Hydrochlorothiazide

Hydrochlorothiazide

Drug Nomenclature

Date of monograph revision: 23-Jul-1997; 05-Aug-1998; 04-Oct-2000; 29-Oct-2001; 27-May-2004; 13-Jul-2006
Synonyms: Hidrochlorotiazidas; Hidroclorotiazida; Hidroklorotiazid; Hydrochlorothiazid; Hydrochlorothiazidum; Hydroklooritiatsidi; Hydroklortiazid
BAN: Hydrochlorothiazide
INN: Hydrochlorothiazide [rINN (en)]
INN: Hidroclorotiazida [rINN (es)]
INN: Hydrochlorothiazide [rINN (fr)]
INN: Hydrochlorothiazidum [rINN (la)]
INN: Гидрохлоротиазид [rINN (ru)]
Chemical name: 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulphonamide 1,1-dioxide
Molecular formula: C7H8ClN3O4S2 =297.7
CAS: 58-93-5
ATC code: C03AA03
Read code: y01UV
Chemical Structure of Hydrochlorothiazide

Chemical Structure of Hydrochlorothiazide

NOTE:

Compounded preparations of hydrochlorothiazide may be represented by the following names:

Co-amilozide (BAN)—hydrochlorothiazide 10 parts and amiloride hydrochloride 1 part (w/w)

Co-amilozide (PEN)—amiloride hydrochloride and hydrochlorothiazide

Co-spironozide (PEN)—spironolactone and hydrochlorothiazide

Co-triamterzide (BAN)—triamterene 2 parts and hydrochlorothiazide 1 part (w/w)

Co-triamterzide (PEN)—triamterene and hydrochlorothiazide

Co-zidocapt (BAN)—hydrochlorothiazide 1 part and captopril 2 parts (w/w).

Use in Sport. Hydrochlorothiazide may be restricted in certain sports (see Go to Drugs in Sport) and competitors should check with the appropriate sports authorities.

Pharmacopoeias:

In Chin., Eur. (see Go to European Pharmacopoeia Convention Signatories), Int., Jpn, Pol., US, and Viet.

Ph. Eur. 5.5 (Hydrochlorothiazide). A white or almost white, crystalline powder. Very slightly soluble in water; sparingly soluble in alcohol; soluble in acetone. It dissolves in dilute solutions of alkali hydroxides.

USP 29 (Hydrochlorothiazide). A white or practically white, practically odourless crystalline powder. Slightly soluble in water; insoluble in chloroform, in ether, and in dilute mineral acids; freely soluble in dimethylformamide, in n-butylamine, and in sodium hydroxide solution; sparingly soluble in methyl alcohol.

Adverse Effects

Hydrochlorothiazide and other thiazide diuretics may cause a number of metabolic disturbances especially at high doses. They may provoke hyperglycaemia and glycosuria in diabetic and other susceptible patients. They may cause hyperuricaemia and precipitate attacks of gout in some patients. Thiazide diuretics may be associated with electrolyte imbalances including hypochloraemic alkalosis, hyponatraemia, and hypokalaemia. Hypokalaemia intensifies the effect of digitalis on cardiac muscle and administration of digitalis or its glycosides may have to be temporarily suspended. Patients with cirrhosis of the liver are particularly at risk from hypokalaemia. Hyponatraemia may occur in patients with severe heart failure who are very oedematous, particularly with large doses in conjunction with restricted salt in the diet. The urinary excretion of calcium is reduced. Hypomagnesaemia has also occurred. Adverse changes in plasma lipids have also been noted but their clinical significance is unclear.

Signs of electrolyte imbalance include dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain and cramps, seizures, oliguria, hypotension, and gastrointestinal disturbances.

Other side-effects include anorexia, gastric irritation, nausea, vomiting, constipation, diarrhoea, sialadenitis, headache, dizziness, photosensitivity reactions, orthostatic hypotension, paraesthesia, impotence, and yellow vision. Hypersensitivity reactions include skin rashes, fever, pulmonary oedema, pneumonitis, anaphylaxis, and toxic epidermal necrolysis. Cholestatic jaundice, pancreatitis, and blood dyscrasias including thrombocytopenia and, more rarely, granulocytopenia, leucopenia, and aplastic and haemolytic anaemia have been reported.

Intestinal ulceration has occurred after the use of tablets containing thiazides with an enteric-coated core of potassium chloride (see also under Potassium, Go to Adverse Effects).

Carcinogenicity.

Several studies have suggested that long-term diuretic therapy may be associated with the development of cancer. A meta-analysis1 of 9 case control studies and 3 cohort studies found an increased risk of renal cell carcinoma in patients receiving diuretics, and a further retrospective study2 found that the risk of colon cancer was also increased. While the risk is probably not significant in most patients, it was suggested1,2 that it should be taken into consideration when choosing long-term therapy for younger patients.

  1. 1. Grossman E, et al. Does diuretic therapy increase the risk of renal cell carcinoma? Am J Cardiol 1999; 83: 1090–3. PubMed
  2. 2. Tenenbaum A, et al. Is diuretic therapy associated with an increased risk of colon cancer? Am J Med 2001; 110: 143–5. PubMed

Effects on the blood.

There have been case reports of intravascular immune haemolysis in patients taking hydrochlorothiazide and methyldopa.1-3 In each of these 3 cases the hydrochlorothiazide was identified as the probable cause of haemolysis on serological data, although methyldopa could have been a contributory factor. One of these patients died3 during the haemolytic episode although post-mortem examination failed to reveal a cause of death.

  1. 1. Vila JM, et al. Thiazide-induced immune hemolytic anemia. JAMA 1976; 236: 1723–4. PubMed
  2. 2. Garratty G, et al. Acute immune intravascular hemolysis due to hydrochlorothiazide. Am J Clin Pathol 1981; 76: 73–8. PubMed
  3. 3. Beck ML, et al Fatal intravascular immune hemolysis induced by hydrochlorothiazide. Am J Clin Pathol 1984; 81: 791–4. PubMed

Effects on electrolyte balance.

Magnesium and potassium.

The clinical consequences of diuretic-induced hypokalaemia have been controversial.1-3 Of major concern has been the possibility that diuretic-induced hypokalaemia could predispose to cardiac arrhythmias and sudden cardiac death in some patients, and it has been suggested that this could explain the lower than expected reduction in deaths due to ischaemic heart disease found in some hypertension trials. Indeed, some case-control studies4,5 have suggested an association between an increased risk of sudden cardiac death and the use of thiazides or other non-potassium-sparing diuretics; the addition of a potassium supplement had little effect on this risk, whereas addition of a potassium-sparing diuretic to the thiazide lowered the risk.4 However, no reduction in cardiac arrhythmias after the correction of hypokalaemia has been seen6 nor any evidence of increased arrhythmias associated with diuretic-induced hypokalaemia.7 Several reviews8,9 have argued that there is no proof of a causal relationship between hypokalaemia and serious dysrhythmias and this was endorsed by a randomised study.10

It is generally agreed that routine potassium supplementation in patients taking diuretics is unnecessary; however, supplementation will be required if the serum-potassium concentration falls below 3.0 mmol/litre. Potassium replacement or conservation is also likely to be necessary in patients at risk from the cardiac effects of hypokalaemia11 such as those with severe heart disease, those taking digitalis preparations or high doses of diuretics, and in patients with severe liver disease.

The amount of potassium in fixed combination diuretic and potassium preparations has long been considered insufficient to correct hypokalaemia and the effectiveness of oral potassium supplements in increasing body stores of potassium has been questioned.12-14 Hypokalaemia may be overcome by adding a potassium-sparing diuretic such as amiloride or triamterene15 to the regimen, but there is a danger of hyperkalaemia if they are used indiscriminately. The routine use of fixed-dose combination preparations of a thiazide or loop diuretic with a potassium-sparing diuretic is considered unnecessary.16 Potassium-sparing diuretics will not correct the potassium deficit unrelated to diuretic therapy in patients with severe heart failure.17 When thiazides are given with drugs that may induce hyperkalaemia, such as beta blockers, ACE inhibitors, or angiotensin II receptor antagonists, the diuretic-induced hypokalaemia may be ameliorated, but not necessarily corrected completely. Hypokalaemia has been reported18-20 in patients taking fixed-dose combinations of thiazides and beta blockers.

