Diuretics PDF

DIURETICS by Dr Iribhogbe Osede Ignis (Ass. Prof) MBBS, MPH, PhD, Cert. Clin. Pharm  Highlights Introduction Classification Transport Mechanisms of the Nephron/Site of Action of Diuretics Pharmacology of Specific Agents Conclusion  Intro...

DIURETICS by Dr Iribhogbe Osede Ignis (Ass. Prof) MBBS, MPH, PhD, Cert. Clin. Pharm  Highlights Introduction Classification Transport Mechanisms of the Nephron/Site of Action of Diuretics Pharmacology of Specific Agents Conclusion  Introduction Diuretics are agents used to increase the renal excretion of salt and water by increasing urinary outflow and decreasing ECF volume In other words they are used to induce diuresis in patients  Classification Classified into: Osmotic diuretics e.g. Mannitol, inulin Carbonic anhydrase inhibitors: e.g. acetazolamide, dorsolamide, and brinzolamide Loop diuretics: e.g. bumetanide, furosemide, torsemide, and ethacrynic acid Thiazide and Thiazide-like diuretics: e.g. bendroflumethiazide, benzothiazide, hydrochlorothiazide, chlorthalidone, indapamide, and metolazone  CONTD Potassium-sparing diuretics: sub-classified into: (a) Agents that directly antagonize mineralocorticoid receptors e.g. spironolactone, eplerenone (b)Inhibitors of sodium ion transport channels in the luminal epithelial membrane e.g. triamterene and amiloride (c) Agents that suppress renin or angiotensin II action: ACE inhibitors such as lisinopril, fosinopril, and captopril  CONTD Angiotensin receptor blockers e.g. losartan, valsartan, and remisartan Other agents that inhibit the RAAS pathway include β- blockers and the NSAIDS ADH antagonists e.g. lithium, and demeclocyclin  Transport Mechanism/Site of Action of Diuretics To understand the MOAs of Diuretics a base line understanding of the physiological function and the electrolyte transport mechanisms of the nephron is required The Bowman’s capsule: responsible for ultrafiltration Urine is formed after the process of ultra-filtration, secretion, and reabsorption of substances from other segments of the nephron The Nephron  CONTD PCT: Electrolytes such as NaHCO3- (85%), Nacl (40%) glucose, amino acid and other organic solutes are preferably absorbed in the early segment of the PCT H2O (60%) reabsorption occurs passively to maintain osmolality of proximal tubular fluid NaHCO3- reabsorption by the proximal tubule is initiated by the action of a Na+/H+ exchanger in the luminal membrane of the proximal tubule epithelial cell This allows for one-for-one exchange of Na with a proton (H+) from inside the cell  CONTD Na+/K+ ATPase in the basolateral membrane of the PCT pumps the reabsorbed Na+ into the interstitium to keep the intracellular concentration low Carbonic acid is formed in the lumen from H+ and HCO3- The Na2HCO3 dissociates into CO2 and H2O via the action of carbonic anhydrase (CA) Na2HCO3 reabsorption in the PCT, thus, depends on the activity of CA Osmolality of the tubular fluid and its Na conc is maintained in the PCT by tubular membrane permeability to H2O  CONTD Glucose, mannitol and inulin are impermeable solute, hence, H20 reabsorption in the PCT cause increased conc of the solute and increased tubular fluid osmolality thereby inhibiting further H20 reabsorption and increasing H20 excretion Loop of Henle: The thin limb is involved in the reabsorption of H20 via an osmotic gradient generated by the medullary interstitium Osmotic diuretics further drive the excretion of H20 in this segment  CONTD The thick limb is impermeable to H20, but absorbs 35 % of Na+ cl via a Na+/K+/2Cl- co-transporter in the luminal membrane This transporter is selectively blocked by the loop diuretics The luminal positive potential created by this transporter provides the driving force for the reabsorption of divalent cations such as Mg2+ and Ca2+ via the paracellular pathway  CONTD DCT: Responsible for the absorption of 10% of Na+ and Cl- load via the Na+/Cl- co-transporter and it is impermeable to water causing dilution of the tubular fluid The transporter can be blocked by the thiazide diuretics, however, there is no lumen positive potential to drive the reabsorption of Ca2+ and Mg2+ ion CT: Acts as the major site of K+ secretion and final site for determining urinary Na+ conc (5-10% of Na+ & Cl are reabsorbed) via the Na+/H+ & Na+/K+ exchanger regulated by mineralocorticoids and urinary Na+ conc  RAAS Pathway RAAS is activated via low plasma Na+ conc and via sympathetic stimulation Renin is secreted from the JGA resulting in the conversion of angiotensinogen to AG 1 which is converted to AG II by ACE AG II is a potent vasoconstrictor and also stimulates the release of aldosterone Aldosterone causes increased Nacl & H20 reabsorption in the DCT, stimulates Na+/k+ exchange and