Diuretics - Overview PDF

DIURETICS ▪ Assist. Prof. Dr. Rümeysa MKAYA ▪ University of Health Sciences ▪ International School of Medicine ▪ Department of Medical Pharmacology  DIURETICS Diuretic drugs ▪ Increase the urine volume output ▪ are inhibitors of renal ion transporters that decrease the reabsorption of Na+ a...

DIURETICS ▪ Assist. Prof. Dr. Rümeysa MKAYA ▪ University of Health Sciences ▪ International School of Medicine ▪ Department of Medical Pharmacology  DIURETICS Diuretic drugs ▪ Increase the urine volume output ▪ are inhibitors of renal ion transporters that decrease the reabsorption of Na+ at different sites in the nephron Natriuresis vs Diuresis (Increase Na and water output) https://doi.org/10.1016/B978-0-444-63359-0.00005-7 They affect certain segments of the nephrons and increase the loss of water and salt from the kidneys. Treatment of hypertension Management of excessive fluid retention (edema) They reduce systolic and diastolic blood pressure. Diuretics preferred as antihypertensives are thiazide group diuretics. They are used in other diseases that require the removal of water and salt from the body. DIURETICS MECHANISMS OF ANTIHYPERTENSIVE EFFECTS Short-term application: leads to volume depletion. They inhibit hypovolemia by inhibiting water and sodium Diuresis =increment in urine excretion and urine volume Long-term application: vasodilatation Intracellular sodium decrement thus intracellular calcium decreases and vasodilatation Diuretic and hypotensive actions Diuretic agents used in antihypertensive treatment Hydrochlorothiazide, Chlorthalidone  DIURETICS They can be used alone in mild hypertension cases. They are used in combination with other antihypertensives in moderate and severe hypertension. Prolonged use may cause hyperlipidemia and the possibility of developing atherosclerosis. Clinical Conditions Requiring Diuretic Therapy; Treatment of edematous states Edema is an Cerebral Edema abnormal accumulation of fluid Pulmonary Edema in the intercellular spaces of connective Congestive Hearth Failure tissue. Glaucoma Acute Renal Failure Liver Cirrhosis SIDE EFFECTS OF DIURETICS Hyponatremia Hypocalcemia (especially loop diuretics) Hypomagnesemia Hypochloremia Hyperglycemia (They reduce insulin release from the pancreas due to hypokalemia. Especially thiazide and furosemide groups) Hyperlipidemia (especially thiazide and furosemide) Hyperuricemia (They inhibit the tubular secretion of uric acid. Especially furosemide) Hyperammonemia DIURETICS AND HYPOKALEMIA Diuretics increase Na+ in the filtrate arriving at the distal tubule, more K+ is also exchanged for Na+, resulting in a continual loss of K+ from the body with prolonged use of these drugs Thus, serum K+ should be measured periodically (more frequently at the beginning of therapy) to monitor for the development of hypokalemia. Potassium supplementation or combination with a potassium-sparing diuretic may be required. Low-sodium diets blunt the potassium depletion caused by thiazide diuretics. Associated with loop and thiazide diuretics Clinical use of diuretics Hypertension (alone or combined) Coronary disease Acute glomerulonephritis Nephrotic syndrome (spironolactone) Cirrhosis of the liver (tiazids, spironolactone, triamterene, furosemide) Hyperaldosteronism Treatment of edematous diseases  DIURETICS 1-Proximal tubule 2- Henle loop (loop diuretics) 3- Distal tubule Carbonic anhydrase inhibitors Furosemide Thiazides and thiazide-like diuretics Osmotic diuretics Bumetanide Xanthine compounds Etacrynic acid 4- Cortical collecting tubule Aldosterone antagonists (Spironolactone) Triamterene Amiloride I. CARBONIC ANHYDRASE INHIBITORS Acetazolamide, Dorzolamide Bind to the carbonic anhydrase enzymes & inhibit them Excretion of bicarbonate with urine. The major renal effect is bicarbonate diuresis (ie, sodium bicarbonate is excreted); body bicarbonate is depleted, and metabolic acidosis results. Water, sodium and potassium depletion. Very weak diuretic effect. Indications Carbonic anhydrase inhibition causes significant HCO3- losses and may lead to hyperchloremic metabolic acidosis. The diuretic efficacy of acetazolamide decreases significantly with use over several days because HCO3 depletion leads to enhanced NaCl reabsorption by the remainder of the nephron. Indications Treatment of (open-angle) glaucoma (reduction of aqueous humor formation) Topical dorzolamide, brinzolamide - Chronic glaucoma treatment Epilepsy Edema Acute mountain sickness Metabolic alkalosis Side effects metabolic acidosis, electrolyte imbalances, nausea, vomiting and diarrhea, Polyuria The drug should be avoided in patients with hepatic cirrhosis, because it could lead to a decreased excretion of NH4+. Asetazolamide (Diazomid®) Oral, i.m or i.v application. Develops quick tolerance to effects. Diuretics and natriuretics are very weak. It is also used for glaucoma treatment.  II. OSMOTIC DIURETICS Mannitol, Urea, Glucose, Isosorbide When filtered through glomeruli, they increase osmotic pressure in the lumen of the proximal tubule. As a result, there is a decrease in the reabsorption of water and sodium and chlorine due to hyperosmolarity. They are not reabsorbed from the tubules (mannitol) or are restricted (such as glucose and urea). They provide water diuresis rather than sodium diuresis.  II. OSMOTIC DIURETICS Mannitol, Urea, Glucose, Isosorbide They provide water diuresis rather Hydrophilic substances that are filtered through the than sodium diuresis glomerulus such as mannitol, result in diuresis These agents are not useful for treating conditions in which Na+ retention occurs. Filtered substances that undergo little or no reabsorption result in a higher osmolarity of the tubular fluid This prevents further water reabsorption at the descending loop of Henle and proximal convoluted tubule They are given by intravenous infusion. this results osmotic diuresis with little additional Na+ excretion Clinical Uses During acute drug intoxications They are used to prevent acute renal failure. Against oliguria due to kidney disease Intracranial pressure Intraocular pressure Contraindications Mannitol is contraindicated in Pulmonary edema and Pulmonary congestion. should not be used in patients with active cranial bleeding Chronic Renal disease (not metabolized therefore patients with renal failure will not have the ability to clear mannitol) and anuria  III. LOOP DIURETICS Mechanism of effect Inhibits Na+/K+/2Cl− pump. Reabsorption of these ions into the renal medulla is decreased By lowering the osmotic pressure in the medulla, less water is reabsorbed, causing diuresis. Impact of Loop Diuretic on Outcomes in Patients with Heart Failure and Reduced Ejection Fraction - Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Mechanism-of- action-for-loop-diuretics_fig1_357886585  III. LOOP DIURETICS Furosemide (Lasix amp.,tb), Torsemide, Bumetanide, Ethacrynic acid Loop diuretics produce a more potent diuresis & less vasodilation than thiazide diuretics. Therefore, they are less effective in lowering BP than thiazide diuretics. p.o, i.v, i.m administration The effects of loop diuretics, thiazides & The effects starts quickly. K-sparing diuretics depend on renal prostaglandin production & their diuretic Bumetanide, more potent loop diuretic effects can be reduced by NSAIDs. NSAIDs may reduce the effects of loop diuretics Furosemide The onset of action; p.o; 30 min i.v.; 15 min. The duration of action; 6 hours LASIX: ‘’Lasts Six (hours) Increased urinary calcium excretion; Unlike thiazides, loop diuretics increase the Ca2+ content of urine. Loop diuretics reduce Ca2+ and Mg2+ reabsorption in the ascending