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Drugs Used in Renal Disorders: 

Drugs Used in Renal Disorders Drugs that modify water excretion Diuretics ADH agonists: Vasopressin, Desmopressin. ADH antagonists: Conivaptan, Lithium & Demeclocycline. Drugs that modify salt excretion Natriuretics

Diuretics - Introduction : 

Diuretics - Introduction Fluid volume and electrolyte composition abnormalities - common and important clinical disorders Role of diuretics Need for a safer diuretic


DIURETICS Diuretics are the agents that increase the urine volume Natriuretics cause an increase in renal sodium excretion Because sodium excretion almost always is accompanied by equivalent volume of water, increasing water excretion so natriuretics are usually called diuretics


DIURETICS… Natriuretics act by interfering with transport mechanism for the reabsorption of sodium from various segments of the nephron The nephron is divided structurally & functionally into several segments ---- PCT, TAL, DCT, CCT.


Definition Greek - "dia-", thoroughly + "ourein", to urinate = to urinate thoroughly Diuretics are the drugs which increase the rate of urine formation causing a net loss of solute (mainly NaCl) along with equivalent volume of water, by interfering with transport mechanism responsible for the reabsorption of solutes from various segments of the nephron


Diuretics Classification Mechanism of Action Site of action Potency Chemistry

Classification… According to Mechanism of Action: 

A. Drugs interfering with ionic transport I. Drugs interfering with ionic transport of HCO 3 Systemic Acetazolamide. Dichlorphernamide Methazolamide Local (instilled in eye) Dorzolamide Brinzolamide Classification… According to Mechanism of Action

Classification-MOA… : 

Classification-MOA… II. Inhibitors of active transport of Cl - a. Thiazide & Related Diuretics Short Acting (t ½ 1.5 -7.3 hrs) Chlorothiazide , Hydrochlorothiazide , Bendroflumethiazide , Trichlormethiazide Intermediate Acting (t ½ 14 -17 hrs) Indapamide , Hydroflumethiazide Long Acting (t ½ 24 -47 hrs) Polythiazide , Chlorthalidone Quinethazone , Metolazone

Classification-MOA… : 

Classification-MOA… b. Loop Diuretics Sulfonamide Derivatives Furosemide, Bumetanide, Torsemide Phenoxy Acetic Acid Derivative Ethacrynic acid, Indacrinone III. Potassium Sparing Diuretics Aldosterone receptor antagonist Spironolactone , Eplerenone Non-aldosterone antagonist ( ENaC blockers ) Amiloride, Triamterene

Classification-MOA… : 

B. Osmotic diuretics Mannitol Urea Glycerine C. Drugs increasing GFR / Secondary Diuretics Xanthines Caffeine Aminophylline Theophylline Classification-MOA…

Classification… According to Site of Action : 

Classification… According to Site of Action (A) Proximal Tubule Osmotic Diuretics ( Loop of Henle, collecting duct as well) Carbonic Anhydrase Inhibitors Xanthine Diuretics (B) Ascending Limb of Loop of Henle Loop Diuretics (C) Distal Tubule Thiazide Diuretics (D) Collecting Tubule K + - Sparing Diuretics ADH Antagonists

Carbonic Anhydrase Inhibitors : 

Carbonic Anhydrase Inhibitors Drugs interfering with ionic transport of HCO 3 These drugs inhibit carbonic anhydrase enzyme and selectively increase sodium bicarbonate excretion

Carbonic Anhydrase Inhibitors : 

Carbonic Anhydrase Inhibitors Site of action is PCT solutes relevant to diuretic action are NaHCO 3 & NaCl

Slide 19: 

Systemic Acetazolamide. Dichlorphernamide Methazolamide Local (instilled in eye) Dorzolamide Brinzolamide

Carbonic Anhydrase Inhibitors…: 

Carbonic Anhydrase Inhibitors… Chemistry Unsubstituted sulfonamide derivatives SO 2 NH 2 (sulfonamide gp) - Essential for activity

Carbonic Anhydrase Inhibitors…: 

Pharmacokinetics Well absorbed after oral administration. After a single dose : OOA ---- 30 min ( ↑ in urine pH due to HCO 3 - diuresis) Max effect --- 2 hrs. DOA ---- 12 hrs Excretion is by secretion into PCT S 2 segment Routes: Oral, parenteral & tropical eye drops. Carbonic Anhydrase Inhibitors…

