• structurally related to sulphonamides
• inhibit the Na/Cl co-transportera the luminal (apical) surface of the distal convoluted tubule
• have lower efficacy than loop diuretics: natriuresis of about 5-8% of the filtered Na load
• have a shallow dose-response curve
• the onset of diuresis is slow (~2-4 weeks)
• less effective in renal failure (GFR < 20ml/min) -> thiazide is not getting to site of action

Short term

• decrease blood volume --> decrease CO

Long term

• decrease Na content of smooth muscle cells --> decrease muscle sensitivity to vasopressors --> decrease peripheral vascular resistance

1. hypokalemia
2. hyponatremia
3. hyperuricemia (gout) - increased reabsorption at the PCT or decreased excretion at the PCT due to competition with diuretics
4. progressive increase in plasma glucose
5. hyperlipidemia
6. erectial dysfunction
7. nocturia

1. increased delivery of Na to the collecting duct activates the Na/K exchanger resulting in K loss and Na reabsorption
2. activation of renin-angiotensin-aldosterone system acts as a compensatory mechanism

• the first drugs of choice for essential hypertension without any other underlying diseases
• NOT recommended for the hypertensive patients with gout or dyslipidemia
• cross the placenta; no direct adverse effect on the fetus but can cause placental hypoperfusion
• excreted in breast milk
• decrease urinary excretion of Ca2+ (protection against osteoporosis)

• hypokalemia increases the risk of quinidine-induced development of polymorphic ventricular tachycardia (torsades de pointes)
• can potentiate arrhythmias that arise from digitalis toxicity
• corticosteroids can amplify the hypokalemia produced by diuretics (mimicking the actions of aldosterone)

hypertension

edema

heart failure (especially congestive)

diabetes insipidus -> HCTZ can treat diabetes insipidus by retaining more volume

hypercalciuria

• inhibit Na/2Cl/K co-transporter in the thick ascending limb of the loop of henle
• inhibit reabsorption of 20-25% of the filtered Na load
• direct vascular effects; increase venous capacitance and thereby decrease left ventricular filling pressure
• block TGF by inhibiting salt transport into the macula densa (stimulates renin release)
• short duration of action (furosemide and bumetanide); rebound Na retention offsets the effectiveness of natriuresis

1. excessive salt and water depletion
2. excessive Na loss
3. hypokalemia
4. hypomagnesemia
5. hypocalcemia - opposite of thiazides
6. hyperuricemia - similar to thiazides
7. ototoxicity with deafness

aminoglycosides

anticoagulants - increased activity

digitalis glycosides - increased arrhythmias

lithium - increased plasma levels

propanolol - increased plasma levels

sulfonylureas - hyperglycemia

• loop diuretics are less effective than thiazide diuretics in the treatment of hypertensive patients with normal renal function
• loops diuretics interfere with NaCl transport by the macula densa -> they are powerful stimulators of renin release
• rebound Na retention due to short half-lives

1. acute pulmonary edema
2. congestive heart failure
3. hypertension
4. edema and ascites of cirrhosis
5. hypercalcemia

• act at the late distal convoluted tubule and cortical collecting duct
• spironolactone and its active metabolite canrenone compete with aldosterone for its cytoplasmic receptors (mineralocorticoid receptors)
• amiloride and triamterene block the Na channel at the luminal surface of the renal tubule
• the maximum natriuresis achieved by K-sparing diuretics is small (< 2-3% of filtered Na)
• used together with thiazide or loop diuretics

1. hyperkalemia - more common in the presence of pre-existing renal disease, in the elderly, and during combination treatment with ACEI
2. hyponatremia - more common with thiazide-amiloride combinations
3. spironolactone has a progestogenic and anti-androgenic effect (impotence, menstrual irregularities)
4. nausea, vomiting, leg cramps

• amilaride and triamterene are contraindicated in patients with hyperkalemia and renal failure, patients receiving other K-sparing diuretics, and patients taking ACEI or K supplements
• spironolactone can induce metablic acidosis in cirrhotic patients
• salicylates may reduce the tubular secretion of canrenone

1. hypertension
2. hypokalemia
3. edema
4. heart failure
5. hyperaldosteronism

Glycerol, Mannitol

• increases osmotic pressure of the plasma
• used to treat cerebral edema and acute glaucoma
• glycerol administered orally and mannitol administered intravenously
• mannitol is filtered at the glomerulus but is not reabsorbed in the renal tubules
• reduces the concentration gradient of Na and thereby retards reabsorption
• mannitol improves renal function in the oliguric phase of renal failure
• the primary adverse effect of mannitol is excessive plasma volume expansion

Acetazolamide

• weak diuretic, seldom used to promote diuresis
• indicated for high-altitude sickness and glaucoma
• carbonic anhydrase is required for the reabsorption of sodium bicarbonate from the PCT and for secretion of H ions in the collecting duct
• acetazolamide causes alkalinization of urine and produces a mild form of metabolic acidosis
• counteracts respiratory alkalosis
• inhibition of CA in the CNS elevates the seizure threshold
• by increasing the pH of the renal tubular fluid, acetazolamide decreases the excretion of weak bases, amphetamine, pseudoephedrine, quinidine

Loop Diuretic

• Short duration of action
• Can cause ototoxicity with deafness

Loop Diuretic

Short duration of action

K⁺- Sparing Diuretic

• Blocks the Na+ channel at the luminal surface of the renal tubule
• Amiloride is contraindicated in patients with hyperkalemia and renal failure, patients receiving other K⁺- Sparing Diuretics, and patients taking ACEI or K⁺ supplements

K+- Sparing Diuretic

• Blocks the Na+ Channel at the luminal surface of the renal tubule
• Contraindicated in patients with hyperkalemia and heart failure, patients receiving other K+- Sparing diuretics, and patients taking other ACEI or K+ supplements

K+- Sparing Diuretic

Spironolactone and its active metabolite canrenone compete with aldosterone for its cytoplasmic  receptors

Adverse Effect:

1. spironolactone has a progestogenic and anti-androgenic effect (impotence, menstrual irregularities)
2. can induce metabolic acidosis in cirrhotic patients