arm of the Henle loop Loop diuretics increase the excretion of divalent cations (Ca & Mg) & this can be useful in treating disorders causing hypercalcemia (Note: this is an effect opposite from that caused by thiazide diuretics). Makes vasodilatation of kidney vessels. (Vasodilatory effect occurs immediately - the difference from thiazides) Increases renal blood flow and glomerular filtration rate. INDICATIONS Edema Treatment of acute pulmonary edema during acute left heart failure Hypercalcemia Hyperkalemia Acute and chronic renal failure (Loop agents can increase the rate of urine flow and enhance K excretion in acute renal failure) Nephrotic syndrome (furosemide)  Adverse effects and Contraindications Reversible ototoxicity Hypovolemia (cause a severe and rapid reduction in blood volume), Contraindications hypotension, dehydration Hypersensitivity to sulfonamides Hyponatremia Gout (Hyperuricemia) Hypokalemia (The heavy load of Na+ presented to the collecting tubule Liver cirrhosis results in increased exchange of tubular Na+ for K+) Hypokalemic alkalosis Hyperuricemia Hyperglycemia Hypocalcemia and hypomagnesemia may develop IV. THIAZIDES All thiazides are secreted in the proximal tubule They compete with the secretion of uric acid Drug as; Chlorothiazide (parenteral) Hydrochlorothiazide As a result, thiazides may elevate serum uric acid Chlorthalidone level. (hyperuricemia) Metolazone Hydrochlorothiazide Indapamide The onset of action; 2 hours The duration of action; 6-12 h.  Mechanism of action of thiazide diuretics inhibits the Na/Cl cotransporter in the distal convoluted tubule. cause diuresis with increased Na+ and Cl− excretion, which can result in the excretion of very hyperosmolar (concentrated) urine lowering of intracellular Na+ by thiazide-induced blockade of Na+ entry enhances Na+/Ca2+ exchange in the basolateral membrane and increases overall reabsorption of Ca2+ In contrast to the situation in the thick ascending limb, in which loop diuretics inhibit Ca2+ reabsorption, thiazides Pharmacogenomics of Hypertension Treatment - Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Effects-of-action-of-thiazide-diuretics_fig4_342631931 [accessed 25 Nov, 2023] actually enhance Ca2+ reabsorption. INDICATIONS Mild and moderate hypertension (cheap-well tolerated). Edema due to congestive heart failure Acid and edema due to liver cirrhosis (combined with K+ sparing diuretics) Edema due to nephrotic syndrome Hypercalciuria (to increase calcium re-absorption and decrease renal calcium stones) Nephrogenic Diabetes Insipidus (decrease blood volume and GFR) Mechanism of antidiuretic effect of thiazide in Diabetes insipidus Thiazide Urine volume Distal tubular Na+ Distal delivery of Na+ & reabsorption water Urinary Proximal Na+ & excretion Water reabsorption Extracellular volume Side Effects Fluid and electrolyte imbalance Hypokalemia (Potassium supplementation or combination with a potassium-sparing diuretic may be required) Hyperuricemia (As an acute effect, it is due to the secretion of thiazides through the uric acid-bearing carrier (anionic carrier) in the renal tubules and thus reducing uric acid excretion by competition.) Hypomagnesemia Hypotension Hyponatremia Hypercalcemia Hyperglycemia (It is mainly due to decreased insulin secretion from the pancreas as a result of hypokalemia.)  