Drugs And The Kidney

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  • 1. Drugs and the Kidney
  • 2. Drugs and the Kidney
    • 1 Renal Physiology and Pharmacokinetics
    • 2 Drugs and the normal kidney
    • 3 Drugs toxic to the kidney
    • 4 Prescribing in kidney disease
  • 3. Normal Kidney Function
    • 1 Extra Cellular Fluid Volume control
    • 2 Electrolyte balance
    • 3 Waste product excretion
    • 4 Drug and hormone elimination/metabolism
    • 5 Blood pressure regulation
    • 6 Regulation of haematocrit
    • 7 regulation of calcium/phosphate balance
    • (vitamin D3 metabolism)
  • 4. Clinical Estimation of renal function
    • Clinical examination
    • pallor, volume status, blood pressure measurement, urinalysis
    • Blood tests
    • Routine Tests
    • haemoglobin level
    • electrolyte measurement (Na ,K , Ca, PO 4 )
    • urea
    • creatinine normal range 70 to 140 μ mol/l
  • 5. Serum Creatinine and GFR
    • Muscle metabolite - concentration proportional to muscle mass
      • High: muscular young men
      • Low: conditions with muscle wasting
        • elderly
        • muscular dystrophy
        • Anorexia
        • malignancy
    • “ Normal” range 70 to 140 μ mol/litre
  • 6. Serum Creatinine and GFR Serum creatinine Glomerular filtration rate (GFR)
  • 7. GFR Estimation
    • Cockroft-Gault Formula
      • CrCl=Fx(140-age)xweight/Crea P
      • F ♀=1.04
      • F♂=1.23
      • Example
      • 85♀, 55kg, Creatinine=95
      • CrCl=33ml/min
    • MDRD Formula
  • 8. Tests of renal function cont.
    • 24h Urine sample-Creatinine clearance
    • chromium EDTA Clearance
    • gold standard Inulin clearance
  • 9. The nephron and electrolyte handling
  • 10.  
  • 11. Pharmacokinetics
    • Absorption
    • Distribution
    • Metabolism
    • Elimination
          • filtration
          • secretion
  • 12. Diuretics
    • Loop
    • Thiazide
    • Aldosterone antagonist
    • Osmotic
  • 13. Diuretics
    • Indications for use
      • heart failure ( acute or chronic )
      • pulmonary oedema
      • hypertension
      • nephrotic syndrome
      • hypercalcaemia
      • hypercalciuria
  • 14. Loop diuretics
    • Frusemide, Bumetanide
    • Indication
      • Fluid overload
      • Hypertension
      • Hypercalcaemia
    • Mechanism of action
    • Blockade of NaK2Cl (NKCC2) transporter in the thick ascending loop of Henle
  • 15.  
  • 16. Loop diuretics
    • Frusemide
      • oral bioavailability between 10 and 90%
      • Acts at luminal side of thick ascending limb(NaK2Cl transporter)
      • Highly protein bound
      • Rebound after single dose
      • Half-life 4 hours
  • 17. Loop diuretics continued
    • Caution
      • Electrolyte imbalance - hypokalaemia
      • Volume depletion (prerenal uremia)
      • Tinitus (acts within cochlea – can synergise with aminoglycoside antibiotics)
  • 18. Thiazide diuretics
    • Bendrofluazide, Metolazone
    • Site of action distal convoluted tubule
    • blocks electroneutral Na/Cl exchanger (NCCT)
    • Reaches site of action in glomerular filtrate
          • Higher doses required in low GFR (ineffective when serum creatinine >200 μ M)
          • T ½ 3-5 hours
  • 19.  
  • 20. Thiazides
    • Indications
      • Antihypertensive: especially in combination with ACE inhibitor/ARB (A+D)
      • In combination with loop diuretic for profound oedema
      • Cautions
        • Metabolic side effects – hyperuricaemia, impaired glucose tolerance & electrolyte disturbance (hypokalaemia and hyponatraemia)
        • Volume depletion
  • 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
  • 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
  • 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
  • 24. Amiloride and Spironolactone
    • Amiloride
      • Blocks ENaC (channel for Na secretion in collecting duct under aldosterone control)
    • Spironolactone
      • Aldosterone receptor antagonist
      • Reaches DCT via blood stream (not dependent on GFR)
    • Often Combined with loop or thiazides to capitalise on K-sparing action
  • 25.  
  • 26. Nephrotoxic Drugs
    • Dose dependant toxicity
      • NSAIDs including COX 2
      • Aminoglycosides
      • Radio opaque contrast materials
    • Idiosyncratic Renal Damage
      • NSAIDs
      • Penicillins
      • Gold, penicillamine
  • 27. NSAIDs (Non-steroidal anti inflammatory drugs)
    • Commonly used
      • Interfere with prostaglandin production, disrupt regulation of renal medullary blood flow and salt water balance
    • Chronic renal impairment
      • Habitual use
      • Exacerbated by other drugs ( anti-hypertensives, ACE inhibitors)
      • Typical radiological features when advanced
  • 28.  
