Lange Pharm Ch 15

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Drugs that modify salt excretion in the PCT

Back 1

carbonic anhydrase inhibitors

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Drugs that modify salt excretion in the TAL (thick ascending loop of Henle)

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loop diuretics

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Drugs that modify salt excretion in the DCT

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thiazides

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Drugs that modify salt excretion in the CCT (cortical collecting tubule)

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K+ sparing diuretics

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Drugs that modify salt excretion

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osmotic diuretics

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Drugs that modify water excretion

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osmotic diuretics

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Drugs that modify water excretion

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ADH agonists & antagonists

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Bicarbonate diuretic

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a diuretic that selectively increases Na+ bicarbonate excretion. Example: a carbonic anhydrase inhibitor (acetazolamide)

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Diluting segment

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a segment of the nephron that removes solute without water; the thick ascending limb and the distal convoluted tubule are active salt-absorbing segments that are not permeant to water

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Hyperchloremic metabolic acidosis

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A shift in body electrolyte and pH balance involving elevated chloride, diminished bicarbonate concentration, and a decrease in pH in the blood. Typical result of bicarbonate diuresis.

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Hypokalemic metabolic alkalosis

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A shift in body electrolyte balance and pH involving a decrease in serum potassium and an increase in blood pH. Typical result of loop and thiazide diuretic actions.

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Nephrogenic diabetes insipidus

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Loss of urine-concentrating ability in the kidney caused by lack of responsiveness to antidiuretic hormone (ADH is normal or high)

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Pituitary diabetes insipidus

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Loss of urine-concentrating ability in the kidney caused by lack of antidiuretic hormone (ADH is low or absent)

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Potassium-sparing diuretic

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A diuretic that reduces the exchange of K+ for Na+ in the collecting tubule; a drug that increases sodium and reduces potassium excretion. Example: aldosterone antagonists. (spironolactone, eplerenone, amiloride, triamterene)

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Uricosuric diuretic

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A diuretic that increases uric acid excretion, usually by inhibiting uric acid reabsorption in the proximal tubule. Example: ethacrynic acid

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Proximal convoluted tubule (PCT)

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isosmotic reabsorption of amino acids, glucose and numerous cations. Major site for NaCl and NaHCO3. The proximal tubule is responsible for 60-70% of the total reabsorption of sodium. No currently available drug directly acts on NaCl reabsorption in the PCT.

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Thick ascending limb of the loop of Henle (TAL)

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This segment pumps Na+, K+ and Cl- out of the lumen into the interstitium. It is also a major site of Ca+ and Mg++ reabsorption. Reabsorption of Na+, K+ and Cl- are all accomplished by a single carrier, which is the target of the loop diuretics. This cotransporter provides part of the concentration gradient for the countercurrent concentrating mechanism and is responsible for the reabsorption of 20-30% of the Na+ filtered at the glomerulus.

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Distal convoluted tubule (DCT)

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Actively pumps Na+ and Cl- out of the lumen of the nephron via their carrier. This cotransporter is the target for the thiazide diuretics. The DCT is responsible for approximately 5-8% of Na+ reabsorption. Ca+ is also reabsorbed in this segment under the control of PTH. Removal of the reabsorbed Ca+ back into the blood requires the Na+/Ca+ exchange process.

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Cortical collecting tubule (CCT)

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The final segment of the nephron is the last tubular site of Na+ reabsorption and is controlled by aldosterone. This segment is responsible for reabsorbing 2-5% of the total filtered sodium. The reabsorption of Na+ occurs via channels (not a transporter) and is accompanied by an equivalent loss of K+ or H+. The collecting tubule is the primary site of acidification of the urine and of K+ excretion. The aldosterone receptor and the Na+ channels are sites potassium-sparing diuretics. Reabsorption of water occurs in the medullary collecting tubule under the control of ADH.

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Carbonic anhydrase inhibitors prototypes

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Acetazolamide is the prototypical carbonic anhydrase inhibitor

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Per Krueger:
Carbonic anhydrase inhibitor

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Acetazolamide

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Per Krueger:
Diuretic used for mountain sickness and glaucoma

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Acetazolamide

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Per Krueger
SE of acetazolamide

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Paresthesias, alkalization of the urine (which may ppt. Ca salts), hypokalemia, acidosis, and encephalopathy in patients with hepatic impairment

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MOA of acetazolamide (carbonic anhydrase inhibitor)

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Inhibition of carbonic anhydrase in the brush border and intracellular carbonic anhydrase in the PCT cells. Inhibition of carbonic anhydrase occurs in other cells of the body.

