DIURETIC AGENTS

Lourdes T. M. Dominguez, M.D. University of Santo Tomas

Faculty of Pharmacy

DIURETIC AGENTS

DIURETIC AGENTS

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

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

DIURETIC AGENTS RENAL TRANSPORT MECHANISM 2. Thick Ascending Limb of the Loop of Henle (TAL) •  Reabsorption of sodium (20-30%), 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, an escape route must be provided, this occurs into the lumen via a potassium channel; since the potassium diffusing back is not accompanied by an anion, a net positive charge is set up in the lumen, this positive potential drives the reabsorption of calcium and magnesium

DIURETIC AGENTS

DIURETIC AGENTS RENAL TRANSPORT MECHANISM 3. 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

DIURETIC AGENTS RENAL TRANSPORT MECHANISM 4. 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

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DIURETIC AGENTS CARBONIC ANHYDRASE INHIBITORS A. 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. Prototypes and Mechanism of Action •  Well absorbed orally •  Latency = 30 min; 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

DIURETIC AGENTS CARBONIC ANHYDRASE INHIBITORS B. Effects •  Major renal effect is bicarbonate diuresis (eg. 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, resulting in a significant potassium “wasting”

DIURETIC AGENTS CARBONIC ANHYDRASE INHIBITORS B. 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, 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

DIURETIC AGENTS CARBONIC ANHYDRASE INHIBITORS B. Effects •  Urinary alkalinization (excretion of uric acid, cystine, other weak

acids can be enhance by increasing urine pH) •  Metabolic alkalosis •  Adjuvants for the treatment of epilepsy, hypokalemic periodic

paralysis, to increase urinary phosphate excretion during hyperphosphatemia

DIURETIC AGENTS CARBONIC ANHYDRASE INHIBITORS C. 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,

interstitial nephritis •  Contraindications Decrease urinary excretion of NH4 and may contribute to

hyperammonemia and hepatic encephalopathy in patients with cirrhosis

DIURETIC AGENTS LOOP DIURETICS A. Prototypes and Mechanism of Action •  Furosemide (prototype), Bumetanide, and Torsemide

– Sulfonamide derivatives •  Ethacrynic acid

– Phenoxy acid derivative – Acts by the same mechanism – Uricosuric drug

•  Inhibit the cotransport of sodium, potassium and chloride •  Short-acting (diuresis over a 4-hour period) •  Rapidly absorbed •  Excreted by glomerular filtration and tubular secretion

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 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- transporter •  Potassium wasting and proton excretion hypokalemic

alkalosis •  Non-steroidal anti-inflammatory drugs (NSAIDS) decreases the

efficacy •  Pulmonary vasodilating effect

DIURETIC AGENTS LOOP DIURETICS C. Clinical uses •  Treatment of edematous states (heart failure, acute pulmonary

edema, ascites) •  Used in HPN if response to thiazides is inadequate •  Treatment of hypercalcemia (induced by malignancy); managed

by parenteral volume and electrolyte supplementation •  Hyperkalemia •  Acute renal failure – can increase urine flow and enhance K

excretion, can help flush large pigment load and intratubular casts, ameliorate intratubular obstruction

•  Anion overdose – toxic ingestion of bromide, fluoride, iodide

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, eosinophilia, severe

dehydration, hyponatremia •  Contraindication 1. Cirrhosis 2. Borderline renal failure 3. Heart failure

DIURETIC AGENTS THIAZIDE DIURETICS A. 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.  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. Hydrochlorothiazide •  Prototype drug •  Sulfonamide derivative 2. Chlorothiazide •  Not very lipid soluble and must given in large doses •  Slowly absorbed and longer duration of action •  Only thiazide available as parenteral administration

DIURETIC AGENTS THIAZIDE DIURETICS B. 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, carcinoma, sarcoidosis)

DIURETIC AGENTS THIAZIDE DIURETICS B. Effects •  Reduce BP (initially, 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

