PRESCRIBING IN LIVER AND RENAL DISEASE

THERAPEUTICS FOR INDEPENDENT PRESCRIBERS PRESCRIBING IN LIVER AND RENAL DISEASE Number 6 in a series of 15 articles on Therapeutics Aims and Objectives To outline the pathophysiological changes that occur in liver disease and renal disease and how they affect the pharmacokinetics and pharmacodynamics of commonly used medicines. To describe how prescribing should be modified in liver disease and renal disease in order to optimise drug efficacy and minimise toxicity. Additional Resources British National Formulary http://www.bnf.org/ Drugs and the Liver. Merck Manual f Diagnosis and Therapy http://www.merck.com/mmpe/sec03/ch024/ch024a.html Kappel J and Calissi P. Safe drug prescribing for patients with renal insufficiency CMAJ. 2002;166: 473 http://www.cmaj.ca/cgi/content/full/166/4/473 Pathophysiology of Liver disease The liver is the largest organ that eliminates medicines and it is, quantitatively, by far the most important, although the skin, gut, lungs, kidney and white cells have some limited capacity to clear medicines. Many drugs are lipid soluble (this is necessary for them to cross lipid membranes and reach their site of action). Lipid soluble drugs generally tend to Page 1 of 11

be substantially protein-bound in the blood and cannot therefore be effectively cleared by glomerular filtration in the kidney. Although unbound lipid-soluble medicine can cross the glomerulus, even that portion tends to be passively reabsorbed through the renal tubular cell, down a concentration gradient. Several metabolic pathways therefore exist to convert these agents to more water-soluble metabolites in the liver. These water soluble metabolites are, in general, less active than the parent compound, although there are several important exceptions. Phase 1 metabolism involves the mono-oxygenase system in the smooth endoplasmic reticulum of the hepatocytes (the principal liver cells). Here, a variety of subtypes of cytochrome P450 enzymes (CYP450) catalyze oxidation, reduction, hydrolysis and dealkylation reactions. These enzymes are not specific and drugs may compete with each other for metabolism via one particular pathway. A given drug may be metabolized via several routes mediated by several subtypes of CYP450. Phase 2 metabolism involves the conjugation of parent drug or metabolite with a watersoluble molecule such as glucuronic acid (glucuronidation), sulphate, amino acid such as glutathione or glycine, or acetyl coenzyme A (acetylation). As with phase 1 reactions, the metabolites are generally less active and therefore of low toxicity, but there are important exceptions. The liver has a significant capacity to perform phase 2 reactions, although there is also some, more limited, activity in the gut wall. Finally, drugs with a high molecular weight (e.g. rifampicin) may be excreted in the bile, particularly as conjugates. The drug or its conjugate may be reabsorbed, either directly or after deconjugation by intestinal microflora, resulting in an enterohepatic recycling, which Page 2 of 11

offsets the effects of biliary excretion. In obstructive jaundice, enterohepatic circulation is impaired, leading to an accumulation of drugs excreted in the bile (e.g. rifampicin and fusidic acid). Chronic liver disease is often associated with an impairment of drug metabolism and, in particular, phase 1 metabolic processes. The effect of impairment of metabolism in liver disease will be greater for those drugs with extensive presystemic (first pass) metabolism. The bioavailability (see Principles of Therapeutics) of propranolol is much greater in patients with chronic liver disease, not because of better absorption (absorption is virtually complete) but because it cannot be efficiently metabolised when all that is absorbed passes through the liver for the first time. This reduction in the "first-pass effect" is due not only to the reduced metabolic activity of the hepatocytes, but also to intra- and extra-hepatic shunting of blood past those liver cells and also due to a reduction in effective liver blood flow (normally 1.5 l/min in healthy individuals) in liver disease. In addition, plasma albumin concentrations may fall in liver disease since this important plasma protein is produced by the liver. Low albumin concentrations may mean that the total drug concentration may underestimate the free (active) drug concentration in plasma, because of a reduced extent of plasma protein binding (e.g. diphenylhydantoin). Measurement of free drug concentration may therefore be useful in such circumstances (see Monitoring of Drug Therapy). Pharmacodynamic changes also occur in liver disease. There is a reduced production of vitamin K-dependent clotting factor, leading to increased warfarin sensitivity. Encephalopathy can be precipitated by drugs causing electrolyte disturbance (e.g. thiazide Page 3 of 11

