Diuretic Agents. Learning Objectives Classify the diuretic agents Describe the mechanism of diuretic agents Demonstrate the pharmacological effects.

Diuretic Agents

Learning Objectives

① Classify the diuretic agents

② Describe the mechanism of diuretic agents

③ Demonstrate the pharmacological effects of typical diuretic agents

④ Propose the rational clinical application

At the end of this session, you will be able to:

Three stages of urine forming

A: Glomerular filtration

B: Reabsorption in renal tubule

C: Excretion in dismal and collecting tubule

Review of Kidney Function

■ Glomerular Filtration Rate 130ml /min, ■ Normal urine production rate 1 ml/min,

which indicates that 129/130 (>99%) of glomerular ultrafiltrate (filtered plasma, tubular fluid) is reabsorbed

>99% of salt is reabsorbed >99% of H2O is reabsorbed

GFR = 130 ml min-1

Urine flow = 1 ml min-1

DIURETICS

▲ Diuretics are drugs which increase the excretion of sodium and water from the body by an action on the kidney.

▲ Their primary effect is to decrease the reabsorption of sodium and chloride from the filtrate, increase water loss being secondary to the increased excretion of salt.

Classification of Diuretic Agents

Loop diuretics: furosemide, ethacrynic acid Thiazides: hydrochlorothiazide, indapamide K+-sparing diuretics: spironolactone, amiloride and

triamterene Carbonic anhydrase inhibitors: acetazolamide and

dorzolamide Osmotic diuretics: Mannitol

1. High-effective diuretics: Loop diuretics

2. Mid-effective diuretics: Thiazide diuretics

3. Low-effective diuretics: K+-sparing diuretics

& CAIs

According to the efficacy

Excretion rates of typical diuretics, values observed at peak

diuresis after a maximally effective dose

Loop diuretic ， 12ml/min=0.72L/h

Normal urine production rate 1 ml/min

Nephron sites of action of diuretics

Mechanisms of Action: Loop diuretics

No transport systems in descending loop of Henle

Ascending loop contains Na+-K+-2Cl- cotransporter from lumen to ascending limb cells■ Inhibit Na+-K+-2Cl- transport system to reduce the

reabsorption of NaCl in the thick ascending limb of the loop of Henle

■ Inhibition of this transporter system leads to the reduction of K+ back diffusion into the tubular lumen, which reduces the lumen positive potential, and then causes an increase in Mg2+ and Ca2+ excretion

Loop Diuretics

FurosemideBumetanideTorsemideEthacrynic acid

High efficacy diuretics

§ Pharmacological effects:▲ Diuresis▲ Increase Ca2+ excretion§ Pharmacological kinetics:

Onset in 5 min by i.v. ; 30 min by p.o. t 1/2=1h last for 4-6 h , even to 10h

CLINICAL APPLICATIONS OF LOOP DIURETICS

1. EDEMA due to CHF, nephrotic syndrome or cirrhosis

2. Acute heart failure with PULMONARY EDEMA3. HYPERCALCEMIA

4. Accelerate the excretion of poisons

Adverse reaction

1. Ototoxicity (ethacrynic acid> lasix> bumetanide)

2. Disturbance of water and electrolyte

3. Hyperuricemia

4. Others toxicities: allergic reactions, nausea et al.

Thiazide Diuretics in the Distal Convoluted Tubule

■ Less reabsorption of water and electrolytes in the distal convoluted tubule than proximal tubule or loop

■ Thiazides block Na+-Cl- cotransporter

Thiazide Diuretics

HydrochlorothiazideMetolazone

Pharmacol-effects & Clinical uses

■ Diuresis & Edema ■ Anti-hypertension & Hypertension ■ Decrease [Ca2+ ]in urine by increasing Ca2+

reabsorption & Idiopathic hypercalciuria or renal calculus

■ Anti-diuretic effect & Nephrogenic diabetes insipidus

• - PDE , + cAMP, + permeability of H2O

• + NaCl excretion, - plasma osmotic pressure , - Thirsty feeling & drinking quantity

Adverse reactions

① Hypokalemia ---

② Hyperlipidemia

③ Hyperuricemia

④ Hyperglycemia

⑤ Allergic reactions

be careful when use with digitalis.

