DIURETICS

DIURETICS

• Drugs inducing a state of increased urine flow • These agents are inhibitors of renal ion

transporters that decrease 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, which is carried passively to maintain osmotic equilibrium.

• Diuretics thus increase the volume of urine and often change its pH as well as the ionic

composition of the urine and blood.

• Normal Regulation of Fluid and Electrolytes by the Kidneys

• Approximately 16 to 20 percent of the blood plasma entering the kidneys is filtered from the glomerular capillaries into the Bowman's capsule.

• The filtrate, although normally free of proteins and blood cells, does contain most low-molecular-weight plasma components in approximately the same concentrations as are found in the plasma.

• These include glucose, sodium bicarbonate, amino acids, and other organic solutes as well as electrolytes, such as Na+, K+, and Cl-.

• The kidney regulates the ionic composition and volume of urine by the active reabsorption or secretion of ions and/or the passive reabsorption of water at five functional zones along the nephron

• The proximal convoluted tubule • The descending loop of Henle• The ascending loop of Henle• The distal convoluted tubule• The collecting tubule and duct

Nephron sites of action of diuretics

Proximal convoluted tubule

• Proximal convoluted tubule• In the proximal convoluted tubule located• almost all the glucose, bicarbonate, amino

acids, and other metabolites are reabsorbed• Approximately 65% of the filtered Na+ (and

water) is reabsorbed. • The Na+ that is reabsorbed is pumped into the

interstitium by the Na+/K+- adenosine triphosphatase (ATPase) pump.

• about 60% of water is reabsorbed from the lumen to the blood to maintain osmolarequality.

• Chloride enters the lumen of the tubule in exchange for an anion, such as oxalate,

• Carbonic anhydrase in the luminal membrane and cytoplasm of the• proximal tubular cells modulates the reabsorption of bicarbonate.• Despite having the highest percentage of filtered Na+ that is reabsorbed,

diuretics working in the proximal convoluted tubule display weak diuretic properties.

• The presence of a high capacity Na+ and water reabsorption area (loop of Henle) allows reabsorption of Na+ and water kept in the lumen by diuretics acting in the proximal convoluted tubule, and limits effective diuresis.

loop of Henle

• B. Descending loop of Henle• The remaining filtrate, which is isotonic, next enters the

descending limb of the loop of Henle and passes into themedulla of the kidney. The osmolarity increases along the

descending portion of the loop of Henle because of the countercurrent mechanism that is responsible for water reabsorption.• This results in a tubular fluid with a three-foldincrease in salt concentration. Osmotic diuretics exert part of their action in this region

• C. Ascending loop of Henle• The cells of the ascending tubular epithelium are unique in being impermeable to

water.• Active reabsorption of Na+, K+, and Cl- is mediated by a Na+/K+/2Cl-

cotransporter. Both Mg2+ and Ca2+ enter the interstitial fluid via the paracellular pathway. The ascending loop is thus a diluting region of the nephron. Approximately 25 to 30 percent of the tubular sodium chloride returns to the interstitial fluid, thus helping to maintain the fluid's high osmolarity.

• Because the ascending loop of Henle is a major site for salt reabsorption, drugs affecting this site, such as loop diuretics, are the most efficacious of all the diuretic classes

D.Distal convoluted tubule

• D. Distal convoluted tubule• The cells of the distal convoluted tubule are also impermeable to water. About 10 percent of

the filtered sodium chloride is reabsorbed via a Na+/Cl- transporter that is sensitive to thiazide diuretics. Calcium reabsorption is mediated by passage through a channel and then transported by a Na+/Ca2+-exchanger into the interstitial fluid.

• The mechanism thus differs from that in the loop of Henle. Additionally, Ca2+ excretion is regulated by parathyroid hormone in this portion of the tubule.

Collecting duct

• E. Collecting tubule and duct• The principal cells of the collecting tubule and duct are responsible for

Na+, K+, and water transport, whereas the intercalated cells affect H+ secretion.

• The sodium enters the principal cells through channels but relies on a• Na+/K+-ATPase to be transported into the blood. Aldosterone receptors in

the principal cells influence Na+ reabsorption and K+ secretion. Antidiuretic hormone (ADH; vasopressin) receptors promote the reabsorption of water from the collecting tubules and ducts .

