Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Diuretic Agents.

Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved.

Diuretic AgentsDiuretic Agents


Pharmacy Pharmacology: Pharmacy Pharmacology: DiureticsDiuretics


WARNING!!!!!! WARNING!!!!!!!WARNING!!!!!! WARNING!!!!!!!

• DEPENDENCE on these slides ALONE, DEPENDENCE on these slides ALONE, without ADEQUATE note-taking and use of without ADEQUATE note-taking and use of other Resources, WILL result in ADVERSE other Resources, WILL result in ADVERSE CONSEQUECES to your ACADEMIC CONSEQUECES to your ACADEMIC HEALTH.HEALTH.



• Drugs that accelerate the rate of urine Drugs that accelerate the rate of urine formation.formation.

• Result: removal of sodium and waterResult: removal of sodium and water


BackgroundBackground• Primary effect of diuretics is to increase solute excretion, mainly as Primary effect of diuretics is to increase solute excretion, mainly as

NaClNaCl

• Causes increase in urine volume due to increased osmotic pressure Causes increase in urine volume due to increased osmotic pressure in lumen of renal tubule.in lumen of renal tubule.

• Causes concomitant decrease in extra-cellular volume (blood volume)Causes concomitant decrease in extra-cellular volume (blood volume)

• Certain disease states may cause blood volume to increase outside of Certain disease states may cause blood volume to increase outside of narrowly defined limitsnarrowly defined limits

– HypertensionHypertension

– Congestive heart failureCongestive heart failure

– Liver cirrhosisLiver cirrhosis

– Nephrotic syndromeNephrotic syndrome

– Renal failureRenal failure

• Dietary Na restriction often not enough to maintain ECF and prevent Dietary Na restriction often not enough to maintain ECF and prevent edema edema diuretics needed diuretics needed


Review of Kidney StructureReview of Kidney Structure


Functions of the Nephron

Filtration

Reabsorption

Secretion

Excretion


HUMAN RENAL PHYSIOLOGY

• Four Main Processes:

– Filtration

– Reabsorption

– Secretion

– Excretion



• Functions of the Kidney:– Filtration:

– First step in urine formation

– Bulk transport of fluid from blood to kidney tubule

» Isosmotic filtrate

» Blood cells and proteins don’t filter

– Result of hydraulic pressure

– GFR = 180 L/day



• Functions of the Kidney:

–Reabsorption:

• Process of returning filtered material to bloodstream

• 99% of what is filtered

• May involve transport protein(s)

• Normally glucose is totally reabsorbed



• Functions of the Kidney:–Secretion:

– Material added to lumen of kidney from blood

– Active transport (usually) of toxins and foreign substances

» Saccharine» Penicillin



• Functions of the Kidney:– Excretion:

– Loss of fluid from body in form of urine

Amount = Amount + Amount -- Amount

of Solute Filtered Secreted Reabsorbed

Excreted


Nephron sites of action of diureticsNephron sites of action of diuretics


SodiumSodium

• Where sodium goes, water follows.Where sodium goes, water follows.

• 20 to 25% of all sodium is reabsorbed 20 to 25% of all sodium is reabsorbed into the bloodstream in the loop of Henle, into the bloodstream in the loop of Henle, 5 to 10% in the distal tubules, and 3% 5 to 10% in the distal tubules, and 3% in collecting ducts.in collecting ducts.

• If it is not absorbed, it is excreted with If it is not absorbed, it is excreted with the urine.the urine.



• Carbonic anhydrase inhibitorsCarbonic anhydrase inhibitors

• Loop diureticsLoop diuretics

• Osmotic diureticsOsmotic diuretics

• Potassium-sparing diureticsPotassium-sparing diuretics

• Thiazide and thiazide-like diureticsThiazide and thiazide-like diuretics


Carbonic Anhydrase InhibitorsCarbonic Anhydrase Inhibitors

(CAIs)(CAIs)

• acetazolamide (Diamox)acetazolamide (Diamox)

• methazolamidemethazolamide

• dichlorphenamidedichlorphenamide


Carbonic Anhydrase Inhibitors: Carbonic Anhydrase Inhibitors: Mechanism of ActionMechanism of Action

• The enzyme carbonic anhydrase helps to make The enzyme carbonic anhydrase helps to make H+ ions available for exchange with sodium and H+ ions available for exchange with sodium and water in the proximal tubules.water in the proximal tubules.

• CAIs block the action of carbonic anhydrase, thus CAIs block the action of carbonic anhydrase, thus preventing the exchange of H+ ions with sodium preventing the exchange of H+ ions with sodium and water.and water.


