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Chlorthalidone

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Brand names, Trade names
   1.6 Manufacturers, Importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Properties of the substance
      3.3.2 Properties of the locally available formulation
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Shelf-life of the locally available formulation
      3.4.3 Storage conditions
      3.4.4 Bioavailability
      3.4.5 Specific properties and composition
4. USES
   4.1 Indications
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall Interpretation of all toxicological analyses and toxicological investigations
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 CNS
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Relevant laboratory analyses
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures and symptomatic/specific treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. Additional information
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)


    PHARMACEUTICALS
    1. NAME
     1.1 Substance
       Chlorthalidone
     1.2 Group
       Thiazide diuretic
     1.3 Synonyms
       1-keto-3-(3'-sulfamyl-4'-chlorophenyl)-3-hydroxyisoindoline
       1-oxo-3-(3-sulfamyl-4-chlorophenyl)-3-hydroxyisoindoline
       2-chloro-5-(1-hydroxy-3-oxoisoindolin-1) benzenesulphonamide
       2-chloro-5-(2,3-dihydroxy-3-oxo-1H-isoindol-1-yl) benzenesul-fonamide
       2-chloro-5-(2,3-dihydroxy-3-oxo-1H-isoindol-1-yl) benzenesulfonamide
       2-chloro-5-(3-hydroxy-1-oxoindolin-3-yl) benzenesulfamide
       3-(4'-chloro-3'-sulfamoylphenyl)-3-hydroxyphthalimidine
       3-hydroxy-3-(4-chloro-3-sulfamyl-phenyl) phthalimidine
       Chlorphthalidolone
       Phthalamodine
       Phthalamudine
     1.4 Identification numbers
       1.4.1 CAS number
             77-36-1
       1.4.2 Other numbers
     1.5 Brand names, Trade names
       Axamin (South Africa); Higrotona (Spain);  Hidro-Long 
       (Germany); Higroton (Brazil); Hygroton (Argentina; Australia; 
       Belgium; Canada; Denmark; France; Netherlands; Norway; South 
       Africa; Sweden; Switzerland; UK; USA); Igrolina (Italy); 
       Novothalidone (Canada); Odemo-Genat (Germany); Renidone (South 
       Africa); Renon (Italy); Thalitone (USA); Urid (Australia); 
       Uridon (Canada); Urolin (Italy); Zambesil (Italy).
       
       The following products have chlorthalidone in association with 
       other drugs:
       
       Combipress (Canada); Demi-Regroton (USA); Hygrotin-K (UK); 
       Lopresoretic (UK); Regroton (USA); Tenoret 50 (UK); Tenoretic 
       (Brazil; UK); Trasitensin (Brazil).
     1.6 Manufacturers, Importers
       Azuchemie, Beiersdorf, Biogalênica, Boehringer Ingelheim, Ciba,
        Geigy, ICI, ICI/Wellcome, ICN, Lennon, Lipha, Novophram, 
       Protea, USV Pharmaceutical Co., Rolab, Rorer, Salus, Stuart.
    2. SUMMARY
     2.1 Main risks and target organs
       Chlorthalidone is generally well tolerated during therapeutic 
       use. Clinical toxicity is relatively infrequent and may result 
       from overdosage, adverse reactions or hypersensitivity.
       
       Acute toxicity
       
       Main risks include: hypokala, hyponatra, hypotension, cardiac 
       arrhythmias (due to hypokala) and central nervous system 
       effects.
       
       Target organs: kidney, heart, CNS
       
       Chronic toxicity and adverse reactions include:

       
       Metabolic disturbances, hypersensitivity reactions, 
       aggravation of renal and/or hepatic insufficiency, 
       gastrointestinal disturbances, blood dyscrasias, and central 
       nervous system effects.
     2.2 Summary of clinical effects
       Acute toxicity
       
       Symptoms may include: hypokala, hyponatra, dehydration, 
       hypovola, cardiac dysrhythmias (ventricular extrasystoles and 
       torsade de pointes due to hypokala), dizziness, lethargy, 
       paresthesias.
       
       Chronic toxicity and adverse reactions
       
       Several disturbances have been reported:
       
            Metabolic: hypokala, hyponatra, hyperglyca, hyperurica, 
       metabolic alkalosis, aggravation of renal insufficiency.
       
       
            Cardiovascular: cardiac arrhythmias, enhancing the effect 
       of digitalis on cardiac muscle, orthostatic hypotension.
       
            Central Nervous System: dizziness, vertigo, paresthesias, 
       headache, xanthopsia.
       
