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thiazides
- 2. Introduction • The thiazides are the most widely used of the diuretic drugs • Thiazide diuretics are sulfonamide derivatives • All thiazides affect the distal tubule, and all have equal maximum diuretic effects • Are moderately potent diuretics. • They are called ceiling diuretics.
- 3. • Act within 1-2 hours of oral administration Duration of action 12-24 hours. • It take 1-3 weeks to produce a stable reduction of blood pressure. • Administer early in the day • Thiazide diuretics include: Chlorothiazide and Hydrochlorthiazide. Bendroflumethiazide. Chlortalidone. Metolazone. Xipamide and Indapamide.
- 4. Mechanism of action • Inhibit reabsorption of Na+ and Cl- in the distal convoluted tubule this results in water retention. • Decrease reabsorption of Sodium by inhibition of Na+/Cl- cotransporter on the luminal membrane of the distal convoluted tubule. • Their effect on the proximal convoluted tubule is less. • The acid-base balance is not usually affected.
- 5. • These drugs must be excreted into the tubular lumen to be effective. Therefore with decreased renal function thiazides are not effective. • Thiazide diuretics decrease the Ca2+ content of urine by promoting the reabsorption of Ca2+.
- 6. Indication • Hypertension: reduce systolic and diastolic blood pressure. Either used alone or with B- BKs, ACEI. • Heart Failure: Diuretic of choice in reduction of extracellular volume in mild to moderate heart failure if they fail loop diuretic can be used.
- 7. • Hypercalciuria: They inhibit urinary Ca2+ excretion thus of benefit for patients with calcium oxalate stones in the urinary tract. • Diabetes insipidus: by production of a hyperosmolar urine, they substitute antidiuretic hormone in treatment of nephrogenic diabetes insipidus.
- 8. Adverse effect • 1- Hypokalaemia • 2- Hyponatremia • 3- Orthostatic hypotension • 4- Hypercalcemia • 5- hyperuricemia
- 9. Adverse effect (cont) • 6- Hyperglycemia 7- Hyperlipidemia • 8- Hypersensitivity 9- Renal impairment
- 10. Diuretic- thiazides • Chlorothiazide: First orally active thiazide with minimum side effects. • Newer derivatives: • Hydrochlorthiazide • Bendroflumethiazide
- 11. Thiazide like analogs • 1- Chlorthalidone: is a nonthiazide derivative that behaves pharmacologically like hydrochlorothiazide. It has a very long duration of action and, therefore, is often used to treat hypertension. • 2- Metolazone : is more potent than the thiazides and, unlike the thiazides, causes Na+ excretion in advanced renal failure.
- 12. • 3- Xipamide and Indapamide: chemically related to chlortalidone cause less metabolic disturbances, less diabetes mellitus. At low dose act as anti HT withminimal diuretic effect.they are excreted primarily by the biliary system.
- 13. Drug –drug Interactions • Many of the interactions of hydrochlorothiazide and other thiazides are due to their effects on fluid and electrolyte balance. 1. Diuretic x digitalis glycosides (hypokalimea & cardiacarrhythmia) 2. Diuretic x astemizole (non-sedating antihistamine) …… (arrhythmias) (QT) 3. Diuretic x atracurium (enhance N M blockerer) . (hypokalaemea)
- 14. • drug may enhance the hypokalemic effect of diuretic. • Corticosteroids • B2 agonists ( salbutamol) • carbenoxolone, (oral ulcer) • amphotericin B (anti B) • Reboxetine ( I reuptake noradrenaline) • Diuretics X antihypertensives may enhance hypotension if used with (a-blockers or ACEI • Orthostatic hypotension associated with diuretics may be enhanced by alcohol, barbiturates, or opioids.
- 15. • The antihypertensive effects of diuretics may be antagonised by drugs that cause fluid retention, such as corticosteroids, NSAIDs, or carbenoxolone • Thiazides X oral hypoglycaemics adjusment require • NAIDs nephrotixicity enhance by thiazides • Toxicity of Lithium & tetracyclines enhance • trimethoprim .A,B (hyponatraemia) with thiazid • hydrochlorothiazide X carbamazepine. (hyponatraemia) • Bile-acid binding resins X hydrochlorothiazide • (reduce GIT absorption of thiazide)
- 16. • Calcium salts X chlorothiazide • induce milk-alkali syndrome, characterized by hypocalcaemia, metabolic alkalosis, and renal failure • Hypercalcaemia may also occur in patients taking thiazides with drugs that increase calcium levels, such as vitamin D.
- 17. contraindication *Hypotension *Allergy to sulphur-containing medications *Gout *Renal failure *Hypokalemia *May worsen diabetes • Thiazides can decrease placental perfusion and adversely affect the fetus so should be avoided in pregnancy.