Drugs and Renal Disease

1. Drugs and Renal Disease Sue Ayers Advanced Pharmacist Palliative Medicine and Chronic Pain April 2006

2. Overview • Effects of renal failure on ADME • Renal Physiology • Estimating Renal Function • Dose Adjustment in Renal Impairment • Principles of dialysis • Drug dosing in dialysis

3. Effects of renal failure on ADME • Adsorption – • If increased nausea and vomiting ? reduced adsorption • Metabolism • Liver metabolism not affected. • Metabolism only significant in conversion of cholecalciferol to 1,25-dihydroxycholecalciferol (25-OH group added in kidney )– use 1 alpha – hydroxycholecalciferol to supplement Vitamin D. • Insulin metabolised in kidney so requirement may be lower.

4. Effects of renal failure on ADME(continued) • Distribution – fluid changes - ascites or oedema - increases volume of distribution, dehydration reduced volume of distribution. Only clinically significant if Vd small (less than 50litres) e.g. aminoglycosides or lithium Reduction of plasma protein binding - (uraemia and other accumulated waste products) or protein loss . Significance of increased free drug once new Css reached?. (Diazepam, morphine, phenytoin, levothyroxine and warfarin affected). Digoxin displaced from skeletal muscle tissue binding sites by toxic waste products – increased drug in plasma = decreased Vd and hence lower loading dose needed (Loading dose = target concentration x Vd)

5. Effects of renal failure on ADME (continued) • Elimination – most important factor in dose decisions • Non-renal and renal clearance should be considered • Fall in renal drug clearance = fall in functioning nephrons(50% reduction ion GFR suggests a 50% decline in renal clearance) • Need to reduce doses in renal impairment depends on renal clearance, clearance of metabolites and potential toxic side effects, or narrow therapeutic index • General considerations – uraemic patients are often more susceptible to adverse drug effects (GI bleeding on anticoagulants or NSAIDs or increase Blood Brain Barrier permeability to hypnotics

8. http://www.nottingham.ac.uk/healthquest/sonet/rlos/bioproc/kidneydrug/index.htmlhttp://www.nottingham.ac.uk/healthquest/sonet/rlos/bioproc/kidneydrug/index.html

9. The Nephron • The major organ for the excretion of drugs is the KIDNEY. The functional unit of the kidney is the nephron in which there are three major processes to consider:-

10. Glomerular filtration • molecules of low molecular weight are filtered out of the blood, unless they are tightly bound to large molecules such as plasma protein or have been incorporated into red blood cells. • Clearance by filtration  fu x GFR • The glomerular filtration rate normal range is 110 to 130 ml/min. • About 10% of the blood which enters the glomerular is filtered. • Inulin is readily filtered in the glomerular, and is not subject to tubular secretion or re-absorption. Thus inulin clearance is equal to the glomerular filtration rate. • Although most drugs are filtered from blood in the glomerular the overall renal excretion is controlled by what happens in the tubules. • More than 90% of the filtrate is reabsorbed. 120 ml/min is 173 L/day. Normal urine output is about 1 to 2 liter per day.

11. Tubular secretion • In the proximal tubule there is re-absorption of water and active secretion of some weak electrolytes but especially weak acids such as penicillins. • There may be competitive inhibition of the secretion of one compound by another. (e.g. inhibition of penicillin excretion by competition with probenecid) • Drugs or compounds which are extensively secreted, such as p-aminohippuric acid (PAH), may have clearance values approaching the renal plasma flow rate of 425 to 650 ml/min, and are used clinically to measure this physiological parameter

12. Tubular re-absorption • In the distal tubule there is passive excretion and re-absorption of lipid soluble drugs (non-ionized or in the unionized form). • Many drugs are either weak bases or acids and therefore the pH of the filtrate can greatly influence the extent of tubular re-absorption • When urine is acidic- weak acid drugs tend to be reabsorbed. Alternatively when urine is more alkaline, weak bases are more extensively reabsorbed. Urine pH can vary from 4.5 to 8.0 depending on the diet • In the case of a drug overdose it is possible to increase the excretion of some drugs by suitable adjustment of urine pH e.g. pentobarbital ( a weak acid) overdose it may be possible to increase drug excretion by making the urine more alkaline with sodium bicarbonate injection. • Effective if the drug is extensively excreted as the unchanged drug . If the drug is extensively metabolized then alteration of kidney excretion will not alter the overall drug metabolism all that much.

