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

Kidney Functions of the Kidney include: Regulation of the water and electrolyte content of the body. Regulation of the water and electrolyte content of the body. Retention of substances vital to the body such as protein and glucose Retention of substances vital to the body such as protein and glucose Maintenance of acid/base balance. Maintenance of acid/base balance. Excretion of waste products, water soluble toxic substances and drugs. Excretion of waste products, water soluble toxic substances and drugs. Endocrine functions ( Endocrine functions (Secretion of hormones e.g. rennin,erythropoietin) Regulation of arterial blood pressure.

Normal kidney structure

Regulation of the Water & Electrolyte Content of the Body :

Cont. :Regulation of the Water & Electrolyte Content of the Body :

The juxtaglomerular complex consists of: The juxtaglomerular complex consists of: 1- Macula densa cells, which are special distal tubular epithelial cells which detect any change in the rate of flow of the filterat and its concentration. 1- Macula densa cells, which are special distal tubular epithelial cells which detect any change in the rate of flow of the filterat and its concentration. 2-Modified smooth muscle cells, juxtaglomerular cells (granular cells), in the walls of the afferent arteriole. These cells produce rennin. 2-Modified smooth muscle cells, juxtaglomerular cells (granular cells), in the walls of the afferent arteriole. These cells produce rennin. Rennin is an enzyme which converts the plasma protein angiotensinogen to angiotensin I. which is converted by ACE to angiotensin II which causes vasoconstriction and an increase in blood pressure.Angiotensin II also stimulates the adrenal gland to produce aldosterone which causes water and sodium retention (which also increase blood volume and thus increase BP). Rennin is an enzyme which converts the plasma protein angiotensinogen to angiotensin I. which is converted by ACE to angiotensin II which causes vasoconstriction and an increase in blood pressure.Angiotensin II also stimulates the adrenal gland to produce aldosterone which causes water and sodium retention (which also increase blood volume and thus increase BP). This is a negative feedback system. i. e. a fall in blood volume will leads to a fall in perfusion pressure in the kidneys and decrease in GFR and this will stimulate the above system. This is a negative feedback system. i. e. a fall in blood volume will leads to a fall in perfusion pressure in the kidneys and decrease in GFR and this will stimulate the above system. When blood volume & renal perfusion as well as GFR improve the system feeds back to switch off( no rennin release) When blood volume & renal perfusion as well as GFR improve the system feeds back to switch off( no rennin release)

Diuretics Osmotic diuretics: used only in special situations, like neurosurgery. ie, Mannitol Osmotic diuretics: used only in special situations, like neurosurgery. ie, Mannitol Carbonic Anhydrase Inhibitors: ie, acetazolamine Used for glaucoma, mountain sickness Carbonic Anhydrase Inhibitors: ie, acetazolamine Used for glaucoma, mountain sickness Loop diuretics: work on the thick ascending limb. ie, Furosemide (Lasix) Loop diuretics: work on the thick ascending limb. ie, Furosemide (Lasix) Thiazide diuretics: work on distal convoluted tubule. ie, hydrochlorothiazide Thiazide diuretics: work on distal convoluted tubule. ie, hydrochlorothiazide Potassium sparing diuretics: this category includes aldosterone antagonists (Spironolactone), and inhibitors of Na transport (triampterine) Potassium sparing diuretics: this category includes aldosterone antagonists (Spironolactone), and inhibitors of Na transport (triampterine)

Diuretic Pharmacology The primary therapeutic goal of diuretic use is to reduce edema by reducing the extracellular fluid volume For this to occur, NaCl output MUST exceed NaCl intake For this to occur, NaCl output MUST exceed NaCl intake Diuretics primarily prevent Na+ reabsorbition (mainly the entry of Na into the tubule cell ) 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 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). –Decreased renal blood flow or renal failure reduce diuretic effectiveness.Also, drugs which compete for the secretory pump (probenecid competes for acidic drugs and cimetidine competes for basic drugs secretion) will decrease the effectiveness of diuretics.

