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Renal lecture 1 and 2 2017 18_jap

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This is the updated (2017-18) version of this lecture series, and it contains some additional and fairly recent information.

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Renal lecture 1 and 2 2017 18_jap

  1. 1. Drugs Acting on the Kidney (1 and 2) Professor John Peters E-mail j.a.peters@dundee.ac.uk
  2. 2. Learning Objectives Following this lecture, students should be able to:  Recall the range of drugs that act upon the kidney  Identify the major sites of diuretic action in the nephron  Describe in detail the mechanism of action of the loop diuretics  List the clinical uses and main adverse effects of the loop diuretics  Describe in detail the mechanism of action of the thiazide diuretics  List the clinical uses and main adverse effects of the thiazide diuretics  Explain why loop and thiazide diuretics cause hypokalaemia  Describe the mechanisms of action of the potassium sparing diuretics noting the distinct modes of action of aldosterone antagonists and blockers of the epithelial sodium channel, ENaC  Describe the clinical uses of the potassium sparing diuretics and their adverse effects  Recommended reading • Neal (2016). ‘Medical Pharmacology at a Glance (8th.ed.) Chapter 14 • Rang, Ritter, Flower and Henderson (2016). 'Rang and Dale's Pharmacology’ (8th. ed.). Chapter 29.
  3. 3. Drugs Acting on the Kidney Drugs acting on the kidney include Diuretics are the most commonly used agents that:  increase urine flow, normally by inhibiting the reabsorption of electrolytes (mainly sodium salts) at various sites in the nephron  Diuretics  Vasopressin (antidiuretic hormone; ADH) receptor agonists and antagonists  Uricosuric drugs (agents promoting excretion of uric acid into the urine)  are used to enhance excretion of salt and water in conditions where an increase in the volume of interstitial fluid (i.e. oedema) causes tissue swelling  Inhibitors of sodium-glucose co-transporter 2 (SGLT2)  Those used in renal failure  Those that alter the pH of the urine
  4. 4.  Formation of interstitial fluid is proportional to: (Pc – Pi) – (p - i)  Disease states that increase Pc or decrease p and produce oedema include: • the nephrotic syndrome Oedema  results from an imbalance between the rate of formation and absorption of interstitial fluid Pc p Pi i Capillary Interstitial fluid • hepatic cirrhosis with ascites • congestive heart failure
  5. 5. Diseases Associated With Oedema Responding to Diuretic Drug Therapy The Nephrotic Syndrome  Involves a disorder of glomerular filtration, allowing protein (largely albumin) to appear in the filtrate (proteinuria) Decreased p formation of interstitial fluid blood volume  cardiac output Oedema Activation of the RAAS Na+ and H20 retention Pc, p
  6. 6. Congestive Heart Failure  Arises from reduced cardiac output. Subsequent renal hypoperfusion activates the renin- angiotensin system  Expansion of blood volume contributes to increased venous and capillary pressures which, combined with reduced p, causes pulmonary and peripheral oedema Hepatic Cirrhosis With Ascites  Increased pressure in the hepatic portal vein, combined with decreased production of albumin, causes loss of fluid into the peritoneal cavity and oedema (ascites)  Activation of the renin-angiotensin system occurs in response to decreased circulating volume Oedema fluid mobilization by diuretics. Note that collapse and danger of thrombosis only occur if massive use of diuretics is employed). From Lüllmann et al. (2000) Color Atlas of Pharmacology
  7. 7. Sodium Reabsorption and the Major Sites of Diuretic Action in the Nephron Proximal convoluted tubule 1. Na+ (passive Cl- absorption) 2. Na+/H+ exchange (blocked by carbonic anhydrase inhibitors) Thick ascending limb of the loop of Henle 3. Na+/K+/2Cl- co-transport (blocked by loop diuretics) Distal convoluted tubule 4. Na+/H+ exchange (blocked by carbonic anhydrase inhibitors) 5. Na+/Cl- co-transport (blocked by thiazide diuretics) Collecting tubule 6. Na+/K+ exchange (blocked by potassium-sparing diuretics) 1 2 3 4 5 6
  8. 8. Diuretics – General Aspects  A very large proportion of NaCl and H2O that passes into the filtrate via the glomerulus is reabsorbed – hence even a small inhibition of reuptake can cause a marked increase in Na+ excretion  The site of action of many diuretics (thiazides, loop agents, potassium sparing) is the apical membrane of tubular cells hence, if hydrophilic, they must enter the filtrate to access that site  Entry to the filtrate is by either: o glomerular filtration (for drug not bound to plasma protein) o secretion via transport process in the proximal tubule o two transport systems are important • the organic anion transporters (OATs) – transport acidic drugs (e.g. thiazides and loop agents) • the organic cation transporters (OCTs) – transport basic drugs (e.g. triamterene and amiloride) o secretion results in the concentration of diuretic in the filtrate being higher than that in blood, contributing to pharmacological selectivity
