Liver and biliary tract

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Chapter 34 Liver and biliary tract

Pharmacokinetic changes in liver disease

The liver has large metabolic reserve and important changes in drug handling occur only with hepatic decompensation. Parenchymal liver disorders, including chronic viral hepatitis or alcohol-related liver disease, have more impact on hepatic drug-metabolising enzyme activity than cholestatic conditions, such as primary biliary cirrhosis, where elimination via biliary excretion may be impaired. Hepatocellular injury leads to decreased activity of drug-metabolising enzymes, reflected in diminished plasma clearance of drugs with hepatic metabolism. There is variation between patients and overlap with healthy subjects.

Prescribing for patients with liver disease

Prescribing of most drugs is safe in well-compensated liver disease. If in doubt, check the prothrombin time and serum bilirubin. Take particular care with:

For drugs with significant hepatic metabolism, a reasonable approach is to reduce the dose to 25–50% of normal and monitor responses. Specific examples include:

Drug-induced liver damage

The spectrum of hepatic abnormalities caused by drugs is broad (Table 34.1). Drugs tend to injure specific hepatocyte components, e.g. plasma membrane, biliary canaliculi, cytochrome P450 enzymes or mitochondria.

Table 34.1 Idiosyncratic drug reactions and the cell components that are affected

Type of reaction Effect on cells Examples of drugs
Hepatocellular Direct effect on production by enzyme–drug combination leads to cell and membrane dysfunction Isoniazid, trazodone, diclofenac, nefazodone, venlafaxine, lovastatin
Immune mediated Cytotoxic lymphocyte response directed at hepatocyte membranes altered by drug metabolite ± additional autoimmune component Nitrofurantoin, methyldopa, lovastatin, minocycline, halothane
Cholestasis Injury to canalicular membrane and transporters Chlorpromazine, oestrogen, erythromycin and its derivatives
Granulomatous Macrophages, lymphocytes infiltrate hepatic lobule Diltiazem, sulfa drugs, quinidine
Microvesicular fat Altered mitochondrial respiration, β-oxidation leads to lactic acidosis and triglyceride accumulation Didanosine, tetracyclines, acetylsalicylic acid, valproic acid
Steatohepatitis (fatty liver) Multifactorial Amiodarone, tamoxifen
Fibrosis Activation of stellate cells Methotrexate, excess vitamin A
Vascular collapse Causes ischaemic or hypoxic injury Nicotinic acid, cocaine, methylenedioxymethylamfetamine (MDMA)
Oncogenesis Encourages tumour formation Oral contraceptives, androgens
Mixed Cytoplasmic and canalicular injury, direct damage to bile ducts Amoxicillin–clavulanic acid, carbamazepine, herbs, ciclosporin, methimazole, troglitazone

Certain drugs interfere with bilirubin metabolism and excretion without causing hepatic injury. Jaundice is induced selectively with minimal or no disturbance of other liver function tests; recovery follows stopping the drug.

Examples are:

Aspects of therapy

Complications of cirrhosis

Variceal bleeding

Varices are dilated vessels, linking the portal and systemic venous systems, which return blood from the splanchnic circulation to the systemic circulation, bypassing the liver, decompressing the portal venous system and reducing portal pressure. Varices can be large, and haemorrhage, sometimes catastrophic, occurs from any of these vessels when intravascular pressures reach a threshold. Lower oesophageal or gastric varices, which are thin-walled and submucosal, are most prone to haemorrhage because intravascular pressures rise beyond that threshold with everyday physiological processes.

Portal pressure is a function of portal venous resistance and blood flow. In cirrhosis, both portal venous resistance and splanchnic blood flow are increased, the latter by a combination of splanchnic vasodilatation and increased cardiac output. Variceal bleeding is more likely once the pressure gradient between the portal and systemic venous systems rises above 12 mmHg (measured as the wedged hepatic venous pressure).

Fifty per cent die from hypovolaemia or associated complications after a first oesophageal or gastric variceal haemorrhage, manifest as melaena or haematemesis. Correct hypovolaemia promptly with plasma expanders and blood transfusion. The use of central venous access and monitoring is recommended; correction of coagulopathy with platelets and clotting factors appears logical. The relation between bacterial infection and haemorrhage is intriguing; bacterial infection is often found at presentation and 60% have evidence of infection within 7 days of haemorrhage. It is unclear whether infection increases the risk of haemorrhage or is a consequence. Bacterial infection should be treated, or anticipated, using broad-spectrum antibiotics with Gram-negative cover in line with local prescribing policy. Proton pump inhibitors are also recommended. Many patients cease bleeding spontaneously, but over half re-bleed within 10 days. Conservative management is rarely acceptable.

Pharmacological reduction of portal pressure

Vasopressin, in addition to its action on renal collecting ducts (through V2 receptors), constricts smooth muscle (V1 receptors) in the cardiovascular system and particularly in splanchnic blood vessels, reducing splanchnic blood flow. Systemic, cerebral and coronary artery vasoconstriction are predictable complications necessitating treatment withdrawal in 20% of older patients. In patients with cardiovascular disease and uncontrolled haemorrhage that precludes definitive endoscopic therapy, simultaneous administration of glyceryl trinitrate (transdermally, sublingually or intravenously) allows continued use of vasopressin, reducing cardiac risk, and also reduces portal venous resistance and pressure directly.

Vasopressin is cleared rapidly from the circulation so is given by continuous intravenous infusion; with concerns about distant ischaemia, the short t½ of vasopressin is advantageous.

The synthetic analogue, terlipressin (triglycyllysine-vasopressin) has supplanted vasopressin. This prodrug is converted in vivo to vasoactive lysine vasopressin, which has biological activity for 3–4 h, and is effective as bolus injections 4-hourly for 2–5 days, reducing the risk of re-bleeding.

Somatostatin and the synthetic analogue octreotide reduce portal pressure by decreasing splanchnic blood flow. Octreotide has the advantage of a longer duration of action and is given as bolus injection. It can be used as an alternative to terlipressin, with similar efficacy and indications, but does not carry a risk of cerebral or cardiac ischaemia.

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