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Diuretics
Diuretic: Substance that promotes the excretion of urine
Uses:
Edema
Hypertension
Congestive heart failure
Processes performed by the kidneys in order to filter (clean) blood :-
1. Glomerular Filtration also called "Ultra-filtration",
2. Tubular Reabsorption also called "Selective Re-Absorption" and
3. Tubular Secretion.
Classification
Proximal Convoluted Tubule Diuretics Osmotic Diuretics: Mannitol, Urea, Isosorbide, Glycerol Carbonic Anhydrase Inhibitors: Acetazolamide
Loop Diuretics Furosemide, Bumetanide, Ethacrynic Acid, Torsemide
Distal Convoluted Tubule Diuretics Thiazides: Benzthiazide, Chlorthiazide, Hydrochlorothiazide, Polythiazid
e, Trichlormethiazide Thiazide like : Metolazone, Indapamide, Chlorthalidone
Collecting Duct Diuretics ( K+ sparing diuretics ) Aldosterone Antagonist: Spironolactone Non-aldosterone Antagonist:Triamterene, Amiloride
High efficacy diuretics
- Inhibitors of Na- K- Cl cotransport
- e.g. Loop diuretics
Medium efficacy diuretics
- Inhibitors of Na-K Symport
- e.g. Thiazides
Weak or adjunctive diuretics
- Carbonic Anhydrase Inhibitors
- K+ sparing diuretics
Also Called:•Loop Diuretics•High Ceiling Diuretics
EthacrynicAcid (Disuse)
Bumetanide(BUMEX)
Furosemide(LASIX)
Loop Diuretics
Selectively inhibit NaCl reabsorption in the thick ascending limb of the loop of Henle.
Chemistry: -
Two prototypical drugs of this group are furosemide and ethacrynic acid
furosemide, bumetanide, and torsemide are sulfonamide derivatives
Pharmacokinetics
Rapidly absorbed.
Eliminated by tubular secretion as well as by glomerular filtration.
Absorption of oral torsemide is more rapid (1 hour) than that of furosemide(2–3 hours) and is nearly as complete as with intravenous administration.
Diuretic response is extremely rapid following intravenous injection.
Duration of effect for furosemide is usually 2–3 hours and that of torsemide is 4–6 hours.
Half-life depends on renal function.
Since loop agents act on the luminal side of the tubule, their diuretic activity correlates with their secretion by the proximal tubule.
Reduction in the secretion of loop diuretics may result from simultaneous administration of agents such as NSAIDs , which compete for weak acid secretion in the proximal tubule.
Pharmacodynamics
Inhibit NKCC-2, the luminal Na+/K+/2Cl- transporter in the thick ascending limb of Henle's loop ---- reduce the reabsorption of NaCl and also diminish the lumen- positive potential that comes from K+ recycling. This positive potential normally drives divalent cation reabsorption in the loop and by reducing this potential, loop diuretics cause an increase in Mg2+ and Ca2+ excretion.
Prolonged use can cause significant hypomagnesemia in some patients.
Since vitamin D-induced intestinal absorption of Ca2+ can be increased and Ca2+ is actively reabsorbed in DCT, that’s why it do not cause hypocalcemia.
In hypercalcemia, Ca2+ excretion can be usefully enhanced by treatment with loop diuretics combined with normal saline infusion.
NKCC2
Electrically neutral
Paracellular pathway
Cont…
Loop diuretics (acts as vasodilators) induce renal prostaglandin synthesis, and these prostaglandins acts as major dilators of kidney vasculature.
NSAIDs (eg, indomethacin) can interfere with the actions of the loop diuretics by reducing prostaglandin synthesis in the kidney. It cancel anti HTN effects of loop diuretics by reducing prostaglandin synthesis.
Furosemide increases renal blood flow.
THERAPEUTIC EFFECTS
Increase Na Excretionto 25% of Filtered Load
Treatment forOliguric ARF
Increase Ca ExcretionTreatment for Hypercalcemia
Increase VenousCapacitance
Treatment forPulmonary
Edema
Increase Urine Volume
Treatment forSevere Edema
Clinical use of Loop diuretics
1.Severe Edema
2. Acute pulmonary edema (acute LVF)
3. Forced diuresis (Oliguric ARF or poisonings)
4. Hypercalcaemia
Hyperkalemia
In mild hyperkalemia—or after acute management of severe hyperkalemia by other measures—loop diuretics can significantly enhance urinary excretion of K+. This response is enhanced by simultaneous NaCl and water administration.
Acute Renal Failure
Increase the rate of urine flow and enhance K+ excretion in acute renal failure.
