DIURETIC DRUGS (DR.Farooq Alam) DIURETIC DRUGS (DR.Farooq Alam)

I. OVER VIEW Drugs inducing a state of increased urine flow are called diuretics. Drugs inducing a state of increased urine flow are called diuretics. Diuretics are inhibitors of renal ion transporters that decreases the reabsorption of Na + at different sites in the nephron. Diuretics are inhibitors of renal ion transporters that decreases the reabsorption of Na + at different sites in the nephron. As a result, Na + and other ions, such as CL -, enter the urine in greater than normal amounts along with water. As a result, Na + and other ions, such as CL -, enter the urine in greater than normal amounts along with water.

 Diuretics thus increase the volume of urine, and often change its pH.  Also changes the ionic composition of the urine and blood.  The efficacy of the different classes of diuretics depend on the Na + secretion.  varying from less than two percent for the weak, potassium-sparing diuretics to over twenty percent for the potent loop diuretics.

CLASSIFICATION OF DIURETIC DRUGS T hiazide Diuretics or MEDIUM EFFICACY DIURETICS Chlorothiazide Chlorothiazide Chlorothalidone Chlorothalidone Hydrochlorothiazide Hydrochlorothiazide Indapamide Indapamide Metolazone Metolazone

LOOP DIURETICS OR HIGH EFFICACY (CEILING) DIURETICS Bumetanide Bumetanide Ethacrynic acid Ethacrynic acid Furosemide Furosemide Torsemide Torsemide

WEAK OR ADJUNCTIVE DIURETICS A. Pottassium-Sparing Diuretics A. Pottassium-Sparing Diuretics 1. Amiloride 1. Amiloride 2. Spironolactone 2. Spironolactone 3.Triamterene 3.Triamterene

B. Carbonic Anhydrase Inhibitors B. Carbonic Anhydrase Inhibitors 1. Acetazolamide 1. Acetazolamide C. Osmotic Diuretics C. Osmotic Diuretics 1.Mannitol 1.Mannitol 2.Urea 2.Urea

THIAZIDE DRUGS PHARMACOKINETICS All Thiazide and related drugs are well absorbed orally, All Thiazide and related drugs are well absorbed orally, they are also given by I/M & I/V route. they are also given by I/M & I/V route. Their action starts within in 1 - hour, but the duration is variable (6-48 hour). Their action starts within in 1 - hour, but the duration is variable (6-48 hour). The more lipid soluble agents have larger volumes of distribution (some are also tissue bound), lower rates of renal clearance and are longer acting. The more lipid soluble agents have larger volumes of distribution (some are also tissue bound), lower rates of renal clearance and are longer acting.

 Tubular reabsorption depends on lipid solubility; the more soluble ones are highly reabsorbed – prolonging duration of action.  The protein binding is also variable.

1.THIAZIDES AND RELATED AGENTS The thiazides are the mostly used diuretic drugs. The thiazides are the mostly used diuretic drugs. They are sulfonamide derivatives. They are sulfonamide derivatives. related in structure to the carbonic anhydrase inhibitors,but greater diuretic activity than carbonic anhydrase. related in structure to the carbonic anhydrase inhibitors,but greater diuretic activity than carbonic anhydrase.

 All thiazides affect the distal tubule.  all have equal maximum diuretic effects.  differing only in potency (expressed on a per milligram basis).  They are sometimes called “Ceiling Diuretic” because increasing the dose above normal does not promote a further diuretic response.

A. MECHANISM OF ACTION The thiazide derivatives act mainly in the distal tubule. The thiazide derivatives act mainly in the distal tubule. they decrease the reabsorption of Na + - apparently by inhibition of Na + /Cl - cotransporter on the luminal membrane of the distal convoluted tubule. they decrease the reabsorption of Na + - apparently by inhibition of Na + /Cl - cotransporter on the luminal membrane of the distal convoluted tubule. They have a lesser effect in the proximal tubule. They have a lesser effect in the proximal tubule. As a result, these drugs increase the concentrations of Na + and Cl - in the tubular fluid. As a result, these drugs increase the concentrations of Na + and Cl - in the tubular fluid. The acid-base balance is not usually affetced. The acid-base balance is not usually affetced.