  • 29. Aminoglycosides
    • Highly effective antimicrobials
      • Particularly useful in gram -ve sepsis
      • bactericidal
    • BUT
      • Nephrotoxic
      • Ototoxic
      • Narrow therapeutic range
  • 30. Prescribing Aminoglycosides
    • Once daily regimen now recommended in patients with normal kidneys
          • High peak concentration enhances efficacy
          • long post dose effect
          • Single daily dose less nephrotoxic
    • Dose depends on size and renal function
          • Measure levels!
  • 31. Intravenous contrast
    • Used commonly
          • CT scanning, IV urography, Angiography
          • Unsafe in patients with pre-existing renal impairment
          • Risk increased in diabetic nephropathy, heart failure & dehydration
          • Can precipitate end-stage renal failure
          • Cumulative effect on repeated administration
    • Risk reduced by using Acetylcysteine ?
          • see N Engl J Med 2000; 343:180-184
  • 32. Prescribing in Kidney Disease
    • Patients with renal impairment
    • Patients on Dialysis
    • Patients with renal transplants
  • 33. Principles
    • Establish type of kidney disease
        • Most patients with kidney failure will already be taking a number of drugs
        • Interactions are common
        • Care needed to avoid drug toxicity
    • Patients with renal impairment and renal failure
        • Antihypertensives
        • Phosphate binders
  • 34. Dosing in renal impairment
    • Loading dose does not change (usually)
    • Maintenance dose or dosing interval does
    • T ½ often prolonged
      • Reduce dose OR
      • Increase dosing interval
      • Some drugs have active metabolites that are themselves excreted renally
          • Warfarin, diazepam
  • 35. Past Papers
    • Write short notes on the following
      • Spironolactone (Dec2000)
      • Amphotericin (June99)
      • Cyclosporin (June99)
  • 36. Past Papers
    • Discuss the treatment of patients with
      • Digoxin toxicity
      • Lithium toxicity
      • Following both deliberate and Iatrogenic overdose.
      • Which treatments have been shown to improve survival?
  • 37. Spironolactone
    • Class
        • Potassium sparing diuretic
    • Mode of action
        • Antagonises the effect of aldosterone at levels MR
        • Mineralocorticoid receptor (MR)–aldosterone complex translocates to nucleus to affect gene transcription
    • Indication
        • Prevent hypokalaemia in patients taking diuretics or digoxin
        • Improves survival in advanced heart failure (RALES 1999 Randomised Aldactone Evaluation Study)
        • Antihypertensive (adjunctive third line therapy for hypertension or first line for conns patients)
        • Ascites in patients with cirrhosis
  • 38. Spironolactone
    • Side effects
          • Antiandrogenic effects through the antagonism of DHT (testosterone) at its binding site.
          • Gynaecomastia, impotence, reduced libido
    • Interactions
          • Other potassium sparing drugs e.g. ACE inhibitors/ARBs & potassium supplements (remember ‘LoSalt’ used as NaCl substitute in cooking)
  • 39. Amphotericin
    • Class
        • Anti fungal agent for topical and systemic use
    • Mode of action
        • Lipid soluble drug. Binds steroid alcohols (ergosterol) in the fungal cell membrane causing leakage of cellular content and death. Effective against candida species
        • Fungistatic or fungicidal depending on the concentration
        • Broad spectrum (candida, cryptosporidium)
  • 40. Amphotericin
    • Indications
          • iv administration for systemic invasive fungal infections
          • Oral for GI mycosis
    • Side effects
          • Local/systemic effects with infusion (fever)
          • Chronic kidney dysfunction
            • Decline in GFR with prolonged use
            • Tubular dysfunction (membrane permeability)
            • Hypokalaemia, renal tubular acidosis (bicarb wasting type 1/distal), diabetes insipidus, hypomagnesaemia
            • Pre hydration/saline loading may avoid problems
    • Toxicity can be reduced substantially by liposomal packing of Amphotericin
  • 41. Lithium toxicity
    • Lithium carbonate - Rx for bipolar affective disorder
    • Toxicity closely related to serum levels
    • Symptoms
          • CVS arrhythmias (especially junctional dysrrythmias)
          • CNS tremor – confusion - coma
    • Treatment
        • Supportive - Haemodialysis and colonic irrigation for severe levels
        • Inadvertent intoxication from interaction with ACEI & loop/thiazide diuretic
        • Carbamezepine and other anti epileptics increase neurotoxicity
  • 42. Digoxin toxicity
    • Incidence
          • High levels demonstrated in 10% and toxicity reported in 4% of a series of 4000 digoxin samples
    • Kinetics
          • large volume of distribution (reservoir is skeletal muscle)
          • about 30% of stores excreted in urine/day
  • 43. Treatment of digoxin toxicity
    • Supportive
          • Correction of electrolyte imbalances
          • Atropine for bradycardia avoid cardio stimulants because arrythmogenic
    • Limitation of absorption
          • Charcoal effective within 8 hours (or cholestyramine)
    • Specific measures
          • DIGIBIND Fab digoxin specific antibodies. Binds plasma digoxin and complex eliminated by kidneys (used when OD is high/near arrest)
    • Enhanced elimination
          • Dialysis is ineffective. Charcoal/cholestyramine interrupt enterohepatic cycling.