Drugs and Renal Transport Systems PDF

Drugs and membrane transporters: Renal transport systems Stephen Kelley, PhD, FHEA, FBPhS Senior Lecturer in Pharmacology [email protected] 1  Learning Objectives After this lecture and personal study, students should b...

Drugs and membrane transporters: Renal transport systems Stephen Kelley, PhD, FHEA, FBPhS Senior Lecturer in Pharmacology [email protected] 1  Learning Objectives After this lecture and personal study, students should be able to have reached the following:  Know the site of action, understand the mechanism of action and side effects for loop diuretics  Know the site of action, understand the mechanism of action and side effects for thiazide diuretics  Know the site of action, understand the mechanism of action and side effects for the potassium-sparing diuretics Further reading: o Medical Physiology, 3rd Edition, Chapter 35, Transport of Sodium and Chloride, pp 1111-1116. o Rang and Dale’s Pharmacology, 10th edition, Chapter 29, The Kidney and Urinary System, pp 402-412. Where do these diuretics act? Osmoti c diuretic s Osmoti c Osmoti diuretic c s diuretic s Site and mechanism of action Diuretic Site of action Mechanism of action Osmotic diuretics Proximal tubules Inhibition of Loop of Henle water and Na+ Collecting duct reabsorption Carbonic Proximal tubules Inhibition of anhydrase bicarbonate inhibitors reabsorption Loop Diuretic Loop of Henle Inhibition of (thick ascending Na+, K+ and Cl- limb) Thiazide Early distal Inhibition of tubule Na+, Cl- co- transport K+ sparing Late distal tubule Inhibition of Na+ diuretics Collecting duct , reabsorption  Loop diuretics E.g. furosemide, bumetanide - act on the chloride- binding site and directly inhibit the carrier. Inhibit the Na+/K+/2Cl- co-transporter (NKCC2) in the thick ascending loop of Henle → decrease in Na+ and Cl- reabsorption (blocks transport of NaCl out of the tubule into the interstitial tissue) 25% of the filtered load of Na+ is reabsorbed in TAL, loop diuretics have a profound diuretic action. Inhibition of NKCC2 → significant ↑ in concentration of ions in the tubule and ↓ hypertonicity in the surrounding interstitium. ↓ water to be reabsorbed into the blood. ↑ urine to ↓  Thick Ascending Limb Interstitium Lumen K+ K+ 2K + 2K + ↓Na + ↑Na+ ↓K+ 3Na+ 3Na+ ↑K+ ↓Cl- Na+ Na+ ↑Cl- K+ K+ K + K+ Blocked by loop KCC NKCC2 ↓Mg2+ Cl- diuretics (furosemide) Cl- ↓Ca2+ 2Cl- 2Cl- Cl- Cl- ↑Mg2+ ↑Ca2+ Mg2+, Ca2+ Mg2+, Ca2+ -ve +ve  Thiazide diuretics Hydrochlorothiazide, chlorothiazide, bendroflumethiazide Thiazide diuretics are used to treat high blood pressure and congestive heart failure % oedema arising due to heart failure, cirrhosis, chronic kidney failure, corticosteroid medications, and nephrotic syndrome. Act to inhibit reabsorption of Na+ and Cl− from the distal convoluted tubules in the kidneys by blocking the thiazide-sensitive Na+-Cl− symporter. Also increase Ca2+ reabsorption at the distal tubule. By lowering the sodium concentration in epithelial cells, thiazides increase the activity of the Na+/Ca2+ antiporter  Distal Convoluted Tubule Interstitium Lumen K+ K+ 2K + 2K + ↓Na + ↑Na+ ↓Cl- 3Na+ 3Na+ ↑Cl- Na+ Na+ ↓Na+ Blocked by thiazide ↑Ca2+ Cl - Cl- NC C diuretics Cl- Cl- Na+ Na+ Na+/Ca2+ Ca2+ Ca2+ exchanger Ca2+ Ca2+ -ve  Thiazide diuretic contraindications  Hypotension  Gout  Renal failure  Lithium therapy  Hypokalemia  May worsen diabetes Thiazides reduce the clearance of uric acid since they compete for the same transporter, and therefore raise the levels of uric acid in the blood. Hence, they are prescribed with caution in patients with gout or hyperuricemia. Chronic administration is associated with hyperglycemia. Thiazides cause loss of blood potassium, while conserving blood calcium.  