Drugs and the kidney


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Drugs and the kidney

  1. 1. Drugs and the Kidney www.freelivedoctor.com
  2. 2. Drugs and the Kidney <ul><li>1 Renal Physiology and Pharmacokinetics </li></ul><ul><li>2 Drugs and the normal kidney </li></ul><ul><li>3 Drugs toxic to the kidney </li></ul><ul><li>4 Prescribing in kidney disease </li></ul>www.freelivedoctor.com
  3. 3. Normal Kidney Function <ul><li>1 Extra Cellular Fluid Volume control </li></ul><ul><li>2 Electrolyte balance </li></ul><ul><li>3 Waste product excretion </li></ul><ul><li>4 Drug and hormone elimination/metabolism </li></ul><ul><li>5 Blood pressure regulation </li></ul><ul><li>6 Regulation of haematocrit </li></ul><ul><li>7 regulation of calcium/phosphate balance </li></ul><ul><li>(vitamin D3 metabolism) </li></ul>www.freelivedoctor.com
  4. 4. Clinical Estimation of renal function <ul><li>Clinical examination </li></ul><ul><li>pallor, volume status, blood pressure measurement, urinalysis </li></ul><ul><li>Blood tests </li></ul><ul><li>Routine Tests </li></ul><ul><li>haemoglobin level </li></ul><ul><li>electrolyte measurement (Na ,K , Ca, PO 4 ) </li></ul><ul><li>urea </li></ul><ul><li>creatinine normal range 70 to 140 μ mol/l </li></ul>www.freelivedoctor.com
  5. 5. Serum Creatinine and GFR <ul><li>Muscle metabolite - concentration proportional to muscle mass </li></ul><ul><ul><li>High: muscular young men </li></ul></ul><ul><ul><li>Low: conditions with muscle wasting </li></ul></ul><ul><ul><ul><li>elderly </li></ul></ul></ul><ul><ul><ul><li>muscular dystrophy </li></ul></ul></ul><ul><ul><ul><li>Anorexia </li></ul></ul></ul><ul><ul><ul><li>malignancy </li></ul></ul></ul><ul><li>“ Normal” range 70 to 140 μ mol/litre </li></ul>www.freelivedoctor.com
  6. 6. Serum Creatinine and GFR Serum creatinine Glomerular filtration rate (GFR) www.freelivedoctor.com
  7. 7. GFR Estimation <ul><li>Cockroft-Gault Formula </li></ul><ul><ul><li>CrCl=Fx(140-age)xweight/Crea P </li></ul></ul><ul><ul><li>F ♀=1.04 </li></ul></ul><ul><ul><li>F♂=1.23 </li></ul></ul><ul><ul><li>Example </li></ul></ul><ul><ul><li>85♀, 55kg, Creatinine=95 </li></ul></ul><ul><ul><li>CrCl=33ml/min </li></ul></ul><ul><li>MDRD Formula </li></ul>www.freelivedoctor.com
  8. 8. Tests of renal function cont. <ul><li>24h Urine sample-Creatinine clearance </li></ul><ul><li>chromium EDTA Clearance </li></ul><ul><li>gold standard Inulin clearance </li></ul>www.freelivedoctor.com
  9. 9. The nephron and electrolyte handling www.freelivedoctor.com
  10. 10. www.freelivedoctor.com
  11. 11. Pharmacokinetics <ul><li>Absorption </li></ul><ul><li>Distribution </li></ul><ul><li>Metabolism </li></ul><ul><li>Elimination </li></ul><ul><ul><ul><ul><li>filtration </li></ul></ul></ul></ul><ul><ul><ul><ul><li>secretion </li></ul></ul></ul></ul>www.freelivedoctor.com
  12. 12. Diuretics <ul><li>Loop </li></ul><ul><li>Thiazide </li></ul><ul><li>Aldosterone antagonist </li></ul><ul><li>Osmotic </li></ul>www.freelivedoctor.com
  13. 13. Diuretics <ul><li>Indications for use </li></ul><ul><ul><li>heart failure ( acute or chronic ) </li></ul></ul><ul><ul><li>pulmonary oedema </li></ul></ul><ul><ul><li>hypertension </li></ul></ul><ul><ul><li>nephrotic syndrome </li></ul></ul><ul><ul><li>hypercalcaemia </li></ul></ul><ul><ul><li>hypercalciuria </li></ul></ul>www.freelivedoctor.com