Therapeutic Uses Hypertension (first choice diuretics). Hypertension (first choice diuretics). - Edema associated with diseases of: - Edema associated with diseases of: a) the heart (i.e. heart failure) a) the heart (i.e. heart failure) b) the liver (i.e. hepatic cirrhosis) b) the liver (i.e. hepatic cirrhosis) c) the kidney (i.e. nephrotic syndrome). c) the kidney (i.e. nephrotic syndrome). - Ascites (due to venous occlusion, cirrhosis, endometriosis, etc.) - Ascites (due to venous occlusion, cirrhosis, endometriosis, etc.) - Calcium nephrolithiasis, idiopathic hypercalciuria. - Calcium nephrolithiasis, idiopathic hypercalciuria. - Meniere’s disease (they can prevent the endolymphatic fluid buildup) - Meniere’s disease (they can prevent the endolymphatic fluid buildup) - Nephrogenic diabetes insipidus (this seemingly paradoxical effect is likely mediated through the extracellular volume contraction which promotes proximal tubular reabsorption of Na+ and water. Therefore a reduced volume is delivered to the distal tubule) - Nephrogenic diabetes insipidus (this seemingly paradoxical effect is likely mediated through the extracellular volume contraction which promotes proximal tubular reabsorption of Na+ and water. Therefore a reduced volume is delivered to the distal tubule)

Contraindications and Precautions Absolute Anuria Sulfonamide hypersensitivity, thiazide diuretic hypersensitivity Precautions Hyperglycemia, Hyperuricemia, breast feeding, electrolyte imbalance, renal failure

 Hypokalemia  Hyperuricemia  Hypercalcemia  Hyperlipidemia  Hyperglycemia Adverse Effects

POTASSIUM SPARING DIURETICS

They are Aldosterone antagonist. They are Aldosterone antagonist. They are used primarily when aldosterone is present in excess. They are used primarily when aldosterone is present in excess. This group antagonize the effects of aldosterone at the DT&CD. This group antagonize the effects of aldosterone at the DT&CD.

SPIRONOLACTONE (ALDOSTERONE ANTAGONIST) It is steroid, chemically related to the mineralocorticoid aldosterone. It is steroid, chemically related to the mineralocorticoid aldosterone.

 SPIRONOLACTONE blocks the Aldosterone receptor by combining with an intracellular mineralocorticoid at late DT and CD cells.  → induces the formation of aldosterone induced proteins (AIPs).  These proteins promote Na + reabsorption and K + secretion.  Triamterene and amiloride directly block Na+ channels in the luminal membrane of late distal tubule and cortical collecting tubule.

PHARMACOKINETICS The oral bioavailability of spironolactone from microfine powder tablet is 75%. The oral bioavailability of spironolactone from microfine powder tablet is 75%. It is highly bound to plasma proteins. It is highly bound to plasma proteins. completely metabolized in liver; completely metabolized in liver;

SPIRONOLACTONE Therapeutic uses Therapeutic uses Most commonly used in combination with other diuretics Most commonly used in combination with other diuretics Absolute contraindications Hyperkalemia Renal failure Precautions Gout Pregnancy Acid base imbalance

PHARMACOLOGY OF ANTI-DIURETIC HORMONE ANTAGONISTS Drugs - Conivaptan, tolvaptan - Conivaptan, tolvaptan Mechanism of action Competitive antagonists at vasopressin receptors (conivaptan at V1a and V2, tolvaptan at V2) Competitive antagonists at vasopressin receptors (conivaptan at V1a and V2, tolvaptan at V2) Renal effects Increased water diuresis (these drugs are also called aquaretics) Increased water diuresis (these drugs are also called aquaretics) Water diuresis increases more than salt diuresis (in this way hyponatremia is relieved). Water diuresis increases more than salt diuresis (in this way hyponatremia is relieved). Increased renal excretion of: Na+, K+, Ca++ Increased renal excretion of: Na+, K+, Ca++ Urine osmolality: decreased Urine osmolality: decreased

ADVERSE EFFECTS Drowsiness Drowsiness hyperkalemia hyperkalemia Acidosis Acidosis confusion confusion abdominal upset abdominal upset hirsutism in female hirsutism in female impotance impotance menstrual irregularities. menstrual irregularities.  Peptic ulcer may be aggravated.