distal tubule

glomerulus

urine

blood(artery)

collectingduct

proximaltubule

K+-sparing

loop diuretics

thiazides

carbonic anhydrase inhibitors

osmotic diuretics

Diuretic Drugs

SITES OF ACTION

pharmacological class

structural class

70%

20%

5%

4.5%

0.5%

Volume 1.5 L/dayUrine Na 100 mEq/L

Na Excretion 155 mEq/day

100%GFR 180 L/day

Plasma Na 145 mEq/LFiltered Load 26,100

mEq/day

CA Inhibitors,Osmotic diureticsProximal tubule

Loop Diuretics,Osmotic diuretics

Loop of Henle

ThiazidesDistal tubule

Antikaliuretics

Collecting duct

Thick Ascending Limb

MethylxanthenesGlomerulus

CA inhibitorsCA inhibitors

AcetazolamideAcetazolamide

DorzolamideDorzolamide

BumetanideBumetanide

Carbonic anhydrase InhibitorsCarbonic anhydrase Inhibitors

Carbonic anhydrase:Carbonic anhydrase:Location: PCTLocation: PCTFunction: Function: catalyzes the dehydration of Hcatalyzes the dehydration of H22COCO33, a , a

critical step in the proximal reabsorption of critical step in the proximal reabsorption of HH22COCO33..

CARBONIC ANHYDRASE INHIBITORSCARBONIC ANHYDRASE INHIBITORS

Developed from sulfanilamide, after it was noticed that sulfanilamide caused metabolic acidosis and alkaline urine

Acetazolamide, dichlorphenamide, methazolamide

MOAMOA

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

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

CARBONIC ANHYDRASE INHIBITORSCARBONIC ANHYDRASE INHIBITORS

CO2 + H2O H2CO3 H+ + HCO3-CA

• mild diuretics

• decrease acidity of urine

• action limited by hyperchloremic

metabolic acidosis

PharmacokineticsPharmacokinetics

Well absorbed after oral administrationWell absorbed after oral administration Increase in urine pH in 30 m9in: due to Increase in urine pH in 30 m9in: due to

Excretion is by tubular secretion in Excretion is by tubular secretion in proximal tubule.proximal tubule.

Bicarbonate diuresis

Pharmacodynamics Pharmacodynamics

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

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

Therapeutic UsesTherapeutic Uses

Glaucoma (Glaucoma (dorzalamide, brinzolamide)dorzalamide, brinzolamide)

Urinary alkalinizationUrinary alkalinizationMetabolic AlkalosisMetabolic AlkalosisAcute mountain SicknessAcute mountain SicknessEpilepsyEpilepsy

Urinary alkalinizationUrinary alkalinization

Uric acid and cystineUric acid and cystineRenal excretion of weak acid “Aspirin” is Renal excretion of weak acid “Aspirin” is

enhanced by acetazolamide enhanced by acetazolamide

Metabolic AlkalosisMetabolic Alkalosis

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

Metabolic alkalosis secondary to Respiratory Metabolic alkalosis secondary to Respiratory acidosisacidosis

Acute mountain sicknessAcute mountain sickness

SymptomsSymptomsWeakness, dizziness, insomnia, Weakness, dizziness, insomnia,

headache, nausea headache, nausea Progressive pulmonary and cerebral Progressive pulmonary and cerebral

edema ------ life threatening.edema ------ life threatening.

What is the role of acetazolamide?

Decrease cerebrospinal fluid formationDecrease cerebrospinal fluid formation

Decrease pH of the cerebrospinal fluid Decrease pH of the cerebrospinal fluid and Brainand Brain

Can be used for prophylaxis 24 hour Can be used for prophylaxis 24 hour before ascent.before ascent.

