Drugs and Renal Drugs and Renal DiseaseDisease

Sue AyersSue AyersAdvanced Pharmacist Palliative Advanced Pharmacist Palliative

Medicine and Chronic PainMedicine and Chronic PainApril 2006April 2006

OverviewOverview

Effects of renal failure on ADMEEffects of renal failure on ADME Renal PhysiologyRenal Physiology Estimating Renal FunctionEstimating Renal Function Dose Adjustment in Renal ImpairmentDose Adjustment in Renal Impairment Principles of dialysisPrinciples of dialysis Drug dosing in dialysisDrug dosing in dialysis

Effects of renal failure on ADMEEffects of renal failure on ADME

Adsorption Adsorption ––

If increased nausea and vomiting ? reduced adsorptionIf increased nausea and vomiting ? reduced adsorption

MetabolismMetabolism

Liver metabolism not affected.Liver metabolism not affected.

Metabolism only significant in conversion of cholecalciferol to 1,25-Metabolism only significant in conversion of cholecalciferol to 1,25-dihydroxycholecalciferol (25-OH group added in kidney )– use 1 dihydroxycholecalciferol (25-OH group added in kidney )– use 1 alpha – hydroxycholecalciferol to supplement Vitamin D. alpha – hydroxycholecalciferol to supplement Vitamin D.

Insulin metabolised in kidney so requirement may be lower.Insulin metabolised in kidney so requirement may be lower.

Effects of renal failure on ADMEEffects of renal failure on ADME (continued)(continued)

Distribution Distribution – –

fluid changesfluid changes - ascites or oedema - increases volume of - ascites or oedema - increases volume of distribution, dehydration reduced volume of distribution. Only distribution, dehydration reduced volume of distribution. Only clinically significant if Vd small (less than 50litres)clinically significant if Vd small (less than 50litres)

e.g. aminoglycosides or lithiume.g. aminoglycosides or lithium

Reduction of plasma protein binding -Reduction of plasma protein binding - (uraemia and other (uraemia and other accumulated waste products) or protein loss . Significance of accumulated waste products) or protein loss . Significance of increased free drug once new Css reached?. (Diazepam, increased free drug once new Css reached?. (Diazepam, morphine, phenytoin, levothyroxine and warfarin affected).morphine, phenytoin, levothyroxine and warfarin affected).

Digoxin displaced from skeletal muscle tissue binding sites by toxic Digoxin displaced from skeletal muscle tissue binding sites by toxic waste products – increased drug in plasma = decreased Vd and waste products – increased drug in plasma = decreased Vd and hence lower loading dose needed (Loading dose = target hence lower loading dose needed (Loading dose = target concentration x Vd)concentration x Vd)

Effects of renal failure on ADME Effects of renal failure on ADME (continued)(continued)

Elimination –Elimination – most important factor in dose decisions most important factor in dose decisions

Non-renal and renal clearance should be consideredNon-renal and renal clearance should be considered

Fall in renal drug clearance = fall in functioning nephrons(50% reduction ion GFR suggests a Fall in renal drug clearance = fall in functioning nephrons(50% reduction ion GFR suggests a 50% decline in renal clearance)50% decline in renal clearance)

Need to reduce doses in renal impairment depends on renal clearance, clearance of Need to reduce doses in renal impairment depends on renal clearance, clearance of metabolites and potential toxic side effects, or narrow therapeutic indexmetabolites and potential toxic side effects, or narrow therapeutic index

General considerationsGeneral considerations – uraemic patients are often more susceptible to adverse drug – uraemic patients are often more susceptible to adverse drug effects (GI bleeding on anticoagulants or NSAIDs or increase Blood Brain Barrier permeability effects (GI bleeding on anticoagulants or NSAIDs or increase Blood Brain Barrier permeability to hypnoticsto hypnotics

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

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

Glomerular filtrationGlomerular filtration molecules of low molecular weight are filtered out of the blood, molecules of low molecular weight are filtered out of the blood,

unless they are tightly bound to large molecules such as plasma unless they are tightly bound to large molecules such as plasma protein or have been incorporated into red blood cells. protein or have been incorporated into red blood cells.

