DIURETICSDIURETICS

By: By:

Prof. A. AlhaiderProf. A. Alhaider

Anatomy and Physiology of Renal Anatomy and Physiology of Renal systemsystem

► Remember the nephron is the most important Remember the nephron is the most important part of the kidney that regulates fluid and part of the kidney that regulates fluid and electrolytes.electrolytes.

► Urine formation:Urine formation:1.1. Glomerular filtration rate = 180L/dayGlomerular filtration rate = 180L/day

2.2. Tubular re-absorption (around 98%)Tubular re-absorption (around 98%)

3.3. Tubular secretionTubular secretion

► How could urine output be increased ?How could urine output be increased ?

↑↑ Glomerular filtration Vs Glomerular filtration Vs ↓↓ Tubular reabsorption (the Tubular reabsorption (the most important clinically)most important clinically)

o If you increase the glomerular filtriation If you increase the glomerular filtriation increase increase tubular reabsorption (so you cant use glomerular tubular reabsorption (so you cant use glomerular filtiration)filtiration)

► Purpose of Using DiureticsPurpose of Using Diuretics

1. To maintain urine volume ( e.g.: renal failure) 1. To maintain urine volume ( e.g.: renal failure)

2. To mobilize edema fluid (e.g.: heart failure,liver failure, 2. To mobilize edema fluid (e.g.: heart failure,liver failure, nephrotic syndromenephrotic syndrome) )

3. To control high blood pressure. 3. To control high blood pressure.

►Percentage of reabsorption in each Percentage of reabsorption in each segment:segment: Proximal convoluted tubule 60-70% Proximal convoluted tubule 60-70%

Thick portion of ascending limb of the Thick portion of ascending limb of the loop of Henle. 25%loop of Henle. 25%

Distal convoluted tubule 5-10%Distal convoluted tubule 5-10%

Cortical collecting tubule 5% (Aldosterone Cortical collecting tubule 5% (Aldosterone and ADH) and ADH)

Physiology of tubular reabsorptionPhysiology of tubular reabsorption

The filtirate here is isotonic

The filtirate here is

hypertonic

Classification of DiureticsClassification of Diuretics► The best way to classify diuretics is to look for their Site of The best way to classify diuretics is to look for their Site of

action in the nephronaction in the nephron

A)A) Diuretics that inhibit transport in the Proximal Diuretics that inhibit transport in the Proximal Convoluted Tubule ( Osmotic diuretics, Carbonic Convoluted Tubule ( Osmotic diuretics, Carbonic Anhydrase Inhibitors)Anhydrase Inhibitors)

B)B) Diuretics that inhibit transport in the Medullary Diuretics that inhibit transport in the Medullary Ascending Limb of the Loop of Henle( Loop diuretics)Ascending Limb of the Loop of Henle( Loop diuretics)

C)C) Diuretics that inhibit transport in the Distal Diuretics that inhibit transport in the Distal Convoluted Convoluted Tubule( Thiazides : Indapamide , Metolazone)Tubule( Thiazides : Indapamide , Metolazone)

D)D) Diuretics that inhibit transport in the Cortical Diuretics that inhibit transport in the Cortical Collecting Collecting Tubule (Potassium sparing diuretics)Tubule (Potassium sparing diuretics)

AA. Diuretics that inhibit transport in the . Diuretics that inhibit transport in the Convoluted Proximal TubuleConvoluted Proximal Tubule

1.1. Osmotic Diuretics (e.g.: Mannitol) Osmotic Diuretics (e.g.: Mannitol) Mechanism of action:Mechanism of action: They are hydrophilic compounds that are easily filtered through They are hydrophilic compounds that are easily filtered through the glomerulus with little re-absorption and thus increase urinary output via osmosis.the glomerulus with little re-absorption and thus increase urinary output via osmosis.PK:PK: Given parentrally. If given orally it will cause osmotic diarrhea. Given parentrally. If given orally it will cause osmotic diarrhea. Indications:Indications:

- to decrease intracranial pressure in neurological condition- to decrease intracranial pressure in neurological condition- to decrease intraocular pressure in acute glaucoma- to decrease intraocular pressure in acute glaucoma- to maintain high urine flow in acute renal failure during shock- to maintain high urine flow in acute renal failure during shock

Adverse Reactions:Adverse Reactions:

- Extracellular water expansion may complicate heart failure and produce pulmonary - Extracellular water expansion may complicate heart failure and produce pulmonary edema.edema.

- Dehydration- Dehydration- - HypernatremiaHypernatremia due to loss more water than sodium due to loss more water than sodium

contraindication:contraindication: 1- heart failure1- heart failure 2- renal failure2- renal failure

2.2. Carbonic Anhydrase InhibitorsCarbonic Anhydrase Inhibitors (Acetazol (Acetazolamideamide (Oral) ; (Oral) ; DorzolDorzolamide (Ocular) amide (Ocular) ; Brinzol ; Brinzolamide (Ocularamide (Ocular))Mechanism of actionMechanism of action Simply inhibit reabsorption of sodium Simply inhibit reabsorption of sodium and bicarbonate.and bicarbonate.