Potassium supplementation alone may not be sufficient to correct hypokalaemia in patients who are also deficient in magnesium,21 although it is unlikely to be of clinical significance.22

Magnesium depletion has also been implicated as a risk factor for arrhythmias.9,23

  1. 1. Materson BJ. Diuretic-associated hypokalemia. Arch Intern Med 1985; 145: 1966–7. PubMed
  2. 2. Kaplan NM, et al. Potassium supplementation in hypertensive patients with diuretic-induced hypokalemia. N Engl J Med 1985; 312: 746–9. PubMed
  3. 3. Kassirer JP, Harrington JT. Fending off the potassium pushers. N Engl J Med 1985; 312: 785–7. PubMed
  4. 4. Siscovick DS, et al. Diuretic therapy for hypertension and the risk of primary cardiac arrest. N Engl J Med 1994; 330: 1852–7. PubMed
  5. 5. Hoes AW, et al. Diuretics, β-blockers, and the risk for sudden cardiac death in hypertensive patients. Ann Intern Med 1995; 123: 481–7. PubMed
  6. 6. Papademetriou V, et al. Diuretic-induced hypokalemia in uncomplicated systemic hypertension: effect of plasma potassium correction on cardiac arrhythmias. Am J Cardiol 1983; 52: 1017–22. PubMed
  7. 7. Papademetriou V, et al. Thiazide therapy is not a cause of arrhythmia in patients with systemic hypertension. Arch Intern Med 1988; 148: 1272–6. PubMed
  8. 8. Harrington JT, et al. Our national obsession with potassium. Am J Med 1982; 73: 155–9. PubMed
  9. 9. Freis ED. Critique of the clinical importance of diuretic-induced hypokalemia and elevated cholesterol level. Arch Intern Med 1989; 149: 2640–8. PubMed
  10. 10. Siegel D, et al. Diuretics, serum and intracellular electrolyte levels, and ventricular arrhythmias in hypertensive men. JAMA 1992; 267: 1083–9. PubMed
  11. 11. Anonymous. Potassium-sparing diuretics—when are they really needed? Drug Ther Bull 1985; 23: 17–20. PubMed
  12. 12. Jackson PR, et al. Relative potency of spironolactone, triamterene and potassium chloride in thiazide-induced hypokalaemia. Br J Clin Pharmacol 1982; 14: 257–63. PubMed
  13. 13. Shenfield GM. Fixed combination drug therapy. Drugs 1982; 23: 462–80. PubMed
  14. 14. Papademetriou V, et al. Effectiveness of potassium chloride or triamterene in thiazide hypokalemia. Arch Intern Med 1985; 145: 1986–90. PubMed
  15. 15. Kohvakka A. Maintenance of potassium balance during long-term diuretic therapy in chronic heart failure patients with thiazide-induced hypokalemia: comparison of potassium supplementation with potassium chloride and potassium-sparing agents, amiloride and triamterene. Int J Clin Pharmacol Ther Toxicol 1988; 26: 273–7. PubMed
  16. 16. Anonymous. Routine use of potassium-sparing diuretics. Drug Ther Bull 1991; 29: 85–7. PubMed
  17. 17. Davidson C, et al. The effects of potassium supplements, spironolactone or amiloride on the potassium status of patients with heart failure. Postgrad Med J 1978; 54: 405–9. PubMed
  18. 18. Skehan JD, et al. Hypokalaemia induced by a combination of a beta-blocker and a thiazide. BMJ 1982; 284: 83.
  19. 19. Odugbesan O, et al. Hazards of combined beta-blocker/diuretic tablets. Lancet 1985; i: 1221–2. PubMed
  20. 20. Jacobs L. Hypokalaemia with beta-blocker/thiazide combinations. J R Coll Gen Pract 1986; 36: 39. PubMed
  21. 21. Dyckner T. Relation of cardiovascular disease to potassium and magnesium deficiencies. Am J Cardiol 1990; 65: 44–6. PubMed
  22. 22. Papademetriou V. Magnesium depletion and thiazide hypokalemia. Arch Intern Med 1986; 146: 1026.
  23. 23. Ryan MP. Diuretics and potassium/magnesium depletion: directions for treatment. Am J Med 1987; 82 (suppl 3A): 38–47. PubMed

Sodium.

Diuretics are a common cause of hyponatraemia.1-3 Dilutional hyponatraemia may occur in patients with heart failure, but hyponatraemia may also result from sodium depletion1 or inappropriate antidiuretic hormone secretion.4 Other suggested mechanisms include decreased renal clearance of free water, hypomagnesaemia, and intracellular potassium depletion.3,5 There have been a number of reports suggesting that hyponatraemia may be a particular problem with combinations of hydrochlorothiazide and potassium-sparing diuretics,6-8 especially in elderly patients. The effect may be exacerbated by the relatively high doses of thiazide present in some fixed-dose preparations.9 The symptoms of hyponatraemia may be non-specific and include nausea, lethargy, weakness, mental confusion, and anorexia,1,2 but it may be an important cause of morbidity.2,5 Severe sequelae of hyponatraemia include tonic-clonic seizures10 and clinical features resembling subarachnoid haemorrhage.11,12 Some patients, especially the elderly, may be particularly susceptible to the hyponatraemic effects of thiazides, possibly as a result of inappropriate secretion of antidiuretic hormone.4 Plasma electrolyte concentrations should be monitored in patients receiving long-term diuretic therapy.3,10 Measurement of serum-sodium concentration and body-weight following a single dose of thiazide could be useful in identifying patients at increased risk of developing hyponatraemia.5

  1. 1. Roberts CJC, et al. Hyponatraemia: adverse effect of diuretic treatment. BMJ 1977; 1: 210. PubMed
  2. 2. Kennedy PGE, et al. Severe hyponatraemia in hospital inpatients. BMJ 1978; 2: 1251–3. PubMed
  3. 3. Walters EG, et al. Hyponatraemia associated with diuretics. Br J Clin Pract 1987; 41: 841–4. PubMed
  4. 4. Sonnenblick M, et al. Thiazide-induced hyponatremia and vasopressin release. Ann Intern Med 1989; 110: 751. PubMed
  5. 5. Friedman E, et al. Thiazide-induced hyponatremia: reproducibility by single dose rechallenge and an analysis of pathogenesis. Ann Intern Med 1989; 110: 24–30. PubMed
  6. 6. Strykers PH, et al. Hyponatremia induced by a combination of amiloride and hydrochlorothiazide. JAMA 1984; 252: 389. PubMed
  7. 7. Roberts CJC, et al. Hyponatraemia induced by a combination of hydrochlorothiazide and triamterene. BMJ 1984; 288: 1962. PubMed
  8. 8. Millson D, et al. Hyponatraemia and Moduretic (amiloride plus hydrochlorothiazide). BMJ 1984; 289: 1308–9. PubMed
  9. 9. Bayer AJ, et al. Plasma electrolytes in elderly patients taking fixed combination diuretics. Postgrad Med J 1986; 62: 159–62. PubMed
  10. 10. Johnston C, et al. Hyponatraemia and Moduretic-grand mal seizures: a review. J R Soc Med 1989; 82: 479–83. PubMed
  11. 11. Benfield GFA, et al. Dilutional hyponatraemia masquerading as subarachnoid haemorrhage in patient on hydrochlorothiazide/amiloride/timolol combined drug. Lancet 1986; ii: 341. PubMed
  12. 12. Bain PG, et al. Thiazide-induced dilutional hyponatraemia masquerading as subarachnoid haemorrhage. Lancet 1986; ii: 634. PubMed

Effects on the gallbladder.

