DIURETICS%20Part%201

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DIURETICSPart 1

• Prof. Hanan Hagar
• Pharmacology Department

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• Diuretics
• Are drugs that increase renal excretion of
  sodium and water resulting in increase in urine
  volume.
• Most diuretics act by interfere with the normal
  sodium handling by the kidney.

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• Sites of action for diuretics
• Target molecules for diuretics are specific
  membrane transport proteins in renal tubular
  epithelial cells (transporters).

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Classification of diuretics

• Carbonic Anhydrase Inhibitors
• Loop Diuretics
• Thiazides
• Potassium-Sparing Diuretics
• Osmotic Diuretics

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SITES OF ACTION OF DIURETICS
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kidney

• Nephron is the unit of the kidney
• It is classified structurally and functionally
  into different zones
• Glomerulus
• Proximal convoluted tubule
• Descending loop of Henle
• Ascending loop of Henle
• Distal convoluted tubule
• Collecting duct

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FUNCTION OF THE KIDNEY

• Kidney is responsible for regulation of fluids
  and electrolytes.
• Kidney do its function through three processes
• Glomerular filtration
• Passive tubular re-absorption
• Active tubular secretion

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Regulation of fluids and electrolytes
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Sites for solutions and water transport along the
nephron
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• Glomerular filtration
• 16-20 of blood entering the kidney is filtered
• Filtrate contains water, glucose, amino acids,
  sodium bicarbonates, organic solutes and
  electrolytes (sodium, potassium, chloride).

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• Proximal convoluted tubules
• Responsible for re-absorption of
• all glucose, amino acids
• organic solutes
• electrolytes as
• sodium chloride (NaCl)(66 of Na)
• sodium bicarbonate (NaHCO3,85)
• Potassium (K, 66 )

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• Proximal convoluted tubule (PCT)
• HCO3- is reabsorbed by action of enzyme carbonic
  anhydrase (luminal membrane of proximal tubular
  cells).
• Water (passively following salts to maintain
  osmolarity in tubular fluids (60).
• PCT is the site of organic acids or bases
  secretory systems

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carbonic anhydrase
Lumen
Blood
Luminal membrane
Basolateral membrane
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organic acids or bases secretory systems

• Organic base secretory system responsible for
  secretion of bases into luminal fluid e.g.
  choline and creatinine
• Organic acid secretory system responsible for
  secretion of acids into luminal tubular fluid
  e.g. uric acid, NSAIDs, antibiotics and
  diuretics.

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• Descending loop of Henle
• In thin descending loop of Henle
• water is re-absorbed by osmotic
• forces in hypertonic medullary
• interstitium (counter current
• mechanism)

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• Ascending loop of Henle
• Is impermeable to water
• In thick ascending loop of Henle (TAL) is
  responsible for active re-absorption of Na, K and
  Cl (25-30 Na) via transport system in luminal
  membrane called Na/ K / 2Cl- co-transporter
• TAL is called the diluting segment
• Ca and Mg enter the interstitial fluid via
  paracellular pathway

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Ascending loop of Henle
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• Distal convoluted tubule (DCT)
• Is impermeable to water
• Responsible for active re-absorption of NaCl
  (10) via transport system Na/Cl transporter in
  luminal membrane
• Ca2 actively reabsorbed via apical Ca channel
  and Na/Ca2 exchanger in basolateral membrane

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Distal convoluted tubules (DCT)
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• Collecting tubule
• Principal cells are responsible for
  re-absorption of Na (in exchange for K via
  Na/K-ATPase) and water
• Aldosterone receptors located in the principle
  cells influence Na re-absorption and K secretion
• Intercalated cells affect H secretion
• Water re-absorption (anti-diuretic hormone, ADH).

