Renal Pharmacology (Diuretics) Pharm 382 2024 PDF

Pharm 382 SYSTEMS PHARMACOLOGY I Kwame Nkrumah University of CARDIOVASCULAR AND RENAL PHARMACOLOGY (2024) Science & Technology, Kumasi, Ghana Renal Pharmacology (Diuretics)...

Pharm 382 SYSTEMS PHARMACOLOGY I Kwame Nkrumah University of CARDIOVASCULAR AND RENAL PHARMACOLOGY (2024) Science & Technology, Kumasi, Ghana Renal Pharmacology (Diuretics) Eric Boakye-Gyasi, PhD, B.Pharm Associate professor DEPT. OF PHARMACOLOGY, FPPS, CoHS, KNUST Email: [email protected] [email protected] www.knust.edu.gh www.knust.ed u.gh  Objectives ▪At the end of this class, students should be able to: 1. Give an overview of the features of fluid balance and renal function that are essential to understanding diuretic action 2. Give a detailed description of the various classes of diuretics 3. Explain how to solve the problem of drug-induced hypokalemia 4. Explain causes and management of diuretic resistance 5. Explain the role and classes of diuretics indicated in specific disease conditions www.knust.edu.gh www.knust.ed u.gh  Introduction ▪The term diuretic defines an agent that increases the rate of urine flow via inhibition of electrolyte reabsorption in the kidney oThe primary effect of diuretics is an increase in solute excretion, mainly Na+ salts oThe increase in urine flow is secondary and is a response to the osmotic force of the additional solute within the renal tubule lumen ▪Drugs that increase the net urinary excretion of Na+ salts are called natriuretic ▪ Diuretic therapy provides welcome relief from o pulmonary congestion o Ascites o Edema o hypertension www.knust.edu.gh 7/15/2024 www.knust.ed 3 u.gh A nephron, showing the major sites and percentage (in braces) of sodium absorption along with other features of solute transport 7/15/2024 5 Carbonic Anhydrase Inhibitors (CAIs) Carbonic Anhydrase Inhibitors ▪Acetazolamide (Diamox) ▪Dichlorphenamide (Daranide) ▪Methazolamide (Neptazane) ▪Brinzolamide ▪Dorzolamide MOA ▪Inhibition of proximal tubule brush border carbonic anhydrase decreases bicarbonate reabsorption, and this accounts for their diuretic effect ▪In addition, carbonic anhydrase inhibitors affect both distal tubule and collecting duct H secretion by inhibiting intracellular carbonic anhydrase ▪Na+/H+ antiporter, which is a protein with a hydrophilic C-terminal domain is subject to regulation by a variety of factors, including angiotensin II, which increases its activity  Carbonic Anhydrase Inhibitors ▪Carbonic anhydrase inhibition increases renal excretion of Na, K, and HCO3 ▪Diuresis following carbonic anhydrase inhibition consists primarily of Na and HCO3 with only a small increase of Cl excretion - bicarbonate diuresis ▪Diuresis is self-limiting within 2–3 days oAs a result of HCO3 depletion, NaHCO3 excretion slows—even with continued diuretic administration ▪The fractional excretion of Na is generally limited to 5% obecause of downstream compensatory Na reabsorption oAlthough distal nephron sites recapture much of the Na, they possess only a limited ability to absorb HCO3 ▪Potassium loss is particularly marked (~70%) following carbonic anhydrase inhibition, because of othe presence of poorly reabsorbable HCO3 accompanying Na othe inhibition of the Na–H exchange mechanism oin part secondary to increased delivery of Na+ to the distal nephron ▪Elevated urinary HCO3 excretion leads to the formation of alkaline urine and to metabolic acidosis because of both HCO3 loss and impaired H secretion  CAIs - Uses 1. Main therapeutic use of CA is NOT to produce diuresis but in the treatment of glaucoma –This is true especially of the topically applied compound dorzolamide (Trusopt) 2. Acetazolamide has been used in the treatment of epilepsy, particularly absence epilepsy –it is not known whether the beneficial results are due to carbonic anhydrase inhibition or to the resulting acidosis 3. Oral CA inhibitors are also useful in preventing or treating acute mountain sickness – acidosis of CSF 4. Alkalization of the urine – e.g., in cysteinuria (excretion facilitation) 5. To restore acid–base balance in heart failure patients with metabolic alkalosis due