Carbonic Anhydrase Inhibitors…: 

Carbonic Anhydrase Enzyme (CA) dependant sites of HCO - 3 & fluid transport Proximal convoluted tubule (PCT) Ciliary body - secretion of aqueous humor Choroid plexus - formation of CSF Carbonic Anhydrase Inhibitors…

Carbonic Anhydrase Inhibitors…: 

Carbonic Anhydrase Inhibitors… Mechanism of Action HCO - 3 reabsorption by the PCT is dependent on CA CA i nhibitors depress HCO - 3 reabsorption predominantly in PCT cells by inhibiting CA HCO - 3 reabsorption by PCT is initiated by action of Na + /H + exchanger in the luminal membrane of PCT epithelial cells. Na + enters the cells in exchange for H + from inside the cells Na + is pumped into the interstitium by Na + /K + ATPase in basolateral membrane. H + combines with HCO - 3 to form H 2 CO 3 ( carbonic acid) which is rapidly dehydrated to CO 2 & H 2 O by carbonic anhydrase.

MOA - Carbonic Anhydrase Inhibitors…: 

MOA - Carbonic Anhydrase Inhibitors… CO 2 diffuses into the cell & is rehydrated to H 2 CO 3 by carbonic anhydrase, H 2 CO 3 dissociates into HCO - 3 & H + HCO - 3 is transported out of cell by basolateral membrane transporter. When CA is inhibited there is loss of HCO - 3 & Na + along with equivalent amount of water ---- alkaline diuresis. Body pH ↓ --- hyperchloremic metabolic acidosis. Although 85% of HCO - 3 reabsorption capacity of PCT is inhibited only 45% inhibition of whole kidney HCO - 3 reabsorption is produced as HCO - 3 can be absorbed by mechanisms of other CA.

Carbonic Anhydrase Inhibitors…: 

Carbonic Anhydrase Inhibitors… Clinical Uses Rarely used as diuretic - Eff icacy ↓ over several days because HCO - 3 depletion leads to ↑ NaCl reabsorption by other segments. Glaucoma - reduction of aq.humor formation. Topical agents (dorzolamide, brinzolamide) – reduce IOP without producing detectable plasma levels Urinary alkalinization for enhancing excretion of weak acids (uric acid, cystine etc) by ↑ pH .

Carbonic Anhydrase Inhibitors… Clinical Uses: 

Carbonic Anhydrase Inhibitors… Clinical Uses 4. Metabolic alkalosis due to excessive use of diuretics or respiratory acidosis. 5. Treatment of acute mountain sickness – ch by weakness, dizziness, insomnia, headache & nausea seen in mountain travelers who rapidly ascend above 3000 meters. Usually mild, serious cases-rapidly progressing pulmonary or cerebral edema life threatening. CSF formation & pH of CSF & brain by Acetazolamide ventilation & diminish symptoms 6. Hypokalemic familial periodic paralysis 7. Epilepsy - as adjuvant therapy

Carbonic Anhydrase Inhibitors…: 

Carbonic Anhydrase Inhibitors… Toxicity Hyperchloremic metabolic acidosis – ch reduction of body HCO 3 - stores Renal stones (Calcium & Phosphates) – Ca stones are relatively insoluble in alkaline pH Renal potassium wasting: A s ↑ sodium presented to the collecting tubule, is partially reabsorbed, ↑ lumen –ve electrical potential so potassium secretion is enhanced. counteracted by simultaneous adm of KCl

Carbonic Anhydrase Inhibitors… Toxicity: 

Carbonic Anhydrase Inhibitors… Toxicity Drowsiness and paresthesias with large doses RF pts – accumulation CNS toxicity Reduction of urinary excretion rate of weak organic bases Side effects attributed to sulfonamide moiety Allergic reactions ( fever, rashes, bone marrow suppression , interstitial nephritis)

Carbonic Anhydrase Inhibitors…: 

Carbonic Anhydrase Inhibitors… Contraindication 1. Impaired liver function (Alkalinization of urine decreases urinary excretion of NH 4 leading to hyperammonemia and hepatic encephalopathy) 2. COPD 3. Known allergy to sulfonamide



CLASSIFICATION - Loop Diuretics: 

