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Diuretics, Therapeutic uses, Therapeutic uses, Therapeutic uses,…
Diuretics
Diuretics mainly exert their effect by inhibition of renal tubular reabsorption of sodium and water.
These may be classified according to their efficacy as
high ceiling(loop and osmotic diuretics),
medium ceiling(thiazides) and
low ceiling(carbonic anhydrase inhibitors and potassium sparing) diuretics
Therapeutic uses
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Two products developed specifically for this use are dorzolamide and brinzolamide, which are available only as ophthalmic drops
Carbonic anhydrase inhibitors can be useful for correcting metabolic alkalosis, especially one caused by diuretic-induced increases in H+ excretion
Acetazolamide can provide symptomatic relief
in patients with high-altitude illness or mountain sickness
Carbonic anhydrase inhibitors are also useful in patients with familial periodic paralysis
Dichlorphenamide is now approved for treating this syndrome
The mechanism for the beneficial effects of carbonic anhydrase inhibitors in altitude sickness and familial periodic paralysis may relate to the induction of a metabolic acidosis
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Therapeutic uses
In patients with a drug overdose, loop diuretics can be used to induce forced diuresis to facilitate more rapid renal elimination of the offending drug
main use of loop diuretics is to remove the edema fluid in renal, hepatic or cardiac disease
These can be administered IV for prompt relief of acute pulmonary edema due to vasodilatory action
Thes drugs can cause excretion of ca2+ therefore can be used for the treatment of hypercalcemia
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Loop diuretics combined with hypertonic saline are useful for the treatment of life-threatening hyponatremia
Therapeutic uses
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A spray-dried form of mannitol is FDA approved for managing cystic fibrosis in adults; by hydrating airways,
mannitol improves mucus clearance.
Mannitol is also FDA approved for the diagnosis of bronchial hyperreactivity (by oral inhalation)
and for antihemolytic urologic irrigation during transurethral procedures
Mannitol is often used to treat or prevent acute kidney injury
Therapeutic uses
Thiazide diuretics, which reduce urinary Ca2+ excretion, so
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mainstay for treatment of nephrogenic diabetes insipidus (DI), reducing urine volume by up to 50%
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used for the treatment of edema associated with
diseases of the
heart (CHF)
liver (hepatic cirrhosis)
and kidney (nephrotic syndrome, chronic renal failure, and acute glomerulonephritis)
With the possible exceptions of metolazone and indapamide, most thiazide diuretics are ineffective when the GFR is less than 30 to 40 mL/min
MOA
These drugs act by inhibiting Na+-Cl- symporter at the luminal membrane of early DT.
This part of DT is impermeable to water and absorbs only solutes.
By increasing excretion of solutes, thiazides make the urine concentrated
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MOA
Luminal membrane of proximal tubules contain Na+-H+ antiporter which helps in the excretion of H+ in exchange with the reabsorption of Na+.
The net effect of carbonic anhydrase is to cause the absorption of sodium and bicarbonate
Inhibitors of this enzyme acetazolamide result in excretion of sodium and bicarbonate in the urine
These agents also decrease the secretion of H+
Due to less reabsorption of sodium in the PT, more is delivered to the distal tubules
AT this site also known as cortical diluting segment, Na+ is exchanged with K+ and H+
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Adverse effects
hypokalemia
hypomagnesemia
hyponatremia
alkalosis
hyperglycemia CI in diabetes mellitus
hyperuricemia CI in gout and
dyslipidemia
are seen with both thiazides as well as loop diuretics
Ethacrynic acid can cause more ototoxicity more often than other loop diuretics.
