide results in 
                 diuresis. Another effect is lethargy of various degrees 
                 that may progress to coma within a few hours, even 
                 without dehydration or electrolyte imbalance, or with 
                 minimal depression of respiration, and cardiovascular 
                 function. The mechanism of central nervous system (CNS) 
                 depression is unknown.
                 
                 Gastrointestinal irritation and hypermotility may 
                 occur.
                 
                 Orthostatic hypotension, pancreatitis, potentiation of 
                 parathyroid hormone activity, skin rash, 
                 photosensitivity, and thrombocytopenia have been 
                 observed. Temporary elevation of BUN has been reported.
                 
                 Hypopotassaemia and hypomagnesaemia may be associated 
                 with ventribular ectopic activity.
                 
                 Hyponatraemia may be seen in older patients.
                 
                 Short-term potassium supplementation may induce a fall 
                 in blood pressure.
                 
                 (Ellenhorn & Barceloux, 1988; Reynolds, 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 

                 No data available.

           9.1.6 Other 

                 No data available.

       9.2 Chronic poisoning 

           9.2.1 Ingestion 

                 Potassium depletion may occur with the chronic 
                 administration of large doses of hydrochlorothiazide.

           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 

                 No data available.

           9.2.6 Other 

                 No data available.

       9.3 Course, prognosis, cause of death 

           Overdosage may produce large diuresis, and lethargy of 
           various degrees. The central nervous system depression 
           progresses to coma. Hypopotassemia and hypomagnesaemia may be 
           associated with ventricular arrhythmias.
           
           Death due to pneumonia and central hypoxia has been reported 
           (Ellenhorn & Barceloux, 1988).

       9.4 Systematic description of clinical effects 

           9.4.1 Cardiovascular 

                  Acute poisoning
                 
                 Orthostatic hypotension that may be potentiated by 
                 alcohol, barbiturates, or narcotics has been reported. 
                 The hypokalaemia produced by hydrochlorothiazide has 
                 the potential to increase the developing of ventricular 
                 arrhythmias (reentrant arrhythmias and increasing the 
                 automaticity) (Reynolds, 1989; Weiner, 1990).

           9.4.2 Respiratory 

                 Acute non-cardiogenic pulmonary oedema associated with 
                 hydrochlorothiazide use has been described (Weiner, 
                 1990; Grace, 1989; Kavaru, 1990; Reynolds, 1989).

           9.4.3 Neurological 

                 9.4.3.1 Central nervous system (CNS) 

                          Acute
                         
                         Dizziness, vertigo, paraesthesias, headache, 
                         restlessness, xanthopsia, lethargy, and coma 
                         (Weiner, 1990; Reynolds, 1989).

                 9.4.3.2 Peripheral nervous system 

                         Not relevant.

                 9.4.3.3 Autonomic nervous system 

                         Not relevant.

                 9.4.3.4 Skeletal and smooth muscle 

                          Acute and chronic
                         
                         Muscle pain and cramps.

           9.4.4 Gastrointestinal 

                  Acute and chronic
                 
                 Dry mouth, anorexia, gastric irritation, cramping, 
                 nausea, vomiting, constipation, diarrhoea, intestinal 
                 ulceration and pancreatitis.

           9.4.5 Hepatic 

                  Acute and chronic 
                 
                 Jaundice due to intrahepatic cholestasis.

           9.4.6 Urinary 

                 9.4.6.1 Renal 

                         Hydrochlorothiazide can produce acute renal 
                         failure. Renal insufficiency may be aggravated 
                         after intensive or prolonged therapy.

                 9.4.6.2 Other 

                         During chronic use hydrochlorothiazide may 
                         cause the formation of non-opaque urate 
                         calculi.

           9.4.7 Endocrine and reproductive systems 

                 Chronic use may give rise to impotence, hypercalcaemia, 
                 and hypophosphataemia that simulates 
                 hyperparathyroidism.

           9.4.8 Dermatological 

                  Acute and chronic
                 
                 Skin rashes, eczema, photosensitivity, dermatitis, 
                 lichen planus-like reactions, purpura, urticaria, 
                 Stevens Johnson Syndrome.

           9.4.9 Eye, ear, nose, throat: local effects 

                 No data available.

           9.4.10 Haematological 

                   Acute and chronic
                  
                  Thrombocytopenia, granulocytopenia, aplastic and 
                  haemolytic anaemia.

           9.4.11 Immunological 

                  No data available.

           9.4.12 Metabolic 

                  9.4.12.1 Acid base disturbances

                            Acute and chronic
                           
                           Hypochloraemic alkalosis.
                           
                  9.4.12.2 Fluid and electrolyte disturbances 

                            Acute and chronic
                           
                           Hyponatraemia, hypokalaemia, hypomagnesaemia 
                           and hypovolaemia.

                  9.4.12.3 Others

                            Acute and chronic
                           
                           Hyperglycaemia, hyperuricaemia, increase in 
                           the concentrations of cholesterol and 
                           triglycerides in plasma.