CLASSIFICATION - Loop Diuretics I. Carboxylic Acid Derivatives Furosemide Bumetanide Torsemide Piretanide Phenoxyacetic Acid Derivatives Ethacrynic acid Indacrinone

Slide 33: 

Carboxylic Acid Derivatives They possess carboxyl + sulfamyl group. Some C.A inhibiting activity. May inhibit HCO 3 - excretion to small extent. LOOP DIURETICS…

Slide 34: 

II. Phenoxyacetic acid Derivative Ethacrynic - a pro drug Do not possess sulfonamide group Contains a ketone & Methylene group which is highly reactive Methylene group combines with sulfhydryl group of cysteine and forms the active drug Indacrinone a derivative of ethacrynic acid No carbonic anhydrase inhibitory activity. LOOP DIURETICS…

Chemistry - Loop Diuretics : 

Chemistry - Loop Diuretics

Pharmacokinetics - Loop Diuretics: 

Pharmacokinetics - Loop Diuretics ROA: oral or I/V ( in urgent cases) Absorption: Rapid & complete from GIT Torsemide - 1 hr Furosemide - 2-3 hrs DOA: Furosemide 2-3 hrs , Torsemide: 4-6 hrs & one active metabolite with longer half life. Elimination: GF & tubular secretion NSAIDs & Probenecid can compete for TS. t ½ : depends upon renal function.

Slide 39: 

MOA - Loop Diuretics 1.    Main Mechanism (As Diuretic) Selective Inhibition of luminal Na + / K + / 2Cl - (NKCC2) Co-transporter in thick ascending limb of loop of Henle ↓ re-absorption of NaCl & K +

Slide 40: 

2. Contributory Mechanisms  Filtration Fraction Interference with counter current multiplier exchange system. Change in the renal haemodynamic state  degradation of PGI 2 and PGE 2 MOA - Loop Diuretics

Slide 41: 

The most efficacious diuretics 25% of filtered Na+ is re-absorbed in TAL of LOH The re-absorptive capacity of the distal segments is less The efficacy is not limited by development of acidosis HIGH CEILING DIURETICS MOA - Loop Diuretics

Pharmacological effects – Loop diuretics: 

Pharmacological effects – Loop diuretics Massive NaCl diuresis Excretion of edema fluid  blood volume Significant K + wasting & excretion of protons (H + ) --- hypokalemic alkalosis ↓ re-absorption of Mg ++ & Ca ++ , dependent upon the lumen positive potential derived from K + recycling. ↓ excretion of uric acid on chronic administration.  systemic venous capacitance &  left ventricular filling pressure ----- useful in pulmonary edema Decreased preload and filling pressures in RV and later also in LV – important in HF

Therapeutic Uses - Loop diuretics : 

Therapeutic Uses - Loop diuretics Useful in Edematous & Non-Edematous states A. Edematous states Acute pulmonary edema with LVF Treatment of refractory CHF Renal disease with hyperkalemia ---- diabetic nephropathy , kidney failure. Hepatic cirrhosis: careful use of loop diuretics in combination with aldosetron receptor antagonist may be useful.

Slide 44: 

B: Non-edematous states Hypertension a) Refractory cases. b) Associated with renal sufficiency or heart failure. c) Hypertensive emergencies. Hyperkalemia. Hypercalcemia: along with saline infusion & KCl. Anion over dosage (Bromide, fluoride, Iodide) Acute poisoning – forced diuresis

ADVERSE EFFECTS – Loop Diuretics: 

ADVERSE EFFECTS – Loop Diuretics I. Due to Disturbance in fluid & electrolytes balance Hypokalemia Hypochloremia Hyponatremia Hypocalcemia Hypophosphatemia Hypomagnesemia  Halide level Depletion of fluid volume Hypotension

ADVERSE EFFECTS – Loop Diuretics: 

II. Metabolic Adverse Effects Hyperuricemia- worsens gout Hyperlipidemia-mild  LDL & cholesterol, mild  TGs, m ild  HDL Hyperglycemia Hypokalemic metabolic alkalosis ADVERSE EFFECTS – Loop Diuretics

ADVERSE EFFECTS – Loop Diuretics: 

III. Misc Adverse Effects Ototoxicity Dose related reversible hearing loss. More marked with other ototoxic drugs / ↓ renal function. Nephrotoxicity Hepatotoxicity Gynaecomastia ADVERSE EFFECTS – Loop Diuretics

