Diuretics (1/2)

Dr. C.Adithan

Professor of Pharmacology

Overview of 1st lecture• Definition

• Physiology of Urine formation and drugs modifying it

• Classification

• Pharmacology of Thiazide diuretics and Loop diuretics

• Mechanism of action

• Indications

• Dose

• Side effects

• Drug interactions

•

Kidney functions

Balance of electrolytes, Plasma volume, Acid Base

Activation of Vitamin D

Synthesis of Erythropoietin, Urokinase

Excretion of Urea, Uric acid, Creatinine etc.

Primary Function is to maintain homeostasis. Excretion is a by product of that homeostasis.

Homeostasis is maintained by

Regulation of water volume, blood volume, and interstitial fluid volume. First warning signs about kidneys dysfunction ????

Causes of Generalized Oedema

• Cardiac Cause: Congestive cardiac failure

• Renal Cause: Nephrotic syndrome

• Hepatic Cause: Cirrhosis of liver

• Nutritional cause: Malnutrition

• Allergic reaction

• Drug Induced

DiureticsDrugs which cause a net loss of Na+ and

water in urine. (Except Osmotic diuretics which do not cause Natriuresis

but produce diuresis)

• Causes increase in urine volume due to increased osmotic pressure in lumen of renal tubule.

• Causes concomitant decrease in extra-cellular volume (blood volume)

In order to understand the Diuretics,

we need to know the physiology of Urine formation

PHYSIOLOGY OF URINE FORMATIONThree major steps are involved. 1) Glomerular filtration. 2) Tubular Reabsorption & 3) Active tubular secretion.

Nephron can be divided into four sites. - Proximal tubule - Henle’s loop - DCT - Collecting duct.

Normal GFR is 125ml/min or 180 litres/day, of which 99% gets reabsorbed and only 1.5 litres is excreted as urine.

Introduction

Proximal tubuleFreely permeable to water, Active absorption of NaCl, NaHCO3, Glucose, Amino Acids, Organic SolutesThis is followed by passive absorption of water

Osmotic diuretics act at PCT and also on LH (descending Osmotic diuretics act at PCT and also on LH (descending limb) by interposing a countervailing osmotic forcelimb) by interposing a countervailing osmotic force

Substance % of filtrate reabsorbed in PCT•65-80% of the filtrate is reabsorbed

•Most reabsorption is coupled to sodium ion movement

Sodium and Water ~66%Organic solutes e.g. glucose and amino acids ~100%

Potassium ~65%Urea ~50%Phosphate ~80%

Loop of Henle (LH)• Descending limb-

Permeable to water

• Thick ascending limb – Impermeable to water but Permeable to sodium by Na+K+2Cl- Co transport About 25% of filtered sodium is absorbed here

Loop diuretics act here and blocks the co-transporter.

Macula Densa and Juxtaglomerular (JG) Apparatus

• Contact between Ascending limb with afferent arterioles – by specialized columnar epithelial cells Macula Densa

• Macula Densa sense NaCl conc. in filtrate• Gives signal to JG apparatus present in afferent arterioles• JG of afferent arterioles secrete Renin• In low B.P. or low Na , renin secretion is increased

leading to Angiotensin secretion resulting in vasoconstriction, sodium and water retention.

Distal Convoluted Tubule

• In the Early distal tubule 10% of NaCl is reabsorbed by Na-Cl symport transporter mechanism.

• On reaching the DCT almost 90% of sodium is already reabsorbed.

• Calcium excretion is regulated (Parathomone and Calcitriol, increase absorption of calcium)

• Thiazides block Na-Cl symport transporter system. • Thiazides are called moderate efficacy diuretics as they reabsorb

only 10% of sodium

Collecting Tubule and Collecting Duct

• Aldosterone- On membrane receptor and cause sodium absorption by Na+/H+/ K+ Exchange

• ADH- Collecting tubular epithelium permeable to water (Water enters through aquaporin-2)

Nephron parts and their functions

SEGMENT FUNCTIONGlomerulus Formation of glomerular filtrateProximal convoluted tubule (PCT) Reabsorption: 100 % of glucose and amino acids65% of Na+/K+/ Ca2+ , Mg2+, ;

