Diuretics

A. INHIBITING NaCl REABSORPTION: THIAZIDES: 1. Bendroflumethiazides 2. Benzthiazides 3. Polythiazide 4. Chlorothiazide 5. Quinethazone 6. Chlorthalidone 7. Trichlormethiazide 8. Hydrochlorothiazide 9. Hydroflumethiazide 10. Indapamide 11. Metolazone

LOOP DIURETICS: 1. Furosemide 2. Bumetanide 3. Ethacrynic Acid 4. Torsemide

B. POTASSIUM-SPARING DIURETICS: 1. Spironolactone 2. Triamterene 3. Amiloride C. CARBONIC ANHYDRASE INHIBITORS: 1. Acetazolamide 2. Methazolamide 3. Ethoxzolamide 4. Dichlorphenamide

ACTING AS OSMOTIC-NON ELECTROLYTES: Mannitol INCREASING GLOMERULAR FILTERATION RATE: Aminophylline ANTIDIURETIC HORMONE ANTAGONISTS conivaptan

Renal Physiology at a glance

Reabsorption of Solutes / Fluid Filtered: & (%age Reabsorbed ) Total Solute: m.osmol ( 87%). Na+: ( 99%), K+: ( 93%), Cl-: ( 99%), HCO 3 -: ( 100%) H 2 O: 180 L(>99%)

Proximal Tubule

 At Proximal Tubules: Early Part: Reabsorption of HCO- 3 : 85% NaCl : % Water : 60% ( directly proportional to salt reabsorption ) Organic Solutes: 100% Secretion at middle 3 rd : Uric Acid, NSAIDs, Diuretics, Antibiotics, Creatinine & Choline etc. Later Part: Residual Fluid contains now mainly NaCl. Free H+ here causes luminal pH to fall. Luminal Osmolality & Na conc. Nearly constant.

At the later part: 1. NaCl reabsorption occurs in the form of Na+ with H+ and Cl- with Base Exchange. 2. H+ stimulates this exchange. Base: is to nullify the effects of H+ in lower parts. H2O, NaHCO3, NaCl H2OH2O

More Na+ and H 2 O,esp. Cl- going down & reabsorbed leading to Hyperchloremic Metabolic Acidosis. Acetazolamide etc.

CARBONIC ANHYDRASE INHIBITORS: 85% of HCO 3 - reabsorption is inhibited here but total body HCO 3 - inhibition & loss is 45%.  Remaining HCO 3 - inhibition continues at other sites of nephrone.  Potassium loss also occurs.  Hyperchloremic Metabolic Acidosis, due to decreased HCO 3 - in the blood & enhanced reabsorption Cl ( obviously along with more Na at collecting duct which leads to water retention & decreased efficacy of CA Inhibitors.)

Uses: 1. Glaucoma: for severe attack. To avoid systemic effects topical inhibitors like Dorzolamide, Brinzolamide are useful. 2. Urinary Alkalinization: Some weak acids like uric acid, cystine are easily reabsorbed from acidic urine. For short time urinary alkalinization Acetazolamide may be used to increase urinary excretion.

3. Metabolic Alkalosis: is usually treated by correction of : total body K+ abnormalities, intravascular volume, or mineral corticoid levels  During excessive use of Diuretics in Severe Heart Failure or  In correcting Respiratory Acidosis, metabolic alkalosis occurs which is not treated by saline;  Here Acetazolamide is useful which may also helps for heart failure.

5. Acute Mountain Sickness: persons who rapidly ascend above 3000 m, can have weakness, dizziness, insomnia, headache & nausea. Symptoms are usually mild & last for few days only. In more severe cases rapidly progressing life - threatening pulmonary or cerebral edema can occur.  By decreasing CSF formation & its pH Acetazolamide can enhance performance status & diminish symptoms of mountain sickness 6. Other uses: 1. Epilepsy, 2. Hypokalemic Periodic Paralysis, & 3. to increase urinary Phosphate excretion during 4. Hyperphoaphatemia.