ADVERSE EFFECTS – Loop Diuretics: 

IV. Allergic Reactions Related to sulfonamide moiety Skin rashes Dermatitis Photosensitivity Eosinophilia Interstitial Nephritis Less common with ethacrynic acid ADVERSE EFFECTS – Loop Diuretics

DRUG INTERACTIONS - Loop Diuretics: 

DRUG INTERACTIONS - Loop Diuretics NSAIDs (↓ PG synthesis). Aminoglycoside (potentiate ototoxicity) Digoxin (  toxicity due to hypokalemia)


CONTRAINDICATIONS - Loop Diuretics Severe sodium or volume depletion overzealous use is dangerous in hepatic cirrhosis, borderline renal failure or heart failure Hypersensitivity to sulfonamides

Inhibitors of Na+/Cl– transporter THIAZIDE & THIAZIDE - LIKE DIURETICS: 

Inhibitors of Na + /Cl – transporter THIAZIDE & THIAZIDE - LIKE DIURETICS

Slide 52: 

CHEMISTRY Sulfonamides derivatives – have an unsubstituted Sulfonamide gp in their structure ( H 2 NSO 2 ) Structural analog of 1,2,4 – benzothiadiazine- 1,1- dioxide H 2 NSO 2

Slide 53: 

Chemistry… All thiazides are sulfonamide derivatives Prototype - Hydrochlorothiazide

Slide 54: 

Classification -Thiazide & Related Diuretics Short Acting (t ½ 1.5 -7.3 hrs) Chlorothiazide , Hydrochlorothiazide , Bendroflumethiazide , Trichlormethiazide Intermediate Acting (t ½ 14 -17 hrs) Indapamide , Hydroflumethiazide Long Acting (t ½ 24 -47 hrs) Polythiazide , Chlorthalidone Quinethazone , Metolazone

Thiazide Related Compounds: 

Thiazide Related Compounds Phthalimidine Derivatives . Chlorthalidone Quinazoline Derivatives Quinethazone Chlorobenzamide Clopamide Benzene Disulphonamide Mefruside Xipamide Indapamide


Pharmacokinetics Administered orally--- Only chlorothiazide (not very lipid soluble) given parenterally Differ in potency as compared to prototype. i.e. Hydrochlorothiazide Differ in DOA-- Different t 1/2 , hydrochlorothiazide (12h) others ( >24h) Differ in metabolism All are secreted by organic acid secretary system in PT& compete with uric acid -- uric acid level rises

Slide 58: 

Drug Relative potency Oral availability T ½ hrs Route of Elimination Hydrochlorothiazide 1 70% 2.5 R Hydroflumethiazide 1 50% 17 40-80%R, 20-60%M Chlorthalidone 1 65% 47 65%R, 10%B, 25%U Quinethazone 1 ID ID ID Chlorothiazide 0.1 9-56% (Dose dependent) 1.5 R Pharmacokinetics - Thiazide & Related Diuretics

Slide 59: 

Drug Relative potency Oral availability T ½ hrs Route of Elimination Bendroflumethiazide 10 100% 3-3.9 30%R, 70%M Methylclothiazide 10 ID ID M Metolazone 10 65% ID 80%R, 10%B, 10%M Indapamide 20 93% 14 M Polythiazide 25 100% 25 25% R, 75%U Trichlormethiazide 25 ID 2.3-7.3 R R = Renal excretion of intact drug M = Metabolism B = Excretion of intact drug into bile U = Unknown pathway of elimination ID= Insufficient Data

Pharmacodynamics Site of action DCT: 

Pharmacodynamics Site of action DCT About 10% of filtered NaCl is actively re-absorbed by Na + / Cl - (NCC) transporter. Relatively impermeable to water. K+ does not recycle across the apical membrane . Ca ++ is actively re-absorbed , under control of parathyroid hormone Removal of the re-absorbed Ca ++ requires Na + -Ca ++ exchanger.

M.O.A as diuretic Moderate diuretics: 

M.O.A as diuretic Moderate diuretics Main Mechanism Inhibit Na + / Cl - (NCC) transporter in early DCT &  re-absorption of sodium Chloride. Loss of Na + and Cl - along with equivalent amount of water. Also cause K + loss – hypokalemia. Enhance Ca ++ re-absorption ----  Ca ++ loss May inhibit HCO 3 - absorption to some extent They produce hyperosmolar urine. Contributory Mechanism Increased production of renal PGs.