            Gastrointestinal:  anorexia, gastric irritation, nausea, 
       vomiting, cramping, diarrhoea, constipation, jaundice due to 
       intrahepatic cholestasis, pancreatitis, sialoadenitis, dry 
       mouth, hepatic insufficiency, intestinal ulceration.
       
            Hypersensitivity: purpura, intravascular immune 
       haemolysis, pneumonitis, skin rashes, urticaria, eczema, 
       lichen planus-like reactions; photosensitivity, similar to 
       subacute cutaneous lupus erythematosus; vasculitis; Stevens 
       Johnson Syndrome.
       
            Haematological: thrombocytopenia, granulocytopenia, 
       leucopenia, aplastic anaa, and haemolytic ana.
       
            Respiratory tract: acute noncardiogenic pulmonary edema.
       
            Others: attacks of gout, increasing in plasma 
       concentrations of cholesterol and triglycerides. 
     2.3 Diagnosis
       The diagnosis depends on the patient's history and the 
       clinical presentation.
       
       Blood:    Determination of electrolytes (chloride, magnesium, 
       potassium, and sodium), urea, creatinine, hematocrit blood 
       gases and pH.
       
       Urine:    Determination of electrolytes (sodium, potassium)
       
       Other:    ECG, (electrocardiographic changes associated with 

       hypokal)
     2.4 First aid measures and management principles
       Monitor fluid and electrolyte balance, blood pressure, central 
       venous pressure, ECG, body weight.
       
       Correct urinary water and electrolyte losses and dehydration 
       with infusion of saline and potassium.
       
       Correct hypovolaemic shock with infusion of saline and, if 
       necessary, a plasma expander.
       
       Severe cardiac dysrhythmias, such as torsades de pointes, may 
       be treated with isoprenaline infusion.
       
       Decontamination
       
       Ipecac syrup or gastric lavage may be useful within the first 
       few hours after ingestion.
       
       Methods to enhance elimination are not indicated.
    3. PHYSICO-CHEMICAL PROPERTIES
     3.1 Origin of the substance
       Synthetic.  Thiazides diuretics are sulfonamide-derived drugs.
     3.2 Chemical structure
       C14 H11 ClN2 O4 S2
       
       Molecular weight:  338.78
     3.3 Physical properties
       3.3.1 Properties of the substance
             A white or yellowish-white, odourless or almost odourless, 
             crystalline powder.
             
             Practically insoluble in water, in ether, and in chloroform;  
             slightly soluble in alcohol; soluble in 1 in 25 of methyl 
             alcohol; soluble in solutions of alkali hydroxides 
             (Reynolds, 1989).
       3.3.2 Properties of the locally available formulation
     3.4 Other characteristics
       3.4.1 Shelf-life of the substance
             Shelf-life of the commercially available preparation is 
             5 years.
       3.4.2 Shelf-life of the locally available formulation
       3.4.3 Storage conditions
             Store in well-closed containers, below 40°C (104°F).  
             All preparations should be protected from light (US 
             Pharmacopoeia, 1980).
       3.4.4 Bioavailability
             No data available.
       3.4.5 Specific properties and composition
             No data available.
    4. USES
     4.1 Indications
       Hypertension
       
       Chlorthalidone is indicated in the management of hypertension as
       sole therapeutic agent or in combination with other 

       antihypertensive drugs.
       
       Edema
       
       Chlorthalidone is used as adjunctive therapy in the treatment of 
       edema associated with heart failure, hepatic cirrhosis, and 
       corticosteroid and estrogen therapy (Barnhart, 1987).
       
       
       Chlorthalidone has also been found useful in the edema due to 
       various forms of renal dysfunction such as nephrotic syndrome,
       (Barnhart, 1987).
       
       Chlorthalidone has been used in the treatment of premenstrual 
       tension if there is evidence of fluid retention (Reynolds, 1989).
       
       Chlorthalidone has a paradoxical antidiuretic effect in patients 
       with diabetes insipidus (Reynolds, 1989).
       
       Chlorthalidone may prevent renal calculus formation in patients 
       with hypercalciuria.
       
       Chlorthalidone may improve vertigo associated with Ménière disease 
       (Reynolds, 1989).
     4.2 Therapeutic dosage
       4.2.1 Adults
             General dosing information:
             
             The single daily dose is preferably taken in the morning 
             to minimize the effect of increased frequency of 
             urination on night-time sleep.
             
             Alternate-day dosage may reduce the possibility of 
             electrolyte imbalance or hyperurica resulting from 
             therapy.
             
             The diuretic effect of chlorthalidone lasts 
             approximately 24 to 48 hours.
             