85% of NaHCO3, (activity of Carbonic anhydrase enzyme) Iso-osmotic reabsorption of water., Secretion and reabsorption of organic acids and bases, including uric acid and drugs

penicillin, probenecid and most diureticsThin descending limb of LH Passive reabsorption of water

Thick ascending limb of LH Active reabsorption: 25% of filtered Na+/K+/2Cl−;

Secondary re-absorption of Ca2+ and Mg2+

Distal convoluted tubule (DCT)Active reabsorption of 4–8% of filtered Na+ Cl−; Ca2+ reabsorption under parathyroid hormone control

Cortical collecting tubule (CCT) Na+ reabsorption (2–5%) coupled to K+ and H+ secretion (under Aldosterone)

Medullary collecting duct Water reabsorption under Vasopressin control

The relative magnitudes of Na+ reabsorption at sites

• PT - 65%• Asc LH - 25%• DT - 9%• CD - 1%.

Classifications of Diuretics• Thiazide Diuretics: a) Thiazides: Hydrochlorothiazide, Benzthiazide b) Thiazide like: Chlorthalidone, Metolazone, Xipamide, Indapamide, Clopamide

• Loop Diuretics : Frusemide, Bumetanide, Torasemide, Ethacrynic acid

• Potassium Sparing Diuretics : – Aldosterone Antagonist: Spironolactone, Canrenone, Eplerenone– Directly Acting (Inhibition of Na+ channel): Triamterene, Amiloride

• Carbonic anhydrase inhibitors : Acetazolamide, Brinzolamide, Dorzolamide• Osmotic Diuretics : Mannitol, Glycerine, Urea, Isosorbide

1. Osmotic diuretics2. Carbonic anhydrase inhibitors3. Loop Diuretics (High ceiling)4. Thiazide diuretics5. Potassium sparing diuretics

1. Osmotic diuretics2. Carbonic anhydrase

inhibitors3. Loop diuretics4. Thiazide diuretics5. Potassium diuretics

Thiazide diuretics»Mechanism of action

»Individual drugs

»Pharmacokinetics

»Indications

»Dose

»Side effects and Precautions

THIAZIDES AND THIAZIDE LIKE DIURETICS

Renal tubule

Peritubular capillary

Thiazide Diuretics - Actions• Acts on early part of distal tubules • Inhibit Na+-Cl- symporter and reabsorption• Increase NaCl excretion (5-10% Medium efficacy)• Na exchanges with K+ in the DT K+ loss

Hypokalemia• Not effective in very low GFR of < 30ml/min, may reduce

GFR further– Metolazone additional action on PT, effective at low GFR, can be tried in refractory edema

Thiazide Diuretics - Other actions• Hypotensive action• reduce Ca++ excretion may ppt hypercalcemia in patients

of hyperparathyroidism, bone malignancy with metastasis

• Increase Mg++ excretion• Hypochloremic alkalosis• Hyperuricemia • Hyperglycemia (inhibit insulin release ?)• Hyperlipidemia (Cholesterol and TG)

Thiazide drugs Chlorthalidone: Used only for hypertension, long acting (t1/2 – 50 hr)

Metolazone: Active even in low GFR. Additive with furosemide. Used mainly for edema, occasionally for hypertension.

Xipamide: More strong diuretic. Used for edema and hypertension More incidence of hypokalaemia and

ventricular arrhythmia. Indapamide: Extensively metabolized.

Very less amount reach kidney. Used only as antihypertensive.

Pharmacokinetics Well absorbed orally Rapid acting- within 60 minutes. Thiazides are organic acids they are

secreted into the proximal tubules. Partly excreted by the hepatobiliary

system.

