renal training

Judith Coombes PharmacistPrincess Alexandra Hospital

And School of pharmacy University of Queensland

Material provided by Jo Sturtevant Renal and Transplant pharmacist Princess Alexandra Hospital and

Graham Davies, Kings College London

“a significant % of patients with renal impairment are admitted to hospital on

inappropriately high doses of drugs, with a high fractional renal excretion and low

therapeutic index”

(Pillans et al 2003)

DRUG USE IN RENAL DISEASE

OBJECTIVESAt the end of this series of lectures, students should be able to:

•Identify patients who are at risk of renal failure•Describe how a patient’s renal function should be monitored•Classify renal function•Describe the influence of renal failure on drug pharmacokinetics•List the drugs commonly associated with renal failure•Describe the treatment of the complication of chronic renal failure

At risk patients

Elderly – Glomerular Filtration Rate (GFR) may be significantly reduced due to ↓ muscle mass and protein intake even though creatinine is within normal range.

Transplant patients – all antirejection drugs Diabetics Congestive Heart Failure

Multiple co-morbidities

& complex frequently

changing medication regimens

=

unwanted effects

drug interactions

confusion

MONITORING PATIENTS’ DRUG THERAPYROLE OF THE PHARMACIST

1. Efficacy of treatment, e.g. Oedema and weight following diuretic therapyBP following antihypertensive therapy

2. Adjust drug dosing regimens in line with renal status, e.g. antibiotics

3. Monitor renal function of patients receiving nephrotoxic agents

CLASSIFICATION OF RENAL FILURE

ClassificationClassification GFR (mls/min/1.73mGFR (mls/min/1.73m22)) Serum Creatinine Serum Creatinine ((mol/L)mol/L)

MildMild 20 to 5020 to 50 150 to 300150 to 300

ModerateModerate 10 to 2010 to 20 300 to 700300 to 700

SevereSevere < 10< 10 > 700> 700

Appendix 3 : BNF

MONITORING PATIENTS’ RENAL FUNCTION

1. Patient’s clinical condition

2. Biochemical Data

3. Other biochemical abnormalities

2(a) Serum Creatinine (40 to 120 Micromoles/Litre)

Increased by: Large muscle mass, dietary intake Drugs

Interfere with analysis (Jaffe reaction) e.g. methyldopa, levodopa, dexamethasone, cephalosporinsInhibit tubular secretion e.g. cimetidine, trimethoprim, aspirin

Ketoacidosis

Decreased by: Reduced muscle mass (elderly) Severe renal disease (increased secretion) Cachexia / starvation Immobility Pregnancy

1(a). Clinical Assessment

Basic FunctionBasic Function SignSign SymptomSymptom

Fluid BalanceFluid Balance Oedema, Raised JVPOedema, Raised JVP BreathlessnessBreathlessness

ElectrolyteElectrolyte Abnormal ECGAbnormal ECG NoneNone

Regulation especially KRegulation especially K++, Na, Na++, , POPO44 and calcium and calcium

Absent P wavesAbsent P wavesBroad QRS complexBroad QRS complexPeaked T wavesPeaked T waves

EPO productionEPO production PallorPallor FatigueFatigue

Vitamin D3Vitamin D3 OsteomalaciaOsteomalacia Bone PainBone Pain

ExcretionExcretion Raised urea concentration in Raised urea concentration in bloodblood

PruritisPruritisNausea and vomitingNausea and vomiting

Acid BaseAcid Basebalancebalance

Low pH and bicarb.Low pH and bicarb. Deep and rapid respirationDeep and rapid respiration

Dosing in kidney impairment

What should I use??

Predicting GFR using serum and urine creatinine concentrations.

Cockcroft and Gault Equation

GFR = F (140 – age [yrs]) Ideal Body Wt (kg)Serum creatinine (mol/L)

Where:F = 1.23 for males and 1.04 for females

IBW = 50 kg + 2.23 kg for every 1” > 5 feet in height (male)IBW = 45.5 kg + 2.3 kg for every 1” > 5 feet in height (female)

Examples – estimating renal function using serum creatinine.