Anion Overdose ( Poisoning )
Useful in treating toxic ingestions of bromide, fluoride, and iodide, which are reabsorbed in the thick ascending limb.
Saline solution must be administered to replace urinary losses o
f Na+ and to provide Cl-, so as to avoid extracellular fluid volume depletion.
Adverse effects of loop diuretics
1. Hypokalemia 2. Hypocalcemia 3. Hypomagnesemia 4. Metabolic Alkalosis 5. Profound ECFV Depletion 6. Hyperglycemia 7. Hyperuricemia 8. Ototoxicity
Allergic Reactions
Skin rash, eosinophilia side effects of furosemide, bumetanide, and torsemide therapy.
Allergic reactions are much less common with ethacrynic acid. So, if pulmonary edema with CCF and patient have allergy with sulphur containing groups then ethacrynic acid is prescribed.
Contraindications
Furosemide, bumetanide, and torsemide:- patients who are sensitive to other sulfonamides.
Carbonic anhydrase inhibitors
Carbonic anhydrase is present in many nephron sites, but the predominant location of this enzyme is the luminal membrane of the proximal tubule cells , where it catalyzes the dehydration of H2CO3, a critical step in the reabsorption of bicarbonate.
By blocking carbonic anhydrase, inhibitors block sodium bicarbonate reabsorption and cause diuresis.
Prototype : Acetazolamide (rarely used as diuretics).
Blocks reabsorption of bicarbonate io
n
Treatment forMetabolic alkalosis
Treatment for Glaucoma
Treatment forAcute
mountain sickness
preventing Na/H exchange
Treatment forUrinary alkalin
ization
Acetazolamide
Decreased formation of aqueous humou
r
Raised level of CO2 in brain
2. Carbonic anhydrase inhibitors
Pharmacokinetics
Well absorbed after oral administration
An increase in urine pH from the bicarbonate diuresis is apparent within 30 minutes, maximal at 2 hours, and persists for 12 hours after a single dose.
Excretion of the drug is by secretion in the proximal tubule. Therefore, dosing must be reduced in renal insufficiency.
Mechanism of action:
Decrease H+ formation inside PCT cell.
Decrease Na+/H+ antiport
Increase Na+ and HCO3 in lumen
Increase diuresis
Uses : Glaucoma, acute mountain sickness, metabolic alkalosis
.
Molecular Mechanism of action
Carbonic anhydrase inhibitors
Reversibly inhibits CAse in PT cells slowing of hydration of CO2→ decreased availability of H+ to exchange with luminal Na+ through the Na+-H+ antiporter. → Inhibition of brush border CAse retards dehydration of H2CO3 in the tubular fluid → less CO2 diffuses back into the cells. → The net effect is inhibition of HCO3- (and accompanying Na+) reabsorption in PT
Side effects :
Bicarbonaturia and metabolic acidosis, hypokalemia, hyperchloremia, paresthesia, renal stone and sulfonamide hypersensitivity.
Pharmacodynamics
At its maximal safely administered dosage, 85% of the bicarbonate reabsorptive is inhibited.
By carbonic anhydrase–independent mechanisms : Some bicarbonate absorbed
CA inhibition causes significant bicarbonate losses and metabolic acidosis.
The ciliary body of the eye secretes bicarbonate from the blood into the aqueous humor.
Formation of cerebrospinal fluid by the choroid plexus involves bicarbonate secretion into the cerebrospinal fluid.
Although these processes remove bicarbonate from the blood, they are significantly inhibited by carbonic anhydrase inhibitors.
Clinical Indications & Dosage
Glaucoma :
Most common indication for use of carbonic anhydrase inhibitors.
Reduction of aqueous humor formation by carbonic anhydrase inhibitors decreases the intraocular pressure.
By preventing the dehydration of H2CO3 in PCT.
Topically: dorzolamide, brinzolamide
Treatment of Glaucoma
Drug Usual Oral Dose
Acetazolamide 250 mg 1–4 times daily
Thiazide Diuretics
Also Called:•Thiazide Diuretics•Thiazide-Like Diuretics
Chlorthalidone
MetolazoneChlorothiazide
Hydrochlorothiazide
Pharmacokinetics Thiazide and related diuretics:
Oral administration - absorption poor
Diuresis within one hour
T1/2 for chlorthalidone is 44 hours, used mainly as antihypertensive.
Pharmacodynamics
Inhibit NaCl reabsorption from the luminal side of epithelial cells in the distal convoluted tubule by blocking the Na+/Cl- transporter.
Thiazides actually enhance Ca2+ reabsorption in the DCT due to effects in both PCT and DCT.
