Drugs and the kidney
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Drugs and the kidney Presentation Transcript

  • 1. Drugs and the Kidney www.freelivedoctor.com
  • 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
    www.freelivedoctor.com
  • 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)
    www.freelivedoctor.com
  • 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
    www.freelivedoctor.com
  • 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
    www.freelivedoctor.com
  • 6. Serum Creatinine and GFR Serum creatinine Glomerular filtration rate (GFR) www.freelivedoctor.com
  • 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
    www.freelivedoctor.com
  • 8. Tests of renal function cont.
    • 24h Urine sample-Creatinine clearance
    • chromium EDTA Clearance
    • gold standard Inulin clearance
    www.freelivedoctor.com
  • 9. The nephron and electrolyte handling www.freelivedoctor.com
  • 10. www.freelivedoctor.com
  • 11. Pharmacokinetics
    • Absorption
    • Distribution
    • Metabolism
    • Elimination
          • filtration
          • secretion
    www.freelivedoctor.com
  • 12. Diuretics
    • Loop
    • Thiazide
    • Aldosterone antagonist
    • Osmotic
    www.freelivedoctor.com
  • 13. Diuretics
    • Indications for use
      • heart failure ( acute or chronic )
      • pulmonary oedema
      • hypertension
      • nephrotic syndrome
      • hypercalcaemia
      • hypercalciuria
    www.freelivedoctor.com
  • 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
    www.freelivedoctor.com
  • 15. www.freelivedoctor.com
  • 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
    www.freelivedoctor.com
  • 17. Loop diuretics continued
    • Caution
      • Electrolyte imbalance - hypokalaemia
      • Volume depletion (prerenal uremia)
      • Tinitus (acts within cochlea – can synergise with aminoglycoside antibiotics)
    www.freelivedoctor.com
  • 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
    www.freelivedoctor.com
  • 19. www.freelivedoctor.com
  • 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
    www.freelivedoctor.com
  • 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. 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. 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. 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
    www.freelivedoctor.com
  • 25. www.freelivedoctor.com
  • 26. Nephrotoxic Drugs
    • Dose dependant toxicity
      • NSAIDs including COX 2
      • Aminoglycosides
      • Radio opaque contrast materials
    • Idiosyncratic Renal Damage
      • NSAIDs
      • Penicillins
      • Gold, penicillamine
    www.freelivedoctor.com
  • 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
    www.freelivedoctor.com
  • 28. www.freelivedoctor.com
  • 29. Aminoglycosides
    • Highly effective antimicrobials
      • Particularly useful in gram -ve sepsis
      • bactericidal
    • BUT
      • Nephrotoxic
      • Ototoxic
      • Narrow therapeutic range
    www.freelivedoctor.com
  • 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!
    www.freelivedoctor.com
  • 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
    www.freelivedoctor.com
  • 32. Prescribing in Kidney Disease
    • Patients with renal impairment
    • Patients on Dialysis
    • Patients with renal transplants
    www.freelivedoctor.com
  • 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
    www.freelivedoctor.com
  • 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
    www.freelivedoctor.com
  • 35. 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
    www.freelivedoctor.com
  • 36. 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)
    www.freelivedoctor.com
  • 37. 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)
    www.freelivedoctor.com
  • 38. 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
    www.freelivedoctor.com
  • 39. 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
    www.freelivedoctor.com
  • 40. 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
    www.freelivedoctor.com
  • 41. 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.
    www.freelivedoctor.com
  • 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. Principles important for understanding effects of diuretics
    • Interference with Na + reabsorption at one nephron site interferes with other renal functions linked to it
    • It also leads to increased Na + reabsorption at other sites
    • Increased flow and Na + delivery to distal nephron stimulates K + (and H + ) secretion
    www.freelivedoctor.com
  • 44.
    • 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
    • Diuretic actions at different nephron sites can produce synergism
    • All, except spironolactone, act from the lumenal side of the tubular cellular membrane
    Principles important for understanding effects of diuretics www.freelivedoctor.com
  • 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. THIAZIDE DIURETICS
    • Secreted into the tubular lumen by the organic acid transport mechanisms in the proximal tubule
    • Act on the distal tubule to inhibit sodium and chloride transport and result in a modest diuresis
    • Increase renal excretion of potassium, magnesium
    • Reduce calcium and urate excretion
    • Not effective at low glomerular filtration rates
    • Impair maximal diluting but not maximal concentrating ability
    www.freelivedoctor.com
  • 47. General Structure of Thiazide Diuretics www.freelivedoctor.com
  • 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. 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. Thiazides - Pharmacokinetics
    • Rapid GI absorption
    • Distribution in extracellular space
    • Elimination unchanged in kidney
    • Variable elimination kinetics and therefore variable half-lives of elimination ranging from hours to days.
