DiureticsFrom Diuresis to

Clinical Use

Prof Dr Mahmoud Khattab

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DIURETICS

What are Diuretics? How & Where they work? Osmotic Diuretics Carbonic Anhydrase Inhibitors Thiazide Diuretics Loop Diuretics K+-sparing Diuretics

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DIURETICS

Diuretics work to effectively increase sodium and water excretion (increasing urine volume)

In turn they decrease extra-cellular fluid (ECF) and effective circulating volume

Diuretics interfere with the normal sodium handling by the kidney. How is Na+ handled by kidneys?

Target molecules for diuretics are specific renal tubular membrane transport proteins

Adequate quantities of the diuretic drug must be delivered to its site of action. HOW?

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Sodium Excretion Regulation

Nephron Segment

Filtered Na+ reabsorbed

Na+

TransporterHormone

Proximal CT 60-70% Na+- H+ antiporter

Angiotensin II

Loop of Henle 20-30% Na+-K+-2Cl- symporter

Distal CT 5-10% Na+-Cl- symporter

Cortical Collecting T

1-3% Epithelial Na+ channel

Aldosterone

Medullary Collecting

1-3% Epithelial Na+ channel

ANP

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Osmotic Diuretics

They do not inhibit a specific transport protein They are pharmacologically inert & filtered by GF NOT reabsorbed creating an increased intra-

luminal osmotic pressure inhibiting water/solute re-absorption

The main tubular sites of action are the PCT and the thick descending limb of Henle loop (freely permeable to water)

Osmotic diuretics produce only mild natriuresis

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Osmotic Diuretics

Therapeutic Uses

Mannitol/Urea (IV), Isosorbide/Glycerin (Local & Oral)

Acutely raised intracranial pressure, e.g. after head trauma

Acute attacks of glaucomao Plasma osmolarity is increased by solutes that

does not penetrate into the brain or the eyeo This results in extraction of water from the two

sites but implies no diuretic effect

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Osmotic Diuretics

Acute renal failure to restore glomerular filtration rate that is aggressively diminished

Drug overdose or poisoning

Adverse Effects Hypokalemia Acute increase in intravascular volume

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Carbonic Anhydrase Inhibitors

Acetazolamise & Dichlorphenamide

Site of action? Mechanism of action? CA inhibition→ ↑luminal

PCT H+→↓ bicarbonate reabsrobtion → ↓ Na+ /H+ transporter activity

Only mild natriuresis (1-3%)

Increased bicarbonate in urine

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Carbonic Anhydrase Inhibitors

Therapeutic Uses Glaucoma: CA transports Na+/bicarbonate with

water (osmosis) to anterior chamber CA inhibition lowers aqueous humor formation Urine alkalinization to trap acidic substances

dissolved in urine (e.g., uric acid, Hb, cysteine) Acute mountain sickness Enhancing bicarbonate excretion in chronic

respiratory acidosis (chronic respiratory obstructive diseases with CO2 retention)

Epilepsy

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Carbonic Anhydrase Inhibitors

Adverse EffectsAdverse Effects Hypokalemia Metabolic acidosis Allergic effects Acute renal failure caused by nephrolithiasis,

where acetazolamide may crystallize during chronic use (does not occur with methazolamide)

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Thiazide Diuretics Site & mechanism of Site & mechanism of

action:action: Early distal renal tubule Block Na+/Cl- symporter Efficacy: Moderate 5%

natriuresis Limits the excretion of

electrolyte-free water (urine dilution)

Reduction of Ca2+ excretion: ↑ Ca2+ reabsrobtn by DCT ↓ECF→ enhance passive

Na+/ Ca2+ re-absrobtion by PCT

Luminalmembrane

Basolateral membrane

Hydrochlorthiazide, chlorthalidone, metolazone, indapamide

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Thiazide Diuretics

Therapeutic Uses Treatment of hypertension Treatment of mild heart failure Mild edema Diabetes inspidus Calcium nephrolithisiso Idiopathic recurrent nephrolithisis with or without

hypercalciuria can be prevented by thiazide diuretics

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Thiazide DiureticsSide EffectsSide Effects

