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Lourdes T. M. Dominguez, M.D.
University of Santo Tomas Faculty of Pharmacy
DIURETIC AGENTS RENAL TRANSPORT MECHANISM 1. Proximal convoluted tubule (PCT) • Isosmotic reabsorption of amino acids, glucose, and numerous cation • Major site for sodium chloride (60-70%) reabsorption in exchange for H+ ion • Major site for bicarbonate reabsorption • Bicarbonate is not absorbed through luminal membrane, it is converted to CO2 via carbonic acid to permit reabsorption and regenerated within the tubular cell • Carbonic anhydrase, the enzyme required to reabsorb HCO3 is the target of carbonic anhydrase inhibitor diuretic drugs
DIURETIC AGENTS RENAL TRANSPORT MECHANISM 1. Proximal convoluted tubule (PCT) • Active secretion and reabsorption of weak acids and bases – Weak acid transport occur in the straight S2 segment – Weak bases are transported in the S1 and S2 segments • Uric acid transport .
a net positive charge is set up in the lumen. since the potassium diffusing back is not accompanied by an anion. this occurs into the lumen via a potassium channel. potassium and chloride carried out by a single carrier (cotransporter) [target of loop diuretics] • Major site of calcium and magnesium reabsorption • Potassium is pumped into the cell from both luminal and basal sides. this positive potential drives the reabsorption of calcium and magnesium .DIURETIC AGENTS RENAL TRANSPORT MECHANISM 2. Thick Ascending Limb of the Loop of Henle (TAL) • Reabsorption of sodium (20-30%). an escape route must be provided.
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Distal convoluted tubule (DCT) • Actively pumps sodium and chloride out of the lumen of the nephron • Responsible for the reabsorption of 5-8% of sodium via a contransporter (target of thiazide diuretics) • Calcium is reabsorbed under the control of parathyroid hormone (PTH) • Removal of the reabsorbed calcium back into the blood requires the sodium-calcium exchange process .DIURETIC AGENTS RENAL TRANSPORT MECHANISM 3.
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Cortical Collecting Tubules (CCT) • The principal cells are the major sites of sodium. potassium and water transport • The intercalated cells are the primary sites of H+ secretion • Last tubular site for sodium reabsorption (2-5%) via channels (not a transporter) [controlled by aldosterone] • Reabsorption is accompanied by equivalent loss of K+ or H+ ion • The aldosterone receptor and sodium channels are the sites of K-sparing diuretic action • Primary site of acidification of urine • Reabsorption of water in the collecting tubule is under the control of ADH .DIURETIC AGENTS RENAL TRANSPORT MECHANISM 4.
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Prototypes and Mechanism of Action • Acetozolamide is the prototype • Sulfonamide derivatives • Forerunners of modern diuretics • Inhibition of carbonic anhydrase in the brush border and intracellular carbonic anhydrase in the PCT causing NaHCO3 diuresis and a reduction in total body HCO3 stores • Inhibition of carbonic anhydrase also occurs in other tissues of the body as well as in the kidneys .DIURETIC AGENTS CARBONIC ANHYDRASE INHIBITORS A.
DIURETIC AGENTS CARBONIC ANHYDRASE INHIBITORS A. peak effect in 2 hrs. and persists for 12 hrs. after a single dose • Excreted through the S2 segment of the proximal tubule by tubular secretion • At maximal safely administered dosage. 85% inhibition of proximal bicarbonate reabsorption or 45% inhibition of whole kidney HCO3 reabsorption (Acute HCO3 wasting condition) • CA inhibition causes significant HCO3 losses and hyperchloremic metabolic acidosis . Prototypes and Mechanism of Action • Well absorbed orally • Latency = 30 min.
DIURETIC AGENTS CARBONIC ANHYDRASE INHIBITORS B. Effects • Major renal effect is bicarbonate diuresis (eg. resulting in a significant potassium “wasting” . sodium bicarbonate is excreted) body bicarbonate is depleted and results to metabolic acidosis • Bicarbonate depletion results to slowing of its excretion • Self-limiting diuresis in 2-3 days • As increased sodium is presented to the CCT some of the excess sodium is reabsorbed and potassium is secreted.
acidosis can result to hyperventilation which can protect against high altitude sickness (acute mountain sickness) Used as diuretic if the edema is accompanied by metabolic alkalosis . Effects • Inhibitory effect occurs throughout the body • Useful reduction in IOP in the eye which is not self-limiting Used for the treatment of glaucoma • In the CNS.DIURETIC AGENTS CARBONIC ANHYDRASE INHIBITORS B.