There is an increased risk of cholecystitis in patients taking thiazides, with some indication that risk increases with the duration of use;1,2 some workers concluded that this increased risk was confined to patients with pre-existing gallstones.2 In a study in 10 healthy subjects,3 hydrochlorothiazide was found to induce modest changes in biliary lipid concentrations although it was not associated with supersaturation of the bile. These changes could not wholly explain any increase in gallbladder disease in patients taking thiazides. However, evidence is conflicting; other studies4,5 have found no association between thiazides and cholecystitis, except possibly in women who are not overweight.5

  1. 1. Rosenberg L, et al. Thiazides and acute cholecystitis. N Engl J Med 1980; 303: 546–8. PubMed
  2. 2. van der Linden W, et al. Acute cholecystitis and thiazides. BMJ 1984; 289: 654–5. PubMed
  3. 3. Angelin B. Effect of thiazide treatment on biliary lipid composition in healthy volunteers. Eur J Clin Pharmacol 1989; 37: 95–6. PubMed
  4. 4. Porter JB, et al. Acute cholecystitis and thiazides. N Engl J Med 1981; 304: 954–5. PubMed
  5. 5. Kakar F, et al. Thiazide use and the risk of cholecystectomy in women. Am J Epidemiol 1986; 124: 428–33. PubMed

Effects on glucose metabolism.

The adverse effects of thiazides on glucose metabolism, such as insulin resistance, impaired glucose tolerance, precipitation of overt diabetes, and worsening of diabetic control, are well established but appear to be dose-related and may not be significant at lower doses (for example, hydrochlorothiazide 6.25 or 12.5 mg).1 A study2 in 16 non-diabetic hypertensive patients found that bendroflumethiazide, in a dose of 1.25 mg daily, had no effect on insulin sensitivity whereas a daily dose of 5 mg produced hepatic insulin resistance. Similarly, the high doses, for example bendroflumethiazide 5 mg twice daily, used in the Medical Research Council Study on Mild to Moderate Hypertension3 resulted in an incidence of glucose intolerance that led to withdrawal from the study of 9.38 per 1000 patient-years in men and 6.01 per 1000 patient-years in women compared with 2.51 and 0.82 per 1000 patient-years respectively in patients taking placebo. A later prospective study4 in non-diabetic hypertensive patients found that those taking thiazides [doses not specified] were at no greater risk for developing diabetes than those not receiving antihypertensive therapy. However, a prospective cohort study5 in men aged between 50 and 60 found that those taking antihypertensive treatment (mainly thiazides, beta blockers, or both) showed an increase in blood glucose levels which was an independent risk factor for myocardial infarction, even when baseline insulin resistance was accounted for.

  1. 1. Neutel JM. Metabolic manifestations of low-dose diuretics. Am J Med 1996; 101 (suppl 3A): 71S–82S. PubMed
  2. 2. Harper R, et al. Effects of low dose versus conventional dose thiazide diuretic on insulin action in essential hypertension. BMJ 1994; 309: 226–30. PubMed
  3. 3. Greenburg G. Adverse reactions to bendrofluazide and propranolol for the treatment of mild hypertension: report of Medical Research Council Working Party on Mild to Moderate Hypertension. Lancet 1981; ii: 539–43. PubMed
  4. 4. Gress TW, et al. Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. N Engl J Med 2000; 342: 905–12. PubMed
  5. 5. Dunder K, et al. Increase in blood glucose concentration during antihypertensive treatment as a predictor of myocardial infarction: population based cohort study. BMJ 2003; 326: 681–4. PubMed

Effects on the kidneys.

Thiazides can produce acute renal failure either from over-enthusiastic use producing sodium depletion and hypovolaemia or, occasionally, as a result of a hypersensitivity reaction.1 Acute interstitial nephritis has been reported.2,3 They can occasionally cause the formation of non-opaque urate calculi.4

  1. 1. Curtis JR. Diseases of the urinary system: drug-induced renal disorders: I. BMJ 1977; 2: 242–4. PubMed
  2. 2. Linton AL, et al. Acute interstitial nephritis due to drugs: review of the literature with a report of nine cases. Ann Intern Med 1980; 93: 735–41. PubMed
  3. 3. Anonymous. Case records of the Massachusetts General Hospital: case 42-1983. N Engl J Med 1983; 309: 970–8. PubMed
  4. 4. Curtis JR. Diseases of the urinary system: drug-induced renal disorders: II. BMJ 1977; 2: 375–7. PubMed

Effects on lipid metabolism.

Thiazides have been reported to adversely affect the plasma-lipid profile in the short term by increasing concentrations of low-density and very-low-density lipoprotein cholesterol, as well as of triglycerides, but not of high-density lipoprotein cholesterol.1 These effects are probably dose-related2 and it has been argued that changes in plasma lipids are likely to be slight at the relatively low doses now used in hypertension. There is some evidence to suggest that these lipid changes may not persist long-term.3 In the Treatment of Mild Hypertension Study (TOMHS),4 plasma total cholesterol concentrations were increased after 12 months in patients receiving chlortalidone but this effect was no longer present after 24 months. Although there has been concern that any hyperlipidaemic effect might offset the benefits of treating hypertension in patients at risk of ischaemic heart disease, studies such as ALLHAT5 have shown that thiazide-like diuretics (in this case chlortalidone) are as effective as other antihypertensives in reducing the incidence of cardiovascular events in patients with hypertension and at least one other risk factor for ischaemic heart disease.

  1. 1. Ames R. Effects of diuretic drugs on the lipid profile. Drugs 1988; 36 (suppl 2): 33–40. PubMed
  2. 2. Carlsen JE, et al. Relation between dose of bendrofluazide, antihypertensive effect, and adverse biochemical effects. BMJ 1990; 300: 975–8. PubMed
  3. 3. Freis ED. Critique of the clinical importance of diuretic-induced hypokalemia and elevated cholesterol level. Arch Intern Med 1989; 149: 2640–8. PubMed
  4. 4. Grimm RH, et al. Long-term effects on plasma lipids of diet and drugs to treat hypertension. JAMA 1996; 275: 1549–56. PubMed
  5. 5. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288: 2981–97. PubMed Correction. ibid. 2003; 289: 178.

Effects on the nervous system.

A 40-year old woman appeared sleepy and confused 1 week after starting hydrochlorothiazide.1 Although her plasma-potassium concentrations had fallen they were still in the normal range, and it was concluded that her symptoms were due to an adverse reaction to the drug itself.

  1. 1. Daugherty KK, Subramanian J. Cognitive and neurologic impairment with hydrochlorothiazide. Am J Health-Syst Pharm 2005; 62: 2630–3. PubMed

Effects on respiratory function.

Acute interstitial pneumonitis and acute pulmonary oedema are rare but potentially dangerous complications of thiazides and may be due to a hypersensitivity reaction. Several cases have been reported,1-7 frequently after a single dose of hydrochlorothiazide or chlorothiazide. The presenting symptoms could be mistakenly attributed to myocardial infarction.

  1. 1. Steinberg AD. Pulmonary edema following ingestion of hydrochlorothiazide. JAMA 1968; 204: 167–9.
  2. 2. Beaudry C, Laplante L. Severe allergic pneumonitis from hydrochlorothiazide. Ann Intern Med 1973; 78: 251–3. PubMed
  3. 3. Parfrey NA, Herlong HF. Pulmonary oedema after hydrochlorothiazide. BMJ 1984; 288: 1880.
  4. 4. Watrigant Y, et al. Pneumopathie à l'hydrochlorothiazide d'évolution subaiguë: etude cytologique du lavage broncho-alvéolaire. Rev Mal Respir 1986; 4: 227–9. PubMed
  5. 5. Klein MD. Noncardiogenic pulmonary edema following hydrochlorothiazide ingestion. Ann Emerg Med 1987; 16: 901–3. PubMed
  6. 6. Bowden FJ. Non-cardiogenic pulmonary oedema after ingestion of chlorothiazide. BMJ 1989; 298: 605. PubMed
  7. 7. Bernal C, Patarca R. Hydrochlorothiazide-induced pulmonary edema and associated immunologic changes. Ann Pharmacother 1999; 33: 172–4. PubMed

Effects on sexual function.