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Effect of acetazolamide (carbonic anhydrase inhibitor)

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The major renal effect is bicarbonate diuresis (i.e., sodium bicarbonate is excreted); body bicarb is thus depleted, and metabolic acidosis results. As increased sodium is presented to the cortical collecting tubule, some of the excess sodium is reabsorbed and K+ is secreted resulting in significant potassium "wasting." As a result of bicarb depletion, NaHCO3 excretion slows and the diuresis is self-limiting within 2-3 days. In the eye, a useful reduction in intraocular pressure can be achieved. In the CNS, acidosis of the cerebrospinal fluid results in hyperventilation, which can protect against high-altitude sickness.

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The major application of carbonic anhydrase inhibitors is in the treatment of

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glaucoma. Also high-altitude sickness. These agents are used for their diuretic effect only if edema is accompanied by significant metabolic alkalosis.

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Loop diuretics prototypes

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Furosemide is the prototypical loop agents. Furosemide, bumetanide and torsemide are sulfonamide derivatives. Ethacrynic acid is a phenoxyacetic acid derivative; it is not a sulfonamide but acts by the same mechanism.

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Per Krueger:
MOA of loop diuretics

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inhibits Na+/K+/2Cl- cotransport
(Lange: Loop diuretics inhibit the cotransport of Na+, K+ and Cl-. The loop diuretics are relatively short acting -- over a 4-h period following dose)

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Per Krueger:
Site of action of loop diuretics

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Thick ascending limb

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Per Krueger:
SE of loop (furosemide) diuretics

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Hyperuricemia, hypokalemia and ototoxicity

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Per Krueger:
Aminoglycosides used with loop diuretics potentiate adverse effect

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Ototoxicity

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Per Krueger:
Loops lose and thiazide diuretics retain

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Calcium

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Effects of Loop diuretics (furosemide, etc.)

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The Loop is responsible for a significant fraction of total renal sodium NaCl reabsorption; therefore, a full dose of a loop diuretic produces a massive sodium chloride diuresis. If tissue perfusion is adequate, edema fluid is rapidly excreted and blood volume may be significantly reduced. Inhibition of the Na+/K=/2Cl- transporter also results in loss of the lumen-positive potential which reduces reabsorption of divalent cations as well. As a result, Ca++ excretion is significantly increased.

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Clinical use of loop diuretics

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treatment of edematous states (heart failure, ascites). Particularly valuable in acute pulmonary edema. Sometimes used in hypertension if response to thiazides is inadequate but short duration of action of loops is a disadvantage in this condition. Also treatment of severe hypercalcemia (like in malignancy).

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Loop diuretics usually induce

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hypokalemic metabolic alkalosis. Wasting of K+ may be severe. Because they are so efficacious, loops can cause hypovolemia and cardiovascular complications. Ototoxicity is an important toxic effect.

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Per Krueger:
MOA of thiazide diuretics

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Inhibit Na+/Cl- cotransport

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Per Krueger:
Site of action of thiazide diuretics

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Work at early distal convoluted tubule

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Per Krueger:
Class of drugs that may cause cross-sensitivity with thiazide diuretics

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Sulfonamides

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Per Krueger:
SE of thiazide (HCTZ) diuretics

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Hyperuricemia, hypokalemia and hyperglycemia

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Thiazide diuretics prototypes

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Hydorchlorothiazide is the prototypical agent. All members of this group are sulfonamide derivatives.

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Thiazides are active by the oral route and have a duration of action of

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6-12 h, considerably longer than most loop diuretics.

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The major action of thiazides is

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to inhibit NaCl transport in the early segment of the DCT

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Effects of thiazides

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In full doses, thiazides produce moderate but sustained sodium and chloride diuresis. Hypokalemic metabolic alkalosis may occur. Also, reabsorption of Ca+ is increased which is OPPOSITE of the effect of loops. Thiazides + loops are synergistic with marked diuresis.

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Clinical use of thiazides.

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In hypertension (long duration and moderate intensity). Chronic therapy of edmatous conditions such as mild heart failure is another application although loops are usually preferred. Also chronic renal calcium stone formation can sometimes be controlled with thiazides because of their ability to reduce urine Ca+ concentration.

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Toxicity of thiazides

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massive Na+ diuresis with hyponatremia is uncommon but dangerous. Chronic therapy is often associated iwth K+ wasting since an increased sodium load is presented to the collecting tubules.