Low efficacy diuretics

■ K+ sparing diuretics■ Agent: Antisterone, Triamterene &

amiloride■ Action site: DCT & CT (Collecting Tubule)

Potassium-sparing diuretics

Two cell types in collecting tubule1. Principal cells – transport Na +, K +, water

2. Intercalated cells – secretion of H+ and HCO3

3. Blocking Na+ movement in also prevents K+ movement out

Spironolactone/ Antisterone

▲ Act as antagonists to aldosterone, competes with aldosterone for receptor sites in DCT

▲ Results in decreased Na+ reabsorption in DCT

▲ Promotes Na+ and water loss

▲ Decreased Na+ reabsorption balanced by K+

retention at this site (and H+).

▲ Used in combination with diuretic e.g.. frusomide

Clincal use

1. Obstinate edema

2. Congestive heart failure

ADR

3. Hyperkalemia,

4. sex hormone-like effects

Triamterene and amiloride

■ Take action on distal convoluted tubule and collecting tubule

■ Block Na+ channel to decrease the reabsorption of Na+

■ Secondary to inhibit the excretion of K+

■ Not to antagonize the aldosterone

Carbonic anhydrase inhibitors

■ CAIs work on cotransport of Na+, HCO3- and Cl- that

is coupled to H+ countertransport■ Acts to block carbonic anhydrase (CA),

① CA converts HCO3- + H+ to H2O + CO2 in tubular lumen

② CO2 diffuses into cell (water follows Na+), CA converts CO2 + H2O into HCO3

- + H+ ③ H+ now available again for countertransport with Na+, etc

④ Na+ and HCO3- now transported into peritubular capillary

Site of Action of CAIs

■ Carbonic Anhydrase Inhibitors■ Carbonic anhydrase inhibitors (acetazolamide)

H2O + CO2 H+ + HCO3-

Na+

CA

reabsorption

Clinic uses:

1. Glaucoma

2. Cerebral edema

3. Acute mountain sickness

4. Urine basification

5. Treatment of Metabolic Alkalosis

Adverse reaction

1. Allergic reaction

2. Metabolic Acidosis

3. Urinary calculus

4. Hypokalemia

5. Others: drowsiness,feeling dysfunction, central nerve system toxicity,allergic reaction

Osmotic diuretics

■ No interaction with transport systems■ All activity depends on osmotic pressure exerted in

lumen■ Blocks water reabsorption in proximal tubule,

descending loop, collecting duct■ Results in large water loss, smaller electrolyte loss

can result in hypernatremia

Dehydrant agents /osmotic diuretics

■ Agents : Mannitol, 50% hypertonic Glucose■ Characteristics:

no metabolism/freely filtrable/no reabsorpted

Pharmacological effects and clinical uses:▲ Hyperosmolarity Dehydration▲ Diuresis

USMLE-type questions

Your 60 yr male hypertensive patient who had an MI three months ago is now showing signs of CHF. You therefore add spironolactone to his drug regimen. What side effect should you warm your patient about that is associated with this drug?

A. gynecomastia B. hypokalemiaC. lupus syndromeD. ototoxicityE. uricemia

A/gynecomastia is the correct answer. Spironolactone is a weak agonist at androgen receptors, as well as an aldosterone antagonist. His breasts may become slightly enlarged and tender.

A 70-Y-O woman is admitted to the emergency department because of a “fainting spell” at home. She appears to have suffered no trauma from her fall, but her BP is 120/60 when lying down and 60/20 when she sits up. Neurologic examination and an ECG are within normal limits when she is lying down. Questioning reveals that she has recently started taking diuretics for a heart condition. Which of the following drugs is the most likely cause of her fainting spell?

A. Acetazolamide

B. Amiloride

C. Furosemide

D. Hydrochlorothiazide

E. Spironolactone