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

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

– Distal convoluted tubule 5-10%

– Cortical collecting tubule 5% (Aldosterone and ADH)

Nephron parts and their functions

Therapeutic uses of diuretics

• A. Edematous states• Congestive heart failure• Liver cirrhosis• Nephrotic syndrome• Renal failure• Premenstrual edema• B. Nonedematous states• Hypertension• Hypercalcemia• Diabetes insipidus

Classification of Diuretics• according to their Site of action in the nephron

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

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

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

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

Or according to their efficacy1. High-efficacy (Potassium-depleting)(loop) diuretics ex .Furosemide,bumetanide torasemide .

2.Moderate- efficacy (Potassium-depleting) diureticsa) thiazideses : ex. Hydrochlorothiazide, bendroflumethiazideb) thiazides- related diuretics : ex. metolazone, chlorthalidone, Indapamide3.Low efficacy diuretics

a) potassium- sparing diuretic:

aldosterone antagonists. ex. Spironolactone, eplerenone,

triamterene, amiloride.

b) osmotic diuretics

ex. Mannitol

c) carbonic anhydrase inhibitors

ex. Acetazolamide, dorzolamide

A. Diuretics that act in the Convoluted Proximal Tubule

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

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

Adverse Reactions:- Extracellular water expansion may complicate heart failure and produce

pulmonary edema.- Dehydration

- Hypernatremia due to loss more water than sodium contraindication:

1- heart failure2- renal failure

2. Carbonic Anhydrase Inhibitors (Acetazolamide ; Dorzolamide ; Brinzolamide Mechanism of action Simply inhibit reabsorption of sodium 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

Acetazolamide• has weak diuretic action.• Mechanism of action: Acetazolamide inhibits carbonic

anhydrase • The decreased ability to exchange Na+ for H+ in the presence

of acetazolamide results in a mild diuresis.• Additionally, HCO3 is retained in the lumen, with marked

elevation in urinary pH. • The loss of HCO3– anions decreases blood alkaline reserve

(for 48–72 h) and causes metabolic acidosis. In this state the drug becomes ineffective.

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

•In glaucoma :Acetazolamide blocks not only renal CA, but•also CA in the ciliary body in the eye •(reducing production of eye liquid) 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.

•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:• Sedation and drowsiness• Acidosis (because of decreased absorption of

HCO3 ) • Renal stone (because of alkaline urine)• Hyperchloremia• Hyponatremia • Hypokalemia

B. Diuretics Acting on the Thick Ascending Loop of

Henle (loop diuretics) High ceiling (most efficacious)

• e.g. Furosemide , Torsemide, Bumetanide, Ethacrynic acid.

• Phrmacodynamics:1) Mechanism of Action : Simply inhibit the coupled

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

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

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

Action

• A. Diuresis• B. Increased urinary calcium excretion• C. Venodilation

• Ceiling of effect is high (diuresis goes on increasing with increasing dose) .

• Over-treatment can cause dehydration.

• Onset of action rapid -furosemide (i.v. 30 min), (oral 1h)

• Duration of action: Short- (6h)

• Loop diuretics remain effective in severe renal impairment

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. Side effects:.OtotoxicityHypokalemicmetabolic alkalosis hypocalcemiahypomagnesemiaHypochloremiaHypovolemiaHyperuricemia (the drugs are secreted inproximal convoluted tubule so they compete with

uric acid’s secretion) Therapeutic Uses

a) Edema (in heart failure, liver cirrhosis, nephrotic syndrome)b) Acute renal failurec) Hyperkalemiad) Hypercalcemia

Loop diuretics

Furosemide:

Taken orally or i.v

If taken orally only 50 % is absorbed

Torsemide:

Taken orally.

Better absorption

Fast onset of action

2/1t↑

BumetanideTaken orally

40 times potent than furosemide.Fast onset

Short duration of action

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

• The thiazides are the most widely used diuretics because of their antihypertensive effects.

• Which depend on • Their diuretic actions.• These agents also reduce peripheral vascular

resistance with long-term therapy.