Adverse effects on sexual function have been reported in hypertensive patients receiving thiazides and other antihypertensives but it is not clear how much this is due to the underlying disease and how much is due to the drugs. In the Treatment of Mild Hypertension Study (TOMHS),1 a double-blind randomised controlled trial that allocated patients to treatment with one of five groups of antihypertensives, the incidence of erectile dysfunction in men was relatively low but was highest in the diuretic group (chlortalidone treatment). The incidence was significantly higher in chlortalidone recipients than in placebo recipients at 24 months (17.1 and 8.1% respectively), but the difference was no longer significant at 48 months (18.3 and 16.7% respectively).

  1. 1. Grimm RH, et al. Long-term effects on sexual function of five antihypertensive drugs and nutritional hygienic treatment in hypertensive men and women: Treatment of Mild Hypertension Study (TOMHS). Hypertension 1997; 29: 8–14. PubMed

Effects on the skin.

A variety of rashes and skin reactions has been reported in patients taking thiazides. Photosensitivity reactions are among the most frequently reported skin reactions. In Australia1 co-amilozide was the preparation most commonly implicated in photosensitivity reactions in reports to the Australian Drug Reactions Advisory Committee, although this may reflect the high usage of this preparation. The most likely mechanism is thought to be phototoxicity1,2 involving mainly UVA radiation although UVB may be involved in some cases.2 Chronic photosensitivity does not usually occur after stopping the drug2 although photosensitivity may persist for longer in some patients than in others.2,3 Eruptions resembling lichen planus4 and subacute cutaneous lupus erythematosus5-7 may be due to photosensitivity reactions.

Other reported skin reactions include vasculitis,8,9 erythema multiforme,9 and pseudoporphyria.10

  1. 1. Stone K. Photosensitivity reactions to drugs. Aust J Pharm 1985; 66: 415–18.
  2. 2. Addo HA, et al. Thiazide-induced photosensitivity: a study of 33 subjects. Br J Dermatol 1987; 116: 749–60. PubMed
  3. 3. Robinson HN, et al. Thiazide diuretic therapy and chronic photosensitivity. Arch Dermatol 1985; 121: 522–4. PubMed
  4. 4. Graham-Brown R. Lichen planus and lichen-planus-like reactions. Br J Hosp Med 1986; 36: 281–4. PubMed
  5. 5. Jones SK, et al. Thiazide diuretic-induced subacute cutaneous lupus-like syndrome. Br J Dermatol 1985; 113 (suppl 29): 25.
  6. 6. Reed BR, et al. Subacute cutaneous lupus erythematosus associated with hydrochlorothiazide therapy. Ann Intern Med 1985; 103: 49–51. PubMed
  7. 7. Darken M, McBurney EI. Subacute cutaneous lupus erythematosus-like drug eruption due to combination diuretic hydrochlorothiazide and triamterene. J Am Acad Dermatol 1988; 18: 38–42. PubMed
  8. 8. Björnberg A, Gisslén H. Thiazides: a cause of necrotising vasculitis? Lancet 1965; ii: 982–3. PubMed
  9. 9. Hardwick N, Saxe N. Patterns of dermatology referrals in a general hospital. Br J Dermatol 1986; 115: 167–76. PubMed
  10. 10. Motley RS. Pseudoporphyria due to Dyazide in a patient with vitiligo. BMJ 1990; 300: 1468. PubMed

Gout.

Thiazides have been associated with hyperuricaemia and gout in some patients. In the Medical Research Council Study on Mild to Moderate Hypertension,1 a single-blinded trial, men receiving bendroflumethiazide had higher incidences of gout than those receiving placebo (12.23 and 1.03 per 1000 patient-years, respectively). The risk appears to be dose-related; in a retrospective study2 in patients aged 65 or older receiving antihypertensive therapy, there was a significantly increased risk of starting anti-gout therapy in patients receiving the equivalent of 25 mg hydrochlorothiazide or more daily, but not in those receiving lower doses.

  1. 1. Greenburg G. Adverse reactions to bendrofluazide and propranolol for the treatment of mild hypertension: report of Medical Research Council Working Party on Mild to Moderate Hypertension. Lancet 1981; ii: 539–43. PubMed
  2. 2. Gurwitz JH, et al. Thiazide diuretics and the initiation of anti-gout therapy. J Clin Epidemiol 1997; 50: 953–9. PubMed

Withdrawal.

For a report of oedema following abrupt withdrawal of thiazides, see under Precautions, Go to Withdrawal..

Treatment of Adverse Effects

Hypokalaemia in patients treated with thiazides may be avoided or treated by concurrent use of potassium or a potassium-sparing diuretic (but see the discussion on potassium supplements, under Effects on Electrolyte Balance in Adverse Effects, Go to Effects on electrolyte balance.). Hypokalaemia can also be reduced by moderate sodium restriction. With the exception of patients with conditions such as hepatic failure or renal disease, chloride deficiency is usually mild and does not require specific treatment. Apart from the rare occasions when it is life-threatening, dilutional hyponatraemia is best treated with water restriction rather than salt therapy; in true hyponatraemia, appropriate replacement is the treatment of choice (see Go to Hyponatraemia.).

In massive overdosage, treatment should be symptomatic and directed at fluid and electrolyte replacement. Use of activated charcoal should be considered if the patient presents within 1 hour of ingestion.

Precautions

All diuretics produce changes in fluid and electrolyte balance (see Adverse Effects, Go to Adverse Effects). They should be used with caution in patients with existing fluid and electrolyte disturbances or who are at risk from changes in fluid and electrolyte balance, such as the elderly. They should be avoided in patients with severe hepatic impairment, in whom encephalopathy may be precipitated. Patients with hepatic cirrhosis are also more likely to develop hypokalaemia. Hyponatraemia may occur in patients with severe heart failure who are very oedematous, particularly with large doses of thiazides and restricted salt intake. All patients should be carefully observed for signs of fluid and electrolyte imbalance, especially in the presence of vomiting or during parenteral fluid therapy. Thiazides should not be given to patients with Addison's disease.

Diuretics should also be given with caution in renal impairment since they can further reduce renal function. Most thiazides are not effective in patients with a creatinine clearance of less than 30 mL/minute. They should not be used in patients with severe renal impairment or anuria.

Thiazides may precipitate attacks of gout in susceptible patients. They may cause hyperglycaemia and aggravate or unmask diabetes mellitus. Blood-glucose concentrations should be monitored in patients taking antidiabetics, since requirements may change. Thiazides can reduce urinary excretion of calcium, sometimes resulting in mild hypercalcaemia; they should not be given to patients with pre-existing hypercalcaemia. There is a possibility that thiazides may exacerbate or activate systemic lupus erythematosus in susceptible patients. For a suggestion that thiazides may increase the risk of developing gallstones, see Effects on the Gallbladder, Go to Effects on the gallbladder..

Thiazides cross the placenta and there have been reports of neonatal jaundice, thrombocytopenia, and electrolyte imbalances after maternal use. Reductions in maternal blood volume could also adversely affect placental perfusion. Treatment with large doses can inhibit lactation.

Breast feeding.