V. POTASSIUM SPARING DIURETICS Potassium-sparing diuretics prevent K+ secretion by antagonizing the effects of aldosterone in collecting tubules. Potassium-sparing diuretics reduce Na+ absorption in the collecting tubules and ducts These drugs that increases diuresis without loss of potassium. They are generally weak diuretics and work by interfering with the sodium-potassium exchange (amiloride, triamterene) in the distal convoluted tubule of the kidneys or an antagonist at the aldosterone receptor (spironolactone, eplerenone). Aldosterone promotes the retention of sodium and water, so if potassium-sparing diuretics are used to block this effect, more sodium and water can pass into the collecting ducts of the kidneys, increasing diuresis Pharmacodynamics: urinary Na+ excretion urinary K+ excretion Hyperkalemia H+ excretion (acidosis)  V. POTASSIUM SPARING DIURETICS I. Spironolactone, Eplerenone, Finerenone (Aldosterone Antagonist) Effective in distal tubules and collecting canals. Natriuretic effect is not much. Spironolactone is a competitive antagonist of aldosterone receptors. Spironolactone binds with high affinity and potently inhibits the androgen receptor (side effects; gynecomastia and decreased libido) Eplerenone is a spironolactone analog with much greater selectivity for the mineralocorticoid receptor It is a preferred diuretic in heart failure and liver cirrhosis. In most edematous states, blood levels of aldosterone are high, causing retention of Na+. Spironolactone antagonizes the activity of aldosterone, resulting in retention of K+ and excretion of Na+.  V. POTASSIUM SPARING DIURETICS II. Triamterene, Amiloride (Na Channel Blockers) They directly interfere with Na+ entry through the epithelial Na+ channels in the apical membrane of the collecting tubule Block epithelial sodium channels, resulting in a decrease in Na+/K+ exchange Prevents sodium reabsorption. Diuretic effect is not much. Amiloride; The duration of action is longer than triamterene.  V. Potassium Sparing Diuretics Indications As adjunct (add-on) therapy to a regular (potassium-depleting) diuretic such as a thiazide or loop diuretic to correct for hypokalemia, in the treatment of: Hypertension Congestive heart failure Primary hyperaldosteronism (spironolactone) Edema Hypokalemia It is a preferred diuretic in heart failure and liver cirrhosis. Spironolactone is often used off-label for the treatment of polycystic ovary syndrome. It blocks androgen receptors and inhibits steroid synthesis at high doses, thereby helping to offset increased androgen levels seen in this disorder. Adverse effects: Hyperkalemia Hyponatremia Antiandrogenic effect (inhibits testosterone synthesis and binding to the receptor) Gynecomastia (Spironolactone) Weak anti-estrogenic effect (menstruation disorders, breast tenderness) Metabolic acidosis occurs; by inhibiting H+ secretion in parallel with K+ secretion, Contraindication Severe K+ abnormalities  SODIUM–GLUCOSE COTRANSPORTER 2 INHIBITORS CANAGLIFLOZIN / DAPAGLUFLOZIN / EMPAGLIFLOZIN In the normal individual, the proximal convoluted tubule reabsorbs almost all of the glucose filtered by the glomeruli. The sodium-glucose transporter 2 (SGLT2) accounts for 90% of renal glucose reabsorption. Directly target glucose; reducing renal reabsorption of glucose By inhibiting SGLT2, these agents decrease reabsorption of glucose, increase urinary glucose excretion, and lower blood glucose in patients with type 2 diabetes.  SODIUM–GLUCOSE COTRANSPORTER 2 INHIBITORS CANAGLIFLOZIN / DAPAGLUFLOZIN / EMPAGLIFLOZIN Inhibition of SGLT2 also decreases reabsorption of sodium and causes osmotic diuresis. Therefore, SGLT2 inhibitors may reduce systolic blood pressure. These agents are given once daily in the morning. Canagliflozin should be taken before the first meal of the day. The main adverse effects urinary tract infections genital infections (vulvovaginal candidiasis) Weight loss The osmotic diuresis can also cause intravascular volume contraction and hypotension. Decrease in bone mineral density; fractures  ANTIDIURETIC HORMONE (ADH, VASOPRESSIN) AGONIST Vasopressin / Desmopressin are used in the treatment of central diabetes insipidus. Their renal action appears to be mediated primarily via V2 ADH receptors, although V1a receptors may also be involved. It is a disorder of the posterior lobe of the pituitary gland characterized by a deficiency of ADH, or vasopressin. Great thirst (polydipsia) and large volumes of dilute urine characterize the disorder.  