Toxicity of CA Inhibitors: 1. Hyperchloremic Metabolic Acidosis: from chronic reduction of body bicarbonate stores by CA Inhibitors; diuretic efficacy is limited to 2 or 3 days. 2. Renal Stones: Due to:  decreased excretion of solubilizing factors like: Citrate, Phosphaturia & Hypercalceuria,  Insolubility of Calcium salts in alkaline pH.

3. Renal Potassium Wasting: Due to increased presentation of NaHCO 3 at collecting tubule the -ve electrical potential enhances K+ excretion. 4. Others:  Drowsiness, paresthesias, & other CNS toxicity in renal failure or after large doses.  Hypersensitivity reactions: fever, rashes, bone marrow suppression, and interstitial nephritis.

Thick Ascending Limb of Loop of Henle

(70 mV) (10 mV) ( 60 mV, relatively -ve potential) K+ Cl- (K+ may accumulate) Co - Transport Co - Transport

Loop Diuretics decreased reabsorption also less reabsorbed more Na+ going to collecting tubule so K+ is also lost there. ( Hypokalemic Alkalosis )

LOOP DIURETICS: ( High Ceiling )  Rapidly absorbed; Torsemide( in 1hr.&100%); Duration of Action: 4-6 hrs.; its active metabolite has longer t 1/2.  Inhibit Na /K / 2Cl transport in the thick ascending limb.  Decrease NaCl & K reabsorption leading to decreased +ve potential.  This decreased positive potential increases Mg++ / Ca++ excretion but Ca++ is again reabsorbed at distal convoluted tubule.  K+ loss occurs--- Hypokalemic Alkalosis Renal Prostaglandins are synthesized by Loop Diuretics which maintain their Glomerular Secretion / Filtration so helping in their effectiveness. ( D.I. = NSAIDs, Probenecid ).

 Some direct effects of loop-diuretics are also observed like on blood flow of several beds, e.g., increased renal blood flow by Furosemide.  It also reduces pulmonary congestion & left ventricular filling pressure in heart failure before any diuretic effect and even in anephric patients.

Uses: 1. Acute Pulmonary Edema: They cause a brisk natriuresis which reduces left ventricular filling pressure along with a rapid increase in venous capacitance leading to a rapid relief in pulmonary edema. 2. Edematous States: as in cardiac, renal or vascular diseases or in state of abnormal oncotic pressure. Diuretics mobilize interstitial edema fluid without any significant reductions in plasma volume.

 Usually combined with Thiazides diuretics for severe cases.  During severe loss of renal functions diuretics are of little benefit because of very less glomerular filtration to sustain a natriuretic response.  In Diabetic Nephropathy like diseases associated with Hyperkalemia, Thiazides or loop diuretics are useful.  K+ sparing diuretics & Acetazolamide are usually avoided due to tendency to exacerbate acidosis or alkalosis.. 

3. Acute Hypercalcemia: Loop diuretics effectively promote calcium diuresis because Ca++ is mainly reabsorbed from this site.  However if used alone extensively may cause marked volume contraction due to total body loss of Na+ ; gradually they become ineffective & Ca++ reabsorption starts in the proximal tubule. So saline is given along with loop diuretics to maintain the blood volume. 4. Hyperkalemia: by significant urinary excretion of K+ which is enhanced by simultaneous use of NaCl & Water.

5. Acute Renal Failure: They increase the rate of urine flow & enhance the K+ excretion, however no shortening in duration of renal failure occurs. They also help to flush out the intratubular casts & thus ameliorate intratubular obstruction in large pigment load. 6. Anion Disease ( Br-, Fl-, I- ): They are reabsorbed in Thick Ascending Limb so Loop Diuretics are useful in treating toxic intake However saline is also given to avoid extra – cellular fluid volume depletion.

Toxicity: 1. Hypokalemic Metabolic Alkalosis: It depends upon the level of diuresis; By increasing delivery of salt & water to the collecting duct and thus enhance the renal secretion of K+ & H+ causing Hypokalemic metabolic alkalosis.  It can be reversed by K+ replacement & correction of hypovolemia. 2. Ototoxicity: a dose related hearing loss but usually reversible; esp. in patients with diminished renal functions or with drugs like amino glycosides.

