DiureticsClinical Conditions Requiring Diuretic Therapy:• Cerebral Edema• Pulmonary Edema• Hypertension• Congestive Heart Failure• Glaucoma• Premenstrual Tension • Acute Renal Failure • Liver Cirrhosis

KidneyFunctions of the Kidney include:• Regulation of the water and electrolyte content of

the body. • Retention of substances vital to the body such as

protein and glucose • Maintenance of acid/base balance. • Excretion of waste products, water soluble toxic

substances and drugs. • Endocrine functions (Secretion of hormones e.g.

rennin ,erythropoietin) • Regulation of arterial blood pressure.

Normal kidney structure

Diuretics• Osmotic diuretics: used only in special situations, like

neurosurgery. ie, Mannitol • Carbonic Anhydrase Inhibitors: ie, acetazolamine Used for

glaucoma, mountain sickness• Loop diuretics: work on the thick ascending limb. ie,

Furosemide (Lasix)• Thiazide diuretics: work on distal convoluted tubule. ie,

hydrochlorothiazide• Potassium sparing diuretics: this category includes

aldosterone antagonists (Spironolactone), and inhibitors of Na transport (triampterine)

Diuretic PharmacologyThe primary therapeutic goal of diuretic use is to reduce edema by

reducing the extracellular fluid volume

• Diuretics primarily prevent Na+ reabsorbition (mainly the entry of Na into the tubule cell ).

• All diuretics except spironolactone exert their effects from the luminal side of the nephron ,So it is necessary for diuretics to get into the tubule fluid in order to be effective – Mannitol does this by filtration at the glomerulus

– All other diuretics (except spironolactone) are tightly protein bound and undergo little filtration. They reach the urine via secretion across the proximal tubule ( via organic acid or base secretory pathway).

Diuretic Pharmacology

Osmotic DiureticsAs of now, these include : Glycerol and Mannitol

• Osmotic diuretics are freely filtered and minimally reabsorbed, not metabolized and are basically are Pharmacologically inert.

• They are given usually intravenously in amounts large enough to increase plasma osmolarity. In the past Urea and Glycerin have been used but now mannitol is basically the agent.

• Osmotic Diuretics create an osmotic force within lumen of nephron. So, they prevent H 2 O reabsorption in those segments freely permeable to H 2 O (PCT and descending loop of Henle). There is little effect on loss of K +.

• It does NOT produce its diuretic effects by blocking reabsorption of Na + or Cl -, it just drags out water.

• It can only be used intravenously because mannitol cannot diffuse across GI epithelium.

(if used orally ,it will produce diarrhea)

Clinical Indications

1-prophylaxis against acute renal dysfunction

2-Glucoma&increased intracranial pressure.

Side effects

The major toxicity is due to increased plasma osmolality, with reduced glomerular filtration rate (as in case CHF or chronic renal failure) potentially worsening heart failure

Carbonic Anhydrase Inhibitors

Carbonic Anhydrase Inhibitors

(5) HCO3- leave the proximal tubule to the blood , while H+ is again secreted into the tubule . lumen (again by counter transport with Na)

This results in HCO3- reabsorption. If CA activity is inhibited, HCO3- reabsorption is reduced and exits the proximal tubule in much larger amounts. Because Na+ is the most abundant cation present in proximal tubule fluid, it is the major cation which accompanies HCO3- out of the proximal tubule. In the distal nephron, Na+ is largely reabsorbed (unlike HCO3-) and is exchanged for K+. Therefore acetazolamide primarily causes an increase in urinary HCO3-, K+, and water excretion. Effectiveness is reduced with continued therapy because plasma acidosis

Mechanism of Action:

(1 )Bicarbonate is primarily reabsorbed in the proximal tubule. H+ ion is secreted into the lumen (by counter transport with Na) where it can combine with filtered bicarbonate (HCO3-) to form H2CO3 that is then converted to CO2 and H2O (catalyzed by carbonic anhydrase).

(2)CO2 diffuses into the proximal tubule

(3)where it combines with H2O to form H2CO3(catalyzed by carbonic anhydrase).

(4) that then forms H+ and HCO3-

.

Summary : CAI cause• Increases urine volume• Alkalinization of urine (Increases HCO3-)• Increases K+, Na+ in urine (hyookalemia,hyponatremia)• Decreases HCO3- in blood: metabolic acidosis (lost effectiveness within days.)

Examples of CAI:• Acetazolamide • Dichlorphenamide • Methazolamide • Dorzolamide

Indications: 1-Generally given for reasons other than diuresis. Because ocular fluid

production is dependent on CA enzyme, CA inhibitors can be used to treat glaucoma .