Furosemide and bumetanide are sulphonamides in chemical structure
so they should be avoided in persons allergic to sulphonamides
Drugs
mannitol, glycerol, urea and isosorbide are inert
drugs that can cause osmotic diuresis
Previously it was thought that osmotic diuretics act primarily in proximal tubules
but recent studies have suggested these drugs act both in PT as well as loop of henle
But the latter is the major site of action
MOA
When administered IV mannitol increases the osmotic pressure in the blood vessels
and the consequent removal of excess fluids from cells basis of its use in glaucoma and cerebral edema
results in expansion of extracellular fluid volume
Consequently renal blood flow and GFR increases
Further it is filtered at the glomerulus and reaches the proximal tubule(PT) and loop of henle
It inhibits the reabsorption in ascending loop of henle by decreasing medullary tonicity
Decreased medullary tonicity prevents the reabsorption of water from descending limb
that results in decreased absorption of solutes from ascending limb
Along with water, excretion of all the cations and anions increased
Contraindications
It is contraindicated in acute renal failure because ECF volume increases but it cant be filtered
It is also contraindicated in cerebral haemorrhage(active bleeding)
because in this situation mannitol can leak from ruptured cerebral blood vessels resulting in the
increased ICT(more fluid retention due to its osmotic effect in the cells)
If given orally mannitol can result in osmotic diarrhea
Isosorbide and glycerol can be used orally for the treatment of glaucoma and cerebral edema
patients with heart failure or pulmonary congestion, this may cause frank pulmonary edema
MOA
these diuretics act in the late DT and CD cells to preserve k+
Luminal membrane of these portions of renal tubule contain epithelial Na+ channels responsible for reabsorption of Na+
Due to decreased positive charge in the lumen, a transepithelial potential difference is generated(lumen negative)
Under this potential gradient K+ and H+ are secreted
These actions are promoted by aldosterone
Drugs that inhibit the epithelial Na+ channels or the actions of aldosterone can decrease
the reabsorption of Na+(diuretic effect) and
excretion of K+(potassium sparing effect) and H+
ADR
Amiloride is more potent and longer acting than triamterene
Triamterene is less often used because of incomplete absorption, photosensitivity and impairment of glucose tolerance
It is also associated with interstitial nephritis and renal stones
Triamterene is a weak folic acid antagonist and can lead to megaloblastic anemia especially in cirrhotic patients
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ADRs
Acetazolamide is a sulphonamide derivative and can result in bone marrow suppression and hypersensitivity reaction
Other adverse effects include metabolic acidosis(urinary alkalosis) and hypokalemia
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Drugs
Furosemide, bumetanide, torsemide and ethacrynic acid
They have greater maximal natriuretic effect than all other diuretics(high ceiling diuretics)
These drugs are faster acting with short duration of action
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other important points
These drugs are also weak CA inhibitors(except ethacrynic acid, it doesn’t increase bicarbonate excretion in the urine)
Loop diuretics also change intrarenal hemodynamics resulting in decreased absorption of Na+ and water in the PT
these changes are mediated by the release of PGs(NSAIDS attenuate diuretic effect)
Since GFR not altered, loop diuretics are the diuretics of choice in presence of moderate to severe renal failure
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other loop diuretics
Ethacrynic acid is highly ototoxic with steep DRC
Mersalyl like organomercuicals are not used now due to the risk of kidney damage
Torsemide has longest half life
effect on calcium
But the effect on calcium excretion is opposite to thiazides( loop looses calcium)
Loop diuretics cause hypocalcemia by increasing the excretion of Ca2+
whereas thiazides cause hypercalcemia by decreasing its excretion
MOA
loop diuretics and act by causing inhibition of Na+K+2cl- symporter present at the luminal membrane of the ascending limb of loop of henle
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Low ceiling effect
Thiazides are moderate efficacy diuretics with low ceiling effect(flat DRC)
natriuretic effect doesn’t increase appreciably with increase in dose
These drugs tend to reduce GFR, therefore are not indicated in renal failure patients
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ADRs
Adverse effects of thiazides: these are similar to loop diuretics except the effect on Ca2+ excretion
Incidence of erectile dysfunction is greater with thiazides than with other antihypertensive drugs
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Cystic fibrosis
Aerosolized amiloride has been shown to improve mucociliary clearance in patients with cystic fibrosis
By inhibiting Na+ absorption from the surfaces of airway epithelial cells,
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Finerenone - newer drug
finerenone was FDA approved to reduce the risk of end-stage kidney disease, cardiovascular death, and heart failure in diabetic patients with CKD
Aldosterone antagonists
spironolactone, eplerenone antagonize the action of aldosterone and produce effects similar to amiloride
These drugs act from interstial side of tubular cell(all other diuretics act from luminal side)
Maximum effect
These agents have maximum effect when aldosterone levels are high. E.g. hepatic cirrhosis, CHF, nephrotic syndrome
and are ineffective in its absence like addisons disease
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Therapeutic uses
these are weak diuretics and are used only in combination with thiazides or loop diuretics to counteract K+ loss
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• Edema associated with congestive heart failure, liver cirrhosis, chronic kidney disease
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Spironolactone can be used for the treatment of hirsutism because of its anti-androgenic action
Its structure is similar to testosterone and thus it acts as a competitive antagonist at testosterone receptors
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Antidiuretics
The drugs that decrease urine volume are called antidiuretics
Primary indication of antidiuretics is the treatment of diabetes insipidus
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V2 receptor agonist
Desmopressin (DDAVP)
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• Prevention of blood loss in patients with specific bleeding disorders like Von Willebrand disease and Hemophilia A
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