Patient detailsMr JB 75 yr old gentleman admitted to the renal unit with a longstanding history of NIDDM and hypertension.Ideal body weight = 80 kg, serum creatinine = 400 mol/L, urine creatinine = 3.7 mmol/L, 24 hr urine volume = 2400 mls

Method 1: British National Formulary Appendix 3

Classification GFR (mls/min/1.73m2) Serum Creatinine (mol/L)

Mild 20 to 50 150 to 300

Moderate 10 to 20 300 to 700

Severe < 10 > 700

Patient detailsMr JB 75 yr old gentleman admitted to the renal unit with a longstanding history of NIDDM and hypertension.Ideal body weight = 80 kg, serum creatinine = 400 mol/L, urine creatinine = 3.7 mmol/L, 24 hr urine volume = 2400 mls

Method 2: Cockcroft and Gault Equation

GFR = 1.23 (140 – (age) 75) x 80400

= 1.23 x 65 x 80400

= 13 x 1.23 = 16 ml/min = Moderate renal impairment

Limitations of Cockcroft-Gault equation

1. Accurate only when renal function is stable2. Inaccurate when serum creatinine values > 450 mol/L3. Becomes inaccurate when GFR < 20 mls/min4. Not valid in pregnancy

Limitations of creatinine as a marker:

1. Retrospective indicator of renal function2. May only increase when < 50% of nephrons not functioning

Method 3:Method 3: 24 hr urine collection24 hr urine collection

Urine is collected over 24 hours (or 12 hours)Urine is collected over 24 hours (or 12 hours)Blood sample taken at the midpoint of the collection period and creatinine measuredBlood sample taken at the midpoint of the collection period and creatinine measured

GFR (mls/min)GFR (mls/min) == UVUVPP

Where:Where:U = urine creatinine concentration (U = urine creatinine concentration (mol/L)mol/L)V = volume of urine collected (mls)V = volume of urine collected (mls)P = serum creatinine concentration (P = serum creatinine concentration (mol/L)mol/L)

Dosage AdjustmentMr JB 75 yr old gentleman admitted to the renal unit with a

longstanding history of NIDDM and hypertension.Ideal body weight = 80 kg, serum creatinine = 400 mol/L, urine creatinine = 3.6 mmol/L, 24 hr urine volume = 2400 mls

What dose of:-a) Ciprofloxacin would you recommend for a UTI?b) Metformin would you recommend for NIDDM?

Patient has moderate renal impairment

Dosage Adjustment in Renal Impairment

DrugDegree of

Renal Impairment

Action Reason

Ciprofloxacin Moderate Halve normal dose

Accumulation - can cause fitting.

Metformin Mild Avoid Accumulation -can cause lactic acidosis

Serum Urea (BUN – blood urea nitrogen)

(2.5 – 7.5 mmoles/Litre) Limitations as a marker: It varies with the dietary protein intake Reabsorbed by the tubules Reabsorption varies with urine flow. Its clearance is independent of GFR at low urine

flow ratesFactors increasing serum urea High protein diet Hypercatabolic conditions e.g. severe infection, burns, hyperthyroidism Gastrointestinal bleeding Muscle injury Drugs e.g. Glucocorticoids (with catabolism) Tetracycline HypovolaemiaFactors decreasing serum urea Malnutrition Liver disease Sickle cell anaemia

. Other biochemical abnormalities seen in renal impairment

a) Raised Serum Potassium (3.5 to 5 mmol/L)When GFR < 5 ml/min – hyperkalaemia developsWhen serum potassium > 7 mmol/L – life threatening

b) Raised Serum Phosphate (0.8 to 1.2 mmol/L)Chronic Renal Failure leads to hyperphosphataemia

c) Decreased Serum Calcium (2.2 to 2.6 mmol/L)

Linked to vitamin D productionPatients with CRF are typically hypocalcaemic

Managing Complications

1. Hypertension2. Fluid retention3. Electrolyte control

- Potassium

4. - Calcium & Phosphate5. Anaemia

1.Principle Drug Classes used in initial 1.Principle Drug Classes used in initial treatment of Hypertensiontreatment of Hypertension

Diuretics (thiazides)Diuretics (thiazides) Beta blockersBeta blockers ACE-IACE-I AT II receptor antagonistsAT II receptor antagonists Calcium channel blockersCalcium channel blockers Alpha adrenergic blockersAlpha adrenergic blockers

2 FLUID RETENTION

Fluid restriction - 800 to 1000 ml/day Low salt diets Loop diuretics

Oral Frusemide Effective when GFR as low as 5 ml/min

Thiazides – ineffective (as a diuretic) if GFR < 25 ml/min Metolazone – synergism with loop diuretics – short term therapy Avoid potassium sparing diuretics - hyperkalaemia

