Pharmacology Notes

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.

Mycophenolate mofetil is a potent immunosuppressant that interferes with DNA synthesis and acts through suppression of B and T lymphocytes. Australian marketing approval is for prevention of rejection of solid organ allografts. It also has a well-recognised range of off-label uses including treatment of some autoimmune diseases; in these diseases, benefits may be apparent in several weeks, but it may take a number of months for maximum benefit. Because of its potency, mycophenolate should be used only under appropriate specialist supervision.

When given orally, mycophenolate mofetil is well absorbed with a bioavailability of about 94%, which is not affected by food. It is a prodrug that is hydrolysed to active mycophenolic acid in the liver. Mycophenolic acid is metabolised by hepatic glucuronidation and also undergoes enterohepatic recirculation which can result in secondary increases in the serum level 6 to 12 hours post dose. Mycophenolate is ultimately excreted in the urine, mainly (87%) as the glucuronide. Care is required in dosing in renal failure.

The most common adverse effects are gastrointestinal, including nausea, vomiting and diarrhoea. These can be minimised by taking mycophenolate with food. Other adverse effects include bone marrow suppression (eg anaemia, thrombocytopenia, leucopenia) or stimulation, hypertension, chest pain, cough, dyspnoea, electrolyte and metabolic disturbances, renal damage, haematuria, acne, lymphoproliferative disease, headache, dizziness, insomnia and tremor. There is also a potential for increased infections and some cancers.

Blood level testing is poorly developed, and regular full blood counts are required to monitor for neutropenia. A full blood count should be performed weekly for 1 month, twice monthly for 2 months, then monthly for the rest of the first year. Dose reduction or cessation is required if the patient becomes neutropenic.

Mitozantrone (also known as mitoxantrone) is a cytotoxic drug with Australian marketing indications for chemotherapy of breast cancer, lymphomas and leukaemias but also has recognised off-label indications for treatment of some immune-mediated diseases.

Its mechanism of action is unclear but is understood to be DNA-reactive.

Principal effects are myelosuppression and lymphocyte depletion of the lymphoid organs, both requiring haematological monitoring. Transient leucopenia may follow use of mitozantrone.

Main adverse effects are as for cytotoxic drugs, including nausea, vomiting, alopecia, mucositis and stomatitis. Mitozantrone, like the anthracycline cytotoxics, is cardiotoxic and this cardiotoxicity is additive to any prior or subsequent anthracycline exposure.

As a cytotoxic drug, mitozantrone requires specialised facilities for reconstitution and handling. Because of its toxicity, mitozantrone should be used only under appropriate specialist supervision

Methotrexate is a folic acid analogue, which binds to dihydrofolate reductase and antagonises folic acid. As folic acid is essential for DNA synthesis, methotrexate impairs cell division. It is cytotoxic at high doses.

Methotrexate has a very long half-life and, for noncancer indications, is given on one day per week.

The most common adverse effects are nausea and mouth ulcers, which occur in about 5% of individuals, but can decrease with continued use. These adverse effects can be limited by a dose reduction, co-administration of folic acid, and parenteral delivery of the methotrexate. Folic acid supplementation is always recommended with methotrexate therapy—at a dose of around 10 mg weekly in a single or split doses, generally not on the day that the methotrexate is administered.

Abnormal liver function tests are common, particularly in those with diabetes, obesity, abnormal renal function, or excessive alcohol intake. Hepatotoxicity correlates with total cumulative dose, and manifests as fibrosis of increasing severity, culminating in cirrhosis. The mechanism is unknown. It is rare in appropriately selected patients in the absence of abnormalities in albumin or transaminases. However, regular monitoring of liver function tests is essential (see Monitoring). Liver biopsy is necessary for early detection and characterisation of this complication, but whether this is justified and how often it should be performed is controversial. Methotrexate should be used cautiously in patients with pre-existing liver disease, or alcohol abuse. A liver biopsy prior to commencement of methotrexate may be useful in these patients; specialist advice should be sought.

Methotrexate can also cause leucopenia, thrombocytopenia and anaemia. The frequency of these haematological events is low, but is higher in the elderly, those with reduced renal function, and in patients with acute illness (eg viral infection, dehydration). Treatment should be ceased temporarily in patients who are acutely unwell.

Dose reduction is required when using methotrexate in patients with mild renal impairment, and methotrexate is contraindicated in moderate to severe renal impairment.

Methotrexate has also been associated with rash, menorrhagia, pneumonitis, fatigue, alopecia and depression.