• Chlorthalidone is approximately twice as potent as hydrochlorothiazide. Chlorthalidone,

• indapamide, and metolazone are referred to as thiazide-like diuretics because they lack the characteristic benzothiadiazine chemical structure; however, their mechanism of action, indications, and adverse effects are similar to those of hydrochlorothiazide.

• Mechanism of action: • inhibition of a Na+/Cl− cotransporter. • As a result, these drugs increase the

concentration of Na+ and Cl− in the tubular fluid.

• Thiazides must be excreted into the tubular lumen at the proximal convoluted tubule to be effective .

• Therefore, decreasing renal function reduces the diuretic effects. when the glomerular filtration rate is below 30 mL/min/1.73 m2.

• Onset of action :slow - 2h (orally); so they are not suitable for clinical situations that require rapid diuresis.i.e. acute pulmonary oedema or sever hypertension.

• Pharmacokinetics

• thiazides are effective orally, with a bioavailability of 60% to 70%.

• Chlorothiazide has a much lower bioavailability (15% to 30%) and is the only thiazide with an intravenous dosage form.

• Most thiazides take 1 to 3 weeks to produce a stable reduction in blood pressure and exhibit a prolonged half-life (approximately 10 to 15 hours).

• Indapamide differs from the class because it undergoes hepatic metabolism and is excreted in both the urine

and bile.

Most thiazides are primarily excreted unchanged in the urine.

Side effects:• Hypercalcemia• Hyponatremia• Hypokalemic• Hyperglycemia (due to both impaired pancreatic release

of insulin and diminished utilization of glucose)• Hyperlipidemia • Hyperurecemia • metabloic alkalosis.

• Drug interactions of loop and thiazides diuretics:

• hypokalaemia induced by these drugs enhances digoxine toxicity.

• NSAIDs reduce effect of diuretics .• Diuretics precipitate lithium toxicity by inhibiting

its excretion.• Loop diuretics potentiate aminoglycosides-

induced ototoxicity

• Clinical uses:

a) Hypertension Drug of Choice(Hydrochlorthiazide; Indapamide)

b) Refractory Edema(doesn’t respond well to ordinary treatment) together with the Loop diuretics (Metolazone).

c) Nephrolithiasis (Renal stone) due to idiopathic hypercalciuria .

d) hypocalcemia.

e) Nephrogenic Diabetes Insipidus.

Indapamide is a potent vasodilator

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

Classification of Potassium Sparing Diuretics:A) Direct antagonist of mineralocorticoid

receptors (Aldosterone Antagonists e.g spironolactone)

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

Spironolactone (AldactoneR)

• Synthetic steroid acts as a competitive antagonist of aldosterone with a slow onset of action.

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

• The action of spironolactone is the opposite

• PKs:• ☣ Metabolized in liver to active metabolite

(canrenone),

• which prolongs the diuretic effect to 48h.

• ☣ Onset of action is slow (about 4 days).

Clinical Uses of K+ sparing Diuretics:

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

– To overcome the hypokalemic action of diuretics

– Hirsutism (the condensation and elongation of female facial hair) because it is an antiandrogenic drug.

• Polycystic ovary syndromeSpironolactone is often used off-label for the treatment of polycystic ovary syndrome. It blocks androgen receptors and inhibits steroid synthesis at high doses

• It saves K+ and Mg2+ ions and has antiarrhythmic effect.

• It also prevents the development of myocardial fibrosis, caused by aldosterone and in this way contributes to enhancing

myocardial contractility.

Side effects:• Hyperkalemia (some times it’s useful other wise it’s a

side effect).• Hyperchloremic (it has nothing to do with Cl)

metabolic acidosis• Antiandrognic effects (e.g. gynecomastia: breast

enlargement in males, impotence) by spironolactone. • Triametrene causes kidney stones.• Contraindications: Oral K administration and using of ACE

inhibitors

• Amiloride and triamterene• ☣ Inhibit Na+ reabsorption by blocking renal

epithelial Na channels in late distal tubule• and collecting duct.• Uses:• ☣ with loop or thiazide diuretics to counteract

hypokalaemia .• Side effects:•   hyperkalaemia•   GIT upset

Electrolyte changes produced by diuretics