Clearance by filtration Clearance by filtration f fuu x GFR x GFR

The glomerular filtration rate normal range is 110 to 130 ml/min.The glomerular filtration rate normal range is 110 to 130 ml/min.

About 10% of the blood which enters the glomerular is filtered.About 10% of the blood which enters the glomerular is filtered.

Inulin is readily filtered in the glomerular, and is not subject to Inulin is readily filtered in the glomerular, and is not subject to tubular secretion or re-absorption. Thus inulin clearance is equal to tubular secretion or re-absorption. Thus inulin clearance is equal to the glomerular filtration rate. the glomerular filtration rate.

Although most drugs are filtered from blood in the glomerular the Although most drugs are filtered from blood in the glomerular the overall renal excretion is controlled by what happens in the tubules.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. 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.Normal urine output is about 1 to 2 liter per day.

Tubular secretionTubular secretion In the proximal tubule there is re-absorption of water and In the proximal tubule there is re-absorption of water and

active secretion of some weak electrolytes but especially active secretion of some weak electrolytes but especially weak acids such as penicillins. weak acids such as penicillins.

There may be competitive inhibition of the secretion of There may be competitive inhibition of the secretion of one compound by another. (e.g. inhibition of penicillin one compound by another. (e.g. inhibition of penicillin excretion by competition with probenecid)excretion by competition with probenecid)

Drugs or compounds which are extensively secreted, Drugs or compounds which are extensively secreted, such as such as pp-aminohippuric acid (PAH), may have -aminohippuric acid (PAH), may have clearance values approaching the renal plasma flow rate clearance values approaching the renal plasma flow rate of 425 to 650 ml/min, and are used clinically to measure of 425 to 650 ml/min, and are used clinically to measure this physiological parameterthis physiological parameter

Tubular re-absorptionTubular re-absorption In the distal tubule there is passive excretion and re-absorption of In the distal tubule there is passive excretion and re-absorption of

lipid soluble drugs (non-ionized or in the unionized form). lipid soluble drugs (non-ionized or in the unionized form).

Many drugs are either weak bases or acids and therefore the pH of Many drugs are either weak bases or acids and therefore the pH of the filtrate can greatly influence the extent of tubular re-absorptionthe filtrate can greatly influence the extent of tubular re-absorption

When urine is acidic- weak acid drugs tend to be reabsorbed. When urine is acidic- weak acid drugs tend to be reabsorbed. Alternatively when urine is more alkaline, weak bases are more Alternatively when urine is more alkaline, weak bases are more extensively reabsorbed. Urine pH can vary from 4.5 to 8.0 extensively reabsorbed. Urine pH can vary from 4.5 to 8.0 depending on the diet depending on the diet

In the case of a drug overdose it is possible to increase the 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. excretion of some drugs by suitable adjustment of urine pH e.g. pentobarbital ( a weak acid) overdose it may be possible to increase pentobarbital ( a weak acid) overdose it may be possible to increase drug excretion by making the urine more alkaline with sodium drug excretion by making the urine more alkaline with sodium bicarbonate injection. bicarbonate injection.

Effective if the drug is extensively excreted as the unchanged drug . Effective if the drug is extensively excreted as the unchanged drug . If the drug is extensively metabolized then alteration of kidney If the drug is extensively metabolized then alteration of kidney excretion will not alter the overall drug metabolism all that much. excretion will not alter the overall drug metabolism all that much.

Renal clearanceRenal clearance Renal clearance can be used to investigate the mechanism of drug Renal clearance can be used to investigate the mechanism of drug

excretion. excretion.

If the drug is filtered but not secreted or reabsorbed the renal clearance will If the drug is filtered but not secreted or reabsorbed the renal clearance will be about 120 ml/min in normal subjects.be about 120 ml/min in normal subjects.