It prevents the reabsorption of HCO3 and Na

•Inhibition of HCO3 reabsorption metabolic acidosis.

•HCO3 depletion enhance reabsorption of Na and Cl hyperchloremea.

•Reabsorption of Na ↑ negative charge inside the lumen ↑K secretion

•Weak diuretic : because depletion of HCO3 enhance reabsorption of Na and Cl

•In glaucoma :The ciliary process absorbs HCO3 from the blood. ↑HCO3 ↑aqueous humor.Carbonic anhydrase inhibitors prevent absorption of HCO3 from the blood.

•Urinary alkalinization : to increase renal excretion of weak acids e.g.cystin and uric acid.

•In metabolic alkalosis.

•Epilepsy : because acidosis results in ↓seizures.

•Acute mountain sickness.

•Benign intracranial hyper tension.Dorzolamde and brinzolamide are mixed with β blockers (Timolol) to treat glaucoma (as topical

drops)

►Side Effects of Acetazolamide:Side Effects of Acetazolamide:

Sedation and drowsiness; Sedation and drowsiness; Hypersensitivity reaction (because it Hypersensitivity reaction (because it contains sulfur) Acidosis (because of contains sulfur) Acidosis (because of

decreased absorption of HCOdecreased absorption of HCO33 ) ; Renal ) ; Renal stone (because of alkaline urine); stone (because of alkaline urine);

Hyperchloremia, hyponatremia and Hyperchloremia, hyponatremia and hypokalemia hypokalemia

B. Diuretics Acting on the Thick Ascending Loop B. Diuretics Acting on the Thick Ascending Loop

of Henle (loop diureticsof Henle (loop diuretics) High ceiling ) High ceiling (most efficacious)(most efficacious)

► e.g. Furosemide (Lasixe.g. Furosemide (LasixRR), Torsemide, Bumetanide ), Torsemide, Bumetanide (Bumex(BumexRR), Ethacrynic acid.), Ethacrynic acid.

► Phrmacodynamics: Phrmacodynamics: 1)1) Mechanism of ActionMechanism of Action : Simply inhibit the coupled : Simply inhibit the coupled

Na/K/2Cl cotransporter in the loop of Henle. Also, Na/K/2Cl cotransporter in the loop of Henle. Also, they have potent pulmonary vasodilating effects (via they have potent pulmonary vasodilating effects (via prostaglandins).prostaglandins).

2)2) They eliminate more water than Na.They eliminate more water than Na.3)3) They induce the synthesis of prostaglandins in kidney They induce the synthesis of prostaglandins in kidney

and NSAIDs interfere with this action.and NSAIDs interfere with this action.

They are the best diuretics for 2 reasons:1- they act on thick ascending limb which has large capacity of

reabsorption.2- action of these drugs is not limited by acidosis

They are the best diuretics for 2 reasons:1- they act on thick ascending limb which has large capacity of

reabsorption.2- action of these drugs is not limited by acidosis

In loop diuretics and thiazides :The body senses the loss of Na in the tubule.

This lead to compensatory mechanism (the body will try to reabsorb Na as much as possible)

So the body will increase synthesis of aldosterone leading to :1- increase Na absorption2- hypokalemia3- alkalosis

2.2. Side effects:Side effects:..OtotoxicityOtotoxicity; Hypokalemic metabolic alkalosis; ; Hypokalemic metabolic alkalosis; hypocalcemia and hypomagnesemia; hypocalcemia and hypomagnesemia; hypochloremia; Hypovolemia; hyperuricemia hypochloremia; Hypovolemia; hyperuricemia (the drugs are secreted in proximal convoluted (the drugs are secreted in proximal convoluted tubule so they compete with uric acid’s tubule so they compete with uric acid’s secretion) hypersensitivity reactions(contain secretion) hypersensitivity reactions(contain sulfur)sulfur)

3.3. Therapeutic UsesTherapeutic Usesa) Edema (in heart failure, liver cirrhosis, a) Edema (in heart failure, liver cirrhosis, nephrotic syndrome)nephrotic syndrome)b) Acute renal failureb) Acute renal failurec) Hyperkalemia c) Hyperkalemia d) Hypercalcemiad) Hypercalcemia

Dosage of loop diuretics:Dosage of loop diuretics:FurosemideFurosemide 20-80 mg20-80 mgTorsemideTorsemide 2.5-20 mg2.5-20 mgBumetanideBumetanide 0.5-2.0 mg 0.5-2.0 mg

C. Diuretics that Inhibit Transport in the C. Diuretics that Inhibit Transport in the Distal Convoluted Tubule (e.g.: Thiazides Distal Convoluted Tubule (e.g.: Thiazides and Thiazide-like (Indapamide; and Thiazide-like (Indapamide; Metolazone)Metolazone)►Pharmacodynamics:Pharmacodynamics:

Mechanism of action: Inhibit NaMechanism of action: Inhibit Na++ via via inhibition of Nainhibition of Na++/Cl/Cl-- cotransporter. cotransporter.