  14. 14. Loop diuretics <ul><li>Frusemide, Bumetanide </li></ul><ul><li>Indication </li></ul><ul><ul><li>Fluid overload </li></ul></ul><ul><ul><li>Hypertension </li></ul></ul><ul><ul><li>Hypercalcaemia </li></ul></ul><ul><li>Mechanism of action </li></ul><ul><li>Blockade of NaK2Cl (NKCC2) transporter in the thick ascending loop of Henle </li></ul>www.freelivedoctor.com
  15. 15. www.freelivedoctor.com
  16. 16. Loop diuretics <ul><li>Frusemide </li></ul><ul><ul><li>oral bioavailability between 10 and 90% </li></ul></ul><ul><ul><li>Acts at luminal side of thick ascending limb(NaK2Cl transporter) </li></ul></ul><ul><ul><li>Highly protein bound </li></ul></ul><ul><ul><li>Rebound after single dose </li></ul></ul><ul><ul><li>Half-life 4 hours </li></ul></ul>www.freelivedoctor.com
  17. 17. Loop diuretics continued <ul><li>Caution </li></ul><ul><ul><li>Electrolyte imbalance - hypokalaemia </li></ul></ul><ul><ul><li>Volume depletion (prerenal uremia) </li></ul></ul><ul><ul><li>Tinitus (acts within cochlea – can synergise with aminoglycoside antibiotics) </li></ul></ul>www.freelivedoctor.com
  18. 18. Thiazide diuretics <ul><li>Bendrofluazide, Metolazone </li></ul><ul><li>Site of action distal convoluted tubule </li></ul><ul><li>blocks electroneutral Na/Cl exchanger (NCCT) </li></ul><ul><li>Reaches site of action in glomerular filtrate </li></ul><ul><ul><ul><ul><li>Higher doses required in low GFR (ineffective when serum creatinine >200 μ M) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>T ½ 3-5 hours </li></ul></ul></ul></ul>www.freelivedoctor.com
  19. 19. www.freelivedoctor.com
  20. 20. Thiazides <ul><li>Indications </li></ul><ul><ul><li>Antihypertensive: especially in combination with ACE inhibitor/ARB (A+D) </li></ul></ul><ul><ul><li>In combination with loop diuretic for profound oedema </li></ul></ul><ul><ul><li>Cautions </li></ul></ul><ul><ul><ul><li>Metabolic side effects – hyperuricaemia, impaired glucose tolerance & electrolyte disturbance (hypokalaemia and hyponatraemia) </li></ul></ul></ul><ul><ul><ul><li>Volume depletion </li></ul></ul></ul>www.freelivedoctor.com
  21. 21. Major Outcomes in High Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) The ALLHAT Collaborative Research Group Sponsored by the National Heart, Lung, and Blood Institute (NHLBI) www.freelivedoctor.com
  22. 22. Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by ALLHAT Treatment Group Chlorthalidone Amlodipine Lisinopril www.freelivedoctor.com Years to CHD Event 0 1 2 3 4 5 6 7 Cumulative CHD Event Rate 0 .04 .08 .12 .16 .2 RR (95% CI) p value A/C 0.98 (0.90-1.07) 0.65 L/C 0.99 (0.91-1.08) 0.81
  23. 23. Overall Conclusions Because of the superiority of thiazide-type diuretics in preventing one or more major forms of CVD and their lower cost, they should be the drugs of choice for first-step antihypertensive drug therapy. www.freelivedoctor.com
  24. 24. Amiloride and Spironolactone <ul><li>Amiloride </li></ul><ul><ul><li>Blocks ENaC (channel for Na secretion in collecting duct under aldosterone control) </li></ul></ul><ul><li>Spironolactone </li></ul><ul><ul><li>Aldosterone receptor antagonist </li></ul></ul><ul><ul><li>Reaches DCT via blood stream (not dependent on GFR) </li></ul></ul><ul><li>Often Combined with loop or thiazides to capitalise on K-sparing action </li></ul>www.freelivedoctor.com
  25. 25. www.freelivedoctor.com
  26. 26. Nephrotoxic Drugs <ul><li>Dose dependant toxicity </li></ul><ul><ul><li>NSAIDs including COX 2 </li></ul></ul><ul><ul><li>Aminoglycosides </li></ul></ul><ul><ul><li>Radio opaque contrast materials </li></ul></ul><ul><li>Idiosyncratic Renal Damage </li></ul><ul><ul><li>NSAIDs </li></ul></ul><ul><ul><li>Penicillins </li></ul></ul><ul><ul><li>Gold, penicillamine </li></ul></ul>www.freelivedoctor.com