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COLLECTING TUBULES (CT)
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COLLECTING TUBULES (CT)
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Sodium Excretion Regulation
Nephron Segment Filtered Na reabsorbed Na Transporter
Proximal CT 60-70 Na- H transporter
Ascending Loop of Henle 20-30 Na-K-2Cl- transporter
Distal CT 5-10 Na-Cl- transporter
Cortical Collecting Tubules 5 Aldosterone Na channel ADH
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Site of action of diuretics
Diuretics transporter Function segment
Carbonic anhydrase inhibitors Na/H transporter, Carbonic anhydrase enzyme Re-absorption of 66 Na, K, Ca, Mg, 100 glucose and amino acids 85 NaHCO3 Proximal convoluted tubules
None Acid base transporter Secretion and re-absorption of organic acids and bases Proximal Straight Tubules
Loop diuretics Na/K/2Cl transporter Active reabsorption 25 Na, K, Cl Secondary reabsorption Ca, Mg Thick ascending loop
Thiazide diuretics Na and Cl cotransporter Active tubular reabsorption of 5Na, Cl, Ca Distal convoluted tubules
K-sparing diuretics Na channels K H transporter Na reabsorption K H secretion Collecting tubules
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• Diuretics

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Carbonic Anhydrase Inhibitors

• Acetazolamide dorzolamide
• Mechanism of action
• Inhibits carbonic anhydrase (CA) enzyme in PCT
  thus interferes with NaHCO3 re-absorption and
  causes diuresis.
• CA is required for reversible reaction, in which
  CO2 H2O ? H2CO3

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Blood
Lumen
Basolateral membrane
Luminal membrane
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Carbonic Anhydrase Inhibitors
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• Pharmacological actions
• ? urinary excretion of bicarbonate, sodium,
  potassium alkaline diuresis
• Metabolic acidosis.
• ? urinary phosphate excretion.
• Weak diuretics.
• Decreases after several days (self-limiting as
  the blood bicarbonate falls).

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Carbonic anhydrase inhibitors
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• Pharmacokinetics
• given orally once a day.
• Onset of action is rapid (30 min).
• Duration of action (12 h).
• Excreted by active secretion in proximal
  convoluted tubules forming alkaline urine

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• Therapeutic uses
• Open angle glaucoma (? IOP by reducing aqueous
  humor formation via blocking carbonic anhydrase
  in ciliary body of eye).
• As prophylactic therapy, in acute mountain
  sickness (to decrease CSF and pH of brain).

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• Therapeutic uses
• Urinary alkalinization to enhance renal excretion
  of acidic substances (uric acid and cysteine in
  cystinuria).
• Epilepsy (decrease cerebrospinal fluid, CSF).
• Hyperphosphatemia
• Metabolic alkalosis

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• Adverse effects
• Hypokalemia (potassium loss).
• Metabolic acidosis.
• Renal stone formation (calcium phosphate stones).
• Hypersensitivity reactions

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• Dorzolamide
• Is a carbonic anhydrase inhibitor
• Used topically for treatment of increased
  intraocular pressure in open-angle glaucoma.
• no diuretic or systemic side effects (Why?).

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LOOP DIURETICSHigh Ceiling diuretics

• The most efficacious diuretics
• Efficacy High 25-30 natriuresis
• Drugs as
• Furosemide - torsemide
• Bumetanide - Ethcrynic acid

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LOOP DIURETICS

• Mechanism
• inhibit Na / K / 2 Cl- co-transporter in the
  luminal membrane of the thick ascending loop of
  Henle (TAL).
• inhibit Ca and Mg re-absorption.

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Pharmacokinetics

• Given orally or I. V.
• Has fast onset of action (suitable for emergency)
• Have short duration of action.
• Excreted by active tubular secretion of weak
  acids into urine (compete with uric acid for
  renal secretory system).

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Ascending loop of Henle
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Ascending loop of Henle
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Pharmacological effects

• ? urinary excretion of Na , K, Ca and Mg
• ? urine volume
• ? renal blood flow.

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• Uses
• are drug of choice for emergency situations as
• Acute pulmonary edema
• Edema associated with heart failure, nephrotic
  syndrome
• Acute hyperkalaemia.
• Acute hypercalcemia

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Adverse effects

• Hypokalemia (dietary K supplementation or
  K-sparing diuretics).
• Metabolic alkalosis.
• Acute Hypovolemia, postural hypotension

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Adverse effects

• Hyponatraemia.
• Hypomagnesaemia
• Hyperuricemia (increase gouty attack).
• Ototoxicity (risk increased if combined with
  aminoglycosides)
• Allergic reactions