Hydrochlorothiazide has been shown to pass into breast milk. In a woman taking 50 mg hydrochlorothiazide daily, peak milk concentrations were found1 5 to 10 hours after a dose and were about 25% of peak blood concentrations. No drug could be detected in the infant's blood, and his serum electrolytes, blood glucose, and blood urea nitrogen were normal. The American Academy of Pediatrics considers2 that hydrochlorothiazide is usually compatible with breast feeding.

  1. 1. Miller ME, et al. Hydrochlorothiazide disposition in a mother and her breast-fed infant. J Pediatr 1982; 101: 789–91. PubMed
  2. 2. American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001; 108: 776–89. PubMed Correction. ibid.; 1029. Also available at: online (accessed 06/07/04)

Hyperparathyroidism.

Hypertension is a complication of primary hyperparathyroidism but thiazides have often been withheld for fear of exacerbating hypercalcaemia. However, no differences in plasma-calcium concentrations were found in 13 patients who received thiazides intermittently for up to 18 months. It was therefore concluded that thiazides are not contra-indicated in such patients.1 They should, however, be stopped before parathyroid function is tested.

  1. 1. Farquhar CW, et al. Failure of thiazide diuretics to increase plasma calcium in mild primary hyperparathyroidism. Postgrad Med J 1990; 66: 714–16. PubMed

Porphyria.

Hydrochlorothiazide has been associated with acute attacks of porphyria and is considered unsafe in porphyric patients.

Withdrawal.

In patients with mild hypertension whose blood pressure is consistently controlled, reduction in dosage or withdrawal of antihypertensive drugs may be possible. Serious oedema occurred in 8 patients with controlled hypertension within 2 weeks of abrupt withdrawal of thiazide diuretics.1 Thiazides were resumed and gradually tapered without recurrence of oedema.

  1. 1. Brandspigel K. Diuretic-withdrawal edema. N Engl J Med 1986; 314: 515. PubMed

Interactions

Many of the interactions of hydrochlorothiazide and other thiazides are due to their effects on fluid and electrolyte balance. Diuretic-induced hypokalaemia may enhance the toxicity of digitalis glycosides and may also increase the risk of arrhythmias with drugs that prolong the QT interval, such as astemizole, terfenadine, halofantrine, pimozide, and sotalol. Thiazides may enhance the neuromuscular blocking action of competitive neuromuscular blockers, such as atracurium, probably by their hypokalaemic effect. The potassium-depleting effect of diuretics may be enhanced by corticosteroids, corticotropin, beta2 agonists such as salbutamol, carbenoxolone, amphotericin B, or reboxetine.

Diuretics may enhance the effect of other antihypertensives, particularly the first-dose hypotension that occurs with alpha blockers or ACE inhibitors. Orthostatic hypotension associated with diuretics may be enhanced by alcohol, barbiturates, or opioids. The antihypertensive effects of diuretics may be antagonised by drugs that cause fluid retention, such as corticosteroids, NSAIDs, or carbenoxolone; diuretics may enhance the nephrotoxicity of NSAIDs. Thiazides have been reported to diminish the response to pressor amines, such as noradrenaline, but the clinical significance of this effect is uncertain.

Thiazides should not usually be used with lithium since the association may lead to toxic blood concentrations of lithium. Other drugs for which increased toxicity has been reported when given with thiazides include allopurinol and tetracyclines. Thiazides may alter the requirements for hypoglycaemics in diabetic patients.

Antibacterials.

Severe hyponatraemia has been reported in patients taking trimethoprim with co-amilozide1 and hydrochlorothiazide.2

  1. 1. Eastell R, Edmonds CJ. Hyponatraemia associated with trimethoprim and a diuretic. BMJ 1984; 289: 1658–9. PubMed
  2. 2. Hart TL, et al. Hyponatremia secondary to thiazide-trimethoprim interaction. Can J Hosp Pharm 1989; 42: 243–6.

Antiepileptics.

There has been a report of symptomatic hyponatraemia associated with the use of hydrochlorothiazide or furosemide and carbamazepine.1

  1. 1. Yassa R, et al. Carbamazepine, diuretics, and hyponatremia: a possible interaction. J Clin Psychiatry 1987; 48: 281–3. PubMed

Bile-acid binding resins.

Gastrointestinal absorption of both chlorothiazide and hydrochlorothiazide has been reported to be reduced by colestipol and colestyramine.1-3 In a study in healthy subjects2 colestyramine had the greatest effect on hydrochlorothiazide, decreasing absorption by 85% compared with a decrease of 43% with colestipol. Even when colestyramine was administered 4 hours after hydrochlorothiazide3 reductions of absorption of at least 30 to 35% could be expected.

  1. 1. Kauffman RE, Azarnoff DL. Effect of colestipol on gastrointestinal absorption of chlorothiazide in man. Clin Pharmacol Ther 1973; 14: 886–90. PubMed
  2. 2. Hunninghake DB, et al. The effect of cholestyramine and colestipol on the absorption of hydrochlorothiazide. Int J Clin Pharmacol Ther Toxicol 1982; 20: 151–4. PubMed
  3. 3. Hunninghake DB, Hibbard DM. Influence of time intervals for cholestyramine dosing on the absorption of hydrochlorothiazide. Clin Pharmacol Ther 1986; 39: 329–34. PubMed

Calcium salts.

The milk-alkali syndrome, characterised by hypercalcaemia, metabolic alkalosis, and renal failure, developed in a patient taking chlorothiazide and moderately large doses of calcium carbonate.1 Patients taking thiazides may be at increased risk of developing the syndrome because of their reduced ability to excrete excess calcium. Hypercalcaemia may also occur in patients taking thiazides with drugs that increase calcium levels, such as vitamin D.

  1. 1. Gora ML, et al. Milk-alkali syndrome associated with use of chlorothiazide and calcium carbonate. Clin Pharm 1989; 8: 227–9. PubMed

Dopaminergics.

For a report of increased amantadine toxicity associated with hydrochlorothiazide and triamterene, see Go to Diuretics..

NSAIDs.

NSAIDs cause fluid retention and may antagonise the diuretic actions of thiazides.1

  1. 1. Webster J. Interactions of NSAIDs with diuretics and β-blockers: mechanisms and clinical implications. Drugs 1985; 30: 32–41. PubMed

Pharmacokinetics

Hydrochlorothiazide is fairly rapidly absorbed from the gastrointestinal tract. It is reported to have a bioavailability of about 65 to 70%. It has been estimated to have a plasma half-life of between about 5 and 15 hours and appears to be preferentially bound to red blood cells. It is excreted mainly unchanged in the urine. Hydrochlorothiazide crosses the placental barrier and is distributed into breast milk.

References.

  1. 1. Beermann B, et al. Absorption, metabolism, and excretion of hydrochlorothiazide. Clin Pharmacol Ther 1976: 19: 531–7. PubMed
  2. 2. Beermann B, Groschinsky-Grind M. Pharmacokinetics of hydrochlorothiazide in man. Eur J Clin Pharmacol 1977; 12: 297–303. PubMed
  3. 3. Beermann B, Groschinsky-Grind M. Pharmacokinetics of hydrochlorothiazide in patients with congestive heart failure. Br J Clin Pharmacol 1979: 7: 579–83. PubMed

Uses and Administration

Hydrochlorothiazide and the other thiazide diuretics are used in the treatment of hypertension (Go to Hypertension), either alone or with other antihypertensives such as ACE inhibitors and beta blockers. They are also used to treat oedema associated with heart failure (Go to Heart failure) and with renal and hepatic disorders. Other indications have included the treatment of oedema accompanying the premenstrual syndrome (Go to Premenstrual syndrome.), the prevention of water retention associated with corticosteroids and oestrogens, the treatment of diabetes insipidus (Go to Diabetes insipidus.), and the prevention of renal calculus formation in patients with hypercalciuria (Go to Renal calculi.).

