CHAPTER 9 Calculations in liver disease and renal impairment

Learning outcomes

• Appreciate the need for dosage reduction in patients with liver disease or renal impairment

• Understand the main principles involved in calculating reduced doses for patients with liver disease or renal impairment

Introduction

Following administration and absorption, drugs are metabolised and excreted. Many factors will influence both the pathways and rate of drug metabolism in the liver and excretion by the kidneys. It follows that if these major organs are in any way damaged by disease or, say, circulatory failure, the metabolism and excretion of drugs is reduced. The reduction will depend on the severity of the condition. It also follows that in order to avoid drug and/or metabolite toxicity (due to an accumulation of the drug in the body), the doses of drugs must be adjusted to take account of liver disease or renal impairment. It is especially important to take particular care when treating older people whose liver and renal functions decline with age.

Nurses will not routinely be involved in the actual calculation of drug doses for patients with liver disease or renal impairment but the principles involved are relevant to many aspects of drug therapy. For paediatric aspects, see Chapter 8.

Liver disease

The liver has a very considerable capacity to metabolise drugs. Damage to the liver has to be severe (due to infection, trauma, cirrhosis or neoplastic disease) before the capacity of the liver to metabolise drugs is significantly reduced. The following exercises illustrate the range of dosage reductions that may be required in patients with liver disease.

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Exercises

Answers may be found on page 197.

9.1 The normal adult dose of atomoxetine is 80 mg daily. In patients with severe liver disease, 25% of the usual adult dose should be given. What is the correct dose for this patient?

9.2 A patient is prescribed metronidazole 400 mg every 8 hours. The dose requires to be adjusted for severe liver disease by reducing the total daily dose to one third and given once daily. What dose does the patient take?

9.3 A patient is prescribed rizatriptan 10 mg, but has moderate liver disease and the dose should be halved. What dose should the patient take?

9.4 A 70 kg patient has been prescribed Synercid by intravenous infusion every 8 hours at a dose of 7.5 mg/kg. The patient has moderate hepatic impairment and the recommended dose is 5 mg/kg. What dose should be infused 8-hourly?

Renal impairment (adults)

Patients with reduced renal function are at risk from adverse effects of drugs or their metabolites which are excreted renally.

Other problems such as increased sensitivity and intolerance of side-effects may also be encountered. It follows that great attention needs to be paid to the choice of drug and the dose especially in patients receiving replacement therapy.

Detailed guidance on drugs to be avoided/used with caution is provided in the BNF. Manufacturers’ literature and local protocols should also be consulted.

In deciding on a suitable dose for a patient with renal impairment, it may be necessary to perform a calculation based on physiological parameters which indicate the patient’s degree of renal impairment. The greater the degree of renal impairment, the greater the risk from accumulation of the drug and consequent adverse effects.

Most nurses will not be faced with carrying out calculations to determine renal function although the fundamental principles involved are important to all nurses.

Measuring renal impairment

Glomerular filtration rate (GFR)

This is the volume of fluid filtered by the glomerulus in millilitres per minute and is a measure of the efficacy of the renal excretory capacity. (Most of the fluid filtered is reabsorbed and so GFR must not be confused with urinary output.)

Normal adult values for GFR are 120 ± 25 mL/minute. Males have a higher rate than females. GFR falls with age, an important factor that needs to be taken into account when prescribing for older people. A grading system was formerly included in the BNF (BMA and RPSGB 2007) (see Table 9.1). This is included here as a general indication only of degrees of renal impairment measured in terms of GFR. Chronic kidney disease may also be more accurately classified by GFR rates normalised on body surface area.

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Table 9.1 The three grades of renal impairment

Grade	Glomerular filtration rate (mL/min)
Mild	20–50
Moderate	10–20
Severe	<10

Creatinine clearance (Cr Cl)

Creatinine (a nitrogen-containing substance) is a product of muscle metabolism which is excreted only by glomerular filtration.

The constant rate of the production of creatinine in individuals means that Cr Cl will give an indication of GFR.

A formula (the Cockcroft-Gault formula) can be used to determine Cr Cl. Fairly complex mathematics was involved in working out this approach to Cr Cl which will not be discussed here (Cockcroft and Gault 1976).

