Diuretics Lecture Zeb

Diuretic Drugs

pharmacological class

SITES OF ACTION

thiazides distal tubule

K+-sparing osmotic diuretics collecting duct

carbonic anhydrase inhibitors

glomerulus proximal tubule urine blood (artery)

structural class loop diuretics

Methylxanthenes Glomerulus

CA Inhibitors, Osmotic diuretics Proximal tubule

70%

Loop Diuretics, Osmotic diuretics Loop of Henle

Thiazides Distal tubule

5% Thick Ascending Limb

Antikaliuretics

4.5% Collecting duct

100% GFR 180 L/day Plasma Na 145 mEq/L Filtered Load 26,100 mEq/day

20%

0.5% Volume 1.5 L/day Urine Na 100 mEq/L Na Excretion 155 mEq/day

CA inhibitors Acetazolamide Dorzolamide Bumetanide

Carbonic anhydrase Inhibitors  Carbonic

anhydrase:  Location: PCT  Function:  catalyzes the dehydration of H2CO3, a critical step in the proximal reabsorption of H2CO3.

CARBONIC ANHYDRASE INHIBITORS Acetazolamide, dichlorphenamide, methazolamide Developed from sulfanilamide, after it was noticed that sulfanilamide caused metabolic acidosis and alkaline urine

MOA  Inhibition

of carbonic anhydrase activity profoundly depresses bicarbonate reabsorption in the proximal tubule.

 ------

sodium bicarbonate diuresis  ----- decrease in total bicarbonate stores

CARBONIC ANHYDRASE INHIBITORS

CO2 + H2O •

CA

H2CO3

H+ + HCO3-

mild diuretics

• decrease acidity of urine • action limited by hyperchloremic metabolic acidosis

Pharmacokinetics  Well

absorbed after oral administration  Increase in urine pH in 30 m9in: due to Bicarbonate diuresis  Excretion

is by tubular secretion in proximal tubule.

Pharmacodynamics  Inhibition

of carbonic anhydrase------------------ decrease bicarbonate reabsorption in proximal tubule.

 Maximal

acetazolamide administration ---------- 45 % inhibition of whole kidney bicarbonate reabsorption.

Therapeutic Uses Glaucoma

(dorzalamide, brinzolamide) Urinary alkalinization Metabolic Alkalosis Acute mountain Sickness Epilepsy

Urinary alkalinization  Uric

acid and cystine  Renal excretion of weak acid “Aspirin” is enhanced by acetazolamide

Metabolic Alkalosis  When

the alkalosis is due to excessive use of diuretics in patients with severe heart failure

 Metabolic

acidosis

alkalosis secondary to Respiratory

Acute mountain sickness  Symptoms  Weakness,

dizziness, insomnia, headache, nausea  Progressive pulmonary and cerebral edema ------ life threatening.

What is the role of acetazolamide?

 Decrease

cerebrospinal fluid formation

 Decrease

pH of the cerebrospinal fluid

and Brain 

Can be used for prophylaxis 24 hour before ascent.

Toxicity  Hyperchloremic  Renal

metabolic acidosis

stones  Renal potassium wasting  Hypersensitivity reactions --- fever, rashes, bone marrow supression

Contra indications Hepatic

cirrhosis

THIAZIDE DIURETICS  variable

effects on CA inhibition  block Na+-Cl- co-transport  relax vascular smooth muscle

General Structure of Thiazide Diuretics

Thiazide Diuretics Chlorothiazide Hydrochlorothiazide Indapamide Metolazone

Pharmacokinetics  Chlorothiazide

is less lipid soluble ---- must be given in relatively large doses  Chlorothalidone: slowly absorbed longer duration of action  Idapamide: excreted primarily by biliary system  All thiazides compete with uric acid secretion

Pharmacodynamics

CLINICAL USES Of THIAZIDES 1) HYPERTENSION 2) EDEMA (cardiac, liver, renal) 3) NEPHROLITHIASIS (IDIOPATHIC HYPERCALCIURIA) 4) NEPHROGENIC DIABETES INSIPIDUS

Toxicity Hypokalemic

metabolic alkalosis Hyperuricemia Impaired carbohydrate tolerance – Hyperglycemia Hyperlipidemia Hyponatremia Allergic reactions