Thiazides are moderately potent diuretics and exert their diuretic effect by reducing the reabsorption of electrolytes from the renal tubules, thereby increasing the excretion of sodium and chloride ions, and consequently of water. They act mainly at the beginning of the distal tubules. The excretion of other electrolytes, notably potassium and magnesium, is also increased. The excretion of calcium is reduced. They also reduce carbonic-anhydrase activity so that bicarbonate excretion is increased, but this effect is generally small compared with the effect on chloride excretion and does not appreciably alter the pH of the urine. They may also reduce the glomerular filtration rate.

Their hypotensive effect is probably partly due to a reduction in peripheral resistance; they also enhance the effects of other antihypertensives. Paradoxically, thiazides have an antidiuretic effect in patients with diabetes insipidus.

Administration and dosage. Thiazides are usually given in the morning so that sleep is not interrupted by diuresis. Diuresis starts in about 2 hours after oral doses of hydrochlorothiazide, reaches a maximum in about 4 hours, and lasts for 6 to 12 hours.

The dosage of thiazides should be adjusted to the minimum effective dose. In general lower doses are required for the treatment of hypertension than for oedema, although the maximum therapeutic effect may not be seen for several weeks.

They may be given to patients with mild renal impairment, but thiazides are generally not effective at a creatinine clearance of less than 30 mL/minute.

Hydrochlorothiazide is given by mouth.

In the treatment of hypertension an initial dose of 12.5 mg may be sufficient, increasing to 25 to 50 mg daily if necessary, either alone or with other antihypertensives. Doses of up to 100 mg have been suggested but are rarely necessary.

In the treatment of oedema the usual dose is 25 to 100 mg daily, reduced to a dose of 25 to 50 mg daily or intermittently; in severe cases initial doses of up to 200 mg daily have been suggested, but the more powerful loop diuretics (see Furosemide, Go to Furosemide) are preferred in such patients.

In the treatment of nephrogenic diabetes insipidus an initial dose of up to 100 mg daily may be used.

An initial dose for children has been 1 to 2 mg/kg daily in single or 2 divided doses. Infants under 6 months may need doses of up to 3 mg/kg daily.

For discussion of potassium supplementation in patients taking thiazide diuretics see Effects on Electrolyte Balance, under Adverse Effects, Go to Effects on electrolyte balance..

Bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (Go to Bronchopulmonary dysplasia) is a major cause of chronic lung disease in infants. Treatment often involves the use of corticosteroids. Additional supportive therapy has included the use of diuretics such as furosemide (Go to Bronchopulmonary dysplasia.); results with hydrochlorothiazide or spironolactone have been more ambiguous. No beneficial effects on lung function or oxygenation were found in a study of 12 infants after 1 week of treatment with hydrochlorothiazide and spironolactone.1 However, hydrochlorothiazide and spironolactone therapy was found to improve total respiratory system compliance with decreased lung damage and increased survival rate in 34 premature infants with bronchopulmonary dysplasia after 8 weeks of therapy.2 In the latter study furosemide was also given if clinically indicated.

  1. 1. Engelhardt B, et al. Effect of spironolactone-hydrochlorothiazide on lung function in infants with chronic bronchopulmonary dysplasia. J Pediatr 1989; 114: 619–24. PubMed
  2. 2. Albersheim SG, et al. Randomized, double-blind, controlled trial of long-term diuretic therapy for bronchopulmonary dysplasia. J Pediatr 1989; 115: 615–20. PubMed

Diabetes insipidus.

Thiazide diuretics are used in nephrogenic diabetes insipidus (Go to Diabetes insipidus), sometimes with potassium-sparing diuretics. For instance, hydrochlorothiazide with amiloride was effective in controlling nephrogenic diabetes insipidus in 5 boys and compared favourably with treatment with hydrochlorothiazide and indometacin.1 Treatment was well tolerated in 4 patients. Abdominal pain and anorexia necessitated withdrawal of amiloride in the fifth patient after 6 months. The use of hydrochlorothiazide with amiloride also obviated the need for potassium supplements, which were required with hydrochlorothiazide and indometacin. The use of hydrochlorothiazide with amiloride was also effective and well tolerated in a group of 4 children with nephrogenic diabetes insipidus who were treated for up to 5 years.2

  1. 1. Knoers N, Monnens LAH. Amiloride-hydrochlorothiazide versus indomethacin-hydrochlorothiazide in the treatment of nephrogenic diabetes insipidus. J Pediatr 1990; 117: 499–502. PubMed
  2. 2. Kirchlechner V, et al. Treatment of nephrogenic diabetes insipidus with hydrochlorothiazide and amiloride. Arch Dis Child 1999; 80: 548–52. PubMed

Hypoparathyroidism.

In hypoparathyroidism (Go to Hypoparathyroidism), treatment is usually with oral vitamin D compounds to correct the hypocalcaemia. Thiazides may be useful in some patients. Beneficial effects on serum-calcium concentrations in patients with hypoparathyroidism have been reported following chlortalidone plus dietary salt restriction,1 and with bendroflumethiazide.2 However, chlortalidone has not been found to be effective in all patients,3 and the reduction in urinary calcium excretion by thiazides has been shown to be diminished in patients with hypoparathyroidism,4 suggesting that this effect may be dependent on the presence of active parathyroid hormone. Care should be taken when giving diuretics to hypoparathyroid patients with co-existing adrenal insufficiency3 or metabolic alkalosis.5

  1. 1. Porter RH, et al. Treatment of hypoparathyroid patients with chlorthalidone. N Engl J Med 1978; 298: 577–81. PubMed
  2. 2. Newman GH, et al. Effect of bendrofluazide on calcium reabsorption in hypoparathyroidism. Eur J Clin Pharmacol 1984; 27: 41–6. PubMed
  3. 3. Gertner JM, Genel M. Chlorthalidone for hypoparathyroidism. N Engl J Med 1978; 298: 1478.
  4. 4. Middler S, et al. Thiazide diuretics and calcium metabolism. Metabolism 1973; 22: 139–45. PubMed
  5. 5. Barzel US. Chlorthalidone for hypoparathyroidism. N Engl J Med 1978; 289: 1478.

Ménière's disease.

In Ménière's disease (Go to Ménière's disease) there is an excess of endolymph fluid in the ear and diuretics such as hydrochlorothiazide have been used in attempts to relieve symptoms by reducing the amount of fluid.

Osteoporosis.

Although some epidemiological studies have indicated beneficial effects of thiazides on bone (reduced rates of bone loss1 and a reduced risk of hip fracture2-5) a comprehensive analysis involving 9704 women over the age of 65 years6 showed only a small effect on bone mass, no effect on the risk for falls, and no overall protective effect against fractures. A further prospective study7 reported a reduction in forearm fracture, but hip fracture was only reduced in postmenopausal women. Randomised, controlled studies8,9 have confirmed that hydrochlorothiazide reduces bone loss, but again the effects were small. Thus, thiazides have no established role in the prevention or treatment of osteoporosis (Go to Osteoporosis). They might, however, be useful to reduce hypercalciuria in patients taking glucocorticoids10 but serum-potassium concentrations should be monitored closely.