2-Acute mountain sickness- one way of dealing with this is by preventing it with CA inhibitors before and during duration of mountain exposure. It prevent the pulmonary and cerebral edema that occurs in these patients.

Side effects: 1-Metabolic acidosis due to urinary loss of bicarbonate (self-limiting drugs

…..Why?)

2-Hypokalemia

Loop diuretic (high ceiling diuretics)

• Loop diuretic agents1. Furosemide (Lasix)2. Bumetanide 3. Torsemide 4. Ethacrynic Acid (Edecrin)

Mechanism of action Loop diuretics have the greatest efficacy, regardless of dose, they

cause the excretion of the largest fractional of Na with its water. They work by blocking the Na/K/2Cl co-transporters in the thick ascending limb of the Loop of Henle, preventing passive water reabsorption from the descending limb of the Loop ( counter current mechanism) .

Loop Diuretics

THERAPEUTIC EFFECTS

Treatment forOliguric ARF

Treatment for Hypercalcemia

Treatment forPulmonary

Edema

Treatment forSevere Edema

Indications:

• When we require massive fluid mobilization, like in pulmonary edema.

• Edema (resulting from CHF, nephrotic syndrome, and cirrhosis).

• Sever Hypertension. • Hypercalcaemia (calcium excretion is increased by loop

diuretics i.e. it causes hypocalcaemia), although they are NOT used as such nowadays.

Adverse effects of loop diuretic• Dehydration• Hypotension (sever fluid loss )• Electrolyte Imbalance: -Hyponatremia -Hypochloremia -**Hypokalemia:, losing potassium can cause arrhythmias.

Many of the patients who take these drugs are also taking drugs that are sensitive to the action of potassium e.g. digoxin , disaster may occur unless you monitor it carefully.

-Hypocalcaemia…….Not taken in pat. with renal stones -Hypomagnesaemia -Hyperglycemia ……. Not taken in diabetic pat. -Hyperuricemia………. Not taken in pat. Suffering from gout• Ototoxicity

Thiazide diureticThiazide diuretic agents:• Chlorothiazide • Hydrochlorothiazide• Diazoxide: a non-diuretic thiazide (used in hypertension )• Indapamide The last one is thiazide-like in terms of action, but is not chemically thiazides

Mechanism of Action: They inhibit Na+ and Cl- cotransport in the cortical thick ascending limb

and early distal tubule. They have a milder diuretic action than do the loop diuretics because this nephron site reabsorbs less Na+ than the thick ascending limb.

Thiazide diuretic

THERAPEUTIC EFFECTS

Treatment forHypertension

Treatment for hypocalcemia

Treatment forNephrogenic

Diabetes Insipidus

Indications: • Hypertension (this is the primary use of thiazides)• CHF (but thiazides are not as effective as loop

diuretics for CHF)• Hypercalciuria (thiazides combat the formation of Ca

stones, since they enhance Ca reabsorption)• Nephrogenic Diabetes Insipidus (mechanism

unknown)

Adverse Effects: The adverse effects are similar to loop

diuretics…PLUS:• Hypercalcemia(not hypo –as in loop )so can be

used for pat. With renal calculi. • Hyperlipidemia (they increase LDL

cholesterol, which are bad cholesteroles)• Note: an important exception is that there is

no ototoxity with thiazides

Potassium sparing diuretics

• These cause a moderate increase in urine production, with a decrease in potassium excretion.

• They are rarely employed to promote diuresis they are usually used as adjunct to another diuretic, in order to preserve potassium.

Cont.:Potassium sparing diuretics

1-Aldosterone antagonists (Spironolactone)

• Indication:

1- It is used primarily in states of edema due to excess aldosterone (e.g. CHF, cirrhosis, nephrotic syndrome) You get aldosterone excess in these states because you have diminished renal perfusion, so you get the rennin angiotensin aldosterone system enhanced , so you get excess aldosterone.

2-As adjunct to another diuretic, in order to preserve potassium.

Side effects:

1-Major side effects are hyperkalmia

2-Gynecomastia, and amenorrhea (mild estrogenic activity) .

Contraindications:

Do not use in setting of hyperkalemia

2-Inhibitors of Na transport

Amiloride and TriamtereneMechanism of Action:

Both agents inhibit the Na+ channel in the apical membrane of the late distal tubule and collecting duct. Because K+ secretion in this nephron segment is driven by the electrochemical gradient generated by Na+ reabsorption, K+ transport into the urine is reduced (hyperkalemia).

Side effects:

The most sever side effect is hyperkalemia.

Nausea and vomiting are the most frequent side effects.

Contraindications:

Similar to Spironolactone -- Do not use in setting of hyperkalemia.