             Concurrent administration of potassium supplements or 
             potassium-sparing diuretics may be indicated in patients 
             who tend to develop hypokala (US Pharmacopoeia, 1980).
             
             Administration in hypertension:
             
             Therapy should be initiated with a dose of 25 to 50 mg 
             as a single daily dose.  In some patients a dose of 100 
             mg may lower the blood pressure further but dosage above 
             this level usually does not increase effectiveness.
             
             Maintenance doses may often be lower than initial doses 
             and should be adjusted individually (Barnhart, 1987; 
             Reynolds, 1989).
             
             Geriatric patients may require a reduced dose.
             

             
             Administration in the treatment of edema:
             
             The usual initial dose is 50 to 100 mg daily or 100 to 
             200 mg on alternate days, reduced to a dose of 25 to 50 
             mg daily or intermittently.  The maximum recommended 
             dose is 400 mg, although doses above 200 mg daily might 
             not produce a better response.
             
             In renal failure chlorthalidone dosage should be 
             adjusted to renal function. 
             
             Administration in Diabetes insipidus
             
             An initial dose of 100 mg twice daily has been 
             recommended, reduced to a maintenance dose of 50 mg 
             daily (Reynolds, 1989).
             
             Administration in renal calculus
             
             Patients should start at 25 mg per day, with weakly 
             increases of 25 mg per day, until the maintenance dosage 
             of 50 mg twice a day is reached.
             
             Administration in premenstrual tension
             
             50 to 100 mg daily.
       4.2.2 Children
             A suggested initial dose in children is 2 mg/kg body 
             weight 3 times a week (Reynolds, 1989).
     4.3 Contraindications
       Anuria, hypersensitivity to sulfonamide-derived drugs, hepatic 
            encephalopathy.
       
            Precautions
       
            Chlorthalidone should be used with caution in:
       
            Impaired hepatic function since it may increase the risk 
       of hepatic encephalopathy
       
            Renal impairment since it can further reduce renal 
       function, and precipitate azota.  Cumulative effects of the 
       drug may develop in patients with impaired renal function 
       (Barnhart, 1987)
       
            Patients treated with quinidine-like anti-arrhythmics, 
       amiodarone, sotalol
        
            Gout since it can precipitate attacks of the disease
       
            Patients should be carefully observed for signs of fluids 
       and electrolyte imbalance
       
            Chlorthalidone 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)
       
            Chlorthalidone crosses the placenta and there have been 
       reports of neonatal jaundice, thrombocytopenia, and 
       electrolytes imbalances following maternal treatment
       
            Chlorthalidone is excreted in breast milk.  Treatment can 
       inhibit lactation
       
            Chlorthalidone should be used with caution when the 
       following medical problems exist: diabetes mellitus, 
       hypercalca, hyperurica, history of lupus erythematosus, 
       pancreatitis, sympathectomy
    5. ROUTES OF ENTRY
     5.1 Oral
       The oral route is the commonest 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
       Chlorthalidone is erratically absorbed from the 
       gastrointestinal tract.  Bioavailability after oral 
       administration is approximately 65% (Ellenhorn and Barceloux, 
       1988).
     6.2 Distribution by route of exposure
       The volume of distribution of chlorthalidone is 3.9 +/- 0.8 
       l/kg (Gilman et al, 1990).
       
       About 75% is bound to plasma protein and the blood-to-plasma 
       ratio is 72.5%.
       
       Chlorthalidone crosses the placenta.
     6.3 Biological half-life by route of exposure
       The plasma half-life is about 44 +/- 10 hours and increases 
       with age.
       
       The terminal half-life is 35 to 54 hours.  This may be due to 
       the strong binding of chlorthalidone to red blood cells 
       (Barnhart, 1987; Gilman et al, 1990; Reynolds, 1989).
     6.4 Metabolism
       Chlorthalidone probably undergoes metabolism but the 
       metabolites have not been identified.
     6.5 Elimination by route of exposure
       During long-term administration, 30 to 60% has been reported 

       to be excreted unchanged in the urine (Reynolds, 1989).
       
       The urinary excretion after 50 and 100 mg doses is 65 +/- 9%. 
       
       The clearance of chlorthalidone is 1.6 +/- 0.3 ml/min/kg, and 
       decreases with age and at greater doses (Gilman et al, 1990; 
       Myers, 1990).
       
       Chlorthalidone is excreted in breast milk.  It has a very low 
       milk:plasma ratio of 0.05 (Briggs, 1986).
    7. PHARMACOLOGY AND TOXICOLOGY
     7.1 Mode of action
       7.1.1 Toxicodynamics
             Chlorthalidone is an oral diuretic with prolonged action 
             (48 to 72 hours) and low toxicity.
             