Toxicity Toxicity

Hyperchloremic metabolic acidosisHyperchloremic metabolic acidosisRenal stonesRenal stonesRenal potassium wastingRenal potassium wastingHypersensitivity reactions --- fever, rashes, Hypersensitivity reactions --- fever, rashes,

bone marrow supressionbone marrow supression

Contra indicationsContra indications

Hepatic cirrhosisHepatic cirrhosis

THIAZIDE DIURETICSTHIAZIDE DIURETICS

variable effects on CA inhibitionvariable effects on CA inhibitionblock Nablock Na++-Cl-Cl-- co-transport co-transport relax vascular smooth musclerelax vascular smooth muscle

General Structure of Thiazide Diuretics

Thiazide DiureticsThiazide Diuretics

ChlorothiazideChlorothiazide

HydrochlorothiazideHydrochlorothiazide

IndapamideIndapamide

MetolazoneMetolazone

Pharmacokinetics Pharmacokinetics

Chlorothiazide is less lipid soluble ---- must Chlorothiazide is less lipid soluble ---- must be given in relatively large dosesbe given in relatively large doses

Chlorothalidone: slowly absorbed longer Chlorothalidone: slowly absorbed longer duration of actionduration of action

Idapamide: excreted primarily by biliary Idapamide: excreted primarily by biliary systemsystem

All thiazides compete with uric acid All thiazides compete with uric acid secretion secretion

Pharmacodynamics

CLINICAL USES Of THIAZIDESCLINICAL USES Of THIAZIDES

1) HYPERTENSION1) HYPERTENSION

2) EDEMA 2) EDEMA (cardiac, liver, renal)(cardiac, liver, renal)

3) NEPHROLITHIASIS (IDIOPATHIC 3) NEPHROLITHIASIS (IDIOPATHIC HYPERCALCIURIA)HYPERCALCIURIA)

4) NEPHROGENIC DIABETES INSIPIDUS4) NEPHROGENIC DIABETES INSIPIDUS

Toxicity Toxicity

Hypokalemic metabolic alkalosisHypokalemic metabolic alkalosisHyperuricemiaHyperuricemiaImpaired carbohydrate tolerance – Impaired carbohydrate tolerance –

Hyperglycemia Hyperglycemia HyperlipidemiaHyperlipidemiaHyponatremiaHyponatremiaAllergic reactionsAllergic reactions

LOOP DIURETICSLOOP DIURETICS

Furosemide, Furosemide,

Bumetanide, Bumetanide,

Ethacrynic acidEthacrynic acid

Pharmacokinetics Pharmacokinetics

Rapidly absorbedRapidly absorbedEliminated by renal secretion as well as Eliminated by renal secretion as well as

glomerular filtrationglomerular filtrationRapid diuresis after IV administrationRapid diuresis after IV administration

DOA: 2-3 hoursDOA: 2-3 hours

Pharmacodynamics

strong diureticsstrong diuretics

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

increase K+, Mg++ and Ca++ excretionincrease K+, Mg++ and Ca++ excretion

Actions Actions

Induce renal prostaglandin synthesisInduce renal prostaglandin synthesis These prostaglandins participate in the renal These prostaglandins participate in the renal

actions of these drugs.actions of these drugs. Direct effect on blood flow Direct effect on blood flow Increases renal blkood flow Increases renal blkood flow Redistribution of blood flow within the renal Redistribution of blood flow within the renal

cortex.cortex. Relieve pulmonary congestion Relieve pulmonary congestion Reduce let ventricular filling pressures in CHFReduce let ventricular filling pressures in CHF

Therapeutic usesTherapeutic uses

CLINICAL USES OF LOOP DIURETICSCLINICAL USES OF LOOP DIURETICS

EDEMAEDEMA due to CHF, nephrotic syndrome or due to CHF, nephrotic syndrome or cirrhosiscirrhosis

Acute heart failure with Acute heart failure with PULMONARY PULMONARY EDEMAEDEMA

Acute renal failure ---- Acute renal failure ---- enhance K+ enhance K+ excretion, increase rate of urine flow excretion, increase rate of urine flow

HYPERCALCEMIAHYPERCALCEMIAAnion overdose: bromide, fluoride and Anion overdose: bromide, fluoride and

iodide are reabsorbed in thick ascending iodide are reabsorbed in thick ascending limb limb

Hypokalemic metabolic alkalosis, Hypokalemic metabolic alkalosis, Hyperuricemia Hyperuricemia HyperglycemiaHyperglycemia Hyponatremia Hyponatremia HypocalcemiaHypocalcemia (in contrast to thiazides) (in contrast to thiazides) Hypomagnesemia Hypomagnesemia HypersensitivityHypersensitivity DehydrationDehydration and postural hypotension and postural hypotension OtotoxicityOtotoxicity (especially if given by rapid IV (especially if given by rapid IV

bolus)bolus)

