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

• Few MCQs

•

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: To maintain homeostasis (Excretion is a by product). 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

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.

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 (moderate efficacy) : block only 10% of Na reabsorption

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 functionsSEGMENT FUNCTION

Glomerulus Formation of glomerular filtrateProximal convoluted tubule (PCT) Reabsorption: 100 % of glucose and amino acids

65% 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 drugsChlorthalidone: 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 Rs. 8.00 (5 mg)

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 diureticsFrusemide, Bumetanide, Torasemide, Ethacrynic acid

Mechanism of action Individual drugs Pharmacokinetics Indications Dose Side effects and Precautions Drug interactions

Comparison of Loop and Thiazide diuretics

Loop diuretics Sulfonamide derivative Most popular powerful loop diuretic. 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 reduces efficacy (e.g. probenecid)

Mechanism of action Frusemide blocks the Na+, K+, 2Cl- symporter in the ascending

limb of the LH. Inhibit NaCl reabsorption Enhance the excretion of K+, Ca++ and Mg++ (but Ca++ is

reabsorbed in the distal tubule). Prolonged use can cause hypomagnesemia. Increase reabsorption of uric acid Vasodilation in renal vasculature and increase renal blood flow.

Intravenous frusemide causes vasodilatation and reduces left ventricular filling pressure

High ceiling diuretics (Loop diuretics)

High ceiling diuretics (Loop diuretics)Furosemide –Rapid and short acting, Can be given IM, IV and oralGiven Intravenously (10 mg) acts in 2-5 minutes; Orally (40 mg) it takes 20-40 minutes, Can produce upto 10 L of urine/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 ototoxicityDose: 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

Better tolerated because the adverse effects like hypokalemia, ototoxicity, hyperglycaemia and hyperuricaemia are milder but may cause myopathy

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 Oedema Acute renal failure, In chronic renal failure large doses are needed. Acute pulmonary oedema Cerebral oedema Forced diuresis: In poisoning due to fluoride, iodide and bromide

respond to furosemide with saline infusion. Hypertension: With renal impairment Thiazides are preferred diuretics in primary hypertension. Acute hypercalcemia and hyperkalemia:

Loop diuretics: Adverse effects Hypokalaemia and metabolic alkalosis Hypokalaemia should be particularly prevented in post

MI patients and in patients who are receiving digitalis. Hyponatraemia, hypovolaemia, hypotension and

dehydration, Hypocalcaemia Hypomagnesaemia Hyperuricaemia, Hyperglycaemia Ototoxicity Allergic reactions like skin rashes can occur.

Remember 6 Hypo, 2 Hyper & 1 O

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

MCQ 1sA 50-year old man has a history of frequent episodes of renal colic with high calcium with renal stone. The most useful diuretic in the treatment of recurrent calcium stone is

a) Furosemideb) Spironolactonec) Hydrochlorothiazided) Acetazolamide

MCQ 2sAn elderly patient with h/o of heart disease and having difficulty in breathing. She was diagnosed to have pulmonary oedema. Which of the following drug is indicated?

a) Spironolactone.b) Furosemidec) Acetazolamide.d) Chlorthalidonee) Hydrochlorothiazide.

MCQ 3sA 60 years old male patient with kidney stone has been placed on a diuretic to decrease calcium excretion. After few weeks, he develops an attack of gout. Which diuretic was he taking?

a) Furosemideb) Hydrochlorothiazide.c) Spironolactone.d) Triamterene.

MCQ 4sA 65 years old hypertensive patient was treated with a thiazide. Her B.P was well controlled and reads at 120/76 mm Hg, After few months of medication, she complains of being tired and weak. An analysis of the blood may show low values for

a)Calciumb)Uric acidc) Potassium.d)Sodium.

MCQ 5Indomethacin can antagonize the diuretic action of furosemide by 

a) Blocking the ascending limb of loop of Henleb) Enhancing salt and water reabsorption in distal

tubulesc) Increasing aldosterone secretiond) Preventing prostaglandin mediated intrarenal

hemodynamic action

Useful suggestions Obtain baseline values Monitor periodically

lab values, weight, current level of urine outputElectrolytes, especially potassium, sodium, and chlorideBUN, serum creatinine, uric acid, and blood-glucose levelsfor side effects orthostatic hypotension, hypokalemia, hyponatremia,

polyuria Assess for circulatory collapse, dysrhythmias, hearing loss, renal failure, and anemia Advice to take diuretics in the morning, change position slowly, monitor weight If necessary advice to take potassium supplements, and consume potassium–rich foods

(e.g, tender coconut)

To be continued in the next class

Thank you

To be continued in the next class