             Most of the toxic effects are due to electrolyte 
             imbalance including hypochloraemic alkalosis, hyponatra, 
             hypokala, and hypomagnesa.
             
             The mechanism of hypercalca and hypophosphata are 
             unknown.
             
             Thiazides increase the concentration of cholesterol and 
             triglycerides in plasma (Weiner, 1990).
             
             Chlorthalidone may also cause hypersensitivity 
             reactions.
       7.1.2 Pharmacodynamics
             The diuretic effect of the drug occurs within two hours 
             after an oral dose and continues for up to 72 hours.  It 
             produces copious loss of electrolytes, and consequently, 
             of water.
             
             The site of action is the distal renal tubule (Weiner, 
             1990).
             
             The hypotensive effect is also due to a reduction in 
             peripheral resistance observed mainly in chronic use.
     7.2 Toxicity
       7.2.1 Human data
             7.2.1.1 Adults
                     No precise data are available concerning the 
                     toxic doses of chlorthalidone.  No lethal case 
                     has been reported. 
             7.2.1.2 Children
                     No data available.
       7.2.2 Relevant animal data
             The oral LD50 to rat and mouse is more than 5g/kg body 
             weight (NIOSH).
       7.2.3 Relevant in vitro data
             No data available.
     7.3 Carcinogenicity
       No data available.
     7.4 Teratogenicity
       Chlorthalidone crosses the placental barrier.

       
       In general, diuretics are not associated with teratogenicity.  
       A slight association with respiratory malformation has been 
       suggested (Reynolds, 1989).
            
       Reproduction studies in the rat and the rabbit at doses up to 
       240 times greater than the therapeutic dose have shown no 
       evidence of impaired fertility or harm to the foetus due to 
       chlorthalidone.
     7.5 Mutagenicity
       No data available.
     7.6 Interactions
       Chlorthalidone may increase the toxicity of digitalis 
       glycosides by depleting serum potassium concentrations.
       
       Due to the potassium depletion, chlorthalidone may enhance the 
       neuromuscular blocking action of competitive muscle relaxants 
       such as tubocurarine or gallamine triethiodide (Ellenhorn and 
       Barceloux, 1988).
       
       It may increase the effect of antihypertensive agents such as 
       guanethidine sulphate, methyldopa or ganglionic blocking 
       agents (Ellenhorn and Barceloux, 1988; Reynolds, 1989).
       
       The postural hypotension due to thiazide diuretic therapy may 
       be increased by concomitant ingestion of alcohol, barbiturates,
        or opioids (Reynolds, 1989; Barnhart, 1987).
       
       The potassium-depleting effect of thiazides may be enhanced by 
       corticosteroids, corticotrophin, carbenoxolone, and 
       amphotericin B (Ellenhorn and Barceloux, 1988).
       
       Chlorthalidone may reduce the response to pressor amines such 
       as noradrenaline, but the clinical significance of this effect 
       is uncertain.
       
       Concomitant administration of thiazide diuretics and lithium 
       salts is not recommended since the blood concentration of 
       lithium is increased (Reynolds, 1989).
       
       By depleting the serum potassium concentration, chlorthalidone 
        may increase the risk of cardiac dysryhthmias (torsades de 
       pointes)
       
       The pharmacological effects of oral hypoglycaemic agents may 
       be reduced (Ellenhorn and Barceloux, 1988; Weiner, 1990).
       
       Non-steroidal anti-inflammatory drugs may antagonise the 
       diuretic actions of thiazides (Reynolds, 1989).
       
       The hyperglycaemic, hypotensive, and hyperuricaemic effects of 
       diazoxide may be potentiated by thiazides (Ellenhorn and 
       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 (Ellenhorn and Barceloux, 1988).
       
       Thiazides increase urinary pH and may decrease urinary 
       excretion of amphetamines and quinidine.
       
       The effects of oral anticoagulants may be decreased when used 
       concurrently with chlorthalidone.  
       
       Pre-anaesthetic and anaesthetic drugs used in surgery may be 
       potentiated when used concurrently with chlorthalidone.
       
       The effectiveness of methenamine may be decreased when used 
       with chlorthalidone due to alkalinization of the urine (US 
       Pharmacopoeia, 1980).
       
       A study in two healthy subjects evidenced that chlorthalidone 
       and acetazolamide competed for the same binding sites on blood 
       cells (Reynolds, 1989).
       
