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

I. OVER VIEWI. OVER VIEW Drugs inducing a state of increased Drugs inducing a state of increased

urine flow are called diuretics.urine flow are called diuretics.

Diuretics are inhibitors of renal ion Diuretics are inhibitors of renal ion transporters that decreases the transporters that decreases the

reabsorption of Nareabsorption of Na++ at different sites in at different sites in the nephron.the nephron.

As a result, NaAs a result, Na++ and other ions, such and other ions, such as CLas CL--, enter the urine in greater than , enter the urine in greater than

normal amounts along with water. normal amounts along with water.

Diuretics thus increase the volume Diuretics thus increase the volume of urine, and often change its pH. of urine, and often change its pH.

Also changes the ionic Also changes the ionic composition of the urine and composition of the urine and

blood.blood. The efficacy of the different classes The efficacy of the different classes

of diuretics depend on the Naof diuretics depend on the Na+ +

secretion. secretion. varying from less than two percent varying from less than two percent

for the weak, potassium-sparing for the weak, potassium-sparing diuretics to over twenty percent for diuretics to over twenty percent for

thethe potent loop diuretics. potent loop diuretics.

CLASSIFICATION OF CLASSIFICATION OF DIURETIC DRUGS DIURETIC DRUGS

TThiazide Diureticshiazide Diuretics or or MEDIUM EFFICACY MEDIUM EFFICACY

DIURETICSDIURETICS Chlorothiazide Chlorothiazide Chlorothalidone Chlorothalidone Hydrochlorothiazide Hydrochlorothiazide Indapamide Indapamide Metolazone Metolazone

LOOP DIURETICS ORLOOP DIURETICS OR HIGH EFFICACY (CEILING) HIGH EFFICACY (CEILING)

DIURETICSDIURETICS

Bumetanide Bumetanide Ethacrynic acid Ethacrynic acid Furosemide Furosemide Torsemide Torsemide

WEAK OR ADJUNCTIVE WEAK OR ADJUNCTIVE DIURETICSDIURETICS

A. Pottassium-A. Pottassium-Sparing Diuretics Sparing Diuretics

1. Amiloride 1. Amiloride 2. 2. Spironolactone Spironolactone

3.Triamterene 3.Triamterene

B. Carbonic B. Carbonic Anhydrase InhibitorsAnhydrase Inhibitors

1. Acetazolamide 1. Acetazolamide C. Osmotic DiureticsC. Osmotic Diuretics

1.Mannitol 1.Mannitol

2.Urea 2.Urea

THIAZIDE DRUGSTHIAZIDE DRUGSPHARMACOKINETICS PHARMACOKINETICS

All Thiazide and related drugs All Thiazide and related drugs are well absorbed orally,are well absorbed orally,

they are also given by I/M & I/V they are also given by I/M & I/V route. route.

Their action starts within in 1 - Their action starts within in 1 - hour, but the duration is variable hour, but the duration is variable (6-48 hour).(6-48 hour).

The more lipid soluble agents The more lipid soluble agents have larger volumes of have larger volumes of distribution (some are also tissue distribution (some are also tissue bound), lower rates of renal bound), lower rates of renal clearance and are longer acting. clearance and are longer acting.

Tubular reabsorption Tubular reabsorption depends on lipid depends on lipid solubility; the more solubility; the more soluble ones are soluble ones are highly reabsorbed –highly reabsorbed –prolonging duration prolonging duration of action.of action.

The protein binding The protein binding is also variable.is also variable.

1.THIAZIDES AND RELATED 1.THIAZIDES AND RELATED AGENTSAGENTS

The thiazides are the The thiazides are the mostly used diuretic drugs.mostly used diuretic drugs.

They are sulfonamide They are sulfonamide derivatives.derivatives.

related in structure to the related in structure to the carbonic anhydrase carbonic anhydrase inhibitors,but greater inhibitors,but greater diuretic activity than diuretic activity than carbonic anhydrase. carbonic anhydrase.

All thiazides affect the distal All thiazides affect the distal tubule. tubule.

all have equal maximum all have equal maximum diuretic effects.diuretic effects.

differing only in potency differing only in potency (expressed on a per milligram (expressed on a per milligram basis).basis).

They are sometimes called They are sometimes called “Ceiling Diuretic” because “Ceiling Diuretic” because increasing the dose above increasing the dose above normal does not promote a normal does not promote a further diuretic response. further diuretic response.

A. MECHANISM OF A. MECHANISM OF ACTIONACTION The thiazide derivatives act The thiazide derivatives act

mainly in the distal tubule.mainly in the distal tubule. they decrease the reabsorption of they decrease the reabsorption of

NaNa++- apparently by inhibition of - apparently by inhibition of NaNa++/Cl/Cl- - cotransportercotransporter on the on the luminal membrane of the distal luminal membrane of the distal convoluted tubule. convoluted tubule.

They have a lesser effect in the They have a lesser effect in the proximal tubule.proximal tubule.