to treatment with loop diuretics  CAIs – Adverse Effects ▪Hyperchloremic metabolic acidosis oPredictable loses of the HCO3- stores is also a limitation for both long term safety and efficacy of the treatment ▪Potassium wasting resulting into the hypokalaemia ▪Alkalization of the urine may cause precipitation of calcium salts and formation of renal stones ▪May lead to development of hepatic encephalopathy in patients with hepatic impairment ▪sulfonamide sensitivity (contra-indicated if history of sulfonamide hypersensitivity) ▪loss of appetite, Drowsiness, Confusion, ▪tingling in the extremities (paresthesia) Thiazide Diuretics  Thiazide Diuretics ▪2 distinct groups: othose containing a benzothiadiazine ring, such as hydrochlorothiazide and chlorothiazide, referred to as thiazide diuretics othose that lack this heterocyclic structure but contain an unsubstituted sulfonamide group including metolazone, xipamide, and indapamide – thiazide-like diuretics www.knust.edu.gh 7/15/2024 www.knust.ed 13 u.gh  Thiazide Diuretics - Mechanism of Action ▪Act in the distal convoluted tubule, where they block Na–Cl co- transport oNa–Cl co transport takes place on the luminal surface of DCT oThiazide diuretics are largely bound to plasma proteins and therefore are not readily filtered across the glomeruli oAccess to the luminal fluid is accomplished by the proximal tubule organic acid secretory system oThe drugs then travel along the nephron, presumably being concentrated as fluid is abstracted, until they reach their site of inhibitory action in the DCT oEspecially at higher doses, administration of some of the thiazides results in some degree of CA inhibition. However, at usual doses, only chlorothiazide shows any appreciable carbonic anhydrase inhibitory activity www.knust.edu.gh www.knust.ed u.gh  Thiazide Diuretics - Mechanism of Action ▪At usual clinical doses, thiazide diuretics generally increase excretion of Na and Cl, with an accompanying loss of K and not NaHCO3 oThe urinary K wasting induced by the thiazides is primarily a consequence of the increased Na delivered to the collecting duct Genetic loss of function of NCC underlies Gitelman syndrome, which is characterized by salt wasting much milder than that with Bartter syndrome www.knust.edu.gh www.knust.ed u.gh Two renal responses are unique to the thiazide and thiazidelike diuretics 1. Decrease Ca2+ excretion (Hypocalcuria/hypercalcemia) – Directly by increasing the activity of the Na+/Ca2+ antiporter on the basolateral membrane to transport more Ca2+ into the interstitium – indirectly because of a compensatory elevation of proximal solute absorption – useful in treating hypercalciuria and particularly beneficial in individuals who are prone to calcium stone formation – They also increase bone mineral density and reduces fracture rates attributable to osteoporosis 7/15/2024 16 2. They are use in treating nephrogenic diabetes insipidus – Patients who have an adequate supply of ADH but whose kidneys fail to respond to ADH excrete large volumes of very dilute urine – The thiazides reduce glomerular filtration modestly and decrease positive free water formation, that is, production of dilute urine – hence reduce the ability of the kidney to excrete hypotonic urine (i.e., they reduce free water clearance) – HCTZ can be used to create mild hypovolemia which encourages salt and water uptake in proximal tubule and thus improve nephrogenic diabetes insipidus 7/15/2024 17 Thiazides have antihypertensive properties ▪The initial hypotensive response is mediated by a modest reduction in plasma volume and cardiac output oHowever, the fall in BP is blunted by hypovolemia-induced activation of the renin-angiotensin system ▪However, after chronic use they cause a reduction in BP by lowering peripheral resistance omay open Ca2+-activated ATP dependent K+ channels, leading to hyperpolarization of vascular smooth muscle cells, decreased Ca2+ entry and ultimately reduced vasoconstriction (explains exacerbation of diabetes as well) ▪The effectiveness of thiazides as diuretics or antihypertensive agents diminishes progressively when the glomerular filtration rate is