Carbonic Anhydrase Inhibitors: Carbonic Anhydrase Inhibitors: Mechanism of ActionMechanism of Action

• Inhibition of carbonic anhydrase reduces H+ ion Inhibition of carbonic anhydrase reduces H+ ion concentration in renal tubules.concentration in renal tubules.

• As a result, there is increased excretion of As a result, there is increased excretion of bicarbonate, sodium, water, and potassium.bicarbonate, sodium, water, and potassium.

• Resorption of water is decreased and urine Resorption of water is decreased and urine volume is increased.volume is increased.


Mechanisms of Action: Mechanisms of Action: Carbonic anydrase inhibitorsCarbonic anydrase inhibitors

• CAIs work on cotransport of NaCAIs work on cotransport of Na++, HCO, HCO33-- and Cl and Cl- - that is coupled to Hthat is coupled to H+ +

countertransportcountertransport

• Acts to block carbonic anhydrase (CA), Acts to block carbonic anhydrase (CA),

1.1. CA converts HCOCA converts HCO33-- + H + H++ to H to H22O + COO + CO2 2 in tubular lumen in tubular lumen

2.2. COCO22 diffuses into cell (water follows Na diffuses into cell (water follows Na++), CA converts CO), CA converts CO2 2 + H+ H22O into HCOO into HCO33-- + +

HH++

3.3. HH++ now available again for countertransport with Na+, etc) now available again for countertransport with Na+, etc)

4.4. NaNa+ + and HCOand HCO33-- now transported into peritubular capillary now transported into peritubular capillary

• CA can catalyze reaction in either direction depending on relative concentration CA can catalyze reaction in either direction depending on relative concentration of substratesof substrates


Carbonic Anhydrase Inhibitors: Carbonic Anhydrase Inhibitors: Therapeutic UsesTherapeutic Uses

• Adjunct agents in the long-term management Adjunct agents in the long-term management of open-angle glaucomaof open-angle glaucoma

• Used with miotics to lower intraocular pressure Used with miotics to lower intraocular pressure before ocular surgery in certain casesbefore ocular surgery in certain cases

• Also useful in the treatment of:Also useful in the treatment of:

– GlaucomaGlaucoma

– EdemaEdema

– EpilepsyEpilepsy

– High-altitude sicknessHigh-altitude sickness


Carbonic Anhydrase Inhibitors: Carbonic Anhydrase Inhibitors: Therapeutic UsesTherapeutic Uses

• Acetazolamide is used in the management of Acetazolamide is used in the management of edema secondary to CHF when other diuretics edema secondary to CHF when other diuretics are not effective.are not effective.

• CAIs are less potent diuretics than loop diuretics CAIs are less potent diuretics than loop diuretics or thiazides—the metabolic acidosis they induce or thiazides—the metabolic acidosis they induce reduces their diuretic effect in 2 to 4 days.reduces their diuretic effect in 2 to 4 days.


Carbonic Anhydrase Inhibitors: Carbonic Anhydrase Inhibitors: Side EffectsSide Effects

Metabolic acidosisMetabolic acidosis DrowsinessDrowsiness

AnorexiaAnorexia ParesthesiasParesthesias

HematuriaHematuria UrticariaUrticaria

PhotosensitivityPhotosensitivity MelenaMelena


Loop DiureticsLoop Diuretics

• bumetanide (Bumex)bumetanide (Bumex)

• ethacrynic acid (Edecrin)ethacrynic acid (Edecrin)

• furosemide (Lasix)furosemide (Lasix)


Loop Diuretics: Loop Diuretics: Mechanism of ActionMechanism of Action

• Act directly on the ascending limb of the Act directly on the ascending limb of the loop of Henle to inhibit sodium and chloride loop of Henle to inhibit sodium and chloride resorption.resorption.

• Increase renal prostaglandins, resulting in the Increase renal prostaglandins, resulting in the dilation of blood vessels and reduced peripheral dilation of blood vessels and reduced peripheral vascular resistance.vascular resistance.


Mechanisms of Action: Loop Mechanisms of Action: Loop diureticsdiuretics• No transport systems in descending loop of HenleNo transport systems in descending loop of Henle

• Ascending loop contains NaAscending loop contains Na+ + - K- K++ - 2Cl - 2Cl-- cotransporter from lumen to ascending limb cotransporter from lumen to ascending limb cellscells

• Loop diuretic blocks cotransporter Loop diuretic blocks cotransporter Na Na++, K, K++, and Cl, and Cl-- remain in lumen, excreted remain in lumen, excreted along with wateralong with water


Loop Diuretics: Drug EffectsLoop Diuretics: Drug Effects

• Potent diuresis and subsequent loss of fluidPotent diuresis and subsequent loss of fluid

• Decreased fluid volume causes:Decreased fluid volume causes:

– Reduced BPReduced BP

– Reduced pulmonary vascular resistanceReduced pulmonary vascular resistance

– Reduced systemic vascular resistanceReduced systemic vascular resistance

– Reduced central venous pressureReduced central venous pressure

– Reduced left ventricular end-diastolic pressureReduced left ventricular end-diastolic pressure

• Potassium depletionPotassium depletion


Loop Diuretics:Loop Diuretics:Therapeutic UsesTherapeutic Uses

• Edema associated with CHF or hepatic Edema associated with CHF or hepatic or renal diseaseor renal disease

• Control of hypertensionControl of hypertension


Loop Diuretics: Side EffectsLoop Diuretics: Side Effects

Body SystemBody System EffectEffect

CNSCNS Dizziness, headache, Dizziness, headache, tinnitus, blurred visiontinnitus, blurred vision

GIGI Nausea, vomiting, Nausea, vomiting, diarrheadiarrhea


Loop Diuretics: Side EffectsLoop Diuretics: Side Effects


HematologicHematologic Agranulocytosis, Agranulocytosis, neutropenia, neutropenia, thrombocytopeniathrombocytopenia

MetabolicMetabolic Hypokalemia, Hypokalemia, hyperglycemia,hyperglycemia,hyperuricemiahyperuricemia


Osmotic DiureticsOsmotic Diuretics

• mannitol (Resectisol, Osmitrol)mannitol (Resectisol, Osmitrol)


Osmotic Diuretics: Osmotic Diuretics: Mechanism of ActionMechanism of Action

• Work in the proximal tubuleWork in the proximal tubule

• Nonabsorbable, producing an osmotic effectNonabsorbable, producing an osmotic effect

• Pull water into the blood vessels and Pull water into the blood vessels and nephrons from the surrounding tissuesnephrons from the surrounding tissues


Osmotic Diuretics: Drug EffectsOsmotic Diuretics: Drug Effects

• Reduced cellular edemaReduced cellular edema

• Increased urine production, causing diuresisIncreased urine production, causing diuresis

• Rapid excretion of water, sodium, and other Rapid excretion of water, sodium, and other electrolytes, as well as excretion of toxic electrolytes, as well as excretion of toxic substances from the kidneysubstances from the kidney

• Reduces excessive intraocular pressureReduces excessive intraocular pressure


Osmotic diureticsOsmotic diuretics

• No interaction with transport systemsNo interaction with transport systems

• All activity depends on osmotic pressure All activity depends on osmotic pressure exerted in lumenexerted in lumen

• Blocks water reabsorption in proximal tubule, Blocks water reabsorption in proximal tubule, descending loop, collecting ductdescending loop, collecting duct

• Results in large water loss, smaller Results in large water loss, smaller electrolyte loss electrolyte loss can result in can result in hypernatremiahypernatremia


Osmotic Diuretics: Osmotic Diuretics: Therapeutic UsesTherapeutic Uses

• Used in the treatment of patients in the early, Used in the treatment of patients in the early, oliguric phase of ARFoliguric phase of ARF

• To promote the excretion of toxic substancesTo promote the excretion of toxic substances

• Reduction of intracranial pressureReduction of intracranial pressure

• Treatment of cerebral edemaTreatment of cerebral edema


Osmotic Diuretics: Side EffectsOsmotic Diuretics: Side Effects

• ConvulsionsConvulsions

• ThrombophlebitisThrombophlebitis

• Pulmonary congestionPulmonary congestion

Also headaches, chest pains, tachycardia,Also headaches, chest pains, tachycardia,blurred vision, chills, and feverblurred vision, chills, and fever


Potassium-Sparing DiureticsPotassium-Sparing Diuretics

• amiloride (Midamor)amiloride (Midamor)

• spironolactone (Aldactone)spironolactone (Aldactone)

• triamterene (Dyrenium)triamterene (Dyrenium)


Potassium-Sparing Diuretics: Potassium-Sparing Diuretics: Mechanism of ActionMechanism of Action

• Work in collecting ducts and distal Work in collecting ducts and distal convoluted tubulesconvoluted tubules

• Interfere with sodium-potassium exchangeInterfere with sodium-potassium exchange

• Competitively bind to aldosterone receptorsCompetitively bind to aldosterone receptors

• Block the resorption of sodium and water Block the resorption of sodium and water usually induced by aldosteroneusually induced by aldosterone


Potassium-sparing diureticsPotassium-sparing diuretics

• Have most downstream site of action Have most downstream site of action (collecting tubule)(collecting tubule)

• Reduce K loss by inhibiting Na/K exchangeReduce K loss by inhibiting Na/K exchange