Adverse Effects of Loop DiureticsAdverse Effects of Loop Diuretics

POTASSIUM-SPARING DIURETICSPOTASSIUM-SPARING DIURETICS

Spironolactone Spironolactone

Triamterene,Triamterene,

Amiloride Amiloride

Antagonize the effects of aldosterone Antagonize the effects of aldosterone

at cortical collecting tubule and late distal at cortical collecting tubule and late distal tubuletubule

Mechanisms of inhibitionMechanisms of inhibitionDirect pharmacological Direct pharmacological antagonism of antagonism of

mineralocorticoid receptorsmineralocorticoid receptors --- --- spironolactonespironolactone

Inhibition of Na+ flux through ion channelsInhibition of Na+ flux through ion channels in the luminal membrane --- triamterene, in the luminal membrane --- triamterene, amilorideamiloride

POTASSIUM-SPARING DIURETICSPOTASSIUM-SPARING DIURETICS

• spironolactone is an aldosterone antagonist

• triamterene and amiloride directly inhibit electrogenic Na+ transport

• useful adjuncts with K+-depleting diuretics

Therapeutic usesTherapeutic uses

Mineralocorticoid excess ----- Primary hypersecretion: Conns syndrome, Ectopic ACTH production

Secondary aldosteronism:CHF, Hepatic cirrhosis, Nephrotic syndrome,

Toxicity Toxicity

HyperkalemiaHyperkalemiaHyperchloremic metabolic Hyperchloremic metabolic

acidosisacidosisGynecomastiaGynecomastiaAcute renal failureAcute renal failureKidney stonesKidney stones

Agents that Agents that enhance water enhance water

excretionexcretion

Osmotic diureticsOsmotic diuretics

HO-C-H

HO-C-H

CH2OH

CH2OH

H-C-OH

H-C-OH

--

--

-

Mannitol

O

O

HO

H

OH

H

H

H

Isosorbide

H2N-C-NH2

O

=Urea

H2COH

H2COH

H2COH

Glycerol

OSMOTIC DIURETICSOSMOTIC DIURETICS

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

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

Mannitol Mannitol

Not metabolizedNot metabolizedHandled by glomerular filtrationHandled by glomerular filtrationPoorly absorbedPoorly absorbed

Pharmacodynamics Pharmacodynamics

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

Hypernatremia.Hypernatremia.

Therapeutic UsesTherapeutic Uses

To increase urine volumeTo increase urine volume

Reduction of intracranial and intraocualr Reduction of intracranial and intraocualr pressurepressure

ToxicityToxicity

Extra cellular volume ExpansionExtra cellular volume Expansion

Dehydration and HypernatremiaDehydration and Hypernatremia

OSMOTIC DIURETICSOSMOTIC DIURETICS

relatively inert pharmacologicallyrelatively inert pharmacologically freely filtered at the glomerulusfreely filtered at the glomerulus limited reabsorption by renal tubuleslimited reabsorption by renal tubules

OSMOTIC DIURETICS: OSMOTIC DIURETICS: Therapeutic Therapeutic UsesUses

Prophylaxis of renal failureProphylaxis of renal failureMechanism:Mechanism:

Drastic reductions in GFR cause dramatically Drastic reductions in GFR cause dramatically increased proximal tubular water reabsorption increased proximal tubular water reabsorption and a large drop in urinary excretionand a large drop in urinary excretion

Osmotic diuretics are still filtered under these Osmotic diuretics are still filtered under these conditions and retain an equivalent amount of conditions and retain an equivalent amount of water, water, maintaining urine flowmaintaining urine flow

• Reduction of CSF pressure and volume

• Reduction of intraocular pressure

Adverse Effects of Osmotic DiureticsAdverse Effects of Osmotic Diuretics

Increased extracellular fluid volumeIncreased extracellular fluid volume Hypersensitivity reactionsHypersensitivity reactions Glycerol metabolism can lead to hyperglycemia Glycerol metabolism can lead to hyperglycemia

and glycosuriaand glycosuria Headache, nausea and vomitingHeadache, nausea and vomiting

ADH antagonistsADH antagonists

LithiumLithiumDemeclocycline Demeclocycline

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