diuretics) and by opiates and other psychoactive drugs, because of increased cerebral sensitivity. Prescribing in Liver Disease Important factors to consider include the extent of liver dysfunction, the type of disease, and whether decompensation (i.e. the presence of overt clinical complications such as jaundice or ascites) is present. The INR is a useful measure of acute hepatic damage (e.g. in paracetamol-induced hepatotoxicity) but the serum albumin is a better long-term marker. In liver disease, the serum albumin concentration correlates roughly with the degree of impairment of drug metabolism (i.e. the lower the albumin the more severe the impairment). Liver transaminases (i.e. alanine amnotransferase [ALT] and aspartate aminotransferase [AST]) are poor indicators of the extent of liver damage, since they may be normal, even when there is extensive liver dysfunction. Practical Prescribing Hints in liver disease For the reasons outlined above, the following guidelines can be usefully applied when prescribing to patients with liver disease: Avoid hepatotoxic drugs, (type A and type B ADRs are more common in the setting of liver disease) See Table 1 below. Table 1: Drugs causing acute liver failure Commonest causes Paracetamol, halothane, isoniazid, rifampicin, NSAIDs, sulphonamides, sodium valproate, carbamazepine, flutamide, 3, 4-methylenedioxymethamphetamine ( Ecstasy ). Less frequent or historical causes Phenytoin, isoflurane, enflurane, tetracycline, allopurinol, ketoconazole, monoamine oxidase inhibitors (MAOIs), disulfiram, methyldopa, amiodarone, tricyclic antidepressants, propylthiouracil, gold, 2, 3-dideoxyinosine (ddi). Richardson P, O Grady JG. Diseases of the liver: Acute liver disease. Hospital Pharmacist 2002; 9: 131-136 Page 4 of 11

if possible use drugs not metabolised by the liver. Renally excreted drugs are preferred as long as renal function is normal and is being monitored. avoid drugs causing fluid retention (NSAIDs), normal saline infusions and drugs requiring hepatic activation. Avoid or exercise extreme caution with drugs that increase the risk of bleeding, depending on the severity of the liver disease. use the BNF as a guide, or ask your local medicines information pharmacist for further advice. Pathophysiology of Renal Disease The kidneys are the major route of excretion of many metabolites of commonly used medicines. Some of these metabolites may be active and, therefore, kidney dysfunction may be associated with enhanced effect. Since many drugs are lipid soluble, however, it is often not until they are metabolised by other organs (e.g. the liver) that they can be excreted in the urine. Thus there are relatively few widely used medicines that are predominantly excreted by the kidney in unchanged form. They tend to be water soluble agents which are relatively poorly protein bound in the blood. There are three main mechanisms that affect the extent of renal excretion: Glomerular filtration Small drug or metabolite molecules may undergo the passive process of glomerular filtration into the urinary space in the glomerulus, through pores in the glomerular capillary endothelial cells. This, however, only applies to free (unbound) drug in blood and not drugs bound to plasma proteins. The glomerular filtration rate (GFR) is the parameter that Page 5 of 11

is used to express degree of renal function and is the rate at which plasma is filtered through the glomeruli. In a healthy adult, the normal GFR is about 120 ml/min. The clearance of creatinine (a waste product of muscle turnover) is very similar to the GFR in any particular individual and can, therefore be used to estimate GFR. Active Tubular Secretion Tubular secretion is an active (energy-dependent) process by which some acids and bases are transported into tubular fluid against a concentration gradient. Competition for this relatively nonspecific process between two acidic or two basic drugs may lead to diminished excretion of one or both agents, resulting in drug interactions (see Drug Interactions). Tubular reabsorption This passive process ensures that many drugs (particularly highly lipid-soluble drugs) will be rapidly reabsorbed from the kidney tubule. Since around 99% of the water filtered through the glomerulus is reabsorbed in the kidney tubule, there is a resultant concentrating effect and an increase in drug reabsorption. This effect can be reduced to a small extent by increasing urine flow. Changes in urine ph will have significant effects on reabsorption of weak acids and bases. The excretion of weak acids will be increased in alkaline urine and of weak bases in acid urine. Thus reabsorption may be altered in conditions where the urine ph may be affected (e.g. renal tubular acidosis). Renal disease is associated predominantly with a fall in GFR, with active renal tubular secretion mechanisms less affected. Measurement of serum creatinine or creatinine clearance is, therefore, useful in calculating the optimum dose of drugs excreted Page 6 of 11

predominantly by glomerular filtration. Measurement of GFR is of less value for drugs such as penicillins, which are largely actively secreted at the proximal renal tubule. Active tubular secretion is relatively spared until the late stages of renal impairment so that for those drugs in which this process contributes significantly to total clearance (e.g. penicillins such as amoxicillin), dose-reduction may not be necessary until the renal impairment is severe. The major pharmacodynamic effect seen in renal disease is the enhanced blood brain barrier permeability to opiates, benzodiazepines and other psychoactive drugs. In renal failure, there is an accumulation of toxic waste products, eventually resulting in severe uraemia and encephalopathy with confusion, loss of memory and other neurological signs. It is thought that purine metabolites, amines, indoles, phenols and other substances may contribute to uraemia and retained middle molecules (molecular weight 500-5000 Da) may also contribute to the problem. It is likely that subclinical accumulation of these or other agents may contribute to the increased sensitivity to psychoactive drugs, particularly opioids, although pharmacokinetic factors (e.g. accumulation of active metabolites) may also be important for several drugs. Defining renal impairment In renal disease glomerular filtration rate declines progressively and is generally defined as follows: Grade Mild Moderate Severe GFR 20-50ml/min 10-20ml/min <10ml/min For further information see British National Formulary Appendix 3: Renal Impairment Page 7 of 11

