Diuretic Agents

What are the thiazide diuretics?

Chlorothiazide, hydrochlorothiazide, indapamide, methyclothiazide, and metolazone

How can thiazides be administered?

Orally

What is the protypical thiazide diuretic?

Hydrochlorothiazide

What is the mechanism of action of thiazide diurectics?

They increase the urinary excretion of sodium and chloride by inhibiting the Na+/Cl- symporter in the distal convoluted tubule and early distal collecting tubules of the nephron

What occurs as a result of thiazide diuretic action?

Loss of potassium accompanies natriuresis, increased calcium reabsorption in the DCT, and decreased urinary excretion of calcium

How can thiazide diuretics be used to treat kidney stones?

Decreased urinary excretion helps to treat kidney stones

What are the therapeutic uses of thiazide diuretics?

Hypertension, heart failure, nephrolithiasis, and nephrogenic diabetes insipidus

How can thiazide diuretics be used to treat nephrogenic diabetes insipidus?

They exert a paridoxical ADH effect and reduce the excessive urine volume dramaticaly

What are the adverse effects of thiazide diuretics?

Hypokalemia, hyponatremia, hypercalcemia, hyperuricemia, hyperglycemia, hyperlipidemia, metabolic alkalosis, and allergic reactions

What is the most common adverse effect of thiazide diuretics?

Hypokalemia

Why do thiazide diuretics have the adverse effect of hyperuricemia?

They increase uric acid reabsorption and increase the risk for gout

Why do thiazide diuretics have the adverse effect of hyperglycemia?

They man decrease insulin sensitivity and tissue utilization of glucose in some patients

What is the severity of hyperlipidemia caused by thiazide diuretics?

Total serum cholesterol and LDL increase ~5-12%

Why do thiazide diuretics have the adverse effect of metabolic alkalosis?

There is a loss of H+ due to tubular secretion and primary increase in serum HCO3- concentration

What are contraindications and precautions of thiazide diuretics?

Excessive use of any diuretic agents is dangerous in patient with hepatic cirrhosis and renal failure

What are the most efficacious diuretic agents?

Loop diuretics

What is the protypical loop diuretic?

Furosemide

What are the loop diuretics?

Furosemide (Lasix), bumetanide (Bumex), torsemide (Demadex), and ethancrynic acid (Edecrin)

What loop diuretic is not a sulfonamide derivative?

Ethancrynic acid (Edecrin)

What is the mechanism of action of loop diuretics?

Inhibit the luminal Na+/K+/2Cl- co-transporter (NKCl2) in the thick ascending loop of henle of the nephron to inhibit the reabsorption of Na+

Why are loop diuretics the most efficacious diuretic agents?

They inhibit reabsorption of a much greater proportion of filtered Na+ than other diuretics

What occurs as a result of loop diuretic actions?

Water and electrolyte excretion is increased by several times and the reabsorption of Ca2+ and Mg2+ is also hampered

What are the therapeutic uses of loop diuretics?

Acute pulmonary edema, hypertension (severe or in HT crisis) acute renal failure, hypercalcemia, hyperkalemia, and severe edema from CHF, cirrhosis of the liver, and renal disease

What are the less common therapeutic uses of loop diuretics?

Hyperkalemia and Hypercalcemia

What are the adverse effects of loop diuretics?

Hypokalemia, ototoxicity, hyperuricemia, hyponatremia, hypomagnesemia, allergic reactions, and dehydration

When is ototoxicity a common adverse effect of loop diuretics?

In patients on aminoglycoside antibiotics

How can the adverse effect of ototoxicity with loop diuretics be fixed?

It is usually dose related and reversible

What loop diuretic has the highest risk of ototoxicity?

Ethancrynic acid

What are contraindications of loop diuretics?

Patients who are allergic to sulfonamides (except ethancrynic acid)

What are precautions of loop diuretics?

Hepatic cirrhosis and overzealous use of any diuretic to patients with heart failure

What are the potassium sparing diuretics?

Spironolactone, eplerenone, amiloride, and triamterene

How can potassium sparing diuretics be administered?

Orally

What is spironolactone?

Synthetic steroid

What is eplerenone?

Spironolactone analog

What is the mechanism of action of spironolactone and eplerenone?

Act as a competitive antagonists at aldosterone receptors in the collecting ducts of the nephron

What is the result of spironolactone and eplerenone action?