• Not a strong diuretic because action is Not a strong diuretic because action is furthest downstreamfurthest downstream

• Often used in combination with thiazide Often used in combination with thiazide diuretics to restrict K lossdiuretics to restrict K loss


Potassium-Sparing Diuretics: Potassium-Sparing Diuretics: Drug EffectsDrug Effects

• Prevent potassium from being pumped into Prevent potassium from being pumped into the tubule, thus preventing its secretionthe tubule, thus preventing its secretion

• Competitively block the aldosterone Competitively block the aldosterone receptors and inhibit its actionreceptors and inhibit its action

• The excretion of sodium and water The excretion of sodium and water is promotedis promoted


Potassium-Sparing Diuretics: Potassium-Sparing Diuretics: Therapeutic UsesTherapeutic Uses

spironolactone and triamterenespironolactone and triamterene

• HyperaldosteronismHyperaldosteronism

• HypertensionHypertension

• Reversing the potassium loss caused by Reversing the potassium loss caused by

• potassium-losing drugspotassium-losing drugs

amilorideamiloride

• Treatment of CHFTreatment of CHF


Potassium-Sparing Diuretics: Potassium-Sparing Diuretics: Side EffectsSide Effects


CNSCNS Dizziness, headacheDizziness, headache

GIGI Cramps, nausea, Cramps, nausea, vomiting, diarrheavomiting, diarrhea

OtherOther Urinary frequency,Urinary frequency,weaknessweakness**hyperkalemia**hyperkalemia


Potassium-Sparing Diuretics: Potassium-Sparing Diuretics: Side EffectsSide Effects

spironolactonespironolactone

• gynecomastia, amenorrhea, irregular mensesgynecomastia, amenorrhea, irregular menses


Thiazide and Thiazide-Like DiureticsThiazide and Thiazide-Like Diuretics

• hydrochlorothiazide (Esidrix, HydroDIURIL)hydrochlorothiazide (Esidrix, HydroDIURIL)

• chlorothiazide (Diuril)chlorothiazide (Diuril)

• trichlormethiazide (Metahydrin)trichlormethiazide (Metahydrin)

• Thiazide-likeThiazide-like

• chlorthalidone (Hygroton)chlorthalidone (Hygroton)

• metolazone (Mykrox, Zaroxolyn)metolazone (Mykrox, Zaroxolyn)


Thiazide and Thiazide-Like Thiazide and Thiazide-Like Diuretics: Mechanism of ActionDiuretics: Mechanism of Action

• Inhibit tubular resorption of sodium and chloride ionsInhibit tubular resorption of sodium and chloride ions

• Action primarily in the ascending loop of Henle and Action primarily in the ascending loop of Henle and early distal tubuleearly distal tubule

• Result: water, sodium, and chloride are excretedResult: water, sodium, and chloride are excreted

• Potassium is also excreted to a lesser extentPotassium is also excreted to a lesser extent

• Dilate the arterioles by direct relaxationDilate the arterioles by direct relaxation


Thiazide and Thiazide-Like Thiazide and Thiazide-Like Diuretics: Drug EffectsDiuretics: Drug Effects

• Lowered peripheral vascular resistanceLowered peripheral vascular resistance

• Depletion of sodium and waterDepletion of sodium and water


Thiazide and Thiazide-Like Thiazide and Thiazide-Like Diuretics: Therapeutic UsesDiuretics: Therapeutic Uses

• Hypertension Hypertension (one of the most prescribed group of agents for this)(one of the most prescribed group of agents for this)

• Edematous statesEdematous states

• Idiopathic hypercalciuriaIdiopathic hypercalciuria

• Diabetes insipidusDiabetes insipidus

• Adjunct agents in treatment of CHF, hepatic cirrhosisAdjunct agents in treatment of CHF, hepatic cirrhosis


Thiazide and Thiazide-Like Thiazide and Thiazide-Like Diuretics: Side EffectsDiuretics: Side Effects


CNSCNS Dizziness, headache, Dizziness, headache, blurred vision, blurred vision,

paresthesias,paresthesias, decreased libidodecreased libido

GIGI Anorexia, nausea, Anorexia, nausea, vomiting,vomiting, diarrheadiarrhea


Thiazide and Thiazide-Like Thiazide and Thiazide-Like Diuretics: Side EffectsDiuretics: Side Effects


GUGU ImpotenceImpotence

IntegumentaryIntegumentary Urticaria, photosensitivityUrticaria, photosensitivity

MetabolicMetabolic Hypokalemia, glycosuria,Hypokalemia, glycosuria,hyperglycemia hyperglycemia

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Copyright © 2002, 1998, Elsevier Science (USA). All rights reserved. Diuretic Agents.

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