  9. 9. Secretion of Diuretics in the Proximal Tubule  Organic anion transporters (OATs) o At the basolateral membrane organic anions (OA-) enter cell by either diffusion, or in exchange for α-ketoglutarate (α-KG) via OATs o α-KG is transported into cell (against a concentration gradient) via a Na+- dicarboxylate transporter o At the apical membrane, OA- enters the lumen via either multidrug resistance protein 2 (MRP2), or OAT4 (in exchange for α-KG)  Organic cation transporters (OCTs) o At the basolateral membrane organic cations (OC+) enter the cell either by diffusion, or OCT, (both driven by negative potential of cell interior and against a concentration gradient) o At the apical membrane, OC+ enters the lumen via either multidrug resistance protein 1 (MRP1), or OC+/H+ antiporters (OCTN)
  10. 10. Mechanism of Action of Loop Diuretics Na+ Na+ Na+ K+K+ K+ K+ Cl-2Cl- Cl- Zona occludens +ve -ve4-10 mV Lumen Interstitium Mg2+ Ca2+ Mg2+ Ca2+ Loop diuretics block Maintainhightonicity ofthemedulla Tubular epithelium of the TAL Triple transporter (Na+/K+/2Cl- co- transporter; NKCC2) K+/Cl- co-transporter Na+/K+ ATPase Key K channel (ROMK) Cl channel TAL = thick ascending limb of the loop of Henlé
  11. 11. Pharmacodynamics  Inhibit the Na+/K+/2Cl- carrier by binding to the Cl- site and thus: Loop Diuretics (1) Principal drugs: Furosemide and Bumetanide  Possess an additional, indirect, venodilator action (before diuresis) that is beneficial in pulmonary oedema cause by heart failure– possibly results from: 1) increased formation of vasodilating prostaglandins; 2) decreased responsiveness to angiotensin II and noradrenaline; 3) opening of K+ channels in resistance vessels o increase the load of Na+ delivered to distal regions of the nephron (causing K+ loss) o decrease the tonicity of the interstitium of the medulla o prevent dilution of the filtrate in the thick ascending limb o increase excretion of Ca2+ and Mg2+  Are ‘high ceiling’ agents causing 15-25% of filtered load of Na+ to be excreted – rapid onset following IV administration
  12. 12. Loop Diuretics (2) To treat hypertension (in patients resistant to other diuretics or anti- hypertensive drugs - usually in the presence of renal insufficiency) To reduce acutely elevated calcium levels in the serum (hypercalcaemia) - note paracellular pathway in the thick ascending limb of the loop of Henle To increase urine volume in acute kidney failure Clinical indications To reduce salt and water overload associated with: Acute pulmonary oedema (IV) Chronic heart failure Chronic kidney failure Nephrotic syndrome Hepatic cirrhosis with ascites Pharmacokinetics Well absorbed from the G.I. tract Strongly bound to plasma protein Enter nephron by the organic anion transport mechanism
  13. 13. Loop Diuretics (3)  Potassium loss producing low serum potassium levels (hypokalaemia) – corrected by the concomitant use of potassium sparing diuretics or potassium supplements (note increases toxicity of digoxin and Class III antidysrhythmic drugs)  Increased plasma uric acid (hyperuricaemia) – partially explained by competition between uric acid and loop agents for the organic acid secretory mechanism in the proximal tubule  Depletion of calcium and magnesium (paracellular pathway)  Decreased volume of circulating fluid (hypovolaemia) and hypotension (particularly in the elderly)  Shift in acid-base towards alkaline side (metabolic alkalosis) – caused by increased H+ secretion from intercalated cells in collecting tubule Adverse effects
  14. 14. Mechanism of Action of Thiazide Diuretics Na+ Na+ Na+ + K+ K+ Cl- Cl- Cl- Zona occludens Lumen Interstitium Thiazide diuretics block Tubular epithelium of the early distal tubule Na+/Cl- co-transporter K+/Cl- co-transporter Na+/K+ ATPase Key Cl- channel K+ channel K+ K+
  15. 15. Pharmacodynamics  Inhibit the Na+/Cl- carrier by binding to the Cl- site and thus:  Cause up to 5% of Na+ to be excreted, producing a modest diuresis  Possess an additional, indirect, vasodilator action (mechanism uncertain) that contributes to their effectiveness in the treatment of hypertension (where they are used in combination with other antihypertensive agents) Thiazide Diuretics and Thiazide-Like (1) Principal drugs: Bendroflumethiazide (thiazide): indapamide and chlortalidone (thiazide-like) o prevent the dilution of filtrate in the early distal tubule o increase the load of Na+ delivered to the collecting tubule (causing K+ loss) o increase reabsorption of Ca2+ (cf. loop agents) (mechanism debatable)