If the renal clearance is less than 120 ml/min then we can assume that at 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 least two processes are in operation, glomerular filtration and passive tubular re-absorption (tubular re-absorption (total renal clearance < ftotal renal clearance < fuu x GFR,) x GFR,)

If the renal clearance is greater than 120 ml/min then active tubular If the renal clearance is greater than 120 ml/min then active tubular secretion must be contributing to the elimination process (secretion must be contributing to the elimination process (total renal total renal clearance > fclearance > fuu x GFR) x GFR)

It is also possible that all three processes are occurring simultaneously. It is also possible that all three processes are occurring simultaneously. Renal clearance is then:- Renal clearance is then:-

Estimating renal function - GFREstimating 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

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

Calculating Ideal Body WeightCalculating Ideal Body Weight

GFRs (ml/min/kg) for various species: GFRs (ml/min/kg) for various species:

Cow 1.8Cow 1.8 Horse 1.7Horse 1.7 Human 1.8Human 1.8 Sheep 2.0Sheep 2.0 Goat 2.2Goat 2.2 Dog 4.0Dog 4.0 Rat 10.0Rat 10.0

4vMDRD4vMDRD(modification of diet in renal disease)(modification of diet in renal disease)

( eGFR )( eGFR )

4-variable MDRD = 186 x  [Pcr X0.011312]-1. 154 x [Age]-0.203 x [0.742 female] x [1.212 black

race] 

• 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)

Dose Adjustments in Renal Dose Adjustments in Renal ImpairmentImpairment

Alter dose or dose interval or bothAlter dose or dose interval or both

DRrf = DRn x ((1-Feu) + (Feu x RF)) DRrf = DRn x ((1-Feu) + (Feu x RF))

where DRrf = dosing rate in renal failurewhere DRrf = dosing rate in renal failure

DRn = normal dosing rateDRn = normal dosing rate

RF = extent of renal failure RF = extent of renal failure

= = patient’s creatinine clearance (ml/min)patient’s creatinine clearance (ml/min)

Ideal creatinine clearance (120ml/min)Ideal creatinine clearance (120ml/min)

Feu = fraction of drug normally excreted unchanged in the Feu = fraction of drug normally excreted unchanged in the

urineurine

Dose Adjustments in Renal Dose Adjustments in Renal ImpairmentImpairment (continued) (continued)

Use the most appropriate resource Use the most appropriate resource

(e.g. SPC or Renal Drug Handbook)(e.g. SPC or Renal Drug Handbook)

Ideal Drug in Renal FailureIdeal Drug in Renal Failure Less than 25% excreted unchanged in the urineLess than 25% excreted unchanged in the urine

No active (or toxic) metabolitesNo active (or toxic) metabolites

Disposition unaffected by fluid balance changesDisposition unaffected by fluid balance changes

Disposition unaffected by altered protein bindingDisposition unaffected by altered protein binding

Response unaffected by altered tissue sensitivityResponse unaffected by altered tissue sensitivity

Wide therapeutic rangeWide therapeutic range

Not nephrotoxicNot nephrotoxic

DialysisDialysis (Renal Replacement Therapy)(Renal Replacement Therapy)

Remove ToxinsRemove Toxins

Remove Excess FluidsRemove Excess Fluids

Correct acid/base balanceCorrect acid/base balance

Correct electrolyte disturbanceCorrect electrolyte disturbance

General principles of dialysisGeneral principles of dialysis

Semi-permeable membraneSemi-permeable membrane

Blood one side / dialysis fluid the otherBlood one side / dialysis fluid the other

Method of delivering blood to membrane (pump)Method of delivering blood to membrane (pump)

Method of delivering dialysis fluid/removing Method of delivering dialysis fluid/removing excess water and waste products (pump or PD excess water and waste products (pump or PD cathetercatheter

Passage through the semi-Passage through the semi-permeable membrane (SPM)permeable membrane (SPM)

DiffusionDiffusion – Passage of – Passage of SOLUTESOLUTE from a high from a high concentration to a low concentration through a SPM (ie concentration to a low concentration through a SPM (ie in haemodialysis waste out Ca and HCO3 in)in haemodialysis waste out Ca and HCO3 in)

UltrafiltrationUltrafiltration – passage of – passage of FLUIDFLUID under pressure (+ve under pressure (+ve or –ve ) across a SPMor –ve ) across a SPM