  1. 1. Wasnich R, et al. Effect of thiazide on rates of bone mineral loss: a longitudinal study. BMJ 1990; 301: 1303–5. PubMed Correction. ibid. 1991; 302: 218.
  2. 2. Ray WA, et al. Long-term use of thiazide diuretics and risk of hip fracture. Lancet 1989; i: 687–90. PubMed
  3. 3. LaCroix AZ, et al. Thiazide diuretic agents and the incidence of hip fracture. N Engl J Med 1990; 322: 286–90. PubMed
  4. 4. Felson DT, et al. Thiazide diuretics and the risk of hip fracture: results from the Framingham Study. JAMA 1991; 265: 370–3. PubMed
  5. 5. Schoofs MWCJ, et al. Thiazide diuretics and the risk for hip fracture. Ann Intern Med 2003; 139: 476–82. PubMed
  6. 6. Cauley JA, et al. Effects of thiazide diuretic therapy on bone mass, fractures, and falls. Ann Intern Med 1993; 118: 666–73. PubMed
  7. 7. Feskanich D, et al. A prospective study of thiazide use and fractures in women. Osteoporosis Int 1997; 7: 79–84. PubMed
  8. 8. Reid IR, et al. Hydrochlorothiazide reduces loss of cortical bone in normal postmenopausal women: a randomized controlled trial. Am J Med 2000; 109: 362–70. PubMed
  9. 9. LaCroix AZ, et al. Low-dose hydrochlorothiazide and preservation of bone mineral density in older adults: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2000; 133: 516–26. PubMed
  10. 10. Lukert BP, Raisz LG. Glucocorticoid-induced osteoporosis: pathogenesis and management. Ann Intern Med 1990; 112: 352–64. PubMed

Renal calculi.

A thiazide diuretic may be given to prevent the recurrence of calcium-containing renal calculi (Go to Renal calculi) in patients with hypercalciuria.1,2

  1. 1. Pearle MS, et al. Meta-analysis of randomized trials for medical prevention of calcium oxalate nephrolithiasis. J Endourol 1999; 13: 679–85. PubMed
  2. 2. Tiselius H-G, et al. European Association of Urology guidelines on urolithiasis. Eur Urol 2001; 40: 362–71. PubMed Also available at: online (accessed 11/08/05)