3. Hyperuricemia: Hypovolemia-associated enhancement of uric acid reabsorption in the proximal tubule & can precipitate attacks of gout; may be avoided by using lower doses. 4. Hypomagnesaemia: esp. in patients with dietary magnesium deficiency.  can be reversed by oral magnesium.

5. Allergic Reactions: occasionally skin rashes, eosinophilia and interstitial nephritis ( less with ethacrynic acid);  resolve rapidly after drug withdrawal. 6. Others:  Severe dehydration; so to correct severe thirst increased intake of water can lead to hyponatremia due to dilution.  Hypercalcemia esp. with severe volume depletion in oat cell carcinoma of lung

Distal Convoluted Tubule

No luminal +ve potential, as no K+ recycling occurs here.

Thiazides

THIAZIDES: ( sulfonamides, similar to CA Inhibitors )  Inhibit NaCl reabsorption from luminal side of epithelium( some retain CA Inhibtion activity also).  K- loss occurs due to increased Na + at collecting duct.  Due to blocked Na + entry into cells, Na / Ca - exchange is enhanced, increasing overall Ca ++ reabsorption; thus may unmask Hypercalcemia due to hyperthyroidism, carcinoma, acidosis.  Due to Cl- loss, Hypochloremic Alkalosis occurs.  Thiazides also synthesize PG in kidney

Uses: 1. Hypertension:  Initial fall is due to salt & water depletion with reduction in cardiac output but after about 4-8 weeks peripheral resistance falls due to decreased vascular stiffness as a result of local salt depletion,  may be useful in 2/3 rd of essential hypertensives;  may also enhance the activity of ACEIs, Calcium Blockers; also used with vasodilators which may cause salt & water retention.  almost similar out come to ACEIs or Ca++ Blocker therapy.

2. Edematous States:  usually ineffective if GFR falls below 30 mL/min.  Loop Diuretics are best choice.  they reduce the peripheral or pulmonary edema that has accumulated as a result of cardiac, renal or hepatic diseases. 3. Nephrolithiasis: ( Calcium Phosphate or Oxalate ) by enhancing calcium reabsorption from distal tubules and thus reducing its urinary excretion. Decreased calcium & sodium intake may help because excess of Na+ may overwhelm the hypocalciuric effects of Thiazides.

4. Osteoporosis: thus by preserving the calcium plasma levels. 5. Nephrogenic Diabetes Insipidus: Exact mechanism unknown but probably by reducing the plasma volume associated with:  fall in GFR,  enhanced proximal reabsorption of NaCl & Water,  & decreased delivery of fluid to the diluting segments; thus significantly reducing urine flow in the polyuric patients.

Dietary sodium restriction can potentiate the beneficial effects of Thiazides on urine volume in this segment. They are also useful in lithium-induced diabetes Insipidus, but lithium levels may be raised due to its reduced renal clearance by Thiazides.

Toxicity: 1. Hypokalemic Metabolic Alkalosis & Hyperurecemia: similar to loop diuretics. 2. Impaired Carbohydrate Tolerance: Hyperglycemia in patients who are overtly diabetic or who have even mild abnormal glucose tolerance tests; this is due to impaired pancreatic release of insulin & diminished tissue utilization of glucose. This hyperglycemia may be partially reversible with correction of hypokalemia.

3. Hyperlipidemia: Initially may cause 4 – 15% rise in serum cholesterol & LDL levels which may fall after prolonged use of thiazides. 4. Hyponatremia: due to a combination of:  hypovolemia – induced elevation of ADH,  reduction in diluting capacity of the kidney,  & increased thirst. It can be prevented by reducing the dose of the drug or limiting water intake.

5. Allergic Reactions: being sulfonamides they share cross reactivity with others. Photosensitivity or generalized dermatitis, Serious Reactions: ( rare ) ; hemolytic anemia, thrombocytopenia and acute necrotizing pancreatitis. 6. Other Toxicity: weakness, fatigability & paresthesias; Impotence probably related to volume depletion

Late Distal Tubule and Collecting Duct