Pharmacology Notes

Ursodeoxycholic acid is a naturally occurring bile acid, which constitutes about 3% of normal human bile acids. Its synthetic form is used in the management of chronic cholestatic liver disease and in cholestasis of pregnancy, but the mechanism of action is not clear. After oral administration, there is an increase in the concentration of ursodeoxycholic acid in bile acids and a reduction in the amount of more hydrophobic and potentially toxic bile acids (cholic and chenodeoxycholic acids). It also increases bile acid output and bile flow. Immunological effects may also contribute with reduced abnormal expression of antigens on hepatocytes and a decline in immunoglobulin and cytokine production.

Following administration, ursodeoxycholic acid is solubilised by other bile acids and absorbed with about 50% taken up by the liver and secreted as conjugates into bile. These conjugates are absorbed from the distal ileum and compete with endogenous bile acids for active transport and undergo enterohepatic circulation. Nonabsorbed ursodeoxycholic acid conjugates are deconjugated by colonic bacteria and excreted in the faeces.

Ursodeoxycholic acid is generally well tolerated and no serious adverse effects have been identified. Pruritus may be exacerbated in some individuals. Absorption is reduced by cholestyramine and aluminium hydroxide. Reduced absorption of ciprofloxacin has been reported when ursodeoxycholic acid was taken concurrently and there is potential for increased absorption of drugs that require solubilisation, such as cyclosporin.

Terlipressin is a prodrug of vasopressin. It is slowly converted in the circulation to vasopressin, providing an effective half-life of approximately 6 hours. Vasopressin causes direct vasoconstriction by stimulating vasopressin V1-receptors on vascular smooth muscle. It also has renal (antidiuretic hormone) effects via V2-receptors and central effects via V3-receptors. The density of V1-receptors in the mesenteric arterial circulation provides a basis for the relative benefit of terlipressin in the management of portal hypertension and hepatorenal syndrome. Vasoconstriction of the mesenteric circulation leads to decreased portal venous inflow and therefore reduced portal venous pressure. This can reduce bleeding from oesophageal varices; it may also reduce the sympathetic response to systemic vasodilation, which contributes to reduced renal blood flow and consequently to the hepatorenal syndrome.

Terlipressin is given by intravenous injection every 4 to 6 hours and is preferred to vasopressin, which requires continuous infusion. In hepatorenal syndrome, terlipressin is administered in conjunction with concentrated albumin . Terlipressin is less likely than vasopressin to cause ischaemic complications (intestinal, myocardial and limb ischaemia), cardiac arrhythmias and cerebrovascular events. Terlipressin, unlike vasopressin, can be administered out of intensive care and without cardiac monitoring.

Octreotide is indicated for the treatment of acromegaly, symptom relief associated with gastro-entero-pancreatic tumours (eg carcinoid tumours, VIPomas), and to reduce complications following pancreatic surgery. Intravenous infusions are used in the management of variceal bleeding. Octreotide has been useful in the palliation of the symptoms of malignant bowel obstruction that have not responded to other palliative measures.

Octreotide decreases splanchnic blood flow and inhibits the secretion of serotonin, growth hormone, and the gastroenteropancreatic peptides (gastrin, glucagon, insulin, motilin, pancreatic polypeptide, secretin and vasoactive intestinal peptide [VIP]). Octreotide reduces portal and collateral pressures by inhibiting the release of vasodilatory peptides (including glucagon and VIP), which are increased after gastrointestinal haemorrhage. It also has a direct vasoconstrictive action. Octreotide promotes reabsorption of electrolytes in the gut. In hormone-secreting tumours (eg carcinoid) it improves symptoms by reducing hormone secretion, and it has a direct antitumour effect on solid tumours of the gastrointestinal tract.

Octreotide is usually given subcutaneously to control symptoms of carcinoid tumours and other secretory neoplasms such as VIPomas and glucagonomas. It is also available as a long-acting preparation with octreotide incorporated into microspheres. This formulation is given intramuscularly and provides an extended elevation of octreotide levels—allowing monthly dosing. For patients stabilised on a normal therapeutic dose of subcutaneous octreotide, conversion to the long-acting preparation should be at a dose of 20 mg monthly, and can start the day following the last subcutaneous dose. The dose required for each injection is titrated according to growth hormone levels (in acromegaly) and clinical symptoms.