       
       Laboratory test interactions:
       
       Chlorthalidone may decrease serum protein-bound iodine levels 
       without signs of thyroid disturbances (Barnhart, 1987).
       
       Chlorthalidone may interfere with phenolsulfophthalein test 
       (excretion may be decreased), phentolamine test (false 
       negative results), and tyramine test (false negative results) 
       (US Pharmacopoeia, 1980).
     7.7 Main adverse effects
       Chlorthalidone may cause a number of metabolic disturbances.
       
       Therapeutic use of chlorthalidone may be associated with 
       electrolytes imbalances including hypochloraemic alkalosis, 
       hyponatra, and hypokala.
       
       It may induce hyperglyca and glycosuria and may aggravate pre-
       existing diabetes mellitus.
       
       It may cause hyperurica and precipitate attacks of gout in 
       some patients.
       
       Thiazide diuretics increase the concentrations of cholesterol 
       and triglycerides in plasma by unknown mechanisms (Weiner, 
       1990).
            
       Hypokala increases the effect of digitalis on cardiac muscle.  
       Patients with severe coronary artery diseases and cirrhosis of 
       the liver are particularly at risk from hypokala (Reynolds, 
       1989).  
       
       Prolonged therapy with chlorthalidone may cause hypercalca and 
       hypophosphata that simulate hyperparathyroidism (Myers, 1990). 
        Hypomagnesa has also occurred.
       

       Renal and/or hepatic insufficiency may be aggravated by 
       Chlorthalidone.
       
       In patients with cirrhosis, deterioration of mental function 
       has been attributed to thiazide 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, mood and 
       mental changes and yellow vision (Reynolds,  1989; US 
       Pharmacopoeia, 1980).
       
       Hypersensitivity reactions may occur and include skin rashes, 
       eczema, lichen planus-like reactions, Stevens-Johnson Syndrome,
        photosensitivity, similar to subacute cutaneous lupus 
       erythematosus, pneumonitis, and pulmonary edema.
       
       Cases of cholestatic jaundice, pancreatitis, and necrotizing 
       vasculitis have been reported.
       
       Blood dyscrasias include thrombocytopenia, more rarely, 
       granulocytopenia, leucopenia, aplastic and haemolytic ana 
       (Weiner, 1990; Reynolds, 1989).
       
       Intestinal ulceration has occurred following the 
       administration of tablets containing thiazides with an enteric-
       coated core of potassium chloride.
       
       Thiazide diuretics can induce acute renal failure by producing 
       saline depletion and hypovola and also by a hypersensitivity 
       reaction.  They may also increase the risk of formation of non-
       opaque urate calculi.
       
       chlorthalidone may cause intense diuresis leading to insomnia 
       in the elderly, because of its long half-life.
    8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
     8.1 Material sampling plan
       8.1.1 Sampling and specimen collection
             8.1.1.1 Toxicological analyses
             8.1.1.2 Biomedical analyses
             8.1.1.3 Arterial blood gas analysis
             8.1.1.4 Haematological analyses
             8.1.1.5 Other (unspecified) analyses
       8.1.2 Storage of laboratory samples and specimens
             8.1.2.1 Toxicological analyses
                     Blood should be placed in heparinised tubes, be 
                     protected from light and frozen at -20° C.
             8.1.2.2 Biomedical analyses
             8.1.2.3 Arterial blood gas analysis
             8.1.2.4 Haematological analyses
             8.1.2.5 Other (unspecified) analyses
       8.1.3 Transport of laboratory samples and specimens
             8.1.3.1 Toxicological analyses
                     Blood samples should be frozen and protected 

                     from light.
             8.1.3.2 Biomedical analyses
             8.1.3.3 Arterial blood gas analysis
             8.1.3.4 Haematological analyses
             8.1.3.5 Other (unspecified) analyses
     8.2 Toxicological Analyses and Their Interpretation
       8.2.1 Tests on toxic ingredient(s) of material
             8.2.1.1 Simple Qualitative Test(s)
             8.2.1.2 Advanced Qualitative Confirmation Test(s)
             8.2.1.3 Simple Quantitative Method(s)
             8.2.1.4 Advanced Quantitative Method(s)
       8.2.2 Tests for biological specimens
             8.2.2.1 Simple Qualitative Test(s)
             8.2.2.2 Advanced Qualitative Confirmation Test(s)
             8.2.2.3 Simple Quantitative Method(s)
             8.2.2.4 Advanced Quantitative Method(s)
             8.2.2.5 Other Dedicated Method(s)
       8.2.3 Interpretation of toxicological analyses
     8.3 Biomedical investigations and their interpretation
       8.3.1 Biochemical analysis
             8.3.1.1 Blood, plasma or serum
                     Should include blood and urine electrolytes, 
                     serum urea creatinina and hematocrite
             8.3.1.2 Urine
             8.3.1.3 Other fluids
       8.3.2 Arterial blood gas analyses
             Determination of arterial blood gases.
       8.3.3 Haematological analyses
       8.3.4 Interpretation of biomedical investigations
     8.4 Other biomedical (diagnostic) investigations and their 
       interpretation
       The identification of electrolyte imbalance, especially 
       hyperkala and hyponatra, are most important. Functional renal 
       insufficiency with an increase in serum urea and creatinine 
       may be observed.  An increase in hematocrit is a sign of 
       extracellular dehydration.  Hypochloraemic alkalosis may be 
       present.
       
