WSAVA 2001 - Drugs and Liver Disease

Drugs and Liver Disease

Jill Maddison Australia

The liver is the major site of metabolism of many drugs hence the clinician is rightly concerned about the safety of administering drugs to patients with hepatic disease. Hepatic disease can alter the bioavailability and disposition of a drug as well as influence the pharmacological effects of the drug. For example, significant hepatic dysfunction can reduce the first pass effect of the anti-ulcer drug omeprazole, increasing the systemically available drug and prolonging its duration of action. Liver disease may also affect the metabolism of pro-drugs such as cyclophosphamide into active metabolites.

The enhanced effect of drugs in patients with liver disease is primarily due to decreased drug metabolism. Fortunately, glucuronidation, a common method by which lipid soluble drugs are metabolised in dogs, appears to be relatively unaffected by hepatic disease. Hepatic elimination of drugs is influenced by hepatic clearance and hepatic extraction that are in turn dependant on hepatic blood flow, protein binding, and intrinsic hepatic clearance. For some drugs such as propranolol, the rate of hepatic elimination is influenced by hepatic blood flow but they are insensitive to changes in hepatic metabolism. Clearance of lignocaine is also prolonged by poor hepatic perfusion (e.g., in heart failure, in shock, and with propranolol administration).

For other drugs, such as diazepam, phenylbutazone, prednisolone, theophylline and cimetidine, changes in hepatic metabolism but not changes in hepatic blood flow will affect hepatic elimination. However, for many drugs, the effects of hepatic disease on drug disposition are complex and difficult to predict.

Unfortunately, in veterinary laboratory medicine, there are no satisfactory indices of liver dysfunction that can be used to predict the magnitude of changes in hepatic clearance of drugs. In general, when administering drugs that are extensively metabolised by the liver such as benzodiazepines, NSAIDs and opioids to patients with liver disease the dosage interval should be prolonged. Use of barbiturates and several cytotoxic drugs (which have a narrow therapeutic index) such as cyclophosphamide, dacarbazine, thiotepa and l�asparaginase should be avoided in patients with liver disease.

For drugs that have high plasma protein binding and are predominantly cleared by the liver, liver disease would be expected to increase the volume of distribution of the drug and decrease drug clearance. However, reduced protein binding due to reduced albumin levels associated with advanced hepatic disease may actually increase hepatic clearance and therefore compensate for reduced hepatic metabolism (if this is occurring). Increased serum globulin levels may occur in inflammatory hepatic disease or when the hepatic reticuloendothelial system is compromised. In these circumstances, increased protein binding can occur for some basic drugs such as lignocaine due to increased production of acute-phase proteins.

The dose of drugs that are primarily eliminated in bile should be reduced in patients with significant cholestasis particularly if the drug has a narrow therapeutic window (e.g., digitoxin). Although only about 15% of digoxin is metabolized in the liver, bile duct ligation increases its half-life from an average of 26 hours to 35 hours in experimental dogs.

Antimicrobial drugs that are believed to potentially accumulate in hepatic disease and may cause toxicity, include chloramphenicol, lincosamides, macrolides, metronidazole, sulphonamides and tetracyclines.

Drugs that have been reported to directly cause hepatic toxicity in dogs include primidone, phenobarbitone (rarely), rifampin, and triazole antifungals such as ketoconazole. Lignocaine is administered parenterally because it is extensively metabolized by the liver to toxic metabolites if given orally.

Whether the use of certain drugs should be avoided in animals experiencing liver dysfunction is controversial. Ultimately, it depends on whether that drug leads to toxicity at concentrations close to therapeutic concentrations (i.e., those drugs with a low therapeutic index) and whether other available drugs are suitable alternatives.

Specific drugs used in the management of liver disease

Ursodeoxycholic acid (Ursodiol)

Clinical applications. Ursodeoxycholic acid is a naturally occurring bile acid found in the bile of the Chinese black bear. Black bear bile has been used for many years by practitioners of Eastern medicine and has been commercially synthesised and available for use as a hepatoprotective agent in Japan since the 1930s. Since the 1970s, ursodeoxycholic acid has been used in Western human medicine for dissolution of gallstones. More recently, ursodeoxycholic acid has been used in the management of chronic hepatic diseases in humans such as primary biliary cirrhosis, biliary disease secondary to cystic fibrosis, nonalcoholic steatohepatitis, idiopathic chronic hepatitis, autoimmune hepatitis, primary sclerosing cholangitis, and alcoholic hepatitis. However, its therapeutic efficacy in some of these disorders has not been firmly established.

In veterinary medicine, ursodeoxycholic acid has been used in the management of dogs with chronic hepatitis and cats with lymphocytic plasmacytic cholangitis. It is believed to be most beneficial in disorders where bile toxicity plays an important role in the ongoing pathology. The efficacy of ursodeoxycholic acid in veterinary patients has not been definitely established although anecdotal reports suggest it may have some benefit in patients with chronic inflammatory hepatobiliary disease. It may be of some benefit in slowing disease progression especially if used at an early stage of the disease. Some authors recommend ursodeoxycholic acid treatment for all cats with cholangiohepatitis where extrahepatic biliary obstruction has been eliminated.

Mechanism of action. Ursodeoxycholic acid decreases intestinal absorption and suppresses hepatic synthesis and storage of cholesterol. This is believed to reduce cholesterol saturation of bile and thereby allowing solubilization of cholesterol-containing gall stones. It has little effect on calcified gallstones or on radiolucent bile pigment stones and therapy is only successful in patients with a functional gall bladder. Ursodeoxycholic acid, a relatively hydrophilic bile acid, is also believed to protect the liver from the damaging effects of hydrophobic bile acids, which are retained in cholestatic disorders. The hepatoprotective effect may however, be less in cats and dogs than in humans as the major circulating bile acid in dogs and cats is taurocholate. This is more hydrophilic and less hepatotoxic than the major circulating bile acids in humans. The immunomodulatory effects of ursodeoxycholic acid are believed to involve decreased immunoglobulin production by B lymphocytes, decreased interleukin-1 and interleukin-2 production by T lymphocytes, decreased expression of hepatocyte cell surface membrane HLA class I molecules and possibly stimulation of the hepatocyte glucocorticoid receptor.

