71. Pharmacology - Renal Pharmacology

Renal Pharmacology 1 & 2 - Learning Objectives

• Identify different classes of drugs that modify kidney function, and apply knowledge of their mechanisms of action to understand normal kidney function.
• Identify different classes of diuretic agents and their actions on specific nephron segments.
• Differentiate diuretic classes based on cellular site of action, mechanisms, effects on sodium, volume, and acid-base balance.
• Distinguish potassium-sparing from potassium-wasting diuretics and their uses.
• Describe drugs used to alter fluid balance.
• Identify targets in the renin-angiotensin-aldosterone system that affect renal function.
• Evaluate potential side effects of NSAIDs on kidney function.
• Explain the use of drugs stimulating mitochondrial biogenesis in kidneys and their impact on kidney function.

Renal Pharmacology 1 & 2 - Lecture Outline

• Introduction
• Diuretics
  • Overview: Formation of urine, diuretic action sites.
  • Proximal tubule: Carbonic anhydrase inhibitors, osmotic diuretics.
  • Loop of Henle: Loop diuretics, NKCC2.
  • Distal convoluted tubule: Thiazides, NCC, Ca2+ reabsorption.
  • Collecting tubule system:Aldosterone, ENaC, and ADH.
• Potassium-wasting and potassium-sparing diuretics.
• Drugs that alter water balance: ADH agonists and antagonists.
• Drugs targeting the renin-angiotensin system (RAS).
• Effects of NSAIDs on renal function.
• Pharmacologic agents that modulate mitochondrial biogenesis.
• Summary

Renal Pharmacology 1 & 2 - Question 1

• Pharmacologic agents can be investigative tools to understand normal physiological function.
• Specific proteins are sometimes only studied through inhibition of their activity.
• Genetic mutations in proteins can markedly alter their activity e.g., Polycystins in ADPKD.

Renal Pharmacology 1 & 2 - Question 2

• Repetition of learning about drugs is useful, as the mechanisms of action in various nephron segments will be later applied to understand disease processes in the M2 curriculum.
• Example: Diuretics, drugs targeting the RAAS, Vaptans (used for hypertension).
• Drugs that modulate mitochondrial biogenesis are used to treat acute and chronic kidney injury.

Renal Pharmacology 1 & 2 - Diuretics A. Overview

• Diuretics are drugs that increase urine volume.
• Natriuretics cause increased renal sodium excretion.
• Aquaretics increase excretion of solute-free water.
• Osmotic diuretics and ADH antagonists are aquaretics, but not directly natriuretic.
• More recently, urea transport blockers have been developed, increasing urea excretion but not electrolyte excretion.

Renal Pharmacology 1 & 2 - Sites of Action of major diuretic agents

• Carbonic anhydrase inhibitors (PCT).
• Osmotic agents (PCT, thin descending limb, CD).
• Loop agents (TAL).
• Thiazides (DCT).
• Aldosterone antagonists (CT).
• ADH antagonists (CD).
• Adenosine (Glomerulus, PCT, TAL, CD).

Renal Pharmacology 1 & 2 - Major Segments of the Nephron and their functions (Table 1)

• Lists nephron segment functions, water permeability, drug targets, and major actions
• Includes glomerulus, proximal convoluted tubule (PCT), proximal straight tubules, thin descending limb, thick ascending limb, thin limb of Henle's loop, distal convoluted tubule, cortical collecting tubule, medullary collecting duct.

Renal Pharmacology 1 & 2 - Hydrochlorothiazide and related agents (Figure 6)

• Thiazides were researched as carbonic anhydrase inhibitors but are now primarily known for inhibiting NaCl transport in the DCT, not NaHCO3.
• Still retain some carbonic anhydrase inhibitory activity.
• All thiazides have an unsubstituted sulfonamide group.

Renal Pharmacology 1 & 2 - Collecting Tubule System: Aldosterone, ENaC, and ADH

• Principal cells are the major sites of Na+, K+, and water transport in the collecting tubule system.
• Intercalated cells (α and β subtypes) are the main sites for H+ or HCO3- secretion, respectively.
• H+-ATPase and Cl-/HCO3- exchangers have reversed membrane localizations in α and β intercalated cells, respectively.

Renal Pharmacology 1 & 2 - Potassium-wasting and Potassium-sparing Diuretics

• Loop diuretics and Thiazides cause K+ loss (hypokalemia).
• ENaC inhibitors (e.g., Amiloride, Triamterene) and aldosterone antagonists (e.g., Spironolactone) help conserve K+.
• Amiloride and Triamterene are direct Na+ influx inhibitors in the cortical collecting tubule.

Renal Pharmacology 1 & 2 - Drugs that alter water balance: ADH agonists and antagonists

• ADH (arginine vasopressin) agonists are often used in diabetes insipidus and enhance ADH function.
• ADH antagonists are used in syndromes of inappropriate ADH secretion, or situations needing reduced ADH effects;
  • Examples are Lithium and Demeclocycline.
  • More recent drugs are Vaptans (e.g., Tolvaptan, Satavaptan, Lixivaptan, Mozavaptan)

Renal Pharmacology 1 & 2 - Effects of NSAIDs on renal function

• NSAIDs inhibit COX-1 and/or COX-2, which reduces prostaglandin production.
• Reduced prostaglandins can lead to ischemia, glomerular filtration decline, and acute kidney injury (AKI).
• NSAID use with reduced eGFR may increase risk of AKI.

Renal Pharmacology 1 & 2 - Pharmacologic agents that modulate mitochondrial biogenesis

• Sirtuins (SIRT1 or SIRT3) activators are commonly used to improve kidney function.
• These agents are found in both natural compounds (e.g., resveratrol) and synthetic derivatives.
• SIRT activators improve renal function by reducing apoptosis and preserving mitochondrial function.

Renal Pharmacology 1 & 2 - Summary of key diuretic agents

• Summary of different diuretic classes, mechanism of action, and effects.
• Includes carbonic anhydrase inhibitors, loop diuretics, thiazides, potassium-sparing diuretics, osmotic diuretics and vasopressin antagonists.

This quiz tests your knowledge of the pharmacology related to diuretics and their effects on kidney function. It covers various classes of diuretics, the renin-angiotensin system, and the mechanisms through which these drugs operate. Perfect for students studying renal pharmacology or related medical fields.