Hypokalemia & Metabolic alkalosis Hyperuricemia Hyperglycemia & glucose intolerance related to: Hypokalemia-induced decrease of insulin release Intravascular V↓→ sympathetic stimulation Increased plasma cholesterol, VLDL cholesterol,

and TG (high doses) Hyponatremia in elderly HTN patients, mild renal

failure (Intravascular V↓→ increased ADH→ water moves to ECF → decreased Na+ concentration

Occasionally sustained hypercalcemia, GIT intolerance, pancreatitis, allergic manifestations

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LOOP DIURETICS (HIGH-CEILING DIURETICS)

Site of action: thick ascending limb of Hele’s loop

Loop diuretics inhibit Na+-K+-2C1- symporter at the apical membrane

Frusemide, Bumetanide, Ethacrynic acid, Torasemide

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LOOP DIURETICSPharmacological Actions

They decrease the re-absorption of Na+, K+ & Cl- → increases their urinary elimination

Increased urinary elimination of CaCa2+2+ /Mg /Mg22++,, the the ascending loop is important site forascending loop is important site for Ca2+ handling

They may enhance glomerular blood flow & filtration (prostaglandins–dependent)

Loop diuretics are the most potent diuretics “high ceiling” increasing sodium excretion up to 25-30% of the filtered load. Why?

They impair free water clearance (ability to dilute urine)

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LOOP DIURETICS Pharmacokinetics

They reach the lumen by glomerular filtration & tubular secretion

They have good bioavailability, peak plasma level after 30 min of oral intake

Loop diuretics have fast onset of few minutes They have short duration - <6 hours after oral

administration & < two hours after parenteral administration

Torasemide has the longest duration

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LOOP DIURETICSTherapeutic Uses

Treatment of CHF: lower peripheral edema (↓preload) ameliorating pulmonary edema (dyspnea,

orthopnea, cough) especially acute cases standard formulation (not SR), are preferred

because of potency & fast onset Treatment of arterial hypertension Sustained release preparations of longer duration

of action & gradual BP lowering effect can be used

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LOOP DIURETICS Therapeutic Uses

Acute pulmonary edema Renal failure Hepatic cirrhosis with ascites Treatment of hypercalcemia as those occuring

with hyperparathyroidism & malignancy

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LOOP DIURETICSSide Effects

Hypokalemia, that might be associated with muscle weakness & cardiac dysrhythmias

Increased Na+ to collecting tubules increases its exchange with K+

↑Na+ loss & ↓ECF→ renin- aldosterone releaseMetabolic alkalosis, related to hypokalemiaOccasional glucose intolerance in pred-

diabetic patients Hyperuricemia (gout attacks) is frequent

because of increased PCT solute re-absorption

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LOOP DIURETICSSide Effects

Ototoxicity: Rapid IV injection of large doses of loop diuretics produced transient deafness

Ethacrynic permanent deafness was reported Loop diuretic ototoxicity is magnified by concurrent

administration of other ototoxic drugs Hyponatremia is much less frequent than is with

thiazide diuretics NSAIDs blunt natriuresis Large doses, in low GFR patients, increase serum

creatinine (↓ BP & ↓ GFR)

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Loop versus Thiazide Diuretics D-R Relationship

Thiazide diuretics have almost flat D-R curve

Loop diuretics have steep D-R curve with higher efficacy

How does this affect

drug selection in HTN

& CHF?