As a result, these drugs increase As a result, these drugs increase the concentrations of Nathe concentrations of Na+ + and Cland Cl-- in the tubular fluid. in the tubular fluid.

The acid-base balance is not The acid-base balance is not usually affetced. usually affetced.

Therapeutic UsesTherapeutic 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, - Ascites (due to venous occlusion, cirrhosis,

endometriosis, etc.)endometriosis, etc.) - Calcium nephrolithiasis, idiopathic hypercalciuria.- Calcium nephrolithiasis, idiopathic hypercalciuria. - Meniere’s disease - Meniere’s disease (they can prevent the (they can prevent the

endolymphatic fluid buildup)endolymphatic fluid buildup) - Nephrogenic diabetes insipidus - Nephrogenic diabetes insipidus (this seemingly (this seemingly

paradoxical effect is likely mediated through the paradoxical effect is likely mediated through the extracellular volume contraction which promotes extracellular volume contraction which promotes proximal tubular reabsorption of Na+ and water. proximal tubular reabsorption of Na+ and water. Therefore a reduced volume is delivered to the distal Therefore a reduced volume is delivered to the distal tubule)tubule)

Contraindications and PrecautionsAbsoluteAnuriaSulfonamide hypersensitivity, thiazide diuretic hypersensitivityPrecautionsHyperglycemia, Hyperuricemia, breast feeding, electrolyte imbalance, renal failure

Hypokalemia

Hyperuricemia

Hypercalcemia

Hyperlipidemia

Hyperglycemia

Adverse Effects

POTASSIUM SPARING DIURETICS

POTASSIUM SPARING POTASSIUM SPARING DIURETICSDIURETICS

They are Aldosterone They are Aldosterone antagonist.antagonist.

They are used primarily They are used primarily when aldosterone is present when aldosterone is present in excess.in excess.

This group antagonize the This group antagonize the effects effects of aldosterone at of aldosterone at the DT&CD.the DT&CD.

SPIRONOLACTONE SPIRONOLACTONE (ALDOSTERONE (ALDOSTERONE ANTAGONIST)ANTAGONIST)

It is steroid , It is steroid , chemically related chemically related to the to the mineralocorticoid mineralocorticoid aldosterone . aldosterone .

SPIRONOLACTONESPIRONOLACTONE blocks the blocks the Aldosterone receptor by Aldosterone receptor by combining with an intracellular combining with an intracellular mineralocorticoid at late DT and mineralocorticoid at late DT and CD cells. CD cells.

→ → induces theinduces the formation of formation of aldosterone induced proteins aldosterone induced proteins (AIPs).(AIPs).

These proteins promote NaThese proteins promote Na+ +

reabsorption and Kreabsorption and K++ secretion . secretion . Triamterene and amiloride Triamterene and amiloride

directly block Na+ channels in the directly block Na+ channels in the luminal membrane of late distal luminal membrane of late distal tubule and cortical collecting tubule.tubule and cortical collecting tubule.

PHARMACOKINETIPHARMACOKINETICSCS

The oral bioavailability of The oral bioavailability of spironolactone from spironolactone from microfine powder tablet is microfine powder tablet is 75%.75%.

It is highly bound to plasma It is highly bound to plasma proteins.proteins.

completely metabolized in completely metabolized in liver; liver;

SPIRONOLACTONESPIRONOLACTONE

Therapeutic Therapeutic usesuses

Most Most commonly used commonly used in combination in combination with other with other diureticsdiuretics

Absolute Absolute contraindicationscontraindications

HyperkalemiaHyperkalemia Renal failureRenal failure

PrecautionsPrecautions

GoutGout PregnancyPregnancy Acid base imbalanceAcid base imbalance

PHARMACOLOGY OF ANTI-PHARMACOLOGY OF ANTI-DIURETIC HORMONE DIURETIC HORMONE

ANTAGONISTSANTAGONISTSDrugsDrugs- Conivaptan, tolvaptan- Conivaptan, tolvaptan

Mechanism of actionMechanism of actionCompetitive antagonists at vasopressin receptors Competitive antagonists at vasopressin receptors (conivaptan at V1a (conivaptan at V1a and V2, tolvaptan at V2)and V2, tolvaptan at V2)

Renal effectsRenal effectsIncreased water diuresis (these drugs are also Increased water diuresis (these drugs are also called called aquareticsaquaretics))Water diuresis increases more than salt diuresis Water diuresis increases more than salt diuresis (in this way hyponatremia is relieved).(in this way hyponatremia is relieved).Increased renal excretion of: Na+, K+, Ca++Increased renal excretion of: Na+, K+, Ca++Urine osmolality: decreasedUrine osmolality: decreased

ADVERSE EFFECTSADVERSE EFFECTS DrowsinessDrowsiness hyperkalemia hyperkalemia AcidosisAcidosis confusion confusion abdominal upsetabdominal upset hirsutism in female hirsutism in female impotance impotance menstrual irregularities.menstrual irregularities. Peptic ulcer may be aggravated.Peptic ulcer may be aggravated.