Diuretics

DISTAL CONVOLUTED TUBULES

• The DCT are impermeable to water.
• A least amount of NaCl (nearly 10%) is reabsorbed through Na⁺/Cl^–
• 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⁺
• 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)
   1. Sulphamoyl derivatives
      • Furosemide
      • Bumetanide
      • Torasemide
   2. Medium efficacy diuretics (Inhibition of Na⁺, Cl^– symport)
      1. Benzothiadiazine (Thiazides)
         • Hydrochlorothiazide
         • Benzthiazide
         • Hydroflumethiazide
         • Bendroflumethiazide
      2. Thiazide like
         • Chlorthalidone
         • Metolazone
         • Xipamide
         • Indapamide
         • Clopamide
      3. Weak or adjunctive diuretics
         1. Carbonic anhydrase inhibitor
            • Acetazolamide
         2. Potassium sparing diuretics
            1. Aldosterone antagonist
               • Spironolactone
            2. Inhibition of renal epithelial Na⁺ channel
               • Amiloride
            3. 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.

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⁺

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 :
  • Hydrochlorothiazide: 3-4 hours (persists 6-12 hours)
  • 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⁺
• 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⁺
• 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⁺

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.