DIURETICS Part 1 Prof. Hanan Hagar Pharmacology Department.
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Transcript of DIURETICS Part 1 Prof. Hanan Hagar Pharmacology Department.
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DIURETICSPart 1
Prof. Hanan HagarPharmacology 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 interfering with the normal sodium reabsorption by the kidney.
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Sites for water and electrolyte
s transport along the nephron
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Mechanism of action of diuretics
Most diuretics act by inhibiting carriers or transporters in luminal membrane of renal tubular cells required for tubular reabsorption of sodium from filtrate back into blood.
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Sodium Excretion RegulationNephron Segment
Na+ Transporter Filtered Na+ re-absorbed
Proximal convoluted
tubules
Na+/H+ transporter Carbonic anhydrase
85 %
As NaHCO3
AscendingLoop of Henle
Na+/K+/2Cl- cotransporter
20-30%Active
reabsorption Na, K, Cl
Distal convoluted
tubules
Na+/Cl-
transporter
5-10%Active
reabsorption Na, Cl
Cortical Collecting Tubules
Na+ channelAldosteroneAntidiuretic
hormone
5%Na reabsorptionK & H secretion
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Types of diuretics
Nephron Segment
Na+
Transporter DiureticsProximal
convoluted tubules
Na+/H+ transporter
Carbonic anhydrase
Carbonic anhydrase inhibitors
Ascending
Loop of Henle
Na+/K+/Cl- cotransporter
Loop diuretics
Distal convoluted
tubules
Na+/Cl-
transporterThiazide diuretics
Cortical Collecting Tubules
Na+ channel
AldosteroneK-sparing diuretics
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Site of action of diureticssegment Function transporter DiureticsProximal convoluted tubules
Re-absorption of 66% Na, K, Ca, Mg, 100% glucose and amino acids; 85% NaHCO3
Na/H transporter, Carbonic anhydrase enzyme
Carbonic anhydrase inhibitors
Proximal Straight Tubules
Secretion and re-absorption of organic acids and bases
Acid & base transporter
None
Thick ascending loop
Active reabsorption 25% Na, K, Cl
Secondary reabsorption Ca, Mg
Na/K/2Cl transporter
Loop diuretics
Distal convoluted tubules
Active tubular reabsorption of 5%Na, Cl, Ca
Na and Cl cotransporter
Thiazide diuretics
Collecting tubules
Na reabsorptionK & H secretion
Na channelsK & H transporter
K-sparing diuretics
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Classification of diuretics
Carbonic anhydrase inhibitors Loop diuretics Thiazide diuretics Potassium-sparing diuretics Osmotic diuretics
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CARBONIC ANHYDRASE
Luminal membrane Basolateral membrane
Lumen Blood
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ASCENDING LOOP OF HENLE
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Distal convoluted tubules (DCT)
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COLLECTING TUBULES (CT)
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COLLECTING TUBULES (CT)
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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.
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Carbonic Anhydrase Inhibitors
CA is required for reversible reaction,
in which CO2 +H2O H2CO3
H+ HCO3-
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Luminal membraneBasolateral membrane
Lumen Blood
Proximal tubules
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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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Pharmacological actions:↑ urine volume↑ urinary excretion of sodium, potassium , bicarbonate (alkaline urine).
Metabolic acidosis.↑ urinary phosphate excretion. Weak diuretic properties. (decreases after several days ; self-limiting as the blood bicarbonate falls).
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Carbonic anhydrase inhibitors
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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).
Note that IOP: intraocular pressureCSF: cerebrospinal fluid
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Therapeutic uses:
Epilepsy (decrease cerebrospinal fluid, CSF).
Urinary alkalinization to enhance renal excretion of acidic substances (cysteine in cystinuria).
HyperphosphatemiaMetabolic 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 - Bumetanide Torsemide - 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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Ascending loop of Henle
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ASCENDING LOOP OF HENLE
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Pharmacokinetics
Given orally or I. V.Have fast onset of action (suitable for emergency)
Have short duration of action.Bumetanide is the most potentExcreted by active tubular secretion of weak acids into urine.
Interfere with uric acid secretion.
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Pharmacological effects:↑ urinary excretion of Na+ and K+
↑ urinary excretion Ca++ and Mg ++
↑ urine volume↑ renal blood flow.
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Uses:are drug of choice for emergencysituations as:Acute pulmonary edema due to heart failure
Edema due to nephrotic syndrome
Acute hyperkalaemia.Acute hypercalcemia
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Adverse effects :
Acute hypovolemia (volume depletion).
Hyponatraemia.Hypokalemia (dietary K
supplementation or K-sparing diuretics).
HypomagnesaemiaMetabolic alkalosis.Postural hypotension
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Adverse effects :
Hyperuricemia (increase gouty attack).
Ototoxicity (risk increased if combined with aminoglycosides)
HyperglycemiaAllergic reactions