DIURETIC AGENTS CARBONIC ANHYDRASE INHIBITORS B. other weak acids can be enhance by increasing urine pH) • Metabolic alkalosis • Adjuvants for the treatment of epilepsy. hypokalemic periodic paralysis. Effects • Urinary alkalinization (excretion of uric acid. cystine. to increase urinary phosphate excretion during hyperphosphatemia .
DIURETIC AGENTS CARBONIC ANHYDRASE INHIBITORS C. interstitial nephritis • Contraindications Decrease urinary excretion of NH4 and may contribute to hyperammonemia and hepatic encephalopathy in patients with cirrhosis . Toxicities • Drowsiness and paresthesias occur after oral intake • Alkalinization of the urine may cause precipitation of calcium salts and formation of renal stones • Renal potassium wasting • Patients with renal impairment may develop encephalopathy due to ammonia reabsorption • Hypersensivity reactions – fever rashes. BM suppression.
Prototypes and Mechanism of Action • Furosemide (prototype). potassium and chloride • Short-acting (diuresis over a 4-hour period) • Rapidly absorbed • Excreted by glomerular filtration and tubular secretion . Bumetanide. and Torsemide – Sulfonamide derivatives • Ethacrynic acid – Phenoxy acid derivative – Acts by the same mechanism – Uricosuric drug • Inhibit the cotransport of sodium.DIURETIC AGENTS LOOP DIURETICS A.
Prototypes and Mechanism of Action • Loop diuretic reduce the reabsorption of both Na and Cl by inhibiting the Na/K/Cl transporter • Diminish the normal lumen-positive potential across the tubule and cause an increase in Mg and Ca excretion (chronic use has been associated with Mg wasting and severe hypomagnesemia) • Increase of calcium excretion can be useful in acute management of hypercalcemia • Loop agents appear to have direct effects on blood flow through several vascular beds • Reduction in secretion if simultaneously administered with NSAIDs or Probenacid .DIURETIC AGENTS LOOP DIURETICS A.
transporter • Potassium wasting and proton excretion hypokalemic alkalosis • Non-steroidal anti-inflammatory drugs (NSAIDS) decreases the efficacy • Pulmonary vasodilating effect .DIURETIC AGENTS LOOP DIURETICS B. Effects • Full dose produces massive sodium chloride diuresis • Diluting ability of the nephron is reduced (site of significant dilution of urine) • Calcium excretion is increased due to the inhibition of the Na+/K +/2Cl.
ameliorate intratubular obstruction • Anion overdose – toxic ingestion of bromide. managed by parenteral volume and electrolyte supplementation • Hyperkalemia • Acute renal failure – can increase urine flow and enhance K excretion. iodide .DIURETIC AGENTS LOOP DIURETICS C. can help flush large pigment load and intratubular casts. acute pulmonary edema. fluoride. Clinical uses • Treatment of edematous states (heart failure. ascites) • Used in HPN if response to thiazides is inadequate • Treatment of hypercalcemia (induced by malignancy).
DIURETIC AGENTS LOOP DIURETICS D. Toxicity • Can induce hypokalemic metabolic alkalosis • Potassium wasting maybe severe • Can cause hypovolemia and cardiovascular complications • Ototoxicity and sulfonamide allergy • Hypomagnesemia • Hyperruricemia • Allergic and other reactions – skin rashes. Borderline renal failure 3. eosinophilia. Cirrhosis 2. severe dehydration. hyponatremia • Contraindication 1. Heart failure .
Prototype • Hydrochlorothiazide • Sulfonamide derivative • Active by the oral route • 6-12 hours duration of action • Inhibit sodium chloride transport in the early segment of the DCT • Produces moderate sodium and chloride diuresis • Secreted by the organic acid secretory system in the proximal tubule • Competes with the secretion of uric acid [can elevate levels of uric acid] .DIURETIC AGENTS THIAZIDE DIURETICS A.
Chlorothiazide • Not very lipid soluble and must given in large doses • Slowly absorbed and longer duration of action • Only thiazide available as parenteral administration . Hydrochlorothiazide • Prototype drug • Sulfonamide derivative 2.DIURETIC AGENTS THIAZIDE DIURETICS A. Prototype Hypokalemic metabolic alkalosis may occur Few sulfonamide derivatives lack the typical thiazide ring in their structure but have effects similar to thiazides therefore are considered thiazide-like 1.
sarcoidosis) . carcinoma. Effects • Reduction in the transport of sodium into the tubular cell reduces intracellular sodium and promotes sodium-calcium exchange reabsorption of calcium urine calcium content is decreased • Opposite of loop diuretics • Rarely cause hypercalcemia but may unmask hypercalcemia due to other causes (hyperparathyroidism.DIURETIC AGENTS THIAZIDE DIURETICS B.
reflects reduction in blood volume) • Reduce vascular resistance (continued use) [effect is modest but significant and maximal at doses lower than the maximal diuretic dosage] • Synergistic effect with loop diuretic producing marked diuresis • Actions of thiazides can be inhibited by NSAIDs . Effects • Reduce BP (initially.DIURETIC AGENTS THIAZIDE DIURETICS B.
