Pharmacology Notes

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.

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.