Diuretics PDF

# Normal regulation of fluid and electrolytes by the kidneys: - 16 to 20% of the blood plasma get filtered from the glomerular capillaries into Bowman's capsule - Normally they are free of proteins and blood cells - Contains: Na, K, Cl, Ca, glucose, sodium bicarbonate, amino acids... ## Electrolyt...

# Normal regulation of fluid and electrolytes by the kidneys: - 16 to 20% of the blood plasma get filtered from the glomerular capillaries into Bowman's capsule - Normally they are free of proteins and blood cells - Contains: Na, K, Cl, Ca, glucose, sodium bicarbonate, amino acids... ## Electrolytes control kidney functions by active reabsorption or secretion of ions and/or passive reabsorption of water *Due to water and sodium retention edema will occur which is accumulation of fluid in the interstitial space;* ## Types of edema are: - **Exudative** (high ptn content), localized (diuretics are not effective) - **Transduative** (low ptn content), generalised (diuretics are effective) ## Functional zones in nephron (5): 1. Proximal convulated tubule (PCT) 2. Decending loop of Henle 3. Ascending loop of Henle 4. Distal convulated tubule 5. Collecting tubule and duct ## 1- Proximal convulated tubule: - 90% of glucose, bicarbonate, amino acids are reabsorbed - 65% of Na and water are reabsorbed - 60% of water is reabsorbed to maintain osmolar equality - PCT secret acids and bases into the tubular fluid; diuretics compete with acids secretion leading to increase uric acid level - Diuretics poorly works on PCT ## 2- Descending loop of Henle: - Passive reabsorption of water due to hypertonicity of medullary interstitium, (Increase Na and Cl concentration) ## 3- Ascending loop of Henle: - They are impermeable to water - Active reabsorption of Na (and water), K and Cl mediated by Na/K/2Cl- cotransporter - Both Mg2 and Ca2 are reabsorbed via the paracellular pathway. - 25 to 30% of the filtered Na is actively reabsorbed (the cause of hypertonicity of the medullary interstitium), Ca and Mg as well ## 4- Distal convulated tubule: - Impermeable to water - 5 to 10% of Na is reabsorbed via sodium/ chloride transporter (active) - Calcium reabsorption is under PTH regulation transported by Na/Ca exchanger into the interstitial fluid ## 5- Collecting tubule and duct: - Reabsorption of water is under the influence of ADH (vasopressin) - ADH binds to V2 receptors to promote the reabsorption through aquaporin channels - Aldosterone increase Na reabsorption and K excretion through Na/K-ATPase pump ## Diuretics drugs classes (5): 1. Thiazide diuretics 2. Loop diuresiss 3. Potassium sparing diuretics 4. Carbonic anhydrase inhibitors (Acetazolamide) 5. Osmotic diuresis (Mannitol) ## Thiazides Diuretics - Most used (due to antihypertensive effects) - Affect distal convulated tubule - Equal maximum diuretic effect (low ceiling diuretics) ## Common Thiazides drugs: 1. Chlorothiazide 2. Hydrochlorothiazide (2nd in potency) 3. Chlorthalidone (Most potent) Due to their high bioavailability ## Thiazide grouping (2): 1. True Thiazides: derivatives of Sulfonamides include: Hydrochlorothiazide, Chlorothiazide 2. Thiazide like diuretics: Chlorthalidone, Inapamide, Metolazone ## MOA of Thiazides: - Mainly in distal convulated tubule - Decrease the reabsorption of Na by inhibiting Na/Cl cotransporter - Antihypertensive effects of Thiazides become poor when GFR is below 30mL/min replace with Loop diuretics - Renal PGs are important in Thiazides action, NSAIDs may impair Thiazide efficacy ## Thiazides Actions: 1. Increase excretion of Na and Cl: they can lead hyperosmolar excretion (concentrated urine) 2. Decreased urinary calcium excretion: PTH regulates calcium reabsorption 3. Reduce peripheral vascular resistance ## Therapeutic uses(4): 1. Hypertension (not commonly used): Hydrochlorothiazide, Chlorthalidone preferred due to their long half life (50 to 60 hours) 2. HF (LOOP diuretics are the diuretics of choice): Thiazidews are given in resistance cases to loop diuretics (careful monitoring for hypokalemia) Metolazone addition to loop diuretics 3. Hypercalciuria: treating idiopathic hypercalciuria and calcium oxalate stones in the urinary tract (inhibiting calcium secretion) 4. Diabetes insipidus (DI): Thiazides can treat nephrogenic diabetes insipidus dropping urination volume from 11 to 3L/d ## Kinetics: - Affective orally - 60 to 70% bioavailability - Chlorothiazide low bioavailability (10 to 15%), only Thiazide with I.V. dosage form - 1 to 3 weeks to produce a stable reduction in BP - Long half life 10 to 15 hours - Most thiazides primarily excreated unchanged in the urine - Inapamide undergoes hepatic metabolism and excreted in both urine and bile ## Adverse effects(7): 1. Hypokalemia: sodium potassium exchange 2. Hypomagnesmia 3. Hyponatremia: elevation of ADH, as well as diminished diluting capacity of the kidney + thirstiness 4. Hypovolemia: cause orthostatic hypotension or light headeness 5. Hyperuricemia: due to acid excretion