VAZOPRESSIN (ADH) ANTAGONISTS Hyponatremia affects 15-28 % of hospitalized patients with heart failure. Arginine vasopressin-AVP predominately mediates serum sodium and serum osmolality by increasing water retention in kidney (antidiuresis) V1a- V1b receptors (vascular smooth muscle cells, CNS)- V2 receptors (kidney) Antidiuretic hormone antagonists inhibit the effects of ADH in the collecting tubule. Conivaptan (currently available only for iv use) prevents arginine vasopressin (AVP) binding on both V1a and V2 receptors (treatment for hyponatremia) The oral agents tolvaptan, lixivaptan and satavaptan are selectively active against the V2 receptors. Conivaptan reduces water reabsorption, increases plasma Na concentration, vasodilation.  ADH ANTAGONISTS Tolvaptan Oral selective vasopressin V2 receptor antagonist Tolvaptan, which is approved by the FDA, is very effective in treatment of hyponatremia and as an adjunct to standard diuretic therapy in patients with CHF. Tolvaptan is effective in correcting hyponatremia in patients with heart failure, cirrhosis, or syndrome of inappropriate ADH Therapeutic applications of diuretics Treatment of hypertension: Thiazide diuretics used alone or in combination with beta-blockers at low-dose (fewer side effects) In presence of renal failure, loop diuretic is used. Edema States Thiazide diuretic is used in mild edema with normal renal function Loop diuretics are used in cases with impaired renal function. Congestive Heart failure Thiazides may be used in only mild cases with well-preserved renal function Loop diuretics are much preferred in severe cases especially when GF is lowered In life-threatening acute pulmonary edema, furosemide is given IV. Renal failure Thiazides are used till GFR ≥ 40-50 ml/min Loop diuretic are used below given values, with increasing the dose with as GFR goes down. Diabetes inspidus Large volume(>10 L/day) of dilute urine thiazide diuretics reduces urine volume Diuretics by their power Strong diuretics Furosemide, bumetanide Etacrynic acid Moderately Strong diuretics Thiazides Chlortalidone Weak diuretics Triamterene Aldosterone antagonists (spironolactone) Carbonic anhydrase inhibitors Osmotic diuretics  Effects Mechanism of Diuretics action ↑ Urinary Na HCO3, K Inhibition of NaHCO3 CA inhibitors Urinary alkalosis reabsorption in PCT Acetohexamide Dorzolamide Metabolic acidosis ↑Urine excretion Osmotic effect in PCT Osmotic diuretic ↑ Little Na Mannitol ↑Urinary Na, K, Ca, Mg Na/K/2Cl transporter Loop diuretics in TAL the most Furosemide effective ↑Urinary Na, K, Mg Na and Cl Thiazide diuretics BUT↓ urinary Ca (hypercalcemia) cotransporter in DCT hydrochlorothiazide Metabolic alkalosis ↑ Urinary Na competitive antagonist K-sparing diuretic ↓ K, H secretion of aldosterone in CCT.Spironolactone Metabolic acidosis  Uses Diuretics Glaucoma, epilepsy CA inhibitors Mountain sickness Acetohexamide Dorzolamide (topically) for Alkalosis glaucoma Phosphatemia Cerebral edema, glaucoma Osmotic diuretic Acute renal failure, drug toxicities Mannitol Acute pulmonary edema (Drug of choice) Loop diuretics Heart failure Furosemide Hyperkalemia, Hypercalcemia Commonly used Thiazide diuretics Hypertension, mild heart failure, hydrochlorothiazide nephrolithiasis, diabetes inspidus Hepatic cirrhosis K-sparing diuretic (Drug of choice).Spironolactone Side effects Diuretics Metabolic acidosis , Urinary alkalosis CA inhibitors Hypokalemia Acetohexamide Dorzolamide Extracellular water expansion Osmotic diuretic Dehydration Mannitol Hypernatremia Hypokalemia, Loop diuretics hypovolemia, hyponatremia, hypomagnesemia, hypocalcemia Furosemide