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……