Potassium Loss with Thiazides Potassium loss (increased excretion or less retention) occurs with the thiazides by one of three mechanisms. NB - kidney is very good at conserving Na+. With the thiazides, this was prevented in the early portion of the DCT….hence later in the nephron a more vigorous attempt to conserve Na will take place. This is primarily mediated by aldosterone, which reabsorbs Na+ at the expense of K+ (via Na+/K+ATPase). Therefore,  Increased aldosterone activity aids in the potassium loss  Increased aldosterone secretion aids in the potassium loss Hyochloraemic alkalosis (caused by the loss of Cl - through the mechanism of thiazides) also aids in potassium loss. This is a compensatory action that occurs with alkalosis due to loss of Cl - ion. Regardless of the exact mechanism, thiazide use will cause loss of Na +,  Obtained from Foxglove, Digitalis, Digoxin toxicity plants. Its medicinal properties were noted by William Withering in 1775 to alter heart rate. Digoxin is an inhibitor of the Na+/K+ ATPase pump and binds to the alpha subunit. This causes an increase in intracellular Na+. The increased Na+ Digoxin concentration reduces the action of the Na+/Ca2+ exchanger in the resulting in increased intracellular Ca2+ which is then stored in the Na+/K+ sarcoplasmic reticulum. The Ca2+ is ATPase pump Na+/Ca2+ exchanger released during a cardiac action 2K+ 3Na+ Ca2+ potential thus increasing the force of a contraction Hypokalaemia resulting from loop diuretics and thiazides will potentiate the effect digoxin, thus 2K+ 3Na+ Ca2+ increasing the risk of cardiac ↑[Ca2+]i arrythmias Depolarisation= disturbs cardiac rhythm at high doses. Note that digoxin has a narrow therapeutic window (0.6-1.2 µg/L). K+ sparing diuretics Aldosterone antagonists (e.g., spironolactone, eplerenone) – Aldosterone evokes expression of Na +/K+ATPase and ENaC promoting Na+ reabsorption – Aldosterone receptor antagonists reduce this expression of Na+/K+ATPase and ENaC thus reducing both Na+ reabsorption and K+ secretion Na+ channel inhibitors (e.g., amiloride, triamterene) – Inhibit Na+ reabsorption by blocking ENaC on the apical membrane and reduce K + secretion by a downstream reduction in Na+/K+ATPase activity on the basolateral membrane. Used in combination with loop diuretics and thiazides to reduce K+ loss particularly where hypokalaemia is a concern. K+ sparing diuretics – adverse effects Hyperkalaemia , so potassium supplements should not be co- prescribed. Caution when used with drugs such as ACE inhibitors that increase blood potassium levels. Increases in K+ can lead to cardiac arrythmias Interstitium Collecting Tubule Lumen K+ K+ ↑Na+ 2K + 2K + ENaC ↓Na + 3Na+ 3Na + Na+ ↓K+ 2K+ 2K+ ↑K + Na+ 3Na+ 3Na+ Hyperkalaemia AD aldostero ne can result R Aldosterone is normally secreted in response to hyponatremia (this is where you get resistance to thiazides) and results in increased expression and activity of Na+/K+ATPase and ENaC. Antagonist action of spironolactone at aldosterone receptors results in a decrease in the number of ENaC and Na+/K+ATPase transporters resulting in a net reduction of blood Na+, urinary K+ and an increase in blood K Potassium sparing diuretics – + Interstitium Collecting Tubule Lumen K+ K+ 2K + 2K+ ENaC ↓Na + 3Na+ 3Na + Na+ ↓K+ ↑K+ Hyperkalaemia can result Blocking ENaC reduces Na+ transport from the apical to basolateral membrane thus reducing Na+ secretion via the Na+/K+ ATPase pump. Potassium sparing diuretics – amiloride, For reference: Blood electrolyte balance Na+ 133-146 mmol/L (hyponatremia / hypernatremia K+ 3.5-5.3 mmol/L (hypokalaemia / hyperkalaemia) Cl- 95-108 mmol/L (hypochloraemia / hyperchloraemia) Ca2+ 2.2 to 2.7 mmol/L (hypocalcaemia / hypercalcaemia) Mg2+ 0.7-1.0 mmol/L (hypomagnesemia / hypermagnesemia) For reference: o Susan Drug Skinner: Understanding interactions Clinical Investigations: A Quick Reference Manual Elsevier 2005. o Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Loop diuretics: Greater risk of digoxin toxicity due to hypokalaemia Change in plasma concentrations of drugs excreted by the kidney Thiazides: Efficacy is reduced by NSAIDs Drugs that contribute to hypokalaemia should be avoided Potassium-sparing diuretics: ACE inhibitors and angiotensin receptor antagonists increase plasma K can significantly contribute to hyperkalaemia +