Preparations

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Captobeta Comp; Captodoc Comp; Captogamma HCT; Captohexal Comp; Captopril Comp; Captopril HCT; Captopril Plus; Cardiagen HCT; Cibadrex; Co-Diovan; CoAprovel; Combiprotect¤; Concor Plus; Coric Plus; Corindocomb; Delix plus; Dignoretik¤; Disalpin¤; Diu Venostasin; Diu-Tonolytril¤; Diuretikum Verla; Diursan; Diutensat comp¤; Diutensat¤; Dociteren; Dociton Dytide H¤; duradiuret; durarese; Dynacil comp; Dynorm Plus; Dytide H; Elfanex¤; Emestar plus; Enabeta comp; Enahexal comp; Enalapril plus; Esimil¤; Esiteren¤; Fempress Plus; Fondril HCT; Fosinorm comp; Haemiton compositum¤; Hydrocomp¤; Hypertorr¤; Isoptin plus; Jenateren comp¤; Jutacor comp; Karvezide; Kinzalkomb; Lorzaar plus; Manimon¤; Meprolol Comp; Meto comp; Meto-comp¤; Meto-Isis comp; meto-thiazid; Metobeta comp; Metodura comp; Metohexal comp; Metoprolol comp; Metostad Comp; MicardisPlus; Minoremed¤; Modu-Puren¤; Moducrin; Moduretik; Nephral; Olivysat compositum¤; Pres plus; Propra comp; Provas comp; Regulaserp forte¤; Renacor; Resaltex¤; Rhefluin¤; Risicordin¤; Sali-Puren; Slimin¤; Sotaziden¤; Spironothiazid; Tensobon comp; Teveten Plus; Thiazid-comp; Trasicor Esidrix¤; Treloc; Tri-Thiazid Reserpin; Tri-Thiazid; Triampur Compositum; Triamteren comp; Triamteren comp; Triamteren-H¤; Triamteren/HCT; Triamthiazid¤; Triarese; triazid; Triniton; Tripranol¤; Turfa; Veratide; Vesdil plus; Greece: Accuretic; Anastol; Atacand Plus; Bumeftyl; Captopress; Captospes+H; Cibadrex; Co-Diovan; Co-Renitec; CoAprovel; Dosturel; Ekzevit¤; Empirol; Fozide; Hydromet¤; Hyzaar; Iperton; Ividol; Karvezide; Kifarol; Micardis Plus; Modinexil¤; Moduretic; Monoplus; Nolarmin; Normolose-H; Penopril; Pentatec; Piesital; Prinzide; Pritor Plus; Protal complex; Return; Savosan; Sedapressin; Siberian; Superace; Tiaden; Triatec Plus; Uresan; Vascase Plus; Zestoretic; Zidepril; Hong Kong: Adelphane-Esidrex; Amilco¤; Amithiazide; Apo-Amilzide; Apo-Triazide; Aprovel HCT¤; Betaloc Comp; Co-Diovan; Co-Renitec; CoAprovel; CP-Metolol Co; Dyazide; Hydrozide¤; Hyzaar; Lodoz; Micardis Plus; Moducren; Moduretic; Secadrex¤; Sefaretic; Triam-Co¤; Trizid¤; Zestoretic; Hungary: Accuzide; Amilozid-B; Atacand Plus; Co-Renitec; CoAprovel; Concor Plus; Diovan HCT; Enap-HL; Hyzaar; Inhibace Plus; Lotensin HCT; PritorPlus; Renitec Plus; India: Adelphane-Esidrex; Alsartan-H; Arkamin-H; Beptazine-H; Biduret; Ciplar-H; Cipril-H; EnAce-D; Hipres-D; Invozide; Lisoril-5HT; Losacar-H; Metolar-H; Ramcor H; Ramipres H; Telma-H; Zaart-H; Ireland: Accuretic; Amilco¤; Amizide¤; Atacand Plus; Capozide; Captor-HCT; Carace Plus; Clonuretic¤; Co-Betaloc; Co-Diovan; CoAprovel; Cozaar Comp; Dyazide; Half Capozide; Hydromet¤; Innozide; Lispril-hydrochlorothiazide; MicardisPlus; Moducren; Moduret; Moduretic¤; Secadrex¤; Sotazide¤; Zestoretic; Israel: Atacand Plus; Co-Diovan; Irban Plus; Kaluril; Naprizide; Ocsaar Plus; Tritace Comp; Vascace Plus; Vasopril Plus; Italy: Accuretic; Acediur; Aceplus; Acequide; Acesistem; Adelfan-Esidrex¤; Aldactazide; Aldotride¤; Blopresid; Cibadrex; CoAprovel; Combisartan; Condiuren; Cotareg; Diertina Ipotensiva¤; Elidiur; Enulid; Femipres Plus; Forzaar; Fosicombi; Gentipress; Hizaar; Idroquark; Inibace Plus; Initiss Plus; Karvezide; Losazid; Medozide; Micardis Plus; Moduretic; Nalapres; Neo-Lotan Plus; Neoprex; Prinzide; PritorPlus; Quinazide; Ratacand Plus; Raufluin¤; Raunova Plus¤; Selozide; Sermidrina¤; Sfigmoreg¤; Sinertec; Spiridazide; Tensadiur; Tensozide; Triamteril Complex¤; Triatec HCT; Uniprildiur; Vallizina¤; Vasoretic; Zestoretic; Zinadiur; Malaysia: Ami-Hydrotride; Amizide; Apo-Amilzide; Apo-Triazide; Atacand Plus; Co-Diovan; CoAprovel; Fortzaar; Hyzaar; Micardis Plus; Moduretic¤; Mexico: Atacand Plus; Avalide; Biconcor; Blopress Plus; Capozide; Co-Captral; Co-Diovan; Co-Renitec; CoAprovel; Diovan HCT¤; Dyazide¤; Gliotenzide; Hyzaar; Micardis Plus; Moducren¤; Moduretic; Predxal Plus; Prinzide; Selopres; Tritazide; Zestoretic; Netherlands: Aceplus¤; Acuzide; Atacand Plus; Capozide; Cibadrex; Co-Diovan; Co-Renitec; CoAprovel; Cozaar Plus; Diurace; Dytenzide; Emcoretic; Enacostad; Fortzaar; Hydromet¤; Hykaten¤; Hyzaar; Lisidigal HCT; Micardis Plus; Moducren¤; Moduretic; Novazyd; Ranezide¤; Renitec Plus; Secadrex; Selokomb; Teveten Plus; Tritazide; Vascase Plus¤; Zestoretic; Norway: Atacand Plus; CoAprovel; Cozaar Comp; Diovan Comp; Lodoz; MicardisPlus; Moduretic; Normorix; Renitec Comp; Vivatec Comp; Zestoretic; New Zealand: Accuretic; Amizide; Capozide; Co-Renitec; Dyazide¤; Hydrozide¤; Hyzaar; Inhibace Plus; Moduretic¤; Prinzide¤; Triamizide; Trizid¤; Zestoretic¤; Portugal: Acuretic; Aldoretic; Amiloride Composto; Blopress 16 mg + 12,5 mg; Chibretico¤; Co-Diovan; Co-Tareg; CoAprovel; Concor Plus; Cozaar Plus; Diurene; Dyazide; Ecamais; Enatia; Fortzaar; Hytacand; Inibace Plus; Laprilen; Lopiretic; Lortaan Plus; Micardis Plus; Moducren; Moduretic; Normotil¤; Ondolen; Prinzide; Pritor Plus; Renidur; Renipril Plus¤; Triam-Tiazida R; Triatec Composto; Vascase Plus; Zestoretic; Russia: Adelphane-Esidrex (Адельфан-эзидрекс); Apo-Triazide (Апо-триазид); Capozide (Капозид); Co-Diovan (Ко-Диован); Co-Renitec (Ко-Ренитек); Enap-H (Енап H); Hyzaar (Гизаар); Triam-Co (Триам-ко); Triampur Compositum (Триампур Композитум); Triresid K (Трирезид К); South Africa: Accuretic; Acumod¤; Adco-Retic; Adelphane-Esidrex¤; Aldoretic¤; Amiloretic; Amizide¤; Aquadrex¤; Arcanaretic¤; Atacand Plus; Betaretic; Capozide; Captoretic; Cibadrex; Cliniretic¤; Co-Diovan; Co-Micardis; Co-Renitec; CoAprovel; Cozaar Comp; Diutec¤; Dyazide; Enap-Co; Fortzaar; Hexaretic; Hydromet¤; Inhibace Plus; Loretic¤; Moducren; Moduretic; Monozide; Pharmapress Co; Renezide; Secadrex¤; Servatrin; Sotazide; Trimolex¤; Urirex-K; Urizide¤; Zapto Co; Zestoretic; Ziak; Singapore: Apo-Amilzide; Apo-Triazide; Atacand Plus; Co-Diovan; Co-Renitec¤; CoAprovel; Dyazide¤; Enap-HL; Hyzaar; Lodoz; Micardis Plus; Spain: Acediur; Acetensil Plus; Adelfan-Esidrex; Alopresin Diu; Ameride; Atacand Plus; Baripril Diu; Bicetil; Bietapres Complex¤; Bietapres¤; Bitensil Diu; Cesplon Plus; Cibadrex; Co-Diovan; Co-Renitec; Co-Vals; CoAprovel; Cozaar Plus; Crinoretic; Dabonal Plus; Decresco; Dilabar Diu; Dilapres¤; Ditenside; Diu Rauwiplus¤; Diuzine; Doneka Plus; Donicer¤; Ecadiu; Ecazide; Emcoretic; Eutiman¤; Flebo Stop¤; Fortzaar; Fositens Plus; Hiperlex Plus; Hipoartel Plus; Hipotensor¤; Hydromet¤; Inhibace Plus; Inocar Plus; Iricil Plus; Kalpress Plus; Kalten; Karvezide; Labodrex; Lidaltrin Diu; Micardis Plus; Miscidon¤; Miten Plus; Neotensin Diu; Parapres Plus; Picten¤; Pressitan Plus; Prinivil Plus; Pritor Plus; Prosanon¤; Renitecmax; Rulun; Secadrex; Secubar Diu; Selopresin; Tensikey Complex; Tensiocomplet; Tenso Stop Plus; Urocaudal Tiazida¤; Zestoretic; Sweden: Accupro Comp; Amiloferm; Atacand Plus; Capozid¤; Cibadrex¤; CoAprovel; Cozaar Comp; Diovan Comp; Enalapril Comp; Esidrex-K¤; Hydromet¤; Inhibace comp; Kinzalkomb; Micardis Plus; Moduretic; Monopril comp; Normorix; Renitec Comp; Sparkal; Synerpril; Triatec Comp; Zestoretic; Switzerland: Accuretic; Adelphan-Esidrex-K¤; Adelphan-Esidrex; Agorex; Aldoretic¤; Amilo-basan; Amilorid comp¤; Amiloride/HCTZ; Atacand Plus; Betadiur¤; Blopress Plus; Capozide; Captosol comp; Cibadrex; Co-Acepril; Co-Amilorid¤; Co-Diovan; Co-Enatec; Co-Epril; Co-Reniten; Co-Vasocor; CoAprovel; Comilorid; Concor Plus; Cosaar Plus; Dyazide; Ecodurex; Elpradil HCT; Escoretic; Esidrex-K¤; Fosicomp; Grodurex; Hydrolid¤; Inhibace Plus; Kalten; Kinzalplus; Lodoz; MicardisPlus; Modisal¤; Moducren; Moduretic; Prinzide; Reniten Plus; Rhefluin; Spironothiazid¤; Synureticum¤; t/h-basan; Tensobon comp; Teveten Plus; Triatec Comp; Zestoretic; Thailand: Amilhydrozide¤; Amilide¤; Aprovel HCT¤; Bilduretic; Blopress Plus; Co-Diovan; CoAprovel; Dazid; Dinazide; Dyazide; Dyterene; Fortzaar; Hydrares; Hydrozide Plus; Hyperretic; Hypery¤; Hyzaar; Mano-Ap-Es; Medeserpine Co¤; Miduret¤; Milorex¤; Miretic; Modulan; Moduretic; Monoplus; Poli-Uretic; Renase; Reser; Sefaretic; Ser-Ap-Es; Skezide¤; United Kingdom: Accuretic; Acezide; Adizem-XL Plus¤; Amil-Co; Amilmaxco¤; Capozide; Capto-Co; Carace Plus; Caralpha; Co-Betaloc¤; Co-Diovan; CoAprovel; Cozaar Comp; Delvas¤; Dyazide; Esidrex-K¤; Hydromet¤; Hypertane¤; Innozide; Kalten; Lisicostad; MicardisPlus; Moducren; Moduret; Moduretic; Monozide¤; Normetic¤; Olmetec Plus; Secadrex¤; Serpasil-Esidrex¤; Sotazide¤; Synuretic¤; Tolerzide¤; Triamaxco¤; Triamco; Vasetic¤; Zestoretic; Zida-Co¤; United States: Accuretic; Aldactazide; Aldoril; Apresazide; Apresoline-Esidrix¤; Aprozide¤; Atacand HCT; Avalide; Benicar HCT; Cam-ap-es¤; Capozide; Diovan HCT; Dyazide; Esimil; HHR¤; Hydra-zide; Hydrap-ES; Hydro-Serp; Hydropres; Hydroserpine; Hydrosine¤; Hyzaar; Inderide; Lopressor HCT; Lotensin HCT; Marpres; Maxzide; Micardis HCT; Moduretic; Monopril-HCT; Normozide¤; Oreticyl¤; Prinzide; Quinaretic; Ser-Ap-Es; Serpasil-Esidrix¤; Teveten HCT; Timolide; Trandate HCT¤; Tri-Hydroserpine; Unipres¤; Uniretic; Vaseretic; Zestoretic; Ziac; Venezuela: Accuretic; Aldactazida; Capozide; Cartazid; Co-Renitec; CoAprovel; Cormatic; Diovan HCT; Hyzaar Plus; Moduretic; Nefrotal H; Priretic; Reminalet; Ziac;



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