DRUGS ACTING ON THE KIDNEY (DIURETICS) -

DRUGS ACTING ON THE KIDNEY

PHYSIOLOGY OF URINE FORMATION

· Urine formation begins from glomerular filtration.

· Normally about 180 liters of fluid is filtrate every day.

· All blood constitutions are filtrated at the glomerulus.

· More than 99% of the glomerular filtrate is reabsorbed in the tubules.

· About 1.85 liters of urine is produced in 24 hours.

· The tubular reabsorption can be divided into following categories.

PROXIMAL TUBULE

· Transport of Na⁺ and K⁺ coupled to active reabsorption of glucose, amino acid etc.

· PT cell secrete H⁺ with the help of Na⁺, H⁺ antiport at the luminal membrane (Na⁺, H⁺exchanger).

· Na⁺ is reabsorbed inside the cell and exchange K⁺ through Na⁺, K⁺ ATPase.

· PT regulates acid, base balance, secrete H⁺ combine with HCO₃^– in the tubular fluid to form carbonic acid.

· This H₂CO₃ is broken into H₂O and CO₂ by the enzyme carbonic anhydrase (CAs).

· Both H₂O and CO₂diffuse inside the cell and recombine to form H₂CO₃ by the enzyme CAs.

· The dissociated HCO₃^– in the cell is transported to basolateral membrane with Na⁺ (Na⁺, HCO₃^– symporter), resulting in net reabsorption of NaHCO₃.

DESCENDING LIMB OF LOOP OF HENLE

· After reabsorbed from PTC, the remaining filtrate which is isotonic, enters the descending limb of loop of Henle and passes into the medulla of the kidney.

· In this portion the water reabsorption takes place due to increased osmolality.

ASCENDING LIMB OF LOOP OF HENLE

· The luminal membrane carrier transports ion in the stoichiometric ratio of Na⁺, K⁺, and 2Cl^–.

· Na⁺ that enters the cell is pumped to extracellular fluid by Na⁺, K⁺ ATPase at the basolateral membrane.

DISTAL CONVOLUTED TUBULES

· The DCT are impermeable to water.

· A least amount of NaCl (nearly 10%) is reabsorbed through Na⁺/Cl^– transporter.

· In this stage the Ca²⁺are transported via Na⁺/Ca²⁺ exchanger into the intestinal fluid. This mechanism Ca²⁺ excretion is regulated by parathyroid hormone.

COLLECTING TUBULE AND DUCT

· The colleting tubule and duct are responsible for Na⁺, K⁺ and water transport, whereas the intercalated cells affect H⁺ secretion.

· Aldosterone influence increase in Na⁺ reabsorption and k⁺ secretion through the Na⁺, K⁺, ATPase pump.

· Antidiuretic hormone (Vasopressin) receptor promote the reabsorption of water from the collecting tubules and ducts.

DIURETICS

· Diuretics promote the removal of excess water, salts, and metabolic products from the body.

· Diuretics increases osmolality and increase water excretion.

· Diuretics are the agents that increase the volume of urine output for the management of hypertension and for the edema.

CLASSIFICATION

1. High efficacy diuretics (Inhibition of Na⁺, K⁺, 2Cl^– cotransporter)

a. Sulphamoyl derivatives

· Furosemide

· Bumetanide

· Torasemide

2. Medium efficacy diuretics (Inhibition of Na⁺, Cl^– symport)

a. Benzothiadiazine (Thiazides)

· Hydrochlorothiazide

· Benzthiazide

· Hydroflumethiazide

· Bendroflumethiazide

b. Thiazide like

· Chlorthalidone

· Metolazone

· Xipamide

· Indapamide

· Clopamide

3. Weak or adjunctive diuretics

a. Carbonic anhydrase inhibitor

· Acetazolamide

b. Potassium sparing diuretics

i. Aldosterone antagonist

· Spironolactone

ii. Inhibition of renal epithelial Na⁺ channel

· Amiloride

c. Osmotic diuretics

· Mannitol

· Isosorbide

· Glycerol

HIGH CEILING (LOOP) DIURETICS

FUROSEMIDE

· The loop diuretics inhibit the Na⁺, K⁺, and 2Cl^– cotransporter in the ascending loop of henle, resulting in retention of Na⁺, Cl^–, and water in the tubule.

ACTION

· Due to high Na⁺ concentration reaching in DT, K⁺excretion is increased.

· Furosemide has weak carbonic anhydrase inhibitory action, so that increase HCO₃^– excretion, but acidosis does not develop due to predominant urinary anion is Cl^–.

· The loop diuretics increase Ca²⁺ concentration of urine, DCT reabsorbed these Ca²⁺ so, hypocalcemia does not occur.

· Loop diuretics may enhance the prostaglandin synthesis (inhibit NSAIDs).

PHARMACOKINETICS

· Rapid oral absorption, but bioavailability is 60%.

· Administration orally or parenterally.

· Duration of action 2-4 hours.

· t ½ – 1-2 hours.

ADVERSE EFFECTS

· Ototoxicity: Reversible or permanent hearing loss.

· Hyperuricemia

· Hypotension

· Acute hypovolemia: Rapid reduction of blood volume.

· Hypomagnesemia: Chronic se of loop diuretics.

THERAPEUTIC USES

· Edema

· Acute pulmonary edema

· Cerebral edema: Fluid buildup around the brain.

· Hypertension

· Hypercalcemia of malignancy: Increase Ca²⁺ level.

MEDIUM EFFICACY DIURESIS (Inhibition of Na⁺, Cl^– symport)

THIAZIDES & THIAZIDES LIKE

· The thiazide and thiazide-like diuretics act mainly in the cortical region of thick ascending limb of loop of henle and distal convoluted tubules.