           9.4.13 Allergic reactions 

                   Acute and chronic
                  
                  Skin rashes, eczema, photosensitivity, dermatitis, 
                  lichen planus-like reactions, purpura, urticaria, 
                  Stevens Johnson Syndrome, similar to subacute 
                  cutaneous lupus erythematosus, necrotising vasculitis, 
                  pneumonitis.

           9.4.14 Other clinical effects 

                   Acute and chronic
                  
                  Thirst, weakness. After 2 weeks of abrupt suspension 
                  of hydrochlorothiazide, 8 patients developed an 
                  intense oedema (Reynolds, 1989).

           9.4.15 Special risks 

                   Pregnancy, breast-feeding
                  
                  Hydrochlorothiazide crosses the placental barrier and 
                  appears in umbilical cord blood. The hazards include 
                  fetal or neonatal jaundice, thrombocytopenia, and 
                  possible other adverse reactions which may have 
                  occurred in the adult. It appears in breast milk 
                  (Reynolds, 1989; Barnhart, 1987).

       9.5 Other 

           No data available.

       9.6 Summary

           Not relevant

    10. MANAGEMENT

        Patients suspected of significant diuretic overdosage should be 
        hospitalized. Symptomatic supportive therapy is indicated. 

        10.1 General principles 

             Discontinuing use of the drug.
             
             Maintaining adequate airway: intubate if comatose, remove 
             mucous secretions from the respiratory tract, if necessary.
             
             Maintaining adequate oxygen intake and CO2 removal. If
             respiration is depressed give O2 as necessary to maintain 
             adequate arterial oxygenation, and ventilate the patient if 
             cyanosis or CO2 retention is present. Provide mechanical 
             ventilation.
             
             Maintaining blood pressure. For hypovolaemic shock, 
             establish an intravenous line, begin fluids (saline or 
             Ringer's lactate); place patient in Trendelenburg position. 
             If these measures are not sufficient, administer dopamine 
             or norepinephrine (adrenaline). (Ellenhorn & Barceloux, 
             1988).
             
             Note: For dose rates of dopamine or norepinephrine 
             (adrenaline), see IPCS Treatment Guideline for Shock. 

             Monitoring the haematocrit and complete blood count. 
             Haemoconcentration must be treated with fluids, carefully 
             (3 L intravenously or 4 L orally in 24 hours).(Ellenhorn & 
             Barceloux, 1988).
             
             Electrolyte disturbances should be evaluated and corrected; 
             hyponatraemia and hypokalaemia are immediate threats and 
             ECG monitoring is required.
             
             Monitor intake and output and body weight daily.
             
             Monitor cardiac function: ECG, pulse, blood pressure.
             
             Monitor renal function: urine output, urinalysis, serum 
             creatinine.
             
             Gastrointestinal effects are usually of short duration, but 
             may require symptomatic treatment.

        10.2 Relevant laboratory analyses

             10.2.1 Sample collection

                    Blood should be placed in heparinised tubes, 
                    protected from light and frozen at -20°C.

             10.2.2 Biomedical analysis

                    Biomedical analysis valuable for the diagnosis, 
                    prognosis and treatment: serum potassium, sodium, 
                    calcium, and magnesium chlorides, glycaemia, serum 
                    creatinine, urinalysis, haematocrit.

             10.2.3 Toxicological analysis

                    Hydrochlorothiazide levels in body fluids is not a 
                    useful guide in therapy.

             10.2.4 Other investigations

                    ECG monitoring.
                    Chest radiograph.

        10.3 Life supportive procedures and symptomatic/specific 
             treatment 

             Monitor serum electrolyte levels and renal function. 
             Maintain hydration, electrolyte balance, respiration and 
             cardiovascular function.

        10.4 Decontamination
                         
             Evacuate gastric contents by using ipecac syrup or gastric 
             lavage if dose is high and ingestion recent. 
             Activated charcoal as an aqueous slurry can be given after 

             emesis induction or through the lavage tube, 50 g in adults 
             and 1 g/kg in children.
             
             Its effectiveness in diuretic overdosage has not been 
             established (Ellenhorn & Barceloux, 1988).
             
             Cathartics are not recommended.
             
        10.5 Elimination 

             No systematic studies have been reported about peritoneal 
             dialysis, haemodialysis, haemoperfusion, or exchange 
             transfusion (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 

             Not relevant

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature 

             Case 1
             
             A 63-year-old woman developed a slightly pruritic eruption 
             on the distal parts of the legs and feet, progressing 
             slowly proximaly. The eruption consisted of purple papules 
             0.5 cm diameter, as well as tiny haemorrhagic vehicles. The 
             patient has a past history of hypertension and headache and 
             has been treated for the last 2 years with propranolol and 
             hydrochlorothiazide daily, and paracetamol occasionally. 
             Positive mast cell degranulation test to 
             hydrochlorothiazide suggested the possible role of 
             immunological "in vitro" tests in the diagnosis (Grunwald, 
             1989).
             
             Case 2
             
             Two female patients developed respiratory distress syndrome 
             suddenly after ingestion of one dose of 25 mg 
             hydrochlorothiazide. Other etiologic factors were excluded 
             (Gonzalez, 1988).
             