Precipitate gout, alkalosis Hypokalemia, hyponatremia, hypovolemia, hypomagnesemia, Thiazide diuretics hypercalcemia Alkalosis, precipitate gout hydrochlorothiazide Hyperlipidemia, hyperglycemia Gynaecomastia K-sparing diuretic Hyperkalaemia, Metabolic acidosis..Spironolactone GIT upset and peptic ulcer THANK YOU…  FLUIDS AND ELECTRILYTE IMBALANCE To achieve homeostasis, the body maintains strict control of water and electrolyte distribution and of acid-base balance. This control is a function of the complex interplay of cellular membrane forces, specific organ activities and systemic and local hormone actionst Water constitutes an average 50 to 70% of the total body weight. Young males - 60% of total body weight Older males – 52% of total body weight Young females – 50% of total body weight Older females – 47% Variation of ±15% in both groups is normal. Obese have 25 to 30% less body water than lean people. Infants 75 to 80% - gradual physiological loss of body water. - 65% at one year of age.  FLUIDS AND ELECTROLYTE IMBALANCE Normally, there is a balance achieved between our total daily intake and output of water. Total fluid intake is modified by the induction of the sensation of thirst. This is produced by a reaction of cells in Hypothalamus to the increased osmotic pressure of the blood passing through this region. Another stimulus of thirst would be the degree of dryness of the oral mucosa.  Regulation of body water Any of the following: Decreased amount of water in body Increased amount of Na+ in the body Increased blood osmolality Decreased circulating blood volume Results in: Stimulation of osmoreceptors in hypothalamus Release of ADH from the posterior pituitary Increased thirst  Problems of Fluid Balance Deficient fluid volume Hypovolemia Dehydration Excess fluid volume; Hypervolemia Water intoxication Electrolyte imbalance Deficit or excess of one or more electrolytes Acid-base imbalance  Hypovolemia Hypovolemia; also known as volume depletion a state of low extracellular fluid volume, generally secondary to combined sodium and water loss. Causes It may result from renal losses (diuresis) or extrarenal losses (from the gastrointestinal tract (vomiting, diarrhea), burn, trauma, bleeding, fever, sepsis) Symptoms Hypotension, tachycardia, and dry oral membranes, along with laboratory findings, such as blood urea nitrogen, increased creatinine and urea, increased urine density, oliguria, and altered mental status.  Hypovolemia Crystalloid solution Dextrose 5%, isotonic 0.9%, balanced crystalloids, ringer lactate, mannitol 20% etc. are solutions Colloids Albumin, fresh frozen plasma, dextran, starch solution %0.9 NaCl sodium chloride, saline Isotonic solution of sodium chloride (0.9 g per 100 ml) for infusion This solution is used for correction of hypovolemia.  Hypovolemia Balanced solutions intravenous fluids having an electrolyte composition close to that of plasma. Ringer's solution The solution contains sodium chloride, potassium chloride, calcium chloride, and sodium bicarbonate in the concentrations in which they occur in body fluids If sodium lactate is used instead of sodium bicarbonate, the mixture is called lactated Ringer’s solution. This solution, given intravenously, is used to rapidly restore circulating blood volume in victims of burns and trauma. It is also used during surgery and in people with a wide variety of medical conditions.  Hyperhydration When too much water enters the body’s cells, water intoxication It may be due to excess intake or large volumes of salt free fluids, renal failure, overproduction of ADH Symptoms; Edema, hypertension, tac-hycardia, dyspnea, pulmonary edema, headache, lethargy, Treatment; stop water intake, diuretics, administration of hypertonic saline- in case of hyponatraemic hydration, i.v. 5%NaCl administration THANK YOU…