Slide 63: 

M.O.A as Anti – Hypertensive : I) Initial fall of blood pressure is because of ↓ in blood volume & cardiac output, PVR may increased. Because blood volume is made up by compensatory mechanism i.e. more NaCl and water re-absorption from PCT, CO returns towards normal.

Slide 64: 

II) After 6-8 weeks Blood Pressure  because of vasodilatation due to Natriuretic effect ----  excretion of Na + .  Na + in the body Sodium is believed to contribute to vascular resistance by: Increasing vessel stiffness Neural reactivity  PVR is possibly related to  sodium-calcium exchange with a resultant  in intracellular calcium. These effects are reversed by diuretics.

Slide 65: 

Effect on cardiac output in heart failure ↓ venous pressure & ventricular preload ↓ edema & its symptoms. Reduction of cardiac size. Improved pump inefficiency .

Therapeutic Uses - Thiazide Diuretics : 

Therapeutic Uses - Thiazide Diuretics I)   Hypertension Important 1 st line monotherapy Enhance efficacy of many agents in combination therapy ----- vasodilators, ACE inhibitors Plus points: cost effective, relatively safer, satisfactory efficacy, synergistic effect with other antihypertensives, few CIs, better compliance, reduced CVS morbidity & mortality in hypertensive pts, action independent of acid-base balance

Therapeutic Uses - Thiazide Diuretics : 

Therapeutic Uses - Thiazide Diuretics II) Mobilisation of Odema of · Cardiac origin (Ch CCF) · Hepatic origin (Hepatic Cirrhosis) · Renal Origin (Chronic Renal Failure, Nephrotic Syndrome, Acute Glomerulonephritis) III) Diabetes insipidus ( central & nephrogenic ) paradoxical beneficial effect is mediated through plasma volume reduction, with an associated fall in GFR rate, enhanced proximal reabsorption of NaCl and water, and decreased delivery of fluid to the downstream diluting segments IV) To reduce stone formation in Idiopathic Hypercalciuria

Therapeutic Uses - Thiazide Diuretics: 

Therapeutic Uses - Thiazide Diuretics V) Osteoporosis VI) Pre-eclampsia of pregnancy VII) Halide poisoning (Br - Intoxication) VIII) Mild Heart Failure.

Adverse Effects - Thiazide Diuretics: 

Adverse Effects - Thiazide Diuretics I. Due to loss/retention of ions Hypokalemia Hyponatremia ---- important A/E may be due to: ↑ ADH due to Hypovolumia ↓ in the diluting capacity of kidney. ↑ thirst Can be prevented by ↓ the dose or limiting water intake. ↑ calcium reabsorption (opposite to loop diuretics) Hypercalcemia rarely occurs but it can unmask Hypercalcemia due to other causes: Hyperthyroidism. Carcinoma. Sarcoidosis

Slide 70: 

II. Metabolic effects Hypokalemic metabolic alkalosis. Hyperglycemia (both impaired release of insulin & diminished tissue utilization of glucose; partially reversible with correction of hypokalemia) Hyperuricemia Hyperlipidemia --- , 5-15%  in total Cholesterol & LDL.

Slide 71: 

III. Allergic reactions sulfonamides 1.      Dermatitis 2.      Photosensitivity 3.      Hemolytic anemia 4.      Thrombocytopenia 5.      Acute necrotizing pancreatitis

Slide 72: 

IV. Other toxicities Weakness , fatigability & paresthesias Impotence ---- related to volume depletion. V. Drug interactions a. NSAIDs attenuate effect of thiazides ----  synthesis of PGs. b. Toxicity of Cardiac Glycosides  --- due to hypokalemia.

Slide 73: 

ADH antagonists Selective ADH receptor antagonist: Conivaptan, Tolvaptan under investigation. Non-selective agent: Lithium & Demeclocycline ADH agonists Vasopressin, Desmopressin.

Slide 74: 

Antidiuretic Hormone Antagonists Ph.K: Conivaptan, Demeclocycline and lithium can be used orally. Conivaptan, Demeclocycline have t ½ 5-10 hrs.