             Case 3
             
             A 51-year-old woman developed unexplained episodes of 
             pulmonary edema.  The first began with nausea and diarrhoea 
             proceeding within half an hour to marked dyspnoea, wheezing 
             and a non-productive cough.  She was found to be in 
             considerable respiratory distress with tachypnoea, 
             tachycardia, and a fever of 38 °C.  Blood pressure was 
             130/90 mmHg.  Widespread crackles and wheezes were heard 
             over the lung fields.  A chest radiograph showed extensive 
             pulmonary shadowing.  An ECG was normal. She had no past 
             medical history other than multiple operations for varicose 
             veins which has resulted in chronic intermittent ankle 
             swelling. She had been taking Moduretic intermittently for 
             14 years to control her ankle swelling. She clearly 
             remembered taking the drug immediately prior to each 
             pulmonary episode.  The authors justified in suggesting a 
             causal relation between hydrochlorothiazide and pulmonary 
             oedema (Grace, 1989).

        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 antidotes.

        12.2 Specific preventive measures 

             The product should be kept out of the reach of children and 
             irresponsible adults.
             
             Precautions in the pregnancy because hydrochlorothiazide 
             may crosses placental barrier.
             
             Because hydrochlorothiazide appears in breast milk, it 
             should be avoided during pregnancy.

        12.3 Other 

             No relevant information.

    13. REFERENCES

        Barnhart ER (1987) Physician's Desk Reference. 41st ed. New 
        Jersey, Medical Economics Co Inc.
        
        Budavari S, ed (1989) The Merck index, an encyclopaedia of 
        chemicals, drugs and biologicals, 11th ed. Rahway, New Jersey, 
        Merck and Co., Inc., p 756.
        
        Ellenhorn MJ & Barceloux DG (1988) Medical toxicology, diagnosis 
        and treatment of human poisoning. New York, Elsevier, pp 272-
        273.
        
        Gonzalez G, Legueros SM, Castro GO, Saavedra CH, Cabello AH, & 
        Paredes MR (1988) Sindrome de distress respiratorio del adulto 
        asociado a hidroclorotiazida: comunicación de 2 casos y revisión 
        de la literatura. Rev Med Chile, 116: 1047 - 1053 (in Spanish).
        
        Gosselin RE, Smith RP & Hodge HC (1984) Clinical toxicology of 
        commercial products, 5th ed. Baltimore, Williams & Wilkins, II-
        400.
        
        Grace AA, Morgan AD & Strickland NH (1989) Hydrochlorothiazide 
        causing unexplained pulmonary edema. British Journal of Clinical 
        Practice, 43(2): 79-81.
        
        Grunwald MH, Halevy S & Livni E (1989) Allergic vasculitis 
        induced by hydrochlorothiazide: confirmation by mast cell 
        degranulation test. Isr J Med Sci, 25: 572-574.
        
        IARC International Agency for Research on Cancer (1990) IARC 
        Monographs on the evaluation of the carcinogenic risk of 
        chemicals to humans: Pharmaceutical Drugs. Vol. 50, Lyon, IARC.
        
        Kavaru MS, Muzaffar A, & Amirthalingam KN (1990) 
        Hydrochlorothiazide induced acute pulmonary edema. Cleveland 
        Clinic Journal of Medicine, 57: 181-184.
        
        Myers MG (1990) Diuretic therapy and ventricular arrhythmias in 
        persons 65 years of age and older. American Journal of 
        Cardiology, 65(9): 599-603.
        
        Randall RV (1987) Diabetes insipidus. In: Rakel RE (ed) Conn's 
        Current Therapy, 39th ed. Philadelphia, W.B. Saunders Co.
        
        Reynolds JEF (ed) (1989) Martindale the extra pharmacopoeia, 
        29th ed. London, The Pharmaceutical Press, pp 991-992.
        
        Sax NI & Lewis RJ (1989) Dangerous properties of industrial 
        materials, 7th ed. New York, Van Nostrand Reinhold, p 803.
        
        Weiner IM (1990) Diuretics. 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 , pp 713-731, 
        785-788, 1684.
        
        WHO (1992) International nonproprietary names (INN) for 
        pharmaceutical substances. Geneva, World Health Organisation,  
        p 262.
        
        WHO (1992) Anatomical Therapeutic Chemical (ATC) classification 
        index. Oslo, WHO Collaborating Centre for Drug Statistics 
        Methodology, p 31.

    14. AUTHOR(S), REVIEWER(S), DATE(S)(INCLUDING UPDATES), COMPLETE 
        ADDRESS(ES)  

        Author         Dr Rosane Maria Salvi
                       Applied Toxicology Centre (PUCRS)
                       Travessa Sul, 270 ap 303 
                       90440 Porto Alegre 
                       Brazil
        
                       Fax: 55 51 2246563
        
        Date           January 1992
        
        Peer Review    Drs Pulce, Rahde, & Mathieu. Newcastle-upon-
                       Tyne, United Kingdom, February 1992