    www.freelivedoctor.com
  • 51. CLINICAL USES Of THIAZIDES-1
    • 1 ) HYPERTENSION
    • Thiazides reduce blood pressure and associated risk of CVA and MI in hypertension
    • they should be considered first-line therapy in hypertension (effective, safe and cheap)
    • Mechanism of action in hypertension is uncertain – involves vasodilation that is not a direct effect but a consequence of the diuretic/natriuretic effect
    www.freelivedoctor.com
  • 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. www.freelivedoctor.com
  • 54. www.freelivedoctor.com
  • 55. CLINICAL USES OF THIAZIDES-2
    • 2) EDEMA (cardiac, liver renal)
    • 3) IDIOPATHIC HYPERCALCIURIA
    • condition characterized by recurrent stone formation in the kidneys due to excess calcium excretion
    • thiazide diuretics used to prevent calcium loss and protect the kidneys
    • 4) DIABETES INSIPIDUS
    www.freelivedoctor.com
  • 56. ADVERSE EFFECTS OF THIAZIDES-1
    • Initially, they were used at high doses which caused a high
    • incidence of adverse effects. Lower doses now used cause
    • fewer adverse effects. Among them are:
    • HYPOKALEMIA
    • DEHYDRATION (particularly in the elderly) leading to POSTURAL HYPOTENSION
    • HYPERGLYCEMIA possibly because of impaired insulin release secondary to hypokalemia
    • HYPERURICEMIA because thiazides compete with urate for tubular secretion
    www.freelivedoctor.com
  • 57. ADVERSE EFFECTS OF THIAZIDES-2
    • HYPERLIPIDEMIA ; mechanism unknown but cholesterol increases usually trivial (1% increase)
    • IMPOTENCE
    • HYPONATREMIA due to thirst, sodium lo s loss, inappropriate ADH secretion (can cause confusion in the elderly), usually after prolonged use
    www.freelivedoctor.com
  • 58.
    • Less common problems
    • HYPERSENSITIVITY - may manifest as interstitial nephritis, pancreatitis, rashes, blood dyscrasias (all very rare)
    • METABOLIC ALKALOSIS due to increased sodium load at the distal convoluted tubule which stimulates the sodium/hydrogen exchanger to reabsorb sodium and excrete hydrogen
    • HYPERCALCEMIA
    ADVERSE EFFECTS OF THIAZIDES-3 www.freelivedoctor.com
  • 59. LOOP DIURETICS
    • Secreted in proximal tubule by acid mechanisms
    • Act on the ascending loop of Henle to inhibit sodium and chloride transport
    • Cause a greater natriuresis than thiazides
    • Effective at low glomerular filtration rates (as occur in chronic renal failure), where thiazides are ineffective
    • Increase potassium, calcium and magnesium excretion
    • Decrease urate excretion
    • Impair maximal concentrating and diluting capacity
    www.freelivedoctor.com
  • 60. www.freelivedoctor.com
  • 61. LOOP DIURETICS
    • Additional non-tubular effects
    • 1. Renal Vasodilation and redistribution of blood flow
    • 2. Increase in renin release
    • 3. Increase in venous capacitance
    • These effects mediated by release of prostaglandins from the kidney.
    www.freelivedoctor.com
  • 62. www.freelivedoctor.com
  • 63. Loop Diuretics - Pharmacokinetics
    • Rapid GI absorption. Also given i.m. and i.v.
    • Extensively protein bound in plasma
    • Short half-lives in general
    • Elimination: unchanged in kidney or by conjugation in the liver and secretion in bile.
    www.freelivedoctor.com
  • 64. www.freelivedoctor.com
  • 65. CLINICAL USES OF LOOP DIURETICS
    • EDEMA due to CHF, nephrotic syndrome or cirrhosis
    • Acute heart failure with PULMONARY EDEMA
    • HYPERCALCEMIA
    • not in widespread use for the treatment of hypertension (except in a few special cases e.g. hypertension in renal disease)
    www.freelivedoctor.com
  • 66.
    • Hypokalemia, metabolic alkalosis, hypercholesterolemia, hyperuricemia, hyperglycemia, hyponatremia
    • Dehydration and postural hypotension
    • Hypocalcemia (in contrast to thiazides)
    • Hypersensitivity
    • OTOTOXICITY (especially if given by rapid IV bolus)
    Adverse Effects of Loop Diuretics similar to thiazides in many respects www.freelivedoctor.com
  • 67. Edema: Therapeutic Considerations
    • Therapy is palliative (except with pulmonary edema).
    • Need a mild sustained response.
    • Specific consideration to potassium homeostasis, i.e. supplement with K-salt or use K-sparing diuretic.
    • Therefore, in most cases start with a thiazide.
    • If resistant, move to Loop diuretic.
    www.freelivedoctor.com
  • 68. www.freelivedoctor.com
  • 69. Conditions treated with Diuretics
    • Edema
    • Hypertension
    • Nephrogenic Diabetes Insipidus
    • Syndrome of Inappropriate ADH Secretion (SIADH)
    • To increase or decrease Ca ++ , K + or H + ion excretion.
    www.freelivedoctor.com
  • 70. Diuretic Resistance
    • Compensatory Mechanisms ( RAAS, SNS )
    • Failure to reach tubular site of action
    • a - Decreased G.I. absorption
    • b - Decreased secretion into tubular lumen
    • (e.g. uremia, decreased kidney perfusion)
    • c - Decreased availability in tubular lumen
    • (e.g. nephrotic syndrome)
    • Interference by other drugs ( e.g. NSAID’s )
    • Tubular adaptation ( chronic Loop diuretic use)
    • Can Use Combination of Diuretics
    • to Induce a S ynergistic Effect
    www.freelivedoctor.com
  • 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