Diuretics From Diuresis to Clinical Use

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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 Transporter Hormone
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 glaucoma
• Plasma osmolarity is increased by solutes that
  does not penetrate into the brain or the eye
• 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 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 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

Luminal membrane
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 nephrolithisis
• Idiopathic recurrent nephrolithisis with or
  without hypercalciuria can be prevented by
  thiazide diuretics

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Thiazide DiureticsSide 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)
Frusemide, Bumetanide, Ethacrynic acid, Torasemide
Site of action thick ascending limb of Heles
loop
Loop diuretics inhibit Na-K-2C1- symporter at
the apical membrane
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LOOP DIURETICSPharmacological Actions

• They decrease the re-absorption of Na, K Cl-
  ? increases their urinary elimination
• Increased urinary elimination of Ca2 /Mg2, the
  ascending loop is important site for Ca2
  handling
• They may enhance glomerular blood flow
  filtration (prostaglandinsdependent)
• 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 - lt6 hours after oral
  administration lt 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 release
• Metabolic alkalosis, related to hypokalemia
• Occasional 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

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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
• Thiazide diuretic proved to be equivalent safety
  efficacy to new agents (ALLHAT study),
• Can be used in combination with new agents
  beta-blockers at low-dose (fewer side effects)
• In presence of renal failure, loop diuretic is
  used
• Edema States (?ECF Na/water retention)
• Thiazide diuretic is used in mild edema with
  normal renal function
• Loop diuretics are used in cases with impaired
  renal function

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Therapeutic Applications of Diuretics

• Congestive 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 furosemide is given IV
• It promptly powerfully decreasing edema
  venodilation (?preload)
• High-dose furosemide may be life-saving

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Therapeutic Applications of Diuretics

• Congestive Heart failure (Continue)
• Diuretic therapy may cause ?GFR (?serum
  creatinine) in cases of severe fall in preload
  CO
• Spironolactone, aldosterone R antagonist, proved
  to improve survival in severe CHF
• It is added to ACEIdiureticß-bloker
• Risk of hyperkalemia must be avoided
• Aldosterone is implicated in myocardial fibrosis

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Therapeutic Applications of DiureticsRenal
Diseases

• 1ry Na/fluid retention as glomerulonephritis,
  acute/chronic renal failure diabetic
  nephropathy
• 2ry 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 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(gt10 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 Henles loop ? structrural/functional
  changes in DCT collecting ducts ?? absorptive
  capacity of late segment of the nephron
• The combination of a loop a thiazide diuretic
  is usually very effective in resistant edema cases