  16. 16. Thiazide Diuretics (2)  Nephrogenic diabetes insipidus [caused by diminished vasopressin responsiveness of the collecting ducts (paradoxically, thiazides decrease the volume of urine – mechanism poorly understood]  Renal stone disease (nephrolithiasis). Reduced urinary excretion of Ca2+ discourages Ca2+ stone formation (mainly aggregates of particles of calcium oxalate)  Severe resistant oedema (with a loop agent) …and additionally in: Clinical indications Widely used in:  Mild heart failure  Hypertension Pharmacokinetics  Well absorbed from the G.I. tract  Enter nephron by the organic anion transport mechanism (proximal tubule)
  17. 17. Thiazide Diuretics (3) Adverse effects  Male sexual dysfunction  Hyperuricaemia – mechanism as for loop agents – may precipitate gout  Metabolic alkalosis  Depletion of magnesium (not calcium)  Hypovolaemia and hypotension (particularly in the elderly)  Hypokalaemia, particularly likely and corrected as for loop diuretics  Impaired glucose tolerance
  18. 18. Mechanism by which Loop and Thiazide Diuretics Cause Potassium Loss – Relevant Physiology Aldosterone, a steroid hormone, acts via cytoplasmic receptors to: 1. increase synthesis of the Na+/K+ATPase 2. increase synthesis of a protein that activates the epithelial Na+ channel (ENaC) increase the number of H2O channels (aquaporins) in the cell membrane ADH (vasopressin), a peptide hormone, acts via G-protein coupled receptors to: Na+ Na+ K+ K+ Zona occludens Lumen Interstitium Late distal and collecting tubule H2O Cl- Cl- H2O Na+ K+ K+ Channels (ROMK), secrete K+ into the urine in the collecting tubule Note that K+ effectively exchanges for reabsorbed Na+
  19. 19. Mechanism by which Loop and Thiazide Diuretics Cause Potassium Loss Na+ Na+ K+ K+ Zona occludens Lumen Interstitium Late distal and collecting tubule H2O Cl- Cl- H2O Na+ K+ 1. Increased Na+ load caused by loop or thiazide diuretic produces enhanced reabsorption of Na+  2. Resulting charge separation makes lumen more negative and depolarizes the lumenal vs. basolateral membrane -ve 3. Increased driving force on K+ across the lumenal membrane leads to enhanced secretion of K+. (Secretion of H+ is similarly affected)  4. Secreted K+ (and H+) ‘washed away’ by increased urinary flow rate – development of hypokalaemia (and metabolic alkalosis)
  20. 20. Mechanism of Action of the Potassium Sparing Diuretics Spironolactone and Eplerenone Compete with aldosterone for binding to intracellular receptors causing: 1. decreased gene expression and reduced synthesis of a protein mediator that activates Na+ channels in the apical membrane (site 1) 2. decreased numbers of Na+/K+ATPase pumps in the basolateral membrane (site 2) Amiloride and Triamterene Block the apical sodium channel decrease Na reabsorption Na+ Na+ K+ K+ Zona occludens Lumen Interstitium Late distal and collecting tubule H2O Cl- Cl- H2O Na+ K+ X site 1 site 2
  21. 21. Potassium Sparing Diuretics Spironolactone and eplerenone Have limited diuretic action (modulated by aldosterone levels) Competitively antagonise the action of aldosterone at cytoplasmic aldosterone receptors, gain access to cytoplasm via the basolateral membrane Increase and decrease the excretion of Na+ and K+ respectively Are well absorbed from the G.I. tract and in the case of spironolactone rapidly metabolised to canrenone (which accounts for most of the action of the drug) Amiloride and Triamterene Block lumenal sodium channels in the collecting tubules. Effect on ion fluxes are similar to those of spironolactone Enter the nephron via the organic cation transport system in the proximal tubule Triamterene is well absorbed from the G.I tract, absorption of amiloride is poor
  22. 22. Clinical indications  The major use of potassium sparing diuretics is in conjunction with other agents that cause potassium loss. Given alone, they cause hyperkalaemia  Aldosterone antagonists are used in the treatment of: o heart failure o primary hyperaldosteronism (Conn’s syndrome) o resistant essential hypertension o secondary hyperaldosteronism (due to hepatic cirrhosis with ascites)  Thiazide and loop diuretics activate the renin-angiotensin- aldosterone system (in response to reduced blood pressure) Aldosterone antagonists potentiate the actions of thiazide and loop agents by blocking the effect of aldosterone

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