DIURETICSPart 1

Prof. Hanan HagarPharmacology Department

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.

Sites for water and electrolyte

s transport along the nephron

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.

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

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

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

Classification of diuretics

Carbonic anhydrase inhibitors Loop diuretics Thiazide diuretics Potassium-sparing diuretics Osmotic diuretics

CARBONIC ANHYDRASE

Luminal membrane Basolateral membrane

Lumen Blood

ASCENDING LOOP OF HENLE

Distal convoluted tubules (DCT)

COLLECTING TUBULES (CT)

COLLECTING TUBULES (CT)

Diuretics

Carbonic Anhydrase Inhibitors

Acetazolamide – dorzolamide

Mechanism of action:Inhibits carbonic anhydrase (CA) enzyme in PCT thus interferes with NaHCO3 re-absorption and causes diuresis.

Carbonic Anhydrase Inhibitors

CA is required for reversible reaction,

in which CO2 +H2O H2CO3

H+ HCO3-

Luminal membraneBasolateral membrane

Lumen Blood

Proximal tubules

Carbonic Anhydrase Inhibitors

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

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).

Carbonic anhydrase inhibitors

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

Therapeutic uses:

Epilepsy (decrease cerebrospinal fluid, CSF).

Urinary alkalinization to enhance renal excretion of acidic substances (cysteine in cystinuria).

HyperphosphatemiaMetabolic alkalosis

Adverse effects:

Hypokalemia (potassium loss).Metabolic acidosis.Renal stone formation (calcium phosphate stones).

Hypersensitivity reactions

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?).

LOOP DIURETICSHigh Ceiling diuretics

The most efficacious diuretics

Efficacy: High 25-30% natriuresis

Drugs as Furosemide - Bumetanide Torsemide - Ethcrynic acid

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.

Ascending loop of Henle

ASCENDING LOOP OF HENLE

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.

Pharmacological effects:↑ urinary excretion of Na+ and K+

↑ urinary excretion Ca++ and Mg ++

↑ urine volume↑ renal blood flow.

Uses:are drug of choice for emergencysituations as:Acute pulmonary edema due to heart failure

Edema due to nephrotic syndrome

Acute hyperkalaemia.Acute hypercalcemia

Adverse effects :

Acute hypovolemia (volume depletion).

Hyponatraemia.Hypokalemia (dietary K

supplementation or K-sparing diuretics).

HypomagnesaemiaMetabolic alkalosis.Postural hypotension

Adverse effects :

Hyperuricemia (increase gouty attack).

Ototoxicity (risk increased if combined with aminoglycosides)

HyperglycemiaAllergic reactions