Prescribing in Renal Disease In renal dysfunction, the creatinine clearance is closely related and similar in magnitude to the GFR. Thus GFR can be calculated by measuring the patient s serum creatinine (which has little diurnal variation) and age, gender and body weight. The Cockcroft Gault equation uses the relationship: Creatinine clearance = [140 - age(y)] x Body weight (kg) 0.82 x plasma creatinine (umol/l) For females, who have less muscle mass at any given weight, the final result must be multiplied by 0.85. This equation is relevant only when the renal function is relatively constant and in the absence of concomitant liver disease. The method is not reliable in children or pregnancy. It is a useful guide to dose adjustment in renal disease and in the elderly when glomerular filtration is the major renal excretory mechanism. When using this equation for obese patients, the ideal body weight (IBW) should be used because adipose tissue (or fat) does not produce creatinine. The IBW can be estimated using the following equations IBW in kg (male) = IBW in kg (female) = 50+ (2.3 x height in inches over 5 feet) 45.5 + (2.3 x height in inched over 5 feet) The proportional dose adjustment will also depend upon the proportion of the drug excreted unchanged by the kidney (F) (since some drug may be cleared by metabolic pathways) in the following formula: Page 8 of 11

Equation 2. Dose (as proportion of normal) = (1-F) + F * GFR (patient) GFR (normal) This relationship can be used to aid in the calculation of the dose of digoxin or gentamicin, for example. The situation is more difficult if renal tubular secretion is a major excretory mechanism since no clinically applicable direct measurements of this pathway are available. In patients with renal disease, several outcomes may occur. Toxicity may occur because of failure to excrete an active agent or its (active or toxic) metabolites. Pharmacodynamic sensitivity may result in enhanced toxicity even if elimination of that particular agent is not impaired. In addition patients with renal failure may not tolerate adverse effects as well as patients with normal renal function so the outcome of any ADR may be more serious Many of these problems can be avoided by reducing the dose or by using alternative drugs. Drugs and dialysis Dialysis (haemo- or peritoneal) is a type of renal replacement therapy, usually indicated when the kidneys are barely or non-functional. The aim of renal relacement therapies is to remove toxins and excess fluid, and to correct biochemical disturbances. The removal of a drug by dialysis depends on a number of factors: Molecular weight Protein binding Water solubility Drugs below molecular weight 500 dialyse easily Highly protein bound drugs e.g. warfarin are not easily dialysed Because dialysis solutions are aqueous, water-soluble drugs enter them preferentially and fat soluble drugs e.g. thiopentone do not dialyse easily. Page 9 of 11

Vol. of distribution Drugs with large Vd s dialyse slowly (e.g. nortriptyline) and dose adjustment of such drugs is not normally necessary in this situation. Practical Prescribing Hints in Renal Disease Avoid nephrotoxic drugs (e.g. tetracyclines)in patients with renal disease because the consequences of nephrotoxicity are likely to be more serious when the renal reserve is already reduced. Use tables (e.g. in BNF a guide to dosage reduction.) Creatinine clearance can be calculated as shown above. Dosage reduction can be achieved by reducing the size of dose or by increasing the interval between doses. Loading doses remain important since half-life (t½) and hence time to reach steady state concentration (4-5 half lives) will be greatly increased for renally handled drugs Avoid drugs which cause fluid retention (e.g. NSAIDS) Ask your local medicines information pharmacist for further advice. Page 10 of 11

INDEPENDENT PRESCRIBING PRESCRIBING IN LIVER AND RENAL DISEASE CASE STUDY Name: Profession: nurse/pharmacist (please delete as appropriate) Mr H J, a 75 year old man weighing 65kg (height 1.73m) is being treated for chronic heart failure with furosemide and digoxin 0.125mg daily. His serum creatinine is 260µmol/l. He complains of severe pain and swelling of his right 1st metatarsophalyngeal joint and you find his serum urate to be raised at 0.6mmol/l. He says this has occurred on two other occasions in the last 6 months. He is otherwise symptom- free. 1.a. What is your initial diagnosis of his symptoms? 1.b. How would you confirm this? 1.c. What would you want to exclude? 2. What new treatment, if any, would you give including doses and durations? a. For this acute problem.. b. For long term treatment? 3. Comment on his long-standing drug therapy. Page 11 of 11