In the PCT : thiazide-induced volume depletion leads to enhance Na+ and passive Ca2+ reabsorption.
In DCT : lowering of intracellular Na+ by thiazide-induced blockade of Na+ entry enhances Na+/Ca2+ exchange in the basolateral membrane and increase overall reabsorption of Ca2+.
Thiazides Low NA
Increased Ca reabsorption
PTH dependent channel
Thiazide and related diuretics Mechanism of Action
Thiazides freely filtered and secreted in proximal tubule.
Bind to the electroneutral NaCl cotransporter.
Thiazides impair Na+ and Cl- reabsorption in the early distal tubule.
Thus, water reabsorption decrease and urine increase.
THERAPEUTIC EFFECTS
Increase Na Excretionto 5% of Filtered Load
Treatment forHypertension
Decrease Ca ExcretionTreatment for Calcium stones in the kindey
Treatment forNephrogenic Ins
ipidus
Treatment forMild Edema
Clinical Indications
Major indications for thiazide diuretics are : (1) Hypertension.
(2) Mild Edema
(3) Nephrolithiasis due to idiopathic hypercalciuria, and
(4) Nephrogenic diabetes insipidus
Adverse effects of thiazide diuretics
1. Hypokalemia 2. Hypomagnesemia 3. ECFV Depletion 4. Hypercalcemia 5. Hyperglycemia 6. Hyperuricemia 7. Increased plasma lipids
Potassium-Sparing Diuretics
Potassium-Sparing Diuretics
Prevent K+ secretion by antagonizing the effects of aldosterone at the late distal tubule and cortical collecting tubule.
Inhibition may occur by direct pharmacologic antagonism of mineralocorticoid receptors (spironolactone, eplerenone) or by inhibition of Na+ influx through ion channels in the luminal membrane (amiloride, triamterene).
MINERALOCORTICOID RECEPTOR ANTAGONISTS
Also Called:•K-Sparing Diuretics•Aldosterone Antagonists
Spironolactone
Eplerenone
Chemistry & Pharmacokinetics
Spironolactone is a synthetic steroid that acts as a competitive antagonist to aldosterone.
Inactivation of spironolactone occurs in the liver.
Spironolactone has slow onset of action, requiring several days before full therapeutic effect is achieved.
Eplerenone, a new spironolactone analog with greater selectivity for the aldosterone receptor, used for the treatment of hypertension.
Aldosterone acts on the late DT and CD cells
Combining with an intracellular mineralocorticoid receptor
induces the formation of aldosterone induced proteins (AIPs)
promote Na+ reabsorption and K+ secretion
Mechanism of ActionAldosterone
THERAPEUTIC EFFECTS
Enhances Natriuresis Caused by Other Diuretics
Blocks Aldosterone
Treatment for Primary Hyper-aldosteronism
Prevents Hypokalemia
Used in Combination with Loo
p &Thiazide Diuret
ics
Treatment for Edema of Liver
Cirrhosis
Treatment forHypertension
Treatment forHeart Failure
ADVERSE EFFECTS
Impotence
Gynecomastia
MetabolicAcidosis
HyperkalemiaHirsutism
CNS SideEffects
Peptic Ulcers
Gastritis
MenstrualIrregularities
Toxicity
Hyperkalemia: more common when Potassium-Sparing Diuretics are used as the sole diuretic agent, especially in patients with renal insufficiency (maximal K+ excretion may be reduced).
With fixed-dosage combinations of potassium-sparing and thiazide diuretics, the thiazide-induced hypokalemia and metabolic alkalosis are ameliorated.
Hyperchloremic Metabolic Acidosis
By inhibiting H+ secretion in parallel with K+ secretion
Gynecomastia : Synthetic steroids may cause endocrine abnormalities by effects on other steroid receptors.
Gynecomastia, impotence, and benign prostatic hyperplasia have all been reported with spironolactone (except eplerenone).
Na CHANNEL INHIBITORS
Also Called:•K-Sparing Diuretics
Amiloride
Triamterene
Chemistry & Pharmacokinetics
Amiloride and triamterene are direct inhibitors of Na+ influx in the CCT.
Triamterene is metabolized in the liver, but renal excretion is a major route of elimination for the active form and the metabolites.
Because triamterene is extensively metabolized, it has a shorter half-life and must be given more frequently than amiloride (which is not metabolized).
THERAPEUTIC EFFECTS
Enhance Natriuresis Caused by Other Diuretics
Prevent Hypokalemia
Used in Combination with Loo
p &Thiazide Diuret
ics
ADVERSE EFFECTS
Renal Stones
InterstitialNephritis
HyperkalemiaHyperkalemia
AmilorideTriamterene
To be continued……