13. Renal clearance • Renal clearance can be used to investigate the mechanism of drug excretion. • If the drug is filtered but not secreted or reabsorbed the renal clearance will be about 120 ml/min in normal subjects. • If the renal clearance is less than 120 ml/min then we can assume that at least two processes are in operation, glomerular filtration and passive tubular re-absorption (total renal clearance < fu x GFR,) • If the renal clearance is greater than 120 ml/min then active tubular secretion must be contributing to the elimination process (total renal clearance > fu x GFR) • It is also possible that all three processes are occurring simultaneously. Renal clearance is then:-

14. Estimating renal function - GFR • Approximately 125mls/min in normal adult • Cockcroft and Gault Equation: • Cl Cr (male) = 1.23 x (140 – age) x IBW • Serum creatinine (micromol/litre) • Cl Cr (female) = 1.04 x (140 – age) x IBW • Serum creatinine (micromol/litre) • Accuracy poor if GFR< 20ml/min • SeCr doubling is equivalent to halving of CrCl ( eg a rise from 60 to 120 micromol/litre is potentially equal to the loss of one kidney • Smallchanges in low Se Cr are as significant as large changes in already high Se Cr

15. Calculating Ideal Body Weight IBW (male) = 50 + (2.3 x height in inches over 5 feet) kg = (Height (cm) -154) x 0.9 +50 kg IBW (female) = 45.5 + (2.3 x height in inches over 5 feet) kg = (Height (cm) -154) x 0.9 +50 kg

16. GFRs (ml/min/kg) for various species: • Cow 1.8 • Horse 1.7 • Human 1.8 • Sheep 2.0 • Goat 2.2 • Dog 4.0 • Rat 10.0

17. 4vMDRD(modification of diet in renal disease)( eGFR ) • Best fit calculation required 6 variables, one of which was urinary urea • needed an equation that required only serum measurements and easy calculation, • Used an equation which has 4 variables (with only a small loss of accuracy) 4-variable MDRD = 186 x  [Pcr X0.011312]-1. 154 x [Age]-0.203 x [0.742 female] x [1.212 black race] 

18. Alter dose or dose interval or both DRrf = DRn x ((1-Feu) + (Feu x RF)) where DRrf = dosing rate in renal failure DRn = normal dosing rate RF = extent of renal failure = patient’s creatinine clearance (ml/min) Ideal creatinine clearance (120ml/min) Feu = fraction of drug normally excreted unchanged in the urine Dose Adjustments in Renal Impairment

19. Dose Adjustments in Renal Impairment (continued) • Use the most appropriate resource (e.g. SPC or Renal Drug Handbook)

20. Ideal Drug in Renal Failure • Less than 25% excreted unchanged in the urine • No active (or toxic) metabolites • Disposition unaffected by fluid balance changes • Disposition unaffected by altered protein binding • Response unaffected by altered tissue sensitivity • Wide therapeutic range • Not nephrotoxic

21. Dialysis(Renal Replacement Therapy) • Remove Toxins • Remove Excess Fluids • Correct acid/base balance • Correct electrolyte disturbance

22. General principles of dialysis • Semi-permeable membrane • Blood one side / dialysis fluid the other • Method of delivering blood to membrane (pump) • Method of delivering dialysis fluid/removing excess water and waste products (pump or PD catheter

23. Passage through the semi-permeable membrane (SPM) • Diffusion – Passage of SOLUTE from a high concentration to a low concentration through a SPM (ie in haemodialysis waste out Ca and HCO3 in) • Ultrafiltration – passage of FLUID under pressure (+ve or –ve ) across a SPM • In Haemodialysis/haemofiltration pressure is hydrostatic • In Peritoneal Dialysis pressure is osmotic