Clinical uses 1. Nephrogenic Diabetes Insipidus . Nephrolithiasis due to Idiopathic hypercalciuria [stone formation can be reduced because of reduction in urine calcium concentration] 3.DIURETIC AGENTS THIAZIDE DIURETICS C. Hypertension and CHF [used for chronic therapy of mild edematous conditions (mild heart failure)] 2.
Allergic and other reactions – skin rashes. Massive sodium diuresis with hyponatremia can be an early dangerous effect 2. Serum uric acid (hyperuricemia) and lipid levels may increase (hyperlipidemia) 5. acute pulmonary edema. fatigability. Sulfonamide allergy 6. impotence . acute pancreatitis. Potassium wasting and metabolic alkalosis 3. Diabetic patients may have significant hyperglycemia 4.DIURETIC AGENTS THIAZIDE DIURETICS D. thrombocytopenia. Impaired carbohydrates tolerance 7. weakness. Toxicity 1. paresthesias. photosensitivity. hemolytic anemia.
Renal failure (renal insufficiency may be intensified) 3. Cirrhosis to avoid K depletion and hepatic encephalopathy 2. Digitalis toxicity may manifest as a result of diuretic-induced K depletion .DIURETIC AGENTS THIAZIDE DIURETICS Contraindications : 1.
Direct antagonism at the level of cytoplasmic mineralocorticoid receptors (Spirolactones) 2. Suppression of renin or angiotensin II generation (ACE inhibitors) 3. Direct inhibition of Na transport through ion channels in the luminal membrane (Triamterene. Prototypes and Mechanism of Action • Prevent K secretion by antagonizing the effects of aldosterone at the cortical collecting tubule • Inhibition may occur by 1.DIURETIC AGENTS POTASSIUM-SPARING DIURETICS A. Amiloride) .
Prototypes and Mechanism of Action • Combine and block intracellular aldosterone receptor reduce expression of genes controlling synthesis of sodium ion channels and Na+/K+ ATPase • Actions can be inhibited by NSAIDs [dependent on renal prostaglandin production] .DIURETIC AGENTS POTASSIUM-SPARING DIURETICS A.
Prototypes and Mechanism of Action SPIRONOLACTONE Synthetic steroids that acts as a competitive antagonist to aldosterone [bind to aldosterone receptors and reduce intracellular formation of active metabolites of aldosterone] Inactivation occurs in the liver Slow onset of action with full therapeutic effect achieved after several days EPLERENONE A spironolactone analog with greater selectivity for aldosterone receptor .DIURETIC AGENTS POTASSIUM-SPARING DIURETICS A.
DIURETIC AGENTS POTASSIUM-SPARING DIURETICS A. Prototypes and Mechanism of Action TRIAMTERENE • Extensively metabolized in the liver • Major route of elimination is via the kidneys • Short half-life. given more frequently • Direct inhibitor of Na influx in the cortical collecting tubule AMILORIDE • Excreted unchanged in the urine • A pyrazine carbonyl-guanidine derivative • 50% oral absorption • Direct inhibitor of Na influx in the cortical collecting tubule .
Effects • Increase sodium clearance and decrease potassium and hydrogen excretion • May cause hyperkalemic metabolic acidosis .DIURETIC AGENTS POTASSIUM-SPARING DIURETICS B.
Clinical use • Treatment of potassium wasting caused by chronic therapy with loop and thiazide diuretics (combination in a single pill) • Treatment of hyperaldosteronism (mineralocorticoid excess) [1° Conn’s syndrome. cirrhosis. ectopic production. nephrotic syndrome] . 2° heart failure.DIURETIC AGENTS POTASSIUM-SPARING DIURETICS C.
may precipitate in the urine] . Hyperchloremic metabolic acidosis (inhibition of H secretion) 3.DIURETIC AGENTS POTASSIUM-SPARING DIURETICS D. BPH (Spironolactone)[endocrine abnormalities] 4. Kidney stones (Triamterene)[slightly soluble. Gynecosmastia. Toxicity 1. Acute renal failure (Triamterene combined with Indomethacin) 5. impotence. Hyperkalemia 2.
DIURETIC AGENTS POTASSIUM-SPARING DIURETICS D. Fatal hyperkalemia with concomitant use of beta blockers and ACE inhibitors . Chronic renal insufficiency 2. Toxicity Contraindications 1. Liver disease 3.
