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