       The electrocardiogram is useful in the diagnosis of 
       arrhythmias, digitalis toxicity and hypokala characteristic 
       changes.
       
       The chest radiograph is useful to identify pulmonary edema.
     8.5 Overall Interpretation of all toxicological analyses and 
       toxicological investigations
     8.6 References
    9. CLINICAL EFFECTS
     9.1 Acute poisoning
       9.1.1 Ingestion
             Overdosage with chlorthalidone may result in excessive 
             polyuria, dehydration, hypovola, shock, hypokala, 
             hyponatra, dizziness, lethargy.  Cardiac arrhythmias due 
             to hypokala may occur.
       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 chlorthalidone.
       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 excessive polyuria lasting for several 
       days, dehydration with hypovolaemic shock, hypokala with 
       ventricular ectopic activity, and severe hyponatra with coma.  
       With symptomatic treatment, prognosis is usually good.
     9.4 Systematic description of clinical effects
       9.4.1 Cardiovascular
             Acute: Hypotension and hypovola shock due to water and 
             sodium losses may occur.  Hypokala (and also 
             hypomagnesa) may induce dysrhythmias, such as 
             ventricular extraystoles and torsades de pointes 
             (Reynolds, l989; Werner 1990).
             
             Chronic:  The same features may be seen in chronic 
             poisoning. 
       9.4.2 Respiratory
             Acute: No data available.
             
             
             Chronic: Non-cardiogenic pulmonary edema has been 
             described (Weiner, 1990; Reynolds, 1989).
       9.4.3 Neurological
             9.4.3.1 CNS
                     Acute: dizziness vertigo, headache, restlessness,
                      xanthopsia, lethargy. (Weiner, 1990; Reynolds, 
                     1989). Severe hyponatra may induce coma.
                     
                     Chronic: No data available.
             9.4.3.2 Peripheral nervous system
                     Acute: paresthesias may be observed in cases of 
                     severe hypokala.
                     
                     Chronic: No data available.
             9.4.3.3 Autonomic nervous system
                     No data available. 

             9.4.3.4 Skeletal and smooth muscle
                     Acute: muscle pain and cramps may occur.
                     
                     Chronic: No data available.
       9.4.4 Gastrointestinal
             Acute:  No data available.
             
             Chronic: dry mouth, anorexia, gastric irritation, 
             cramping, nausea, vomiting, constipation, diarrhoea, 
             intestinal ulceration, and pancreatitis.
       9.4.5 Hepatic
             Acute:  No data available.
             
             Chronic: jaundice due to intrahepatic cholestasis has 
             been reported.
       9.4.6 Urinary
             9.4.6.1 Renal
                     Acute: chlorthalidone can produce acute 
                     functional renal failure.
                     
                     Chronic: renal insufficiency may be aggravated 
                     after intensive or prolonged therapy.  
             9.4.6.2 Other
                     Acute:  No data available.
                     
                     Chronic:  chlorthalidone may increase the risk 
                     of non-opaque urate calculi.
       9.4.7 Endocrine and reproductive systems
             Acute:  No data available.
             
             Chronic: impotence. 
       9.4.8 Dermatological
             Acute:  No data available.
             
             Chronic:  skin rashes, eczema, photosensitivity, 
             dermatitis, lichen planus-like reactions, purpura, 
             urticaria, Stevens Johnson Syndrome (toxic epidermal 
             necrolysis).
       9.4.9 Eye, ear, nose, throat: local effects
             No data available.
       9.4.10 Haematological
              Acute:  No data available.
              
              Chronic: thrombocytopenia, granulocytopenia, aplastic, 
              and haemolytic ana.
       9.4.11 Immunological
              Acute:  No data available.
              