Slide 77: 

Mechanism of Action ADH facilitates water reabsorption from the CT by activation of adenylyl cyclase. ↑ cAMP causes the insertion of additional water channels into the luminal membrane . Conivaptan is a pharmacological antagonist at V 1a & V 2 receptors. Demeclocycline & lithium ↓ generation of cAMP interfere with the insertion of water channels. Exact mechanism of these effects not known

Slide 78: 

Clinical Uses 1. Syndrome of inappropriate ADH secretion (SIADH) Water restriction is treatment of choice. ADH antagonists are used if it fails. Can be treated with Demeclocycline orally. Conivaptan is given I/V, not suitable for chronic use. Previously lithium was used but requires plasma level monitoring 2. Other causes of elevated ADH ---- in CCF Water restriction is treatment of choice Conivatan & Demaclocycline are used if it fails.

Slide 79: 

Nephrogenic Diabetes Insipidus by Lithium & Demeclocycline. Renal failure by Lithium & Demeclocycline Interstitial nephritis by Lithium Bone and teeth abnormalities ---- Demeclocycline, in children under 12 years of age.

Slide 80: 

Antidiuretic Hormone Agonists Mechanism of Action They act via G-protein coupled V 2 & V 1a receptor. V 1a receptors are present on vascular SM cells ---- vasoconstriction. V 2 receptors ----- renal tubule cells ↓ diuresis Extra renal V 2 receptors regulate the release of coagulation factor VIII & von Willebrand factor.

Slide 81: 

Pharmacological Effects ADH and Desmopressin ↓ urine volume through ↑ water permeability & water reabsorption in CT. Clinical Uses Pituitary Diabetes Insipidus. (Not useful in the nephrogenic DI. Salt restriction, thiazides diuretics may be used.) Desmopressin is also used in treatment of hemophilia A & von Willebrand’ s disease


CONTRAINDICATIONS Impaired hepatic functions Impaired renal functions Diabetes mellitus Adrenal diseases Gout Late pregnancy.




POTASSIUM SPARING DIURETICS 1. Aldosterone antagonists Spironolactone Eplerenone 2. Direct inhibitors of Na influx Amiloride Triamterene

Collecting Tubule: 

Collecting Tubule only 2-5% of NaCl is reabsorbed very imp site final site of NaCl abs & responsible for regulation of final conc of urine site of action of aldosterone major site of K secretion in exchange for Na.

Slide 87: 

As final site of reabsorption of NaCl - is responsible for Regulation of body fluid volume Determining the final concentration of the urine. The above effects occur under the influence of ADH. ADH controls the permeability of the this segment to water by regulating the insertion of preformed water channels (aquaporin-2 AQP2) in to the apical membrane. ADH also stimulates insertion of urea transporter UT1 molecules into the apical membrane. ----- important for conc. of urine.


Chemistry Spironolactone is a synthetic steroid Eplerenone is its analog with greater selectivity for aldosterone receptor

Pharmacokinetics : 

Pharmacokinetics Given orally Strongly bound to plasma proteins Spironolactone: Slow OOA (requiring several days) DOA variable – Onset & DOA are determined by the kinetics of aldosterone response in the target tissue, Inactivation in the liver Triamterene is extensively metabolized in the liver, has a short half life, shorter DOA (must be given frequently than Amiloride which is not metabolized)

Slide 91: 

MOA - Aldosterone Antagonists SOA: Collecting tubules & ducts Competitive antagonist at Aldosterone receptor Reduces Aldosterone regulated Na + reabsorption in collecting tubules & ducts by Principal cells reabsorb Na + via ENaC coupled with secretion of K + so Hyperkalemia . Also↓ secretion of H + ion by Intercalated cells Metabolic acidosis. May also reduce intracellular formation of active metabolites of Aldosterone. The action of aldosterone antagonists depends upon renal PGs production – can be inhibited by NSAIDs under certain conditions

Slide 92: 

MOA - Non- aldosterone antagonists ( ENaC blockers ) (Amiloride, Triamterene) SOA: Collecting tubules & ducts Directly interfere with Na + entry through the epithelial sodium channels (ENaC) – K+ secretion is coupled with Na+ entry in this section effective K+ sparing diuretics Do not block Aldosterone receptors

Slide 93: 