24. Haemodialysis • Blood is drawn through the artificial kidney • Dialysis fluid is perfused around the SPM filaments in the artificial kidney – never coming into contact with blood directly • Solutes are cleared by diffusion • Calcium and Bicarbonate may be replaced in ECF across the diffusion gradient • Excess fluid is removed by ultrafiltration under control of dialysis machine • Can be intermittent or continuous

25. Peritoneal Dialysis • PD fluid is introduced into peritoneal cavity and “dwelled” for a specific time, drained and replaced • Diffusion and ultrafiltration takes place across the SPM • Ultrfiltration is controlled by concentration of glucose in PD fluid • Intermittent (Acute) or Continuous

26. Haemofiltration • Blood is drawn through artificial kidney and ECF is removed by ultrafiltration. • ECF is replaced with haemofiltration fluid –rate controlled to lead to overall fluid removal • Solute clearance is achieved by convection • Can be intermittent (mainly to remove fluid if overloaded) or continuous in sicker patients

27. Haemodiafiltration • Combined techniques of dialysis by diffusion and filtration which removes solutes by convection. • Dialysate is haemofiltration or peritoneal dailysis solution and transmembrane pressure is ajusted to remove solutes or water

29. Approximate clearance of dialysis systems • Intermittent Haemodialysis 150 – 200ml/min • Intermittent Haemofiltration 100 - 150ml/min • Acute Intermittent PD 10 - 20ml/min • CAPD 5 - 8ml/min • Continuous haemofiltration 5 - 15ml/min • Continuous Haemodiafiltration 15 - 25ml/min

31. Factors Affecting Drug removal during dialysis • molecular size, steric hindrance • protein binding, • volume of distribution, • water solubility, • plasma clearance. • technical aspects of dialysis procedure (Surface area of membrane,Blood flow rate,Dialysate flow rate,dialysis time (HD),Dialysate volume (PD) )

32. Molecular Weight • Dialytic membrane pore size - synthetic membrane or natural (CAPD) • Size vs pore size • Pore size of the peritoneal membrane is assumed to be larger than that of a HD membrane. • MW > 1,000 daltons “seived” ,< 1,000 “diffuse” • Heamodiafiltration removes 10% more middle molecules (500 – 5,000 daltons) than heamodialysis and 24% more > 5,000 daltons

33. Protein Binding and dialysis • Concentration gradient of unbound (free) drug across the dialysis membrane is important • High degree of protein binding = low plasma conc. of unbound drug available for dialysis. • Uremia may decrease protein binding • If significant, increased dialyzability of free drug may occur. • In peritonitis Increased protein concentrations often occur in peritoneal effluent

34. Volume of distribution and dialysis • A drug with a large Vd is distributed widely throughout tissues and has relatively small amounts in the blood. • Factors that contribute to a large Vd include high lipid solubility and low plasma protein binding. • Drugs with a large volume of distribution are likely to be dialyzed minimally. • Conversely, highly water soluble drugs are likely to be more easily dialysable

35. Plasma Clearance • The inherent metabolic clearance = sum of renal and non-renal clearance ( "plasma clearance“) • In dialysis patients, renal clearance is largely replaced by dialysis clearance. • If non-renal clearance is large vs renal clearance, contribution of dialysis to total drug removal is low. • If renal (and hence dialysis) clearance is >30% more, dialysis clearance is considered to be clinically Important.

36. Digoxin • Molecular weight 750 • Protein binding 20% • Water soluble • ? Is it well dialysed • No – Vd is 7litres/kg – total body clearance low as most of drug not available to be dialysed

37. Dose Adjustment for Renal Replacement Therapy • Only required for drugs that already need dose adjustment in renal failure • Supplementation rarely needed, even if removed - give after intermittent techniques • Dose drugs requiring TDM by blood levels rather than computer models and nomograms • Use recognised resources

38. Dose Adjustment for Renal Replacement Therapy (continued) • Always aim to give drugs at the end of any session of intermittent dialysis or filtration • For continuous RRT dose according to the SPC recommendations for the estimated CrCl of the dialysis system • Never give more than doses recommended in patients with normal renal function • Discuss doses with an experienced colleague