Thiazides - Uses1) Hypertension (Hydrochlorothiazide, Indapamide)

2) Edema : Cardiac, Hepatic, Renal• Less efficacious than loop diuretic

• Useful for maintenance therapy

3) Hypercalciuria and renal Ca stones4) Diabetes Insipidus (DI) (Nephrogenic responds better)

• Paradoxical use,

• MOA - ? Reduce GFR, ? More complete reabsorption in PT

• Convenient, Cheaper than Desmopressin in Neurogenic DI

• Amiloride is the DOC for Lithium induced nephrogenic DI

Metolazone useful even when GFR is as low as 15 ml/min

Thiazides Preparations

Drug Name Dose in mg (oral)

Duration (hr)

Cost (Rs)per tablet

Chlorothiazide (1957) 500-2000 6-12Hydrochlorothiazide 12.5-100 8-12 Rs.1.20 (25 mg)Benzthiazide 25-100 12-18Hydroflumethiazide 25-100 12Chlorthalidone 50-100 48 Rs.2.40 (100 mg)Metolazone 5-20 18 Rs.6 – 10 (2.5

mg)Xipamide, Clopamide

10-40 12-24 Rs.3.20 (20mg)

Indapamide (No CAI) 2.5-5 24-36

Thiazides -Adverse Effects

1) Hyperuricemia

2) Hyperglycemia

3) Hyperlipidemia

4) Hypercalcemia

5) Hyponatraemia

6) Hypokalemia

7) Hypomagnesemia

8) Hypochloremic alkalosis

9) Hypersensitivity

10) May ppt renal failure

11) Not safe in pregnancy

(all diuretics)

Thiazide diuretics - Summary Medium efficacy diuretics – Inhibit Na Cl

symport Cause more hyperuricemia and hypokalaemia

than loop diuretics Not effective in patients with renal dysfunction Decrease Ca excretion. Increase Mg excretion Duration of action varies between 6 – 48 hours

Loop diureticsMechanism of action Individual drugsPharmacokinetics IndicationsDoseSide effects and PrecautionsDrug interactions

Comparison of loop and thiazide diuretics

Loop diuretics Generally cause greater diuresis than thiazides; used

when they are insufficient Can enhance Ca2+ and Mg2+ excretion Enter tubular lumen via proximal tubular secretion

(unusual secretion segment) because body treats them as a toxic drug

Drugs that block this secretion (e.g. probenecid) reduces efficacy

High ceiling diuretics (Loop diuretics)

High ceiling diuretics (Loop diuretics) Furosemide – Also called frusemide. Rapid and short acting.

Can be given IM, IV and oral

Can produce up to 10 litres of urine per day.

Effective even in patients with severe renal failure

Cause peripheral venous dilation and relieves LVF

Cause Ca and Mg excretion through urine

Hyperuricemia and hypokalemia

May cause ototoxicity

Dose: 20 – 80 mg OD in morning

High ceiling diuretics (Loop diuretics)

Bumetanide – similar to furosemide. 40 times more potent

Can respond in patients resistant to furosemide

Can be used in patients allergic to furosemide

Can cause myopathy (rarely)

Less ototoxicity compared to furosemide

Used in CHF and pulmonary edema

Dose: 1 – 5 mg OD in morning

High ceiling diuretics (Loop diuretics)

Torasemide – also called torsemideSimilar to furosemide – 3 times more potentSlightly longer actingUsed in edema and hypertension

Uses - Loop diuretics Peripheral edema Acute pulmonary edema Cerebral edema – (osmotic diuretics more preferred) Hypertension – (not first choice. Only in presence of

CHF, renal insufficiency etc) With blood transfusion to prevent volume overload In hypercalcemia of pregnancy – IV infusion of large

volume saline, followed by furosemide to excrete calcium and prevent volume overload

Loop & Thiazide drugs

InteractionsPotentiate antihypertensive drugsHypokalaemia by diuretics – cause digitalis toxicity, arrhythmiasFurosemide with aminoglycosides – ototoxicity and nephrotoxicCotrimoxazole with diuretics – thrombocytopeniaNSAIDS with furosemide – blunt action of furosemide

Loop & Thiazide drugs: Complications Hypokalaemia

Acute saline depletion Dilutional hyponatremia Hearing loss Hyperuricemia Hyperglycaemia Hypocalcaemia with loop and hypercalcemia with

thiazides Magnesium loss

To be continued in the next class

Thank you

To be continued in the next class