Adverse effects include a high incidence of cholelithiasis (usually asymptomatic and not requiring treatment), abdominal pain and diarrhoea. Octreotide has an elimination half-life of approximately 1.5 hours and about 30% is excreted renally. Intravenous infusions are well tolerated but blood glucose should be monitored.

Azathioprine is converted in the body to mercaptopurine, an immunosuppressant with potent anti-inflammatory properties. Azathioprine primarily acts against rapidly dividing cells, resulting in inhibition of purine synthesis, gene replication, and T-cell activation. It is used alone or in combination with other drugs, usually corticosteroids, in inflammatory autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease. It is also used to prevent organ transplant rejection.

During the first few weeks of therapy, azathioprine may cause hypersensitivity reactions including malaise, headache, nausea, vomiting, diarrhoea, fever, rigors, rash, myalgia, joint pain, hypotension, disturbed liver function, pancreatitis, and renal impairment. These disturbances can be mistaken for a flare in the underlying illness. The nausea associated with azathioprine can be dose-limiting. Other reactions include bone marrow toxicity, liver toxicity, increased susceptibility to infections, hair loss, skin cancers, and other malignancy. Macrocytosis and lymphopenia are common effects of these drugs and are not an indication for cessation of therapy.

Baseline full blood examination, serum creatinine, and liver function tests should be performed. Full blood count should be monitored every 1 to 2 weeks during dosage titration, then every 1 to 3 months. Regular liver function testing should also be performed.

Both azathioprine and mercaptopurine are metabolised to a number of inactive products and to 6-thioguanine nucleotides (6-TGNs). Remission rates are proportional to red blood cell (RBC) levels of 6-TGNs (therapeutic range 235–450 pmol/108 RBCs). The major enzyme catalysing the conversion of mercaptopurine to inactive metabolites is thiopurine methyltransferase (TPMT). There is trimodal distribution of this enzyme in the population controlled by a genetic polymorphism. One in 300 individuals have low or undetectable TPMT activity, 8% to 11% have intermediate, and the remainder normal to high activity. Those with low levels of enzyme produce fewer inactive metabolites but higher concentrations of 6-TGNs resulting in a greater risk of myelotoxicity. Those with very high enzyme content may produce inadequate red blood cell concentrations of 6-TGNs and hence therapeutic inefficacy. Red blood cell 6-TGN concentration or metabolism profiling may be available in specialist centres and could provide a means of predicting patients likely to respond to azathioprine and mercaptopurine. Individuals deficient in this enzyme are particularly susceptible to myelosuppression with azathioprine, especially if they are also taking other drugs that inhibit TPMT, such as sulfasalazine, olsalazine, or mesalazine. TPMT testing does not identify all patients at risk of severe toxicity, and close monitoring of blood counts is still recommended.

Azathioprine and mercaptopurine are used to treat inflammatory bowel disease in patients whose disease is refractory to other therapies or who have frequent relapses. The onset of action of these drugs is slow, with the maximum effect often taking 3 to 6 months. Therapy with these drugs is often initiated with the re-introduction of corticosteroids after the first relapse.

Ribavirin has a broad antiviral spectrum, inhibiting the replication of a wide range of RNA and DNA viruses. It is a nucleoside analogue used in the treatment of chronic hepatitis C in combination with peginterferon alfa or interferon alfa. It has also been used to treat certain haemorrhagic fevers and severe measles infection in immunocompromised patients, and serious lower respiratory tract infection with respiratory syncytial virus (RSV) in hospitalised children.

Haemolytic anaemia is a common adverse effect. Frequent monitoring and dose reduction may be required (particularly in the first 6 weeks). It is contraindicated in patients with haemoglobinopathies or those requiring dialysis. Caution is required in patients with, or suspected of having, ischaemic heart disease. Blood counts must be monitored on a regular basis along with serum electrolytes and creatinine. Skin rashes are occasionally seen early in treatment (10% to 15% of cases), but are usually mild and may not require cessation of therapy.