Therapeutic / Clinical uses 1. Rx of Primary / Secondary Hyperaldosteronism (aldosteronism) – Mineralocorticoid excess Primary hypersecretion of aldosterone (Conn’s syndrome, ectopic ACTH production) Secondary aldosteronism evoked by Heart failure Hepatic cirrhosis Nephrotic syndrome Other conditions associated with diminished effective intravascular volume. (use of thiazides or loop diuretics)

Slide 94: 

Therapeutic / Clinical uses… Hyperaldosteronism There is excessive delivery of sodium to distal nephron sites More K + secretion in exchange for sodium So renal K + wasting occurs K + sparing diuretics may be used to blunt the K + secretary response

Slide 95: 

Therapeutic / Clinical uses… 2. Diuretic 3. Antihypertensive Along with Loop and Thiazide diuretics Eplerenone Low doses (25-50mg/d) – interfere with some of the fibrotic & inflammatory effects of aldosterone reduce the progression of albuminuria in diabetic pts Reduce myocardial perfusion defects after MI – reduce mortality rate by 15% in pts with mild to moderate HF after MI

Slide 96: 

Toxicity Hyperkalemia (reduce urinary excretion of K + ) Mid, moderate, severe life threatening Increased risk in renal disease, use of other drugs that reduce or inhibit renin release ( β blockers, NSAIDs) or Angiotensin II activity (ACEIs & ARIs) Hyperchloremic metabolic acidosis inhibiting H + secretion in parallel with K + secretion

Slide 97: 

Toxicity… Endocrine abnormalities Gynecomastia, impotence & benign prostatic hyperplasia with Spironolactone (synthetic steroid) Not seen with Eplerenone –much more selective for mineralocorticoid receptor, being virtually inactive on androgen or progesterone receptors Acute renal failure Triamterene with Indomethacin Not reported with other drugs Kidney stones Triamterene being slightly soluble may ppt in urine forming kidney stones

Slide 98: 

Contraindications / Drug Interactions K supplements Liver disease (impair metabolism of triamterene & spironolactone) Ketoconazole and Itraconazole (strong CYP3A4 inhibitors) – can increase blood levels ACE inhibitors & Beta blockers – blunt renin – angiotensin system K + NSAIDs – can decrease their effect Renal disease fatal hyperkalemia

Slide 100: 

Diuretics Combinations Loop & Thiazide Diuretics K + Sparing diuretics & Loop or Thiazide diuretics.

Osmotic Diuretics (Mannitol, Urea, Glycerine): 

Osmotic Diuretics (Mannitol, Urea, Glycerine) The proximal tubule and descending limb of loop of Henle are freely permeable to water. Any osmotically active agent that is filtered by the glomerulus but not reabsorbed causes water to be retained in these segments and promotes a water diuresis

Osmotic Diuretics…: 

Osmotic Diuretics… Pharmacologically inert, non-electrolyte osmotically active Freely filtered at the glomerulus, not reabsorbed causes water to retain & promotes a water diuresis Weak diuretics Prototype - MANNITOL


Pharmacokinetics Poorly absorbed - given parenterally If administered orally Mannitol causes osmotic diarrhea. Rapidly distributed in the ECF & prior to diuresis there is expansion of extracellular volume & hyponatremia Mannitol is not metabolized and is excreted within 30-60 minutes without any important tubular reabsorption or secretion

MOA : 

MOA Freely filtered at glomerulus. Major effect in PCT & descending limb of Henle’s loop Oppose the action of ADH in CT – osmotic effect The presence of a non-absorbable solute prevents the absorption of water by interposing a countervailing osmotic force urine volume increases The increase in urine flow rate decreases the contact time b/w fluid and the tubular epithelium excessive water loss and hypernatremia Resulting natriuresis is of lesser magnitude than the water diuresis

Clinical Indications: 

Clinical Indications Used to increase water excretion in preference to sodium excretion (acute sodium retention) Maintain urine volume and to prevent anuria that might result from large pigment load to the kidney (hemolysis & rhabdomyolysis) Reduction of Intracranial pressure in neurologic conditions Reduction of Intraocular pressure before ophthalmologic procedures Dose: 1-2gm/kg

Toxicity : 

Toxicity Extra cellular volume expansion ---- complicate heart failure / pulmonary edema Headache, nausea, vomiting – common complaint Dehydration hyperkalemia & hypernatremia Hyponatremia in pts with diminished renal function as retained IV & causes osmotic extraction of water from cells, leading to Hyponatremia