  27. 27. NSAIDs (Non-steroidal anti inflammatory drugs) <ul><li>Commonly used </li></ul><ul><ul><li>Interfere with prostaglandin production, disrupt regulation of renal medullary blood flow and salt water balance </li></ul></ul><ul><li>Chronic renal impairment </li></ul><ul><ul><li>Habitual use </li></ul></ul><ul><ul><li>Exacerbated by other drugs ( anti-hypertensives, ACE inhibitors) </li></ul></ul><ul><ul><li>Typical radiological features when advanced </li></ul></ul>www.freelivedoctor.com
  28. 28. www.freelivedoctor.com
  29. 29. Aminoglycosides <ul><li>Highly effective antimicrobials </li></ul><ul><ul><li>Particularly useful in gram -ve sepsis </li></ul></ul><ul><ul><li>bactericidal </li></ul></ul><ul><li>BUT </li></ul><ul><ul><li>Nephrotoxic </li></ul></ul><ul><ul><li>Ototoxic </li></ul></ul><ul><ul><li>Narrow therapeutic range </li></ul></ul>www.freelivedoctor.com
  30. 30. Prescribing Aminoglycosides <ul><li>Once daily regimen now recommended in patients with normal kidneys </li></ul><ul><ul><ul><ul><li>High peak concentration enhances efficacy </li></ul></ul></ul></ul><ul><ul><ul><ul><li>long post dose effect </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Single daily dose less nephrotoxic </li></ul></ul></ul></ul><ul><li>Dose depends on size and renal function </li></ul><ul><ul><ul><ul><li>Measure levels! </li></ul></ul></ul></ul>www.freelivedoctor.com
  31. 31. Intravenous contrast <ul><li>Used commonly </li></ul><ul><ul><ul><ul><li>CT scanning, IV urography, Angiography </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Unsafe in patients with pre-existing renal impairment </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Risk increased in diabetic nephropathy, heart failure & dehydration </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Can precipitate end-stage renal failure </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Cumulative effect on repeated administration </li></ul></ul></ul></ul><ul><li>Risk reduced by using Acetylcysteine ? </li></ul><ul><ul><ul><ul><li>see N Engl J Med 2000; 343:180-184 </li></ul></ul></ul></ul>www.freelivedoctor.com
  32. 32. Prescribing in Kidney Disease <ul><li>Patients with renal impairment </li></ul><ul><li>Patients on Dialysis </li></ul><ul><li>Patients with renal transplants </li></ul>www.freelivedoctor.com
  33. 33. Principles <ul><li>Establish type of kidney disease </li></ul><ul><ul><ul><li>Most patients with kidney failure will already be taking a number of drugs </li></ul></ul></ul><ul><ul><ul><li>Interactions are common </li></ul></ul></ul><ul><ul><ul><li>Care needed to avoid drug toxicity </li></ul></ul></ul><ul><li>Patients with renal impairment and renal failure </li></ul><ul><ul><ul><li>Antihypertensives </li></ul></ul></ul><ul><ul><ul><li>Phosphate binders </li></ul></ul></ul>www.freelivedoctor.com
  34. 34. Dosing in renal impairment <ul><li>Loading dose does not change (usually) </li></ul><ul><li>Maintenance dose or dosing interval does </li></ul><ul><li>T ½ often prolonged </li></ul><ul><ul><li>Reduce dose OR </li></ul></ul><ul><ul><li>Increase dosing interval </li></ul></ul><ul><ul><li>Some drugs have active metabolites that are themselves excreted renally </li></ul></ul><ul><ul><ul><ul><li>Warfarin, diazepam </li></ul></ul></ul></ul>www.freelivedoctor.com