DIURETIC AGENTS OSMOTIC DIURETICS A. Isosorbide. Prototype and Mechanism of Action • Mannitol is the prototype • Glycerin. Urea [these are rarely used] • Freely filtered at the glomerulus but poorly reabsorbed in the tubules remains in the lumen and “holds” water by virtue of osmotic effect • Given intravenously • Sodium excretion is increased because the rate of urine flow is accelerated .
Prototype and Mechanism of Action • Major location of action is at the PCT.DIURETIC AGENTS OSMOTIC DIURETICS A. where the bulk of isoosmotic reabsorption normally takes place • Reabsorbtion of water is also reduced in the ascending limb of the loop of Henle and collecting tubule .
DIURETIC AGENTS OSMOTIC DIURETICS B. Effects • Increased urine volume • Increased excretion of most filtered solutes unless they are actively reabsorbed • Increased sodium excretion [because of accelerated urine flow in the tubules and sodium transporters cannot handle the volume rapidly enough] • Reduce brain volume and intracranial pressure (neurologic conditions) by osmotically extracting water from the tissue • With similar effect in the eye (acute glaucoma) .
severe hemolysis. rhabdomyolysis) 3. Reduce IOP in acute glaucoma 4.DIURETIC AGENTS OSMOTIC DIURETICS C. Clinical uses • Used to maintain high urine flow 1. When renal blood flow is reduced 2. Reduce intracranial pressure in neurologic conditions . Solute overload (eg.
hyperkalemia [as water is extracted from cells] .DIURETIC AGENTS OSMOTIC DIURETICS D. nausea and vomiting • Dehydration [leading to hypernatremia]. Toxicities • Extracellular volume expansion [prior to diuresis because mannitol is rapidly distributed in extracellular compartment and extracts water from cells] causing hyponatremia and pulmonary edema in patients with heart failure • Headache.
DIURETIC AGENTS ANTIDIURETIC HORMONE AGONISTS A. Prototypes and Mechanism of Action • Antidiuretic hormone (ADH) [Vasopressin] and Desmopressin Prototypes ADH agonists Peptides Given IV Used in the treatment of central diabetes insipidus Renal action is mediated by V2 receptors and V1a receptors .
DIURETIC AGENTS ANTIDIURETIC HORMONE ANTAGONISTS A. Prototypes and Mechanism of Action Conivaptan • Nonpeptide ADH receptor antagonist (vaptan) approved for use • Orally active • Inhibit effects of ADH in the collecting tubule • Pharmacologic antagonist at V1a and V2 receptors Demeclocycline • A tetracycline antimicrobial drug • Orally active • Inhibit effects of ADH in the collecting tubule • Reduce the formation of cAMP in response to ADH • Interfere with the actions of cAMP in the collecting tubule cells • Mechanism is unknown .
DIURETIC AGENTS ANTIDIURETIC HORMONE ANTAGONISTS A. Prototypes and Mechanism of Action Lithium • Orally active • Has anti-ADH effects but is never used as an ADH antagonist • Inhibit effects of ADH in the collecting tubule • Reduce the formation of cAMP in response to ADH • Interfere with the actions of cAMP in the collecting tubule cells • Mechanism is unknown .
Effects and Clinical uses • Treatment of Syndrome of Inappropriate ADH secretion (SIADH) Condition where peptides are produced by certain tumors Can cause water retention and dangerous hyponatremia Lithium carbonate gives unpredictable response Demeclocycline yields more predictable resulst and less toxic Conivaptan given via IV. not suitable for chronic use in outpatients .DIURETIC AGENTS ANTIDIURETIC HORMONE ANTAGONISTS B.
DIURETIC AGENTS ANTIDIURETIC HORMONE ANTAGONISTS B. Effects and Clinical uses • Pituitary diabetes insipidus ADH and Desmopressin are useful Not useful for nephrogenic diabetes insipidus C. Toxicities Nephrogenic diabetes insipidus If serum sodium is not monitored ADH antagonists may cause severe hypernatremia and Nephrogenic DI Patients with psychiatric disorder and treated with Lithium can develop Nephrogenic DI [can be treated with thiazide diuretic or amiloride] .
Toxicities Renal failure Caused by Lithium and Demeclocycline Lithium can cause chronic interstitial nephritis Demeclocycline causes bone and teeth abnormalities in children younger than 12 years old and those with liver disease .DIURETIC AGENTS ANTIDIURETIC HORMONE ANTAGONISTS C.
Hypercalcemia 4. Heart failure 2. Hypertension 2. Diabetes insipidus . Edematous States 1. Kidney diseases 4. Nonedematous States 1. Idiopathic edema B.DIURETIC AGENTS Clinical Pharmacology of Diuretic Agents A. Hepatic cirrhosis 3. Nephrolithiasis 3.
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