Ribavirin is embryotoxic or teratogenic, or both, at doses well below the recommended human dose in all animal species studied. It is also genotoxic (mutagenic) and reversibly impairs spermatogenesis. It accumulates intracellularly and its half-life in humans is approximately 12 days. Therefore:

Entecavir is a nucleoside analogue of guanosine with activity against the hepatitis B virus. It is registered in Australia for the treatment of chronic hepatitis B and is available through specialist centres.

Entecavir is taken orally once daily and the most common adverse effects are headache, fatigue, dizziness and nausea. Entecavir is eliminated renally and dose reduction is required in renal impairment.

Lamivudine is a nucleoside reverse transcriptase inhibitor developed for treating human immunodeficiency virus infection . It is also used in the treatment of chronic hepatitis B in those with evidence of hepatitis B virus replication. It is given orally and adverse effects are uncommon. When used as monotherapy for hepatitis B, the major limitation of lamivudine is the development of viral resistance (69% after 4 years).

Adefovir is a nucleotide analogue of adenosine with activity against the hepatitis B virus. It is taken orally as a prodrug (adefovir dipivoxil) and is active against wild type hepatitis B virus and lamivudine-resistant variants.

The most common adverse effect of adefovir is gastric intolerance. It can also cause renal impairment.

Adefovir is eliminated predominantly by renal excretion with a half-life of about 8 hours in patients with normal kidney function. Reduced dosage frequency is required in renal impairment.

Interferons are naturally occurring proteins that belong to the family of cytokines and are released in vivo in response to viral infections. Three major classes have been identified: alfa, beta and gamma. After binding to specific cell receptors, interferons lead to increased synthesis of a range of proteins that enhance the cell's immune response to a virus. Five interferons have been synthesised and are available for therapeutic use for conditions such as multiple sclerosis, hairy-cell leukaemia, multiple myeloma and chronic granulomatous disease. Interferon alfa-2a and interferon alfa-2b are used in the treatment of chronic hepatitis B and C.

Pegylated interferons (peginterferons) consist of standard interferon molecules cross-linked to a polyethylene glycol molecule. The characteristics of the conjugate depend on the size of the glycol and strength of the bond, but the aim is to prolong the duration of action of the interferon and improve efficacy. Peginterferon alfa-2a is a stable conjugate that directly affects receptor sites, whereas peginterferon alfa-2b is subject to hydrolysis, releasing interferon alfa-2b into the circulation after injection. Peginterferon alfa-2b has a larger volume of distribution and is more rapidly eliminated than peginterferon alfa-2a, and therefore requires weight-based dosing.

Standard interferons and peginterferons can be used alone, but for chronic hepatitis C, both are more effective in combination with ribavirin). Interferons are given subcutaneously and therapy is continued for prolonged periods. Peginterferons are given as weekly injections and are preferred for hepatitis B and C. The toxicity profile of peginterferons is similar to that of conventional interferons.

Interferons can exacerbate hepatitis in patients with cirrhosis and cause hepatic decompensation. Therapy should be ceased if alanine aminotransferase (ALT) increases despite dose reduction, or is accompanied by increased bilirubin or evidence of hepatic decompensation.

Common adverse effects are influenza-like symptoms, anorexia and weight loss. Influenza-like symptoms can usually be managed with paracetamol.

Neuropsychiatric effects such as depression, anxiety, emotional lability, somnolence and forgetfulness are frequent. Interferons can precipitate psychiatric disorders, especially depression and anxiety, and should be used with caution in patients with a history of these disorders. Severe depression and other major psychiatric illnesses are contraindications.

Interferons can cause serious thyroid dysfunction and therefore thyroid function tests should be performed before, and every 3 months during, therapy.

Transient bone marrow suppression (neutropenia and thrombocytopenia) can require dose reduction. Blood counts should be checked at least monthly.

Some patients develop antibodies to interferon after prolonged use and this may reduce its efficacy.

Interferon alfa can increase theophylline plasma levels, possibly due to inhibition of the cytochrome P450 isoform, CYP1A2. There are also isolated reports of warfarin effects increasing after commencing interferon alfa. These drugs should be monitored after starting interferons but no other interactions have been reported.

The safety of alfa interferons in pregnancy is unclear. Animal tests indicate that high doses can increase abortion rates but there is no evidence of congenital malformations. Human exposure is too limited to define the potential hazards.