Osmotic Diuretics As of now, these include just one: Mannitol Osmotic diuretics are freely filtered and minimally reabsorbed, not metabolized and are basically are Pharmacologically inert. 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. 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 +. 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 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. It can only be used intravenously because mannitol cannot diffuse across GI epithelium. (if used orally,it will produce diarrhea) (if used orally,it will produce diarrhea)

Clinical Indications 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 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 (5) HCO3- leave the proximal tubule to the blood, while H+ is again secreted into the tubule. lumen (again by counter transport with Na) (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 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 Increases urine volume Alkalinization of urine (Increases HCO3-) Alkalinization of urine (Increases HCO3-) Increases K+, Na+ in urine (hyookalemia,hyponatremia) Increases K+, Na+ in urine (hyookalemia,hyponatremia) Decreases HCO3- in blood: metabolic acidosis Decreases HCO3- in blood: metabolic acidosis (lost effectiveness within days.) (lost effectiveness within days.) Examples of CAI: Acetazolamide Acetazolamide Dichlorphenamide Dichlorphenamide Methazolamide Methazolamide Dorzolamide 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. 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 -CA inhibitors can be given in conditions where urine alkalinization is beneficial (certain drug overdoses) 2 -CA inhibitors can be given in conditions where urine alkalinization is beneficial (certain drug overdoses) 3-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. 3-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?) 1-Metabolic acidosis due to urinary loss of bicarbonate (self-limiting drugs …..Why?)2-Hypokalemia

Loop diuretic (high ceiling diuretics) Loop diuretic agents Loop diuretic agents 1. Furosemide (Lasix) 2. Bumetanide 3. Torsemide 4. Ethacrynic Acid (Edecrin) Mechanism of action 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 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

Adverse effects of loop diuretic Dehydration Dehydration Hypotension (sever fluid loss ) Hypotension (sever fluid loss ) Electrolyte Imbalance: Electrolyte Imbalance: Hyponatremia Hyponatremia Hypochloremia 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. **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 Hypocalcaemia…….Not taken in pat. with renal stones Hypomagnesaemia Hypomagnesaemia Hyperglycemia ……. Not taken in diabetic pat. Hyperglycemia ……. Not taken in diabetic pat. Hyperuricemia………. Not taken in pat. Suffering from gout Hyperuricemia………. Not taken in pat. Suffering from gout Ototoxicity Ototoxicity

Indications: When we require massive fluid mobilization, like in pulmonary edema. When we require massive fluid mobilization, like in pulmonary edema. Edema (resulting from CHF, nephrotic syndrome, and cirrhosis). Edema (resulting from CHF, nephrotic syndrome, and cirrhosis). Hypertension. Hypertension. Hypocalcaemia (calcium excretion is increased by loop diuretics i.e. it causes hypocalcaemia), although they are not used as such nowadays. Hypocalcaemia (calcium excretion is increased by loop diuretics i.e. it causes hypocalcaemia), although they are not used as such nowadays.

Thiazide diuretic Thiazide diuretic agents: Chlorothiazide Chlorothiazide Hydrochlorothiazide Hydrochlorothiazide Diazoxide: a non-diuretic thiazide (used in hypertension ) Diazoxide: a non-diuretic thiazide (used in hypertension ) Indapamide 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. 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

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. Hypercalcemia(not hypo –as in loop )so can be used for pat. With renal calculi. Hyperlipidemia (they increase LDL cholesterol, which are bad cholesteroles) Hyperlipidemia (they increase LDL cholesterol, which are bad cholesteroles) Note: an important exception is that there is no ototoxity with thiazides Note: an important exception is that there is no ototoxity with thiazides

Indications: Hypertension (this is the primary use of thiazides) Hypertension (this is the primary use of thiazides) CHF (but thiazides are not as effective as loop diuretics for CHF) 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) Hypercalciuria (thiazides combat the formation of Ca stones, since they enhance Ca reabsorption) Nephrogenic Diabetes Insipidus (mechanism unknown) Nephrogenic Diabetes Insipidus (mechanism unknown)

Potassium sparing diuretics These cause a moderate increase in urine production, with a decrease in potassium excretion. 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. 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

Indication: 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. 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. 2-As adjunct to another diuretic, in order to preserve potassium. Side effects: 1-Major side effects are hyperkalmia 1-Major side effects are hyperkalmia 2-Gynecomastia, and amenorrhea (mild estrogenic activity). 2-Gynecomastia, and amenorrhea (mild estrogenic activity).Contraindications: Do not use in setting of hyperkalemia Do not use in setting of hyperkalemia 1-Aldosterone antagonists (Spironolactone)

2-Inhibitors of Na transport Amiloride and Triamterene Mechanism 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). 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. The most sever side effect is hyperkalemia. Nausea and vomiting are the most frequent side effects. Nausea and vomiting are the most frequent side effects.Contraindications: Similar to Spironolactone -- Do not use in setting of hyperkalemia. Similar to Spironolactone -- Do not use in setting of hyperkalemia.