Blunt aldosterone activity in the collecting ducts of the nephron leading to Na+ loss and K+ reabsorption

How is the action of eplerenone different than spironolactone?

Eplerenone is highly selective with fewer hormonal side effects

What is the mechanism of action of amiloride and triamterene?

It is a direct inhibitor of Na+ influx on the collecting tubule/duct of the nephron

What is the result of amiloride and triamterene action?

Decreased intracellular Na+ levels which leads to the dysfunction of the Na+/K+ ATPase, leading to K+ retention

How is the action of triamterene different than amiloride?

Triamterine is less potent and more toxic than amiloride

What are the therapeutic uses of potassium sparing diuretics?

CHF, hypertension, primary hyperaldosteronism and secondary hyperaldosteronism caused by heart failure and nephrotic syndrome, and edema

What are off-label therapeutic uses of spironolactone?

Antiandrogen for cystic acne and baldness treatment

What is the main adverse effect of potassium sparing diuretics?

Hyperkalemia

What adverse effect is seen in triamterene and amiloride?

Metabolic acidosis

How do triamterene and amiloride cause metabolic acidosis?

By inhibiting H+ secretion in parallel with K+ secretion

What are adverse effects of spironolactone?

Gynecomastia, antiandrogen effects, hepatotoxicity, and CNS depression

What has been reported in patients with triamterene and indomethacin?

Acute renal failure

What may precipitate the adverse effect of hypercalemia in potassium sparing diuretic use?

Drugs such as beta blockers or ACE inhibitors or diseases such as liver or kidney diseases

What are the carbonic anhydrase inhibitors?

Acetazolamide and dorzolamide

What are carbonic anhydrase inhibitors rarely used as?

Diuretics, as they are only weak diuretics

What is the mechanism of action of carbonic anhydrase inhibitors?

Inhibit carbonic anhydrase

What is the result of carbonic anhydrase inhibitor actions?

Decreased H+ secretion at the renal tubule, promotion of excretion of HCO3- that subsequently leads to metabolic acidosis, and decreased production of aqueous humor

What is the main use of acetazolamide?

To inhibit carbonic anhydrase activity in both the eyes and brain

What is the impact of acetazolamide action on aqueous humor production?

Inhibition of carbonic anhydrase of the ciliary body decreases HCO3- formation, reducing sodium and fluid transport into the eye, which lowers aqueous humor production

What is the impact of acetazolamide action on cerebrospinal fluid production?

It inhibits carbonic anhydrase of the choroid plexus, which involves HCO3- secretion in the production of CHF

What are the theraeputic uses of carbonic anhydrase inhibitors?

Glaucoma, acute mountain sickness, and idiopathic intracranial hypertension and epilepsy

What are the adverse effects of carbonic anhydrase inhibitors?

Metabolic acidosis, GI upset, and tinnitus

What common symptoms follow large doses of acetazolamide?

Drowsiness and paresthesia (burning or prickleing sensation)

What is the protypical osmotic diuretic?

Mannitol

How is mannitol absorbed?

Poorly by the GI tract

How is manitol excreted?

By golmerular filtration via original form

What is the mechanism of action of mannitol?

Increases osmotic pressure of glomerular filtrate, thus increasing urine output by decreasing fluid and electrolyte absorption

What are the therapeutic uses of mannitol?

CNS edema to decrease intracranial pressure, glaucoma to decrease intraocular pressure, drug overdose, and as a diuretic agent in drug toxicity patients with renal failure

What drug overdoses is mannitol particularly useful in?

Cardiac glycoside drug toxicity

What are the adverse effects of mannitol?

Dehydration, hyperkalemia, and hypernatremia may occur

What are contraindications of mannitol?

Anuria and heart failure

What are the antidiuretic hormone antagonists?

Conivaptan and tolvaptan

What is the mechanism of action of antidiuretic hormone antagonists?

Inhibit the effects of ADH in the collecting tubule of the nephron

What receptors does conivaptan block?

V1 and V2 receptors in the nephron

What receptor does tolvaptan block?

Only V2 receptors of the nephron

What are the therapeutic uses of antidiuretic hormone antagonists?

Correction of hyponatremia associated with heart failure, liver cirrhosis, and syndrome of inappropriate ADH secretion

What are the adverse effects of antidiuretic hormone antagonists?

Xerostomia, inhibition of CYP450 enzymes, and orthostatic hypotension