LOOP DIURETICS 

Furosemide,



Bumetanide,



Ethacrynic acid

Pharmacokinetics  Rapidly

absorbed  Eliminated by renal secretion as well as glomerular filtration  Rapid diuresis after IV administration  DOA:

2-3 hours

Pharmacodynamics

 strong  block

diuretics

Na+-K+-2Cl- co-transport

 increase

K+, Mg++ and Ca++ excretion

Actions  Induce

renal prostaglandin synthesis  These prostaglandins participate in the renal actions of these drugs.  Direct effect on blood flow  Increases renal blkood flow  Redistribution of blood flow within the renal cortex.  Relieve pulmonary congestion  Reduce let ventricular filling pressures in CHF

Therapeutic uses

CLINICAL USES OF LOOP DIURETICS  EDEMA

due to CHF, nephrotic syndrome or

cirrhosis  Acute heart failure with PULMONARY EDEMA  Acute renal failure ---- enhance K+ excretion, increase rate of urine flow  HYPERCALCEMIA  Anion overdose: bromide, fluoride and iodide are reabsorbed in thick ascending limb

Adverse Effects of Loop Diuretics  Hypokalemic

metabolic alkalosis,  Hyperuricemia  Hyperglycemia  Hyponatremia  Hypocalcemia (in contrast to thiazides)  Hypomagnesemia  Hypersensitivity  Dehydration and postural hypotension  Ototoxicity (especially if given by rapid IV bolus)

POTASSIUM-SPARING DIURETICS Spironolactone Triamterene, Amiloride

 Antagonize  at

the effects of aldosterone

cortical collecting tubule and late distal tubule

 Mechanisms

of inhibition  Direct pharmacological antagonism of mineralocorticoid receptors --spironolactone  Inhibition

of Na+ flux through ion channels in the luminal membrane --- triamterene, amiloride

POTASSIUM-SPARING DIURETICS • spironolactone is an aldosterone

antagonist • triamterene and amiloride directly inhibit electrogenic Na+ transport • useful adjuncts with K+-depleting diuretics

Therapeutic uses Mineralocorticoid excess ----Primary hypersecretion: Conns syndrome, Ectopic ACTH production Secondary aldosteronism: CHF, Hepatic cirrhosis, Nephrotic syndrome,

Toxicity Hyperkalemia Hyperchloremic

metabolic

acidosis Gynecomastia Acute renal failure Kidney stones

Agents that enhance water excretion

Osmotic diuretics

OSMOTIC DIURETICS HO H

H

O

-

-

-

-

-

CH2OH HO-C-H HO-C-H H-C-OH H-C-OH CH2OH

H2COH H2COH H2COH

Glycerol

OH H

Isosorbide O

=

Mannitol

O H

H2N-C-NH2

Urea

 Proximal

tubule and descending limb of loop of henle are freely permeable to water.

 Osmotic

agent causes water to be retained in these segments and promote a water diuresis

Mannitol  Not

metabolized  Handled by glomerular filtration  Poorly absorbed

Pharmacodynamics  Limits

water reabsorption in those segments of nephron that are freely permeable to water ----- the proximal tubule and descending limb of loop of henle by exerting an osmotic force------- increase urine volume with mannitol excretion.  Hypernatremia.



Therapeutic Uses  To

increase urine volume

 Reduction

pressure

of intracranial and intraocualr

Toxicity Extra

cellular volume Expansion

Dehydration

and Hypernatremia

OSMOTIC DIURETICS  relatively

inert pharmacologically  freely filtered at the glomerulus  limited reabsorption by renal tubules

OSMOTIC DIURETICS: Therapeutic Uses  Prophylaxis of renal failure Mechanism: Drastic

reductions in GFR cause dramatically increased proximal tubular water reabsorption and a large drop in urinary excretion Osmotic diuretics are still filtered under these conditions and retain an equivalent amount of water, maintaining urine flow

• Reduction of CSF pressure and volume • Reduction of intraocular pressure

Adverse Effects of Osmotic Diuretics  Increased

extracellular fluid volume  Hypersensitivity reactions  Glycerol metabolism can lead to hyperglycemia and glycosuria  Headache, nausea and vomiting

ADH antagonists  Lithium  Demeclocycline

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