3 ELECTROLYTE DISTURBANCES

1. HYPERKALAEMIA (Normal serum concentration 3.5 to 5.0 mmol/L)

Mainly excreted by active tubular secretion Small contribution from aldosterone When GFR < 5 ml/Min potassium raises rapidly Life-threatening condition when > 7 mmol/L – cardiac

arrhythmias (peaked T-waves)

Electrolyte Disturbances

4. CALCIUM AND PHOSPHATE BALANCE Normal serum values :

Calcium 2.2 to 2.6 mmol/LPhosphate 0.8 to 1.2 mmol/L

Deficiency in vitamin D synthesis – hypocalcaemia Decreased phosphate clearance –

hyperphosphotaemia- deposits on coronary arteries

Electrolyte DisturbancesElectrolyte Disturbances

2.2. CALCIUM AND PHOSPHATE BALANCECALCIUM AND PHOSPHATE BALANCE

TREATMENTTREATMENT Active Vitamin D alfacalcidol or calcitriolActive Vitamin D alfacalcidol or calcitriol Oral phosphate binders – complex phosphate in GITOral phosphate binders – complex phosphate in GIT

Calcium Carbonate or Aluminium HydroxideCalcium Carbonate or Aluminium Hydroxide Dietary controlDietary control

EPO THERAPY WHENEPO THERAPY WHENHb<11-12g/dlHb<11-12g/dlHct <33-37%Hct <33-37%

Chronic Renal Failure – a typical prescription

1. Oral hypoglycaemic or insulin – often2. Antihypertensive – often needed (ACEI should be considered early)3. Loop diuretic – control fluid balance (especially as disease progresses)4. Phosphate binder – beware binding of drugs prescribed5. Active Vitamin D – calcitriol or alfacalcidol6. Iron supplementation – according to degree of anaemia7. EPO – according to degree of anaemia8. Ion-exchange resins – to bind potassium (usually end-stage renal

impairment only)- avoid potassium sparing drugs- consider influence of resin on bioavailability of other drugs

Is the patient on dialysis?

What type of dialysis are they on?

• Haemodialysis

• Continuous Ambulatory Peritoneal Dialysis (CAPD)

• CVVHD

Haemodialysis Access

"Access” is the term used to describe the way we “tap” into your blood stream.

• Fistula - the most common access used. Created by joining your

artery and vein together under the skin.

• Graft - the use of synthetic material

to join an artery to a vein.

• Vascath or Permacath - a catheter surgically placed in a neck or leg vein

How does it work?

1. Sterile dialysis fluid is drained into the peritoneal cavity.

2. Glucose (sugar) in the dialysis fluid attracts excess water from the blood into the peritoneal cavity.

How does it work?

4. Waste products such as creatinine and urea also filter into the dialysis fluid.

5. Drain out the old fluid and re-fill.

Pharmacists Role

“ EDUCATE,

ACHIEVE MAXIMUM EFFICACY

PREVENT HARM”

NSAID/Metformin counselling

Patients should cease NSAIDS/metformin if they are in a situation where they may become dehydrated:

• vomiting

• diarrhoea

• sepsis

• pre-surgery

• excessive exercise If on metformin they should seek medical advice

Metformin induced lactic acidosis

Metformin largely eliminated via kidneys Metformin increases production and

decreases clearance of lactate Impaired ability of liver to remove lactate

as pH falls Hepatic conversion of lactate to glucose

impeded.

Metformin induced lactic acidosis

Typically occurs in patients with renal impairment.

Other pre-disposing factors:• high dose

• chronic hepatic disease

• severe cardiovascular disease

• severe pulmonary insufficiency

• alcohol abuse

• increasing age

• nephrotoxic medication (contrast)

• surgery (cease 2/7 before)

Group 4

Mrs HR 78 years, wt 57kg Admitted to outlying hospital acute

exacerbation COPD Baseline Cr 80mol/L Charted gentamicin 160mg daily for 5/7 CrCl = 45ml/min What action would you take? Level after 1st

dose

Date Gent Dose Level Cr Urea3/6 0.08 8.55/6 160mg6/6 160mg 0.11 15.57/6 160mg 6.2 0.138/6 160mg 9.0 0.17 21.99/6 160mg10/6 ceased 16.9 0.22 28.311/612/6 7.8 0.36 35.013/6 0.3914/6 0.41 33.615/6 0.5016/6 0.59 38.917/6 0.65 40.6

21/6 Gent level still 1.4!!!!

23/6 complaining of dizziness, unsteady feeling, vestibular symptoms, vomiting

1/7 Cr 0.21 recovering

Summary

Identify at risk patients Know which drugs are renally cleared Reduce doses accordingly Empower the patient