  35. 35. Spironolactone <ul><li>Class </li></ul><ul><ul><ul><li>Potassium sparing diuretic </li></ul></ul></ul><ul><li>Mode of action </li></ul><ul><ul><ul><li>Antagonises the effect of aldosterone at levels MR </li></ul></ul></ul><ul><ul><ul><li>Mineralocorticoid receptor (MR)–aldosterone complex translocates to nucleus to affect gene transcription </li></ul></ul></ul><ul><li>Indication </li></ul><ul><ul><ul><li>Prevent hypokalaemia in patients taking diuretics or digoxin </li></ul></ul></ul><ul><ul><ul><li>Improves survival in advanced heart failure (RALES 1999 Randomised Aldactone Evaluation Study) </li></ul></ul></ul><ul><ul><ul><li>Antihypertensive (adjunctive third line therapy for hypertension or first line for conns patients) </li></ul></ul></ul><ul><ul><ul><li>Ascites in patients with cirrhosis </li></ul></ul></ul>www.freelivedoctor.com
  36. 36. Spironolactone <ul><li>Side effects </li></ul><ul><ul><ul><ul><li>Antiandrogenic effects through the antagonism of DHT (testosterone) at its binding site. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Gynaecomastia, impotence, reduced libido </li></ul></ul></ul></ul><ul><li>Interactions </li></ul><ul><ul><ul><ul><li>Other potassium sparing drugs e.g. ACE inhibitors/ARBs & potassium supplements (remember ‘LoSalt’ used as NaCl substitute in cooking) </li></ul></ul></ul></ul>www.freelivedoctor.com
  37. 37. Amphotericin <ul><li>Class </li></ul><ul><ul><ul><li>Anti fungal agent for topical and systemic use </li></ul></ul></ul><ul><li>Mode of action </li></ul><ul><ul><ul><li>Lipid soluble drug. Binds steroid alcohols (ergosterol) in the fungal cell membrane causing leakage of cellular content and death. Effective against candida species </li></ul></ul></ul><ul><ul><ul><li>Fungistatic or fungicidal depending on the concentration </li></ul></ul></ul><ul><ul><ul><li>Broad spectrum (candida, cryptosporidium) </li></ul></ul></ul>www.freelivedoctor.com
  38. 38. Amphotericin <ul><li>Indications </li></ul><ul><ul><ul><ul><li>iv administration for systemic invasive fungal infections </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Oral for GI mycosis </li></ul></ul></ul></ul><ul><li>Side effects </li></ul><ul><ul><ul><ul><li>Local/systemic effects with infusion (fever) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Chronic kidney dysfunction </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Decline in GFR with prolonged use </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Tubular dysfunction (membrane permeability) </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Hypokalaemia, renal tubular acidosis (bicarb wasting type 1/distal), diabetes insipidus, hypomagnesaemia </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Pre hydration/saline loading may avoid problems </li></ul></ul></ul></ul></ul><ul><li>Toxicity can be reduced substantially by liposomal packing of Amphotericin </li></ul>www.freelivedoctor.com
  39. 39. Lithium toxicity <ul><li>Lithium carbonate - Rx for bipolar affective disorder </li></ul><ul><li>Toxicity closely related to serum levels </li></ul><ul><li>Symptoms </li></ul><ul><ul><ul><ul><li>CVS arrhythmias (especially junctional dysrrythmias) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>CNS tremor – confusion - coma </li></ul></ul></ul></ul><ul><li>Treatment </li></ul><ul><ul><ul><li>Supportive - Haemodialysis and colonic irrigation for severe levels </li></ul></ul></ul><ul><ul><ul><li>Inadvertent intoxication from interaction with ACEI & loop/thiazide diuretic </li></ul></ul></ul><ul><ul><ul><li>Carbamezepine and other anti epileptics increase neurotoxicity </li></ul></ul></ul>www.freelivedoctor.com