increase H+ secretion in the PCT resulting in hypokalemia & metabolic alkalosis  Pharmacology of Specific Agents Mannitol: PK: available essentially as an IV agent MoA: filtered by the glomerulus and retained within the proximal tubules, thereby, increasing the osmolality of tubular fluids, decreasing reabsorption of water relative to sodium Clinical Uses: Acute reduction of ICP in patients with head injury and also for the reduction of IOP in glaucoma patients  CONTD It is used to increase urine flow in case of acute renal failure Dilute toxic substances in urine Adverse effects: Dehydration and fluid overload in patients with impaired glomerular function  CONTD Acetazolamide MoA: It inhibits CA and reduces the production and reabsorption of HCO3- from the PCT The depletion of plasma HCO3- limits the diuretic action of the drug and limits their use as diuretic agents Clinical Uses: it reduces aqueous humor formation and decreases IOP, hence, is used for the treatment of glaucoma  CONTD used for the treatment of acute mountain sickness and metabolic alkalosis Adverse effects: drowsiness, metabolic acidosis kidney stone formation and paraesthesia It is contraindicated in patients with liver cirrhosis  CONTD Loop Diuretics: They are called high ceiling diuretic because of their rapid and potent diuretic action and are the most effective natriuretic and diuretic agents MoA: act in the thick segment of the ascending Loop of Henle were it inhibits the Na+/K+/2Cl- co-transporter This results in the inhibition of Cl- ion absorption in the tubular lumen as well as an increase in Na+, K+, and Ca+ excretion and increase in the excreted urine volume  CONTD Clinical Uses: used in the Px of: CCF Pulmonary oedema from left ventricular failure Acute oliguria Hypertension Hypercalcemia Adverse effects: Hyperglycemia, Allergic reaction, Hypokalemia, Hypomagnesemia, Hypocalcemia, Hyperuricemia Dehydration  CONTD Thiazide diuretics: MoA: act in the DCT were it inhibits the Na+/Cl- co- transporter, thus, preventing Na+ reabsorption Decreases Ca+ excretion in the urine Also act as weak inhibitors of CA and cause a small increase in urinary pH Clinical Uses: Used in the treatment of kidney stones Used in combination with other antihypertensive drugs in the treatment of Hypertension  CONTD Adverse Effects: Hyperuricemia Acute renal failure Hypokalemic alkalosis Hyperglycemia due to glucose intolerance Hypercholesterolemia Spironolactone: MoA: It’s a direct antagonist to aldosterone, thereby, inhibiting the synthesis of tubular Na+ channel protein and Na+/K+ ATPase which are involved in Na+, Cl- and water reabsorption.  CONTD Clinical Uses: Used in combination with other antihypertensives in the treatment of hypertension Can be used as replacement for thiazides in hypertensive patients with glucose intolerance, hyperuricemia and hypokalemia Can be used in the treatment of primary aldosteronism Adverse Effects: Diarrhea, nausea, and vomiting  CONTD Headaches, confusion, and somnolence Hyperkalemia Gynaecomastia Triamterene & Amiloride: MoA: inhibits Na+ transport across Na+ channels in the distal convoluted tubule epithelial membrane Clinical Uses: Has weak diuretic action and are used in combination with other antihypertensives in the treatment of hypertension  CONTD The drugs can be co-administered with thiazides to prevent hypokalemia Adverse Effects: Hyperkalemia ADH/ADH Antagonist ADH (vasopressin) is a nanopeptide synthesized in the hypothalamus and released via the posteriot pitiutary gland Desmopressin is a synthetic analog of vasopressin MoA: it acts via stimulating the V1 and V2 receptors present in blood vessels and in the kidneys  CONTD V1 receptor stimulation causes vasoconstriction while V2 receptor stimulation increases water reabsorption in the collecting duct of the renal tubule via a cAMP-dependent pathway Clinical uses: It is used in the Px of neurogenic diabetes insipidus Also used in the Px of nocturnal enuresis in both children and adults Used as an adjunct in hemophilia treatment due to its ability to increase circulatory levels of clotting factor VIII  CONTD Adverse effects: Vasoconstriction Smooth muscle cramps Water intoxication due to fluid overload Hyponatremia Demeclocycline and Lithium carbonate are ADH antagonist, hence, they block the renal action of ADH, resulting in increased urine volume The drugs can be used in the treatment of syndrome of inappropriate ADH secretion (SIADH)  CONCLUSION We have been able to highlight the different classes of diuretic agents, their site of action in the nephron, mechanisms of action and their clinical uses Having a full grasp of the pharmacology of these agents will be of immense benefit in your clinical practice Thank You