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Per Krueger:
Potassium sparing diuretics inhibit

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Na+/K+ exchange

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Per Krueger:
Diuretic used to treat primary aldosteronism

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Spironolactone

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Per Krueger:
SE of spironolactone

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Gynecomastia, hyperkalemia, and impotence

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K+-sparing diuretics prototypes

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Spironolactone and eplerenone are steroid derivaties and act as pharmacologic antagonists of aldosterone in the collecting tubules.By combining with and blocking the intracellular aldosterone receptor, these drugs reduce the expression of genes controlling synthesis of epithelial sodium ion channels and Na+/K+ ATPase. Amiloride and triamterene act by blocking the epithelial sodium channels in the same portion of the nephron.

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Effects of K+ sparing diuretics (spironolactone, etc.)

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All drugs in this class cause an increase in Na+ clearance and a decrease in K+ and H+ excretion and therefore qualify as K+ sparing diuretics. They may cause hyperkalemic metabolic acidosis.

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Clinical use of K+ sparing diuretics

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Aldosteronism (e.g., the elevated serum aldosterone levels that occur in cirrhosis) is an important indication for spironolactone. Aldosteronism is also a feature of heart failure, and spironolactone and eplerenone have been shown to have significant long-term benefits in this condition.

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Toxicity of K+ sparing diuretics

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Most important toxic effect is hyperkalemia. These drugs should never be given with K+ supplements. Other aldosterone antagonists (such as ACE inhibitors and angiotensin receptor blockers) if used at all, should be used with caution.

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Per Krueger:
Osmotic diuretic used to treat increased intracranial pressure

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Mannitol

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Osmotic diuretics prototypes

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Mannitol is given IV. Other drugs often classified with mannitol but rarely used include glycerin, isosorbide and urea.

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MOA of mannitol

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It is freely filtered at the glomerulus but poorly reabsorbed from the tubule so mannitol "holds" water by virtue of its osmotic effect. Major location is the proximal convoluted tubule where the bulk of isosmotic reabsorption normall occurs. Reabsorption of water is also reduced in the descending limb of the loop of Henle and the collecting tubule.

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effects of osmotic diuretics

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The volume of urine is increased. Most filtered solutes will be excreted in larger amounts.

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Clinical use of osmotic diuretics

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Used to maintain high urine flow. Mannitol and several other osmotic agents are useful in reducing intraocular pressure in acute glaucoma and intracranial pressure in neurologic conditions

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Toxicity of osmotic diuretics

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removal of water from the intracellular compartment may cause hyponatremia and pulmonary edema. As the water is excreted, hypernatremia may follow. Headache, nausea and vomiting are common.

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Per Krueger:
ADH agonist used for pituitary diabetes insipidus

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Desmopressin (DDAVP)

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Per Krueger:
Used for SIADH
(Syndrome of inappropriate antidiuretic hormone hypersecretion)

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Demeclocycline

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Per Krueger:
SE of demeclocycline

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Bone marrow and teeth discoloration for children under 8 years of age

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ADH agonists and antagonists prototypes

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ADH and desmopressin are prototypical ADH agonists. Demeclocycline and conivaptan and ADH antagonists.

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ADH MOA

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ADH facilitates water reabsorption from the collecting tubule by activation of V2 receptors which stimulate adenylyl cyclase via Gs. The increased cAMP causes the insertion of the additional aquaporin AQP2 water channels into the luminal membrane in this part of the tubule.

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Conivaptan (ADH antagonist)

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is an ADH inhibitor at V1a and V2 receptors.

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Demeclocycline and lithium (ADH antagonists) inhibit

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the action of ADH at some point distal to the generation of cAMP.

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Effects of ADH and demopressin (agonists)

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reduce urine volume and increase its concentration. Useful in pituitary diabetes insipidus. No value in the nephrogenic form of the disease.

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ADH antagonists (demeclocycline and conivaptan)

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oppose the actions of ADH and other naturally occurring peptides that act on the same V2 receptor.

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Syndrome of inappropriate ADH secretion (SIADH)

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ADH and other naturally occurring peptides act on the V2 receptor. Such peptides are produced by certain tumors (e.g., small cell carcinoma of the lung) and can cause significant water retention and dangerous hyponatremia. SIADH can be treated with demeclocycline and conivaptan.

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Toxicity of ADH agonists

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A large water load may cause dangerous hyponatremia.