Cockcroft-Gault formula

Male

Female

Notes on Cockcroft-Gault formula

• The body weight should be the lean body mass since the breakdown of fat does not produce creatinine. Care is also needed if patients have a large or small muscle mass.

• There are clearly advantages in using a calculator when performing these calculations!

• Although the BNF bases many doses on calculations made by the Cockcroft-Gault formula, other approaches to Cr Cl are increasingly advocated (see p. 185).

• Calculators are available on a number of websites.

Demonstration 9.1

A 70-year-old male patient weighing 78 kg who has a serum creatinine of 123 micromol/litre is to be treated with eprosartan for hypertension. Calculate the creatinine clearance and the dose to be given based on a ‘standard’ dose of 600 mg once daily.

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Using the formula,

The BNF states that the dose of eprosartan should be halved if the Cr Cl is less than 60 mL/min.

Demonstration 9.2

A 58-year-old woman weighing 65 kg with a serum creatinine of 150 micromol/litre is to be treated with ofloxacin for a soft-tissue infection. Calculate the patient’s Cr Cl and the dose to be given based on a normal dose of 400 mg twice daily.

The BNF states that if the Cr Cl is between 20–50 mL/min, half the normal dose is to be used. For the patient, the dose is 400/2 mg = 200 mg twice daily.

This patient is somewhat overweight. A calculation using an ‘ideal’ body weight of say 50 kg would give a Cr Cl of 28.4 mL/min. In this case, the dose would be the same as above. However, it is worthwhile to check if there is any doubt about the dose in relation to the patient’s ideal/actual body weight.

The following exercises (9.5–9.9) are included to give an indication of the levels of dosage reduction needed in renal impairment where the Cr Cl is known.

Exercises

9.5 A patient with angina is prescribed 200 mg acebutolol twice daily. This requires to be adjusted as the patient has a creatinine clearance less than 25 mL/min. The dose is quartered and taken once daily. What is the correct dose?

9.6 The dose of amisulpiride, 600 mg daily in two divided doses, requires adjusting for a patient with a creatinine clearance of 20 mL per minute. The dose is adjusted to one-third. What dose is to be taken?

9.7 A dose of 250 mg of cefradine requires to be adjusted to a quarter of this for a patient with a creatinine clearance of less than 5 mL. What volume of cefradine syrup 250 mg in 5 mL provides the correct dose?

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9.8 Meropenem is prescribed 500 mg every 8 hours. For a patient with a creatinine clearance of 20 mL/min, the normal dose is halved and the dosing interval increased to 12 hours. What dose is infused in 24 hours?

9.9 The dose of capecitabine, 1250 mg/m² is reduced to 75% if creatinine clearance is 30–50 mL/minute. What dose is administered?

Limitations of the Cockcroft-Gault formula

The BNF currently bases many of the dosage adjustments on Cr Cl because most of the information available is based on Cr Cl as a proxy for GFR. As demonstrated above, the Cockcroft-Gault formula can be used to calculate Cr Cl which in turn is used to determine doses. Care is needed when using this approach because in some situations, e.g. where a patient’s GFR is low, GFR may be over-estimated. Situations may arise where actual plasma drug concentration must be determined rather than reliance on a formula to determine a dose.

MDRD equation

Calculations based on the modification of diet in renal disease (MDRD) equation may be preferred (Levey et al 1999). This equation differs from the Cockcroft-Gault formula in that it takes into account the patient’s race, age and serum creatinine level.

For drugs with a small safety margin, and for under/overweight patients, the absolute GFR should be used. This can be calculated from estimated GFR normalised to a BSA of 1.73 m².

It is not possible within the scope of this publication to cover all the complex aspects involved in the determination of renal impairment since so many variables are involved (patient’s age, weight, race, disease state, etc.).

The determination of GFR by physical methods such as the use of radio-isotopes will not be considered here. Whatever formula is used to determine dosage regimens, there can be no substitute for keen observation and recording of clinical responses to all drugs.

References

BMA (British Medical Association) and RPSGB (Royal Pharmaceutical Society of Great Britain). British National Formulary Number 54. London: BMJ Group Ltd and RPS Publishing, 2007.

Cockcroft D., Gault M.D. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31-41.

Levey A.S., Bosch J.P., Lewis J.B., Greene T., Rogers N., Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann. Int. Med.. 1999;130(6):461-470.