Drugs And The Kidney

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Drugs And The Kidney

  1. 1. Drugs and the Kidney
  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>
  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>
  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>
  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>
  6. 6. Serum Creatinine and GFR Serum creatinine Glomerular filtration rate (GFR)
  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>
  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>
  9. 9. The nephron and electrolyte handling
  10. 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>
  11. 12. Diuretics <ul><li>Loop </li></ul><ul><li>Thiazide </li></ul><ul><li>Aldosterone antagonist </li></ul><ul><li>Osmotic </li></ul>
  12. 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>
  13. 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>
  14. 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>
  15. 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>
  16. 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>
  17. 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>
  18. 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) JAMA. 2002;288:2981-2997 ALLHAT
  19. 22. Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by ALLHAT Treatment Group Chlorthalidone Amlodipine Lisinopril Years to CHD Event 0 1 2 3 4 5 6 7 Cumulative CHD Event Rate 0 .04 .08 .12 .16 .2 0.81 0.99 (0.91-1.08) L/C 0.65 0.98 (0.90-1.07) A/C p value RR (95% CI) ALLHAT
  20. 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. ALLHAT
  21. 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>
  22. 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>
  23. 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>
  24. 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>
  25. 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>
  26. 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>
  27. 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>
  28. 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>
  29. 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>
  30. 35. Past Papers <ul><li>Write short notes on the following </li></ul><ul><ul><li>Spironolactone (Dec2000) </li></ul></ul><ul><ul><li>Amphotericin (June99) </li></ul></ul><ul><ul><li>Cyclosporin (June99) </li></ul></ul>
  31. 36. Past Papers <ul><li>Discuss the treatment of patients with </li></ul><ul><ul><li>Digoxin toxicity </li></ul></ul><ul><ul><li>Lithium toxicity </li></ul></ul><ul><ul><li>Following both deliberate and Iatrogenic overdose. </li></ul></ul><ul><ul><li>Which treatments have been shown to improve survival? </li></ul></ul>
  32. 37. 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>
  33. 38. 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>
  34. 39. 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>
  35. 40. 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>
  36. 41. 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>
  37. 42. 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>
  38. 43. 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>

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