  40. 40. Digoxin toxicity <ul><li>Incidence </li></ul><ul><ul><ul><ul><li>High levels demonstrated in 10% and toxicity reported in 4% of a series of 4000 digoxin samples </li></ul></ul></ul></ul><ul><li>Kinetics </li></ul><ul><ul><ul><ul><li>large volume of distribution (reservoir is skeletal muscle) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>about 30% of stores excreted in urine/day </li></ul></ul></ul></ul>www.freelivedoctor.com
  41. 41. Treatment of digoxin toxicity <ul><li>Supportive </li></ul><ul><ul><ul><ul><li>Correction of electrolyte imbalances </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Atropine for bradycardia avoid cardio stimulants because arrythmogenic </li></ul></ul></ul></ul><ul><li>Limitation of absorption </li></ul><ul><ul><ul><ul><li>Charcoal effective within 8 hours (or cholestyramine) </li></ul></ul></ul></ul><ul><li>Specific measures </li></ul><ul><ul><ul><ul><li>DIGIBIND Fab digoxin specific antibodies. Binds plasma digoxin and complex eliminated by kidneys (used when OD is high/near arrest) </li></ul></ul></ul></ul><ul><li>Enhanced elimination </li></ul><ul><ul><ul><ul><li>Dialysis is ineffective. Charcoal/cholestyramine interrupt enterohepatic cycling. </li></ul></ul></ul></ul>www.freelivedoctor.com
  42. 42. From Knauf & Mutschler Klin. Wochenschr. 1991 69:239-250 70% 20% 5% 4.5% 0.5% Volume 1.5 L/day Urine Na 100 mEq/L Na Excretion 155 mEq/day 100% GFR 180 L/day Plasma Na 145 mEq/L Filtered Load 26,100 mEq/day CA Inhibitors Proximal tubule Loop Diuretics Loop of Henle Thiazides Distal tubule Antikaliuretics Collecting duct Thick Ascending Limb www.freelivedoctor.com
  43. 43. Principles important for understanding effects of diuretics <ul><li>Interference with Na + reabsorption at one nephron site interferes with other renal functions linked to it </li></ul><ul><li>It also leads to increased Na + reabsorption at other sites </li></ul><ul><li>Increased flow and Na + delivery to distal nephron stimulates K + (and H + ) secretion </li></ul>www.freelivedoctor.com
  44. 44. <ul><li>Diuretics act only if Na + reaches their site of action. The magnitude of the diuretic effect depends on the amount of Na + reaching that site </li></ul><ul><li>Diuretic actions at different nephron sites can produce synergism </li></ul><ul><li>All, except spironolactone, act from the lumenal side of the tubular cellular membrane </li></ul>Principles important for understanding effects of diuretics www.freelivedoctor.com
  45. 45. N N SO 2 NH 2 SO 2 NH 2 NH 2 NH 2 NH 2 SO 2 NH 2 Cl Cl SO 2 NH 2 SO 2 NH 2 Cl SO 2 NH 2 N C N SO 2 Prontosil Sulfanilamide p-chlorobenzene sulfonamide 1,3 disulfonamide 6 cholrobenzene Cholrothiazide www.freelivedoctor.com
  46. 46. THIAZIDE DIURETICS <ul><li>Secreted into the tubular lumen by the organic acid transport mechanisms in the proximal tubule </li></ul><ul><li>Act on the distal tubule to inhibit sodium and chloride transport and result in a modest diuresis </li></ul><ul><li>Increase renal excretion of potassium, magnesium </li></ul><ul><li>Reduce calcium and urate excretion </li></ul><ul><li>Not effective at low glomerular filtration rates </li></ul><ul><li>Impair maximal diluting but not maximal concentrating ability </li></ul>www.freelivedoctor.com
  47. 47. General Structure of Thiazide Diuretics www.freelivedoctor.com
  48. 48. Inhibition of high-affinity 3 H-metolazone binding by ions www.freelivedoctor.com Ion % Control NaF 143±9 LiCl 4±1 NaCl 20±0.5 KCl 44±2 Choline chloride 36±7 NaBr 24±2 NaI 25±1 KI 12±2 Na acetate 82±5 K acetate 95±5 Disodium sulfate 152±22 Dipotassium sulfate 118±12 Trisodium citrate 112±5