Methotrexate is teratogenic. It should be avoided in pregnancy, and ceased 3 months before conception if possible. For more detail, see the discussion in Use of antirheumatic drugs in pregnancy.

The combination of methotrexate with other drugs that inhibit folic acid synthesis, such as trimethoprim+sulfamethoxazole (cotrimoxazole), trimethoprim alone, or triamterene should be avoided, because of increased risk of haematological toxicity (eg pancytopenia, megaloblastic anaemia).

Methotrexate concentrations are increased if given concurrently with probenecid, penicillins, aspirin or other NSAIDs. These drugs also block the secretion of methotrexate by the renal tubules.

A full blood examination, including haemoglobin, white cell and platelet counts, creatinine, and liver function tests should be performed monthly for the first 6 months, then every 1 to 2 months thereafter. In patients with a low risk of toxicity, consideration may be given to increasing the intervals between blood tests. Patients with abnormal liver function tests should have more frequent monitoring, and may require liver biopsy if there is a persisting rise in transaminases that does not normalise after cessation of methotrexate.

Due to the toxicity of methotrexate, a reminder system should be put in place to ensure that the laboratory monitoring and subsequent clinical review actually occurs.

Methotrexate is valuable in treatment of severe unresponsive psoriasis and a number of other dermatological conditions requiring immunosuppression. Toxicity due to bone marrow depression and mucositis is less likely in dermatological applications than when higher doses are used, but regular monitoring with blood counts is necessary.

The mechanism of action of methotrexate in Crohn’s disease is unknown, but may involve inhibiting inflammatory cell activation and cytokine release. Response to therapy is seen over several months.

For Crohn’s disease, methotrexate is generally commenced as a single weekly dose of 25 mg given intramuscularly or subcutaneously. If there is a clinical response, parenteral therapy can be changed to oral therapy after 16 weeks. Doses less than 15 mg per week are ineffective in active Crohn’s disease.

The mechanism of action of methotrexate, at the comparatively low dose used in rheumatoid arthritis, may involve increasing intracellular adenosine and thus inhibiting inflammatory cell activation. In the treatment of rheumatoid arthritis, methotrexate is generally commenced as a single oral weekly dose of 5 to 10 mg.

Response to therapy is seen after 1 to 2 months. Dose escalation protocols vary depending on the severity of the disease, but should allow 4 to 6 weeks at each dose level to assess response. The dose increment can vary from 2.5 to 10 mg. The maximum recommended dose is usually 15 to 25 mg weekly in rheumatoid arthritis, but higher doses can be needed in inflammatory myopathies or psoriasis.

Methotrexate is generally well tolerated, but dose-limiting toxicity occurs in 10% to 15% of patients with rheumatoid arthritis. Some patients experience a flare of their arthritis for a day or two following each dose.

Subcutaneous and intramuscular methotrexate is sometimes used if adverse effects limit the maximum dose, or when the maximum dose is ineffective when given orally.

Patients taking a combination of leflunomide and methotrexate should have full blood examination and liver function tests performed at least monthly. In patients with a low risk of toxicity, consideration may be given to increasing the intervals between blood tests.

For patients taking a combination of methotrexate, sulfasalazine and hydroxychloroquine (‘triple therapy’), monitoring would include a full blood examination and liver function tests every 2 weeks for 8 weeks and then 4- to 6-weekly thereafter, and yearly eye checks if continuing on hydroxychloroquine.

Interferon beta has both antiviral and immunoregulatory activities. Its mechanism of action in multiple sclerosis is not clearly understood.

Adverse reactions are numerous, the most common being flu-like symptoms that decline with time, local injection site reaction and elevated hepatic transaminase concentrations. Numerous central nervous system adverse effects have also been reported, including weakness, increased stiffness, fatigue, nausea, anxiety, confusion and depression. Neutralising antibodies may also develop in a minority and in high titre are thought to decrease effectiveness

For more information about this drug class, see Interferons

Intravenous immunoglobulin is a blood product, which consists of IgG, although trace quantities of IgA, IgM, dimeric IgG and other plasma proteins are also present. Screening procedures and improved preparation techniques mean that transmission of hepatitis B, hepatitis C, or other detectable blood-borne viruses should not occur.

Adverse effects include tachycardia, chest tightness, headache, lumbar pain, fever and mildly elevated blood pressure. These symptoms usually abate on slowing the infusion rate or after temporary cessation of the infusion. Severe reactions, including Coombs-positive haemolytic anaemia and anaphylaxis, are rare. However, use of intravenous immunoglobulin is contraindicated in patients with selective IgA deficiency because of the risk of anaphylaxis.