DIURETIC AGENTS THIAZIDE DIURETICS C. Clinical uses 1. Hypertension and CHF [used for chronic therapy of mild

edematous conditions (mild heart failure)] 2. Nephrolithiasis due to Idiopathic hypercalciuria [stone formation

can be reduced because of reduction in urine calcium concentration]

3. Nephrogenic Diabetes Insipidus

DIURETIC AGENTS THIAZIDE DIURETICS D. Toxicity 1.  Massive sodium diuresis with hyponatremia can be an early

dangerous effect 2.  Potassium wasting and metabolic alkalosis 3.  Diabetic patients may have significant hyperglycemia 4.  Serum uric acid (hyperuricemia) and lipid levels may increase

(hyperlipidemia) 5.  Sulfonamide allergy 6.  Impaired carbohydrates tolerance 7.  Allergic and other reactions – skin rashes, photosensitivity,

hemolytic anemia, thrombocytopenia, acute pancreatitis, acute pulmonary edema, weakness, fatigability, paresthesias, impotence

DIURETIC AGENTS THIAZIDE DIURETICS Contraindications : 1. Cirrhosis to avoid K depletion and hepatic encephalopathy 2. Renal failure (renal insufficiency may be intensified) 3. Digitalis toxicity may manifest as a result of diuretic-induced K

depletion

DIURETIC AGENTS POTASSIUM-SPARING DIURETICS A. Prototypes and Mechanism of Action •  Prevent K secretion by antagonizing the effects of aldosterone

at the cortical collecting tubule •  Inhibition may occur by 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, Amiloride)

DIURETIC AGENTS POTASSIUM-SPARING DIURETICS A. 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.  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

DIURETIC AGENTS POTASSIUM-SPARING DIURETICS B. Effects •  Increase sodium clearance and decrease potassium and

hydrogen excretion •  May cause hyperkalemic metabolic acidosis

DIURETIC AGENTS POTASSIUM-SPARING DIURETICS C. 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, ectopic production, 2° heart failure, cirrhosis, nephrotic syndrome]

DIURETIC AGENTS POTASSIUM-SPARING DIURETICS D. Toxicity 1. Hyperkalemia 2. Hyperchloremic metabolic acidosis (inhibition of H secretion) 3. Gynecosmastia, impotence, BPH (Spironolactone)[endocrine

abnormalities] 4. Acute renal failure (Triamterene combined with Indomethacin) 5. Kidney stones (Triamterene)[slightly soluble, may precipitate in

the urine]

DIURETIC AGENTS POTASSIUM-SPARING DIURETICS D. Toxicity Contraindications 1. Chronic renal insufficiency 2. Liver disease 3. Fatal hyperkalemia with concomitant use of beta blockers and

ACE inhibitors

DIURETIC AGENTS OSMOTIC DIURETICS A. Prototype and Mechanism of Action •  Mannitol is the prototype •  Glycerin, Isosorbide, 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

DIURETIC AGENTS OSMOTIC DIURETICS A. Prototype and Mechanism of Action •  Major location of action is at the PCT, 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)

DIURETIC AGENTS OSMOTIC DIURETICS C. Clinical uses •  Used to maintain high urine flow 1. When renal blood flow is reduced 2. Solute overload (eg. severe hemolysis, rhabdomyolysis) 3. Reduce IOP in acute glaucoma 4. Reduce intracranial pressure in neurologic conditions

DIURETIC AGENTS OSMOTIC DIURETICS D. 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, nausea and vomiting •  Dehydration [leading to hypernatremia], hyperkalemia [as water

is extracted from cells]

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

DIURETIC AGENTS ANTIDIURETIC HORMONE ANTAGONISTS B. 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. 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]

DIURETIC AGENTS ANTIDIURETIC HORMONE ANTAGONISTS C. 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 Clinical Pharmacology of Diuretic Agents A. Edematous States 1. Heart failure 2. Hepatic cirrhosis 3. Kidney diseases 4. Idiopathic edema B. Nonedematous States 1. Hypertension 2. Nephrolithiasis 3. Hypercalcemia 4. Diabetes insipidus