throup drug competition causing gouty attack (caution in gout or high levels of uric acids) 6. Hypercalcemia 7. Hyperglycemia: impaired insulin release due to hypokalemia (monitor glucose level in diabetic patients) ## Loop diuretics: - Highest efficacy in mobilizing Na and Cl from the body - Gratest diuretics effects due to loss of 25-30% of reabsorption ## Loop diuretics: - Furosemide is the most used - Bumetanide, Torsemine have better bioavailability and more potent (usage is increasing) - Ethacrynic acid High adverse effects profile ## MOA of loop diuretics: - Inhibit the transport of Na/K/2Cl - Decrease absorption in the renal medulla (decrease Osmotic pressure in the medulla) - less water is reabsorbed ## Loop Actions (3): 1. Diuresis (s-shape response) 2. Increases urinary calcium excretion (hypocalcemia doesn't occur -> Ca2 is reabsorbed in the distal convulated tubule) 3. Venodilation (reduce left ventricular filling pressures via enhanced prostaglandin synthesis) ## Therapeutic uses (3): 1. Edema: drugs of choice in pulmonary edema, acute/ chronic peripheral edema caused from HF or renal impairment 2. Hypercalcemia: stimulates tubular Ca excretion 3. Hyperkalemia ## Kinetics: - Administered orally or parentally - Furosemide unpredictable bioavailability from 10 to 90%! - Bumetanide, Torsemide reliable bioavailability from 80 to 100% preferred in oral therapy - Furosemide, Bumetanide the duration of action is about 6 hours - Torsemide little bit higher the 6h of action ## Adverse effects (5): 1. Acute hypovolemia: possibility to cause hypotenistion, shock, cardiac arrhythmia 2. Hypokalemia: increased exchange of tubular Na for K leading to hypokalemia, K exchange for H will leads to hypokalemic alkalosis 3. Hypomagnesmia 4. Ototoxicity: reversals or PERMANENT hearing loss may occur in loop diuretics especially in I.V form (Ethacrynic acid is the most cause in this class), other ototoxic drugs (aminoglycoside antibiotics) 5. Hyperuricemia: loop diuretics compete with uric acid for the renal secretory system may cause gouty attacks. ## Potassium sparing diuretics: - Act in the collecting tubule to inhibit Na reabsorption and K excretion - Increased risk of hyperkalemia (caution in renal dysfunction) - Two different mechanisms: - I. Aldosterone antagonists - II. Epithelial sodium channel blockers ## I. Aldosterone antagonists (Spironolactone and Eplerenone) : ## MOA: - Synthetic steroids that antagonize Aldosterone receptors - They work on the nucleus level of the target cell - Lack of intracellular proteins that stimulate the Na/K exchange sites of the collecting tubules - Eplerenone is more selective and with less endocrine effects (gynaecomastia) than Spironolactone which binds to progesterone and androgen receptors ## Actions: - They cause diuresis and cause other effects in nonrenal sites ## Therapeutic uses (5): 1. Edema: Used in high doses for edema associated with secondary hyperaldosteronism (hepatic cirrhosis*Spironolactone* and nephrotic syndrome) 2. Hypokalemia: Useful as a conjunction with Thiazides or Loop diuretics to prevent K excretion 3. HF: low dose with reduced ejection fraction 4. Resistance hypertension: Defined by the use of three or more medications without reaching the BP goal 5. Polycystic ovary syndrome ## Kinetics: - Well absorbed orally - Spironolactone is extensively metabolized and converted to active metabolites (affect therapy) - Eplerenone metabolized by CYP450 3A4 ## Adverse effects (2) : 1. Hyperkalemia (doese dependent) 2. Gynaecomastia (Spironolactone ONLY) 10% in males ## II. Epithelial sodium channel blockers (Triamterene and Amiloride): - Result in decrease in Na/K exchange - No Aldosterone action dependence - Used in combination due to their low monotherapy effect ## Carbonic Anhydrase inhibitors (Acetazolamide) : ## MOA: - Inhibits carbonic anhydrase located intracellularly (cytoplasm) and on the apical membrane of the proximal tubular epithelium - Carbonic anhydrase ionize H+ and HCO3(bicarbonate) - Loss of HCO3 will lead to hyperchloremic metabolic acidosis ## Theraputic uses (2): 1. Glucoma: block carbonic anhydrase in the ciliary body of the eye (topical form are available e.g. dorzolazmide, brinzolamde) 2. Altitude sickness: prophylaxis treatment by preventing weakness, breathlessnes, dizziness, nausea and cerebral, pulmonary edema ## Kinetics: - Orally or I.V. - 90% ptn bound and eliminated by both active secretion and passive reabsorption ## Adverse effects: - Metabolic acidosis (mild) - Hypokalemia - Renal stones - Drowsiness - Paresthesia - *Contraindicated with hepatic cirrhosis (may cause decrease secretion of NH4+ - Osmotic diuresiss (Mannitol) : - It prevents further water reabsorption at the descending loop of henle andproximal convulated tubule, resulting in osmotic diuresis (aquaresis) - Not useful in Na+ retention - Only I.V form (emergency) ## Adverse effects: - Dehydration - extracellular water expansion - Hyponatremia untill diuresis occurs