  49. 49. Correlation of the daily clinical doses of thiazide diuretics with their affinity for high-affinity 3 H-metolazone binding sites in rat kidney. Correlation coefficient r=0.7513. www.freelivedoctor.com
  50. 50. Thiazides - Pharmacokinetics <ul><li>Rapid GI absorption </li></ul><ul><li>Distribution in extracellular space </li></ul><ul><li>Elimination unchanged in kidney </li></ul><ul><li>Variable elimination kinetics and therefore variable half-lives of elimination ranging from hours to days. </li></ul>www.freelivedoctor.com
  51. 51. CLINICAL USES Of THIAZIDES-1 <ul><li>1 ) HYPERTENSION </li></ul><ul><li>Thiazides reduce blood pressure and associated risk of CVA and MI in hypertension </li></ul><ul><li>they should be considered first-line therapy in hypertension (effective, safe and cheap) </li></ul><ul><li>Mechanism of action in hypertension is uncertain – involves vasodilation that is not a direct effect but a consequence of the diuretic/natriuretic effect </li></ul>www.freelivedoctor.com
  52. 52. Schematic drawing of temporal changes in mean arterial pressure (MAP), total peripheral vascular resistance (TPR), cardiac output (CO) and plasma volume (PV) during thiazide treatment of a hypertensive subject www.freelivedoctor.com
  53. 53. www.freelivedoctor.com
  54. 54. www.freelivedoctor.com
  55. 55. CLINICAL USES OF THIAZIDES-2 <ul><li>2) EDEMA (cardiac, liver renal) </li></ul><ul><li>3) IDIOPATHIC HYPERCALCIURIA </li></ul><ul><li>condition characterized by recurrent stone formation in the kidneys due to excess calcium excretion </li></ul><ul><li>thiazide diuretics used to prevent calcium loss and protect the kidneys </li></ul><ul><li>4) DIABETES INSIPIDUS </li></ul>www.freelivedoctor.com
  56. 56. ADVERSE EFFECTS OF THIAZIDES-1 <ul><li>Initially, they were used at high doses which caused a high </li></ul><ul><li>incidence of adverse effects. Lower doses now used cause </li></ul><ul><li>fewer adverse effects. Among them are: </li></ul><ul><li>HYPOKALEMIA </li></ul><ul><li>DEHYDRATION (particularly in the elderly) leading to POSTURAL HYPOTENSION </li></ul><ul><li>HYPERGLYCEMIA possibly because of impaired insulin release secondary to hypokalemia </li></ul><ul><li>HYPERURICEMIA because thiazides compete with urate for tubular secretion </li></ul>www.freelivedoctor.com
  57. 57. ADVERSE EFFECTS OF THIAZIDES-2 <ul><li>HYPERLIPIDEMIA ; mechanism unknown but cholesterol increases usually trivial (1% increase) </li></ul><ul><li>IMPOTENCE </li></ul><ul><li>HYPONATREMIA due to thirst, sodium lo s loss, inappropriate ADH secretion (can cause confusion in the elderly), usually after prolonged use </li></ul>www.freelivedoctor.com
  58. 58. <ul><li>Less common problems </li></ul><ul><li>HYPERSENSITIVITY - may manifest as interstitial nephritis, pancreatitis, rashes, blood dyscrasias (all very rare) </li></ul><ul><li>METABOLIC ALKALOSIS due to increased sodium load at the distal convoluted tubule which stimulates the sodium/hydrogen exchanger to reabsorb sodium and excrete hydrogen </li></ul><ul><li>HYPERCALCEMIA </li></ul>ADVERSE EFFECTS OF THIAZIDES-3 www.freelivedoctor.com
  59. 59. LOOP DIURETICS <ul><li>Secreted in proximal tubule by acid mechanisms </li></ul><ul><li>Act on the ascending loop of Henle to inhibit sodium and chloride transport </li></ul><ul><li>Cause a greater natriuresis than thiazides </li></ul><ul><li>Effective at low glomerular filtration rates (as occur in chronic renal failure), where thiazides are ineffective </li></ul><ul><li>Increase potassium, calcium and magnesium excretion </li></ul><ul><li>Decrease urate excretion </li></ul><ul><li>Impair maximal concentrating and diluting capacity </li></ul>www.freelivedoctor.com
