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.
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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