              Chronic: lesions similar to subacute cutaneous lupus 
              erythematosus, necrotizing vasculitis, pneumonitis, 
              Lyell's syndrome.
       9.4.12 Metabolic
              9.4.12.1 Acid-base disturbances
                       Acute: hypochloraemic alkalosis may occur.
                       
                       Chronic: See acute.

              9.4.12.2 Fluid and electrolyte disturbances
                       Acute: dehydration, hyponatra and hypokala are 
                       the most frequent abnormalities.  Hypomagnesa 
                       may also occur.  Hypokala and hypophosphata 
                       may simulate hyperparathyroidism.
                       
                       Chronic: See acute.
              9.4.12.3 Others
                       Acute: No data available.
                       
                       Chronic: Hyperglyca, hyperurica, increase in 
                       the concentrations of cholesterol and 
                       triglycerides in plasma.
       9.4.13 Allergic reactions
              Acute:  No data available.
              
              Chronic:  skin rashes, eczema, photosensitivity, 
              dermatitis, lichen planus-like reactions, purpura, 
              urticaria, Stevens Johnson Syndrome lesions, similar to 
              subacute cutaneous lupus erythematosus, necrotizing 
              vasculitis, pneumonitis, Lyell's syndrome.
       9.4.14 Other clinical effects
              Acute: Thirst and weakness due to dehydration.
              
              Chronic: Thirst, weakness (Reynolds, 1989).
       9.4.15 Special risks
              Chlorthalidone crosses the placental barrier. Hazards 
              include fetal and neonatal jaundice, thrombocytopenia, 
              and possibly adverse reactions affecting the mother.
              
              Chlorthalidone is excreted in breast milk (Reynolds, 
              1989; Barnhart, 1987).
     9.5 Other
       No data available.
     9.6 Summary
    10. MANAGEMENT
      10.1 General principles
         Patients suspected of significant chlorthalidone overdose 
         should be hospitalized.
         
         Monitor fluid and electrolyte balance, blood pressure, 
         central venous pressure, ECG, body weight.  Monitor blood 
         and urine electrolytes (sodium, potassium), hematocrit and 
         serum creatinine.
         
         Decontamination by ipecac syrup or gastric lavage may be 
         useful if treatment is initiated early after ingestion.
         
         Treatment is systematic and includes correction of 
         dehydration and hypovola, correction of hypokala and 
         hyponatra.  Severe cardiac dysrhythmias secondary to 
         hypokala may be treated with isoprenaline infusion.
         
         
         Because of the long-lasting effect of chlorthalidone, the 
         patient should remain under medical supervision for 72 

         hours. 
      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 analyses important for the diagnosis and 
                treatment are: serum potassium, sodium, chlorides, 
                serum creatinine, haematocrit and urinary 
                electrolytes.
         10.2.3 Toxicological analysis
                Chlorthalidone levels in body fluids are not useful 
                for clinical management.
         10.2.4 Other investigations
                ECG monitoring should be performed to detect 
                dysrhythmias and hypokalaemic changes.
      10.3 Life supportive procedures and symptomatic/specific 
         treatment
         Hypovolaemic shock should be treated with infusion of saline 
         fluids and/or plasma expanders.
         
         Electrolyte disturbances should be evaluated and corrected.
         
         Treat dehydration and hyponatra with infusions of saline 
         fluids.  Treat hypokala with infusions of potassium chloride 
         with constant ECG monitoring and periodic serum potassium 
         levels.
         
         Severe cardiac dysrhythmias (ventricular extracystoles, 
         torsades de pointes) due to hypokala may be treated with 
         infusion of isoprenaline. Anti-arrhythmic drugs are 
         contraindicated.
         
         Monitor intake and output of water and electrolytes, and 
         body weight for 48 to 72 hours.
      10.4 Decontamination
         Ipecac syrup or gastric lavage may be useful if treatment is 
         instituted within the first few hours after ingestion.
         
         The usefulness of oral activated charcoal has not been 
         established. 
      10.5 Elimination
         Extracorporeal procedures to enhance elimination are not 
         indicated.
      10.6 Antidote treatment
         10.6.1 Adults
                None.
         10.6.2 Children
                None.
      10.7 Management discussion
         Cathartics are not indicated because they aggravate fluid 
         and electrolyte imbalance.
    11. ILLUSTRATIVE CASES
      11.1 Case reports from literature
         Adverse effects
         

         Mean serum-cholesterol concentrations rose by 5.2% and serum 
         triglyceride concentrations by 25.7% in 32 hypertensive 
         patients treated by diet and chlorthalidone 50 mg twice 
         weekly to 100 mg daily for about 6 months (Reynolds, 1989).
         