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Potassium-Sparing Diuretics

Aldosterane Antagonists Spironolactone is a

competitive antagonist for aldosterone on its intracellular receptors

Binding of aldosterone with

the receptors initiates DNA

transcription, initiating transcription of specific proteins resulting in:

early increase in the number of sodium channels

late increase in the number of Na+-K+-ATPase molecules

Mild diuresis 1-3% Spironolactone (Aldosterane Antagonist)

--------

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Potassium-Sparing Diuretics Triametrene & Amiloride (Na+-channel

Blockers) They inhibit Na+ re-absorption & K+ secretion They block the entry of sodium via the Na+

selective channels in the apical membrane of the principal cells

With decreased Na+ entry, there is decreased Na+ extrusion across the basolateral membrane by the Na+-K+-ATPase

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Potassium-Sparing DiureticsPharmacokinetics & Adverse Effects

They have good oral bioavailability

Spironlactone is metabolized into the active metabolite canrenone with t1/2 of 18 hours

Traimetrene & amiloride durations are 9 & 24 hours respectively

Adverse Effects: Hypokalemia, especially when

combined with ACEIs, ARBs, NSAIDs

Spironolactone caused peppermint unpleasant after-taste & nausea/vomiting

Spironolactone steroidal structure is related to gynecomastia in men

Impotence & menstrual irregularities

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Hemodynamic Mechanism of Antihypertensive Effect of

Diuretics

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Molecular Mechanism of Antihypertensive

Effect of Diuretics

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Therapeutic Applications of Diuretics

Treatment of hypertension:Treatment of hypertension:o Thiazide diuretic proved to be equivalent safety &

efficacy to new agents (ALLHAT study),o Can be used in combination with new agents &

beta-blockers at low-dose (fewer side effects)o In presence of renal failure, loop diuretic is used Edema StatesEdema States (↑ECF Na+/water retention):o Thiazide diuretic is used in mild edema with

normal renal functiono Loop diuretics are used in cases with impaired

renal function

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Therapeutic Applications of Diuretics

Congestive Heart failureCongestive Heart failure Diuretics lower peripheral & pulmonary edema Thiazides may be used in only mild cases with

well-preserved renal function Loop diuretics are much preferred in more severe

cases especially when GF is lowered In cases of life-threatening acute pulmonary

edema, high-dose furosemidehigh-dose furosemide is given IVIV It promptly & powerfully decreasing edema +

venodilation (↓preload) High-dose furosemideHigh-dose furosemide may be life-saving

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Therapeutic Applications of Diuretics

Congestive Heart failure (Continue):Congestive Heart failure (Continue): Diuretic therapy may cause ↓GFR (↑serum

creatinine) in cases of severe fall in preload & CO Spironolactone,Spironolactone, aldosterone R antagonist, proved

to improve survival in severe CHF It is added to ACEI+diuretic+β-bloker Risk of hyperkalemia must be avoided Aldosterone is implicated in myocardial fibrosis

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Therapeutic Applications of DiureticsRenal Diseases

o 1ryry Na+/fluid retention as glomerulonephritis, acute/chronic renal failure & diabetic nephropathy

o 2ryry Na+/fluid retention in nephrotic syndrome Thiazides are used till GFR ≥ 40-50 mL/min Loop diuretic are used below given values, with

increasing the dose with as GFR goes down Hepatic Cirrhosis with AscitesHepatic Cirrhosis with Ascites Spironolactone is of choice, loop diuretic may be

added if diuresis was insufficient Rapid powerful diuresis→ ↓plasma volume & renal

hypo-perfusion → irreversible renal failure (hepatorenal syndrome)

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Therapeutic Applications of Diuretics Diabetes Inspidus

Rarely occuring metabolic (lack of ADH) or nephrogenic (ADH-insensitive collecting ducts)

Large volume(>10 L/day) of dilute urine Thiazide diuretics effectively reduce urine volume They cause both natriuresis & water diuresis →

intra-vscular volume decreases → PCT & DCT re-absorptive capacity increases

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Diuretic Resistance

Failure of usual doses of loop diuretics in CHF, nephrotic syndrome, & chronic renal disease

Reduced delivery of diuretic molecules to the site of action

Chronic suppression of Na+ rebsorption in ascending Henle’s loop → structrural/functional changes in DCT & collecting ducts →↑ absorptive capacity of late segment of the nephron

The combination of a loop & a thiazide diuretica loop & a thiazide diuretic is usually very effective in resistant edema cases