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)