· These drugs inhibit the reabsorption of Na⁺ by inhibition of Na⁺, Cl^– cotransporter on the luminal membrane of the tubule, results increase concentration of Na⁺, Cl^– in the tubular fluid.

ACTION

· Thiazides and thiazides-like drugs increased Na⁺, Cl^– excretion, which can results hyperosmolar urine (concentrated urine).

· The acid-base balance of the body and blood does not affect the diuretic action.

· Prolonged use of thiazide and thiazide-like drugs produce loss of K⁺ from the body, due to increase Na⁺ reaching at the distal convoluted tubule, more K⁺ is also exchanged.

· Continues use of these drugs leads to produce magnesium deficiency (the mechanism behind is not understood).

· Increase Ca²⁺ concentration by reabsorption in the DCT.

· Decrease blood volume leads to decrease cardiac output. Continued therapy, volume recovery occurs.

PHARMACOKINETICS

· Well absorbed orally.

· Onset of action within 1 hour.

· Duration of action 6-48 hours (Varies)

· The drugs are filtrated at glomerulus as well as secreted in the PT by organic anion transport.

· Reabsorption depends on lipid solubility: More lipophilic highly reabsorbed – prolonged duration of action.

· t ½ :

o Hydrochlorothiazide: 3-4 hours (persists 6-12 hours)

o Chlorthalidone: 40-50 hours

ADVERSE EFFECTS

· Potassium depletion

· Hyponatremia: (Low Na⁺ concentration in the blood)

· Hyperuricemia: (increase serum uric acid)

· Volume depletion

· Hypercalcemia

· Hyperglycemia

THERAPEUTIC USES

· Hypertension: Combination with adrenergic blockers, ACE inhibitors, angiotensin receptor blockers etc.

· Heart failure: Reducing extracellular volume in heart failure.

· Hypercalciurea

· Diabetes insipidus

WEAK AND ADJUNCTIVE DIURETICS

CARBONIC ANHYDRASE INHIBITORS

· Carbonic anhydrase catalyze the reversible reaction H₂O + CO₂ ⇋ H₂CO₃.

· It transport CO₂ and HCO₃^– and secrete H⁺ ion.

· This enzyme is found in renal tubular cell (PT), gastric mucosa, exocrine pancreas, ciliary body of eye, brain and RBCs etc.

ACETAZOLAMIDE

· In presence of acetazolamide, it inhibit CAs which retards dehydration of H₂CO₃ in the tubular fluid so that less CO₂ diffuses back into the cells.

· The decrease ability to exchange Na⁺ for H⁺ ion (Na⁺, K⁺ antiport), hence HCO₃^– is retained in the lumen.

· Acetazolamide produce alkaline urine.

· Continued action depletes body HCO₃^– and causes acidosis.

PHARMACOKINETICS

· Administered orally or i.v.

· 90% protein bound.

· Action of a single dose 8-12 hours.

ADVERSE EFFECTS

· Metabolic acidosis

· K⁺ depletion

· Renal stone formation

· Drowsiness and paresthesia

· Avoided with hepatic cirrhosis: could leads to decrease excretion of NH₄⁺.

THERAPEUTIC USES

· Glaucoma

· Mountain sickness

· Alkalinize urine: to promote excretion of acidic drugs or used in urinary tract infection.

· Epilepsy

· Cerebral and pulmonary edema

· Periodic paralysis.

POTASSIUM SPARING DIURETICS

SPIRONOLACTONE

· It is a steroid, chemically related to the mineralocorticoid aldosterone.

· Aldosterone penetrates the late DT and CD cells from the interstitial site and combine with mineralocorticoid receptor (MR).

· The complex (MR-Aldo) translocate to the nucleus and promotes gene mediated mRNA synthesis.

· The mRNA then directs towards the synthesis of aldosterone induce protein (AIPs).

· This protein activates the Na⁺, K⁺ ATPase and renal epithelial Na⁺ channels.

· AIPs activate Na⁺ channel and translocate from cytosolic site to luminal membrane, also translocate Na⁺, K⁺ ATPase to basolateral membrane.

· AIPs also increase ATP production by mitochondria.

· Promote Na⁺ reabsorption, more K⁺ and H⁺ secretions are take place.

· Spironolactone binds to MR, prevents the action of aldosterone and produce opposite effects.

· Amiloride blocks the Na⁺ channel from the luminal site – reducing the lumen –ve trans-epithelial potential difference which governs K⁺ and H⁺ secretion.

ACTION

· Spironolactone antagonize the activity of aldosterone, resulting in retention of K⁺ and excretion of Na⁺.

· These action diminished by NSAIDs.

PHARMACOKINETICS

· Absorbed orally

· Significantly bound to plasma protein.

· Metabolized in liver and converted active metabolites.

· t ½ – 1-2 hours.

ADVERSE EFFECTS

· Gastric upset

· Gynecomastia

· Menstrual irregularities

· Hyperkalemia

· Nausea

· Lethargy

· Mental confusion

INTERACTION

· K⁺ supplement – Hyperkalemia.

· Aspirin block spironolactone action.

· Spironolactone increase plasma digoxin level.

· ACE-I / Angiotensin receptor blockers (ABRs) – Hyperkalemia.

THERAPEUTIC USES

· Diuretics

· To counteract K⁺ loss due to thiazide and loop diuretics.

· Edema

· Hypertension

· CHF

· Ascites: liver cirrhosis – fluid development in the abdomen.

· Polycystic ovary syndrome: a hormonal disorder causing enlarged ovaries with small cysts on the outer edges.

Dash Smrutiranjan

Hi….!! My name is Smrutiranjan Dash, From Odisha, India. Professionally I am Assistant Professor at The Pharmaceutical College, Barpali, Odisha, department of Pharmacology.

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