  60. 60. www.freelivedoctor.com
  61. 61. LOOP DIURETICS <ul><li>Additional non-tubular effects </li></ul><ul><li>1. Renal Vasodilation and redistribution of blood flow </li></ul><ul><li>2. Increase in renin release </li></ul><ul><li>3. Increase in venous capacitance </li></ul><ul><li>These effects mediated by release of prostaglandins from the kidney. </li></ul>www.freelivedoctor.com
  62. 62. www.freelivedoctor.com
  63. 63. Loop Diuretics - Pharmacokinetics <ul><li>Rapid GI absorption. Also given i.m. and i.v. </li></ul><ul><li>Extensively protein bound in plasma </li></ul><ul><li>Short half-lives in general </li></ul><ul><li>Elimination: unchanged in kidney or by conjugation in the liver and secretion in bile. </li></ul>www.freelivedoctor.com
  64. 64. www.freelivedoctor.com
  65. 65. CLINICAL USES OF LOOP DIURETICS <ul><li>EDEMA due to CHF, nephrotic syndrome or cirrhosis </li></ul><ul><li>Acute heart failure with PULMONARY EDEMA </li></ul><ul><li>HYPERCALCEMIA </li></ul><ul><li>not in widespread use for the treatment of hypertension (except in a few special cases e.g. hypertension in renal disease) </li></ul>www.freelivedoctor.com
  66. 66. <ul><li>Hypokalemia, metabolic alkalosis, hypercholesterolemia, hyperuricemia, hyperglycemia, hyponatremia </li></ul><ul><li>Dehydration and postural hypotension </li></ul><ul><li>Hypocalcemia (in contrast to thiazides) </li></ul><ul><li>Hypersensitivity </li></ul><ul><li>OTOTOXICITY (especially if given by rapid IV bolus) </li></ul>Adverse Effects of Loop Diuretics similar to thiazides in many respects www.freelivedoctor.com
  67. 67. Edema: Therapeutic Considerations <ul><li>Therapy is palliative (except with pulmonary edema). </li></ul><ul><li>Need a mild sustained response. </li></ul><ul><li>Specific consideration to potassium homeostasis, i.e. supplement with K-salt or use K-sparing diuretic. </li></ul><ul><li>Therefore, in most cases start with a thiazide. </li></ul><ul><li>If resistant, move to Loop diuretic. </li></ul>www.freelivedoctor.com
  68. 68. www.freelivedoctor.com
  69. 69. Conditions treated with Diuretics <ul><li>Edema </li></ul><ul><li>Hypertension </li></ul><ul><li>Nephrogenic Diabetes Insipidus </li></ul><ul><li>Syndrome of Inappropriate ADH Secretion (SIADH) </li></ul><ul><li>To increase or decrease Ca ++ , K + or H + ion excretion. </li></ul>www.freelivedoctor.com
  70. 70. Diuretic Resistance <ul><li>Compensatory Mechanisms ( RAAS, SNS ) </li></ul><ul><li>Failure to reach tubular site of action </li></ul><ul><li>a - Decreased G.I. absorption </li></ul><ul><li>b - Decreased secretion into tubular lumen </li></ul><ul><li>(e.g. uremia, decreased kidney perfusion) </li></ul><ul><li>c - Decreased availability in tubular lumen </li></ul><ul><li>(e.g. nephrotic syndrome) </li></ul><ul><li>Interference by other drugs ( e.g. NSAID’s ) </li></ul><ul><li>Tubular adaptation ( chronic Loop diuretic use) </li></ul><ul><li>Can Use Combination of Diuretics </li></ul><ul><li>to Induce a S ynergistic Effect </li></ul>www.freelivedoctor.com
  71. 71. Maximum Doses of Loop Diuretics www.freelivedoctor.com Clinical Condition Dose of furosemide (mg) intravenous Oral Renal Insufficiency 0 < Cl Cr < 50 80 160 Renal Insufficiency Cl Cr < 20 200 400 Nephrotic Syndrome 120 240 Cirrhosis 40 80 Congestive Heart Failure 40-80 80-160