They have natriuretic action.They have natriuretic action.

Side effects:Side effects:► No ototoxicity; hypercalcemia due to ↑PTH, more No ototoxicity; hypercalcemia due to ↑PTH, more

hyponatremia; hyperglycemia (due to both impaired hyponatremia; hyperglycemia (due to both impaired pancreatic release of insulin and diminished utilization of pancreatic release of insulin and diminished utilization of glucose) hyperlipidemia and hyperurecemia ; hypokalemic glucose) hyperlipidemia and hyperurecemia ; hypokalemic metabloic alkalosismetabloic alkalosis

► Clinical uses:Clinical uses: a) Hypertension Drug of Choicea) Hypertension Drug of Choice

(Hydrochlorthiazide; Indapamide (Natrilex(Hydrochlorthiazide; Indapamide (NatrilexRR)) b) Refractory Edema(doesn’t respond well to ordinary b) Refractory Edema(doesn’t respond well to ordinary treatment) together with the Loop treatment) together with the Loop diuretics (Metolazone).diuretics (Metolazone). c) Nephrolithiasis (Renal stone) due to idiopathic c) Nephrolithiasis (Renal stone) due to idiopathic hypercalciuria . hypercalciuria .

d) hypocalcemia.d) hypocalcemia. e) Nephrogenic Diabetes Insipidus. (it decreases flow of urine e) Nephrogenic Diabetes Insipidus. (it decreases flow of urine more reabsorption) more reabsorption)

Indapamide is a potent vasodilatorIndapamide is a potent vasodilator

اللي الوحيد التفسير هذاالستخدام لقيته

thiazides

►D. Diuretics that inhibit transport in the D. Diuretics that inhibit transport in the Cortical Collecting Tubule (e.g. potassium Cortical Collecting Tubule (e.g. potassium sparing diuretics).sparing diuretics).

Classification of Potassium Sparing Diuretics:

A) Direct antagonist of mineralocorticoid receptors (Aldosterone Antagonists e.g

spironolactone (AldactoneR) or

B) Indirect via inhibition of Na+ influx in the luminal membrane (e.g. Amiloride, Triametrene)

Spironolactone (AldactoneSpironolactone (AldactoneRR))

►SSynthetic steroid acts as a competitive ynthetic steroid acts as a competitive antagonist of aldosterone with a slow onset of antagonist of aldosterone with a slow onset of action.action.

► Mechanism of action:Mechanism of action: Aldosterone cause Aldosterone cause ↑K and H↑K and H++ secretion and ↑Na reabsorption. secretion and ↑Na reabsorption.

►The action of spironolactone is the oppositeThe action of spironolactone is the opposite

Clinical Uses of KClinical Uses of K++ sparing Diuretics sparing Diuretics::

In states of primary aldosteronism (e.g. Conn’s In states of primary aldosteronism (e.g. Conn’s syndrome, ectopic ACTH production) of secondary syndrome, ectopic ACTH production) of secondary aldosteronism (e.g. heart failure, hepatic cirrhosis, aldosteronism (e.g. heart failure, hepatic cirrhosis, nephrotic syndrome)nephrotic syndrome)

To overcome the hypokalemic action of diureticsTo overcome the hypokalemic action of diuretics Hirsutism (Hirsutism (the condensation and elongation the condensation and elongation

of female facial hair) because it is an of female facial hair) because it is an antiandrogenic drug.antiandrogenic drug.

Side effects:Side effects:► Hyperkalemia (some times it’s useful other wise it’s a side effect).Hyperkalemia (some times it’s useful other wise it’s a side effect).► Hyperchloremic Hyperchloremic (it has nothing to do with Cl) (it has nothing to do with Cl) metabolic acidosismetabolic acidosis► Antiandrognic effects (e.g. gynecomastia: breast enlargement in Antiandrognic effects (e.g. gynecomastia: breast enlargement in

males, impotence) by spironolactone. males, impotence) by spironolactone. ► Triametrene causes kidney stones.Triametrene causes kidney stones.► Diuretics Combination preparations Diuretics Combination preparations

these are anti-hypertensive drugs:these are anti-hypertensive drugs: DyazideDyazideRR = Triametrene 50 mg + Hydrochlorothiazide HCT 25 mg = Triametrene 50 mg + Hydrochlorothiazide HCT 25 mg AldactazideAldactazideRR= Spironolactone 25 mg + HCT 25 mg= Spironolactone 25 mg + HCT 25 mg

ModureticModureticRR = Amiloride 5 mg + HCT 50 mg = Amiloride 5 mg + HCT 50 mg ► Note : HCT to decrease hypertension and K sparing diuretics to Note : HCT to decrease hypertension and K sparing diuretics to

overcome the hypokalemic effect of HCTovercome the hypokalemic effect of HCT► Contraindications: Oral K administration and using of ACE Contraindications: Oral K administration and using of ACE

inhibitors inhibitors