         A 58-year-old man was referred a 5-month history of skin 
         fragility and blistering localized in the dorsa of his 
         hands.  The patient's medical history included 
         atherosclerotic cardiovascular disease, essential 
         hypertension, degenerative joint disease, carpal tunnel 
         syndrome, and oesophageal reflux.  His medication included 
         dipyridamole, aspirin, chlorthalidone, potassium supplements,
          clonidine, naproxen, pyridoxine, cimetidine and 
         antacids.The patient discontinued all medications except 
         clonidine, dipyridamole, and chlorthalidone.  After three 
         months the patient continued with the manifestations.  All 
         medications except clonidine were stopped, and within a 
         month no new blisters appeared.  Rechallenge with 
         chlorthalidone quickly resulted in a recurrence of blisters, 
         and this medication was stopped (Baker et al., 1989).
     11.2 Internally extracted data on cases
         A 70 year-old woman was admitted six hours after deliberate 
         ingestion of 375 mg chlorthalidone.  On admission physical 
         examination was normal and biochemical analyses showed: 
         serum sodium 136 mmol/l, chloride 93 mmol/, potassium 3.3 
         mmol/l, osmolality 302 mOsmol/l, hematocrit 45%, urine - 
         sodium 152 mmol/l.  She was treated with 1000 ml glucose 5%, 
         sodium chloride 2 g and potassium chloride 4 g, three 
         times/day.  After 48 hours, she developed coma and 
         hypotension, and blood analyses showed: sodium 108 mmol/l,  
         chloride 67 mmol/l, potassium 3.4 mmol/l, hematocrit 51%, 
         osmolality 226 mOsmol/l.  Correction of hyponatraemia 
         required the infusion of 107 g sodium chloride over four 
         days.  The patient recovered and was discharged on day 6.
      11.3 Internal cases
    12. Additional information
      12.1 Availability of antidotes
         There are no antidotes.
      12.2 Specific preventive measures
         No data available.
      12.3 Other
         No data available.
    13. REFERENCES
    Baker EJ, Reed KD, Dixon SL (1989)  Chlorthalidone induced 
    pseudoporphyria: clinical and microscopic findings of a case.  
    Journal of the American Academy of Dermatology, 21(5): 1026-1029.
    
    Barnhart ER (Ed.) (1987)  Physician's Desk Reference.  41st Ed. 
    New Jersey, Medical Economics Co. Inc.
    
    Briggs GG, Freeman RK, Yaffe SJ (1986)  Drugs in pregnancy and 
    lactation.  2nd Ed. Baltimore, William and Wilkins.
    
    Budavari S (Ed.) (1989)  The Merck Index: an encyclopedia of 
    chemicals, drugs and biological, 11th ed. Rahway, New Jersey, 
    Merck and Co., Inc.

    
    Ellenhorn MJ & Barceloux DG (1988)  Medical Toxicology.  
    Diagnosis and treatment of human poisoning.  New York, Elsevier.
    
    Gilman AG (1990) Gilman AG, Rall TW, Nies As & Taylor P (eds)  
    Goodman and Gilman's the Pharmacological Basis of Therapeutics.  
    8th ed. New York, Pergamon Press.
    
    Reynolds JEF (Ed.) (1989)  Martindale The extra pharmacopoeia 
    29th ed. London.  The Pharmaceutical Press.
    
    Sax NI & Lewis RJ (1989) Dangerous properties of industrial 
    materials, 7th Ed. New York, Van Nostrand Reinhold.
    
    Spector R (1986)  The scientific basis of clinical pharmacology.  
    Boston, Little Brown.
    
    US Pharmacopoeia dispensing information (1980)  United States 
    pharmacopoeia. Pensilvania, Mack Publ. Co.
    
    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.
    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 
    ADDRESS(ES)
    Author:   Rosane Maria Salvi
              Applied Toxicology Centre (PUCRS)
              Travessa Sul, 270  ap 303
              90440 Porto Alegre
              Brazil
    
              Fax: 55 51 224 6563
    
    Date:     January 1992
    
    Reviewer: Albert Jaeger
              Centre Anti-Poisons
              Hôpitaux Universitaires de Strasbourg
              1, place de l'Hôpital
              67091 Strasbourg Cédex
              France
    
              Tel: 33-88161144
              Fax: 33-88161388
    
    Date:     September 1992
    
    Peer Review:   London, United Kingdom, September 1992
                   (Jaeger, Rahde, Ruggerone, Szajewski, Watson)