In Haemodialysis/haemofiltration pressure is hydrostaticIn Haemodialysis/haemofiltration pressure is hydrostatic

In Peritoneal Dialysis pressure is osmoticIn Peritoneal Dialysis pressure is osmotic

HaemodialysisHaemodialysis Blood is drawn through the artificial kidneyBlood is drawn through the artificial kidney

Dialysis fluid is perfused around the SPM filaments in the artificial Dialysis fluid is perfused around the SPM filaments in the artificial kidney – never coming into contact with blood directlykidney – never coming into contact with blood directly

Solutes are cleared by diffusionSolutes are cleared by diffusion

Calcium and Bicarbonate may be replaced in ECF across the Calcium and Bicarbonate may be replaced in ECF across the diffusion gradientdiffusion gradient

Excess fluid is removed by ultrafiltration under control of dialysis Excess fluid is removed by ultrafiltration under control of dialysis machinemachine

Can be intermittent or continuousCan be intermittent or continuous

Peritoneal DialysisPeritoneal Dialysis

PD fluid is introduced into peritoneal cavity PD fluid is introduced into peritoneal cavity and “dwelled” for a specific time, drained and “dwelled” for a specific time, drained and replacedand replaced

Diffusion and ultrafiltration takes place Diffusion and ultrafiltration takes place across the SPMacross the SPM

Ultrfiltration is controlled by concentration Ultrfiltration is controlled by concentration of glucose in PD fluid of glucose in PD fluid

Intermittent (Acute) or ContinuousIntermittent (Acute) or Continuous

HaemofiltrationHaemofiltration

Blood is drawn through artificial kidney and ECF Blood is drawn through artificial kidney and ECF is removed by ultrafiltration.is removed by ultrafiltration.

ECF is replaced with haemofiltration fluid –rate ECF is replaced with haemofiltration fluid –rate controlled to lead to overall fluid removalcontrolled to lead to overall fluid removal

Solute clearance is achieved by convectionSolute clearance is achieved by convection

Can be intermittent (mainly to remove fluid if Can be intermittent (mainly to remove fluid if overloaded) or continuous in sicker patientsoverloaded) or continuous in sicker patients

HaemodiafiltrationHaemodiafiltration

Combined techniques of dialysis by Combined techniques of dialysis by diffusion and filtration which removes diffusion and filtration which removes solutes by convection.solutes by convection.

Dialysate is haemofiltration or peritoneal Dialysate is haemofiltration or peritoneal dailysis solution and transmembrane dailysis solution and transmembrane pressure is ajusted to remove solutes or pressure is ajusted to remove solutes or waterwater

Approximate clearance of dialysis Approximate clearance of dialysis systemssystems

Intermittent Haemodialysis Intermittent Haemodialysis 150 – 150 – 200ml/min200ml/min

Intermittent Haemofiltration Intermittent Haemofiltration 100 - 100 - 150ml/min150ml/min

Acute Intermittent PDAcute Intermittent PD 10 - 20ml/min10 - 20ml/min CAPDCAPD 5 - 8ml/min5 - 8ml/min Continuous haemofiltration Continuous haemofiltration 5 - 15ml/min5 - 15ml/min Continuous Haemodiafiltration Continuous Haemodiafiltration 15 - 25ml/min15 - 25ml/min

Factors Affecting Drug removal Factors Affecting Drug removal during dialysisduring dialysis

molecular size, steric hindrancemolecular size, steric hindrance protein binding, protein binding, volume of distribution, volume of distribution, water solubility,water solubility, plasma clearance. plasma clearance. technical aspects of dialysis procedure (technical aspects of dialysis procedure (Surface Surface

area of membrane,Blood flow rate,Dialysate flow area of membrane,Blood flow rate,Dialysate flow rate,dialysis time (HD),Dialysate volume (PD) )rate,dialysis time (HD),Dialysate volume (PD) )

Molecular WeightMolecular Weight

Dialytic membrane pore size - synthetic membrane or Dialytic membrane pore size - synthetic membrane or natural (CAPD)natural (CAPD)

Size vs pore sizeSize vs pore size

Pore size of the peritoneal membrane is assumed to be Pore size of the peritoneal membrane is assumed to be larger than that of a HD membrane.larger than that of a HD membrane.