Dose rate. Dogs and cats: 10�15 mg/kg q24h or divided and given q12h. It is recommended that ursodeoxycholic acid be administered for 3�4 months after which the patient should be reassessed for improvement in biochemical markers of hepatocellular pathology. If there has been improvement, treatment is continued, but if there has been no improvement or progression, either treatment should be terminated or additional therapies such as glucocorticoids or colchicine added.

Adverse effects. Ursodeoxycholic acid appears to be well tolerated by dogs and cats; vomiting and diarrhoea are reported rarely. There is some concern in human patients that taurine depletion may be potentiated by chronic treatment with ursodeoxycholic acid. This may be important in cats that are obligate taurine conjugators. This potential for taurine depletion may be exacerbated in some cats with hepatobiliary disease that have increased urinary excretion of taurine-conjugated bile acids. Dogs are less likely to become taurine depleted by this mechanism as they can shift to glycine conjugation. Ursodeoxycholic acid should not be used in patients with extra-hepatic biliary obstruction, biliary fistulas, cholecystitis or pancreatitis.

Colchicine

Clinical applications. Colchicine is used in the management of gout in humans providing acute relief of symptoms as well as prophylaxis. In veterinary medicine, it has been used in the management of amyloidosis and chronic hepatic fibrosis. Controlled clinical trials are lacking but there has been anecdotal evidence from a few case studies that colchicine may improve liver function and slow the progression of hepatic fibrosis.

Mechanism of action. Collagen secretion from lipocytes requires microtubles, the assembly of which is inhibited by colchicines, thereby interfering with the transcellular movement of collagen. The drug increases collegenase activity and therefore may promote degradation of existing collagen. It has anti-inflammatory effects by inhibiting leukocyte migration�this may suppress fibrogenesis. It may also have a direct hepatoprotective effect by stabilising hepatocyte membranes.

Dose rate. Doses in dogs have been extrapolated from the human literature. Its use in the cat has not been reported. Colchicine is marketed in combination with probenicid in some countries�this combination should be avoided as probenecid can cause nausea, vomiting, and lethargy.� Dose: 0.025�0.03 mg/kg/day

Adverse effects. Because of the limited veterinary experience with colchicine, little is known about its potential toxicity in dogs and cats.

In humans, the therapeutic window for colchicine is quite narrow with toxic effects occurring after only small overdoses.

Nausea, vomiting and diarrhoea have been reported in dogs.

Bone marrow suppression has occurred in humans after prolonged use.

Myopathy and peripheral neuropathy has been reported rarely in humans

Severe local irritation occurs if the drug is inadvertently administered perivascularly. Thrombophlebitis has also been reported.

Colchicine is contraindicated in patients with serious renal, GI or cardiac disease and should be used with caution in patients with less severe disease of these organs.

Colchicine is teratogenic in mice and hamsters; therefore, it should not be used in pregnant patients unless the benefits outweigh the risks.

Colchicine may decrease spermatogenesis.

Safety to nursing neonates is unknown, as it is not known whether it is excreted in milk.

NSAIDs, especially phenylbutazone increase the risk of thrombocytopenia, leukopenia or bone marrow suppression when used concurrently with colchicine

Many antineoplastic and other potentially marrow-suppressing drugs may cause additive myelosuppression when used concurrently with colchicine.

Penicillamine

Penicillamine is a degradation product of penicillin but has no antimicrobial activity. It was first isolated in 1953 from the urine of a patient with liver disease who was receiving penicillin

Clinical applications. Penicillamine is a monothiol chelating agent which is used in veterinary medicine in the treatment of copper-storage hepatopathy (e.g., Bedlington Terriers), lead toxicity, and cystine urolithiasis. It has also been used in the management of rheumatoid arthritis in humans.

Mechanism of action. Penicillamine chelates several metals including copper, lead, iron, and mercury, forming stable water soluble complexes that are renally excreted. It also combines chemically with cystine to form a stable, soluble, readily excreted complex. Although it usually takes months to years for hepatic copper levels to decrease, clinical improvement is often seen in Bedlington Terriers after only a few weeks suggesting the drug has other beneficial effects other than copper depletion. Penicillamine induces hepatic metallothionein, which may bind and sequester copper in a nontoxic form. It may also have antifibrotic effects as it inhibits lysyl oxidase, an enzyme necessary for collagen synthesis and directly binds to collagen fibrils, preventing cross-linking into stable collagen fibres. However, its efficacy as an antifibrotic agent in humans is doubtful and it has not been evaluated in veterinary medicine. Penicillamine may have immunomodulatory effects and has been demonstrated to reduce IgM rheumatoid factor in humans with rheumatoid arthritis. However, its mechanism of action in this disease remains uncertain.

Dosage and formulations. For management of copper-associated hepatopathy, a dose of 10�15 mg/kg q12h PO is given on an empty stomach. However, if GIT adverse effects are experienced, these may be reduced if it is given with food, although absorption may be reduced. Alternatively, reduce dose and gradually build up to full dose.

Adverse reactions:

GIT adverse effects are common resulting in nausea and vomiting. Smaller doses on a more frequent basis may alleviate adverse effects. Alternatively, the drug can be given with food although this will reduce absorption.

Other adverse effects observed infrequently or rarely include:

Fever.