MW > 1,000 daltons “seived” ,< 1,000 “diffuse”MW > 1,000 daltons “seived” ,< 1,000 “diffuse”

Heamodiafiltration removes 10% more middle molecules Heamodiafiltration removes 10% more middle molecules (500 – 5,000 daltons) than heamodialysis and 24% (500 – 5,000 daltons) than heamodialysis and 24% more > 5,000 daltonsmore > 5,000 daltons

Protein Binding and dialysisProtein Binding and dialysis

Concentration gradient of unbound (free) drug across the dialysis Concentration gradient of unbound (free) drug across the dialysis membrane is importantmembrane is important

High degree of protein binding = low plasma conc. of unbound drug High degree of protein binding = low plasma conc. of unbound drug available for dialysis.available for dialysis.

Uremia may decrease protein bindingUremia may decrease protein binding

If significant,If significant, increased dialyzability of free drug may occur. increased dialyzability of free drug may occur.

In peritonitis Increased protein concentrations often occur in In peritonitis Increased protein concentrations often occur in peritoneal effluent peritoneal effluent

Volume of distribution and dialysisVolume of distribution and dialysis

A drug with a large Vd is distributed widely throughout A drug with a large Vd is distributed widely throughout tissues and has relatively small amounts in the blood.tissues and has relatively small amounts in the blood.

Factors that contribute to a large Vd include high lipid Factors that contribute to a large Vd include high lipid solubility and low plasma protein binding.solubility and low plasma protein binding.

Drugs with a large volume of distribution are likely to be Drugs with a large volume of distribution are likely to be dialyzed minimally.dialyzed minimally.

Conversely, highly water soluble drugs are likely to be Conversely, highly water soluble drugs are likely to be more easily dialysable more easily dialysable

Plasma ClearancePlasma Clearance

The inherent metabolic clearance = sum of renal and The inherent metabolic clearance = sum of renal and non-renal clearance ( "plasma clearance“)non-renal clearance ( "plasma clearance“)

In dialysis patients, In dialysis patients, renal clearance is largely replaced by renal clearance is largely replaced by dialysis clearance.dialysis clearance.

If non-renal clearance is large vs renal clearance, If non-renal clearance is large vs renal clearance, contribution of dialysis to total drug removal is low. contribution of dialysis to total drug removal is low.

If renal (and hence dialysis) clearance is >30% more, If renal (and hence dialysis) clearance is >30% more, dialysis clearance is considered to be clinically dialysis clearance is considered to be clinically Important.Important.

DigoxinDigoxin

Molecular weight 750Molecular weight 750 Protein binding 20%Protein binding 20% Water solubleWater soluble ? Is it well dialysed? Is it well dialysed No – Vd is 7litres/kg – total body clearance No – Vd is 7litres/kg – total body clearance

low as most of drug not available to be low as most of drug not available to be dialyseddialysed

Dose Adjustment for Renal Dose Adjustment for Renal Replacement TherapyReplacement Therapy

Only required for drugs that already need dose Only required for drugs that already need dose adjustment in renal failure adjustment in renal failure

Supplementation rarely needed, even if removed - give Supplementation rarely needed, even if removed - give after intermittent techniquesafter intermittent techniques

Dose drugs requiring TDM by blood levels rather than Dose drugs requiring TDM by blood levels rather than computer models and nomogramscomputer models and nomograms

Use recognised resourcesUse recognised resources

Dose Adjustment for Renal Dose Adjustment for Renal Replacement Therapy (continued)Replacement Therapy (continued)

Always aim to give drugs at the end of any Always aim to give drugs at the end of any session of intermittent dialysis or filtrationsession of intermittent dialysis or filtration

For continuous RRT dose according to the SPC For continuous RRT dose according to the SPC recommendations for the estimated CrCl of the recommendations for the estimated CrCl of the dialysis systemdialysis system

Never give more than doses recommended in Never give more than doses recommended in patients with normal renal functionpatients with normal renal function

Discuss doses with an experienced colleagueDiscuss doses with an experienced colleague