Glatiramer acetate, a mixture of synthetic peptides composed of four amino acids, appears to mimic the antigenic properties of myelin basic protein. Mild pain and pruritus at the injection site are the most common complaints. Some patients experience chest discomfort, flushing and dyspnoea shortly after injection. These episodes are poorly understood and, although frightening for the patient, appear to be benign.

Cyclosporin has Australian marketing approval for suppression of rejection of kidney, liver and heart transplants and treatment of a number of immune-mediated diseases. It also has a range of recognised off-label uses for treatment of other immune-mediated disorders including some autoimmune diseases.

In dermatology, cyclosporin is used in a wide variety of inflammatory conditions (eg psoriasis, atopic dermatitis, lichen planus) but the difficulties in its use, and the reversibility of benefit on ceasing administration markedly limit its usefulness.

In gastroenterology, it is used in patients with refractory ulcerative colitis that has not responded to other drugs such as corticosteroids.

For information on use in rheumatology, see below.

For information on use of cyclosporin in prevention of lung rejection, see Calcineurin inhibitors

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Cyclosporin is an immunosuppressant drug that works by inhibiting cytokine release from activated T cells. Its action is mediated by inhibition of calcineurin. Calcineurin inhibitors react in the cytoplasm of T-lymphocytes with cellular proteins to form a complex, which blocks the phosphorylase activity of calcineurin. This prevents the phosphorylation of nuclear transcription factors, which can then no longer move into the nucleus to activate transcription of growth factors and proinflammatory cytokines. T cells have limited amounts of calcineurin, but they are dependent upon it for their immune activation.

Oral absorption and bioavailability are quite variable, depending on timing of dose, patient population and formulation used. Different brands of oral cyclosporin have different bioavailability and doses are therefore not directly interchangeable between brands. When prescribing cyclosporin, refer to the specific brand. In general, it is not advisable to switch brands in a patient with a stable, well-controlled medical condition, but if undertaken should be accompanied by additional monitoring.

Cyclosporin is extensively metabolised by the liver with the multiple metabolites being eliminated primarily by biliary excretion. The half-life is highly variable, ranging from 6 to 20 hours.

Cyclosporin is a potent immunosuppressant with a high potential for toxicity and adverse effects and should therefore be used only under the supervision of a specialist with expertise in its use. The main toxicity is reversible renal impairment and hypertension. Other common adverse effects include hirsutism, gingival hyperplasia, gastrointestinal disturbances, pancreatitis, weight gain, oedema, hepatic dysfunction, hyperlipidaemia, anaemia and other haematological abnormalities, central nervous system disturbances (eg tremor, fatigue, headache), and a burning sensation in the hands and feet. Hyperkalaemia, hypomagnesaemia and hyperuricaemia can occur. An increased rate of malignancies and infections has been reported.

For nontransplant indications, cyclosporin is contraindicated in patients with uncontrolled hypertension, uncontrolled infection, primary or secondary immunodeficiency, IgA deficiency and in patients with impaired baseline renal function.

Clinically significant drug interactions include increased cyclosporin levels with CYP3A4 inhibitors (such as diltiazem, ketoconazole, and erythromycin) and decreased cyclosporin levels with enzyme inducers (including phenytoin, rifampicin, and St John’s wort). The bioavailability of cyclosporin has been shown to increase when the drug is taken concomitantly with grapefruit juice.

Creatinine should be measured every two weeks until the dosage is stable, then monthly. A full blood count, liver function tests and potassium should be measured periodically. Blood pressure should be closely monitored. Routine cyclosporin level monitoring is generally not required when it is used for indications other than transplantation; however, use of high doses should be guided by monitoring of blood levels. Patients not responding may also benefit from therapeutic drug monitoring, to rule out absorption problems and noncompliance.

In the treatment of rheumatoid arthritis, the initial dose of cyclosporin is 2.5 to 3 mg/kg/day (in divided doses) for 6 weeks. Onset of effect is 2 to 4 months. In the absence of a clinical response, the dose can be increased every 1 to 2 months by 0.5 to 1 mg/kg/day to a maximum dose of 5 mg/kg/day. Once a patient has been stable for 3 months, an attempt should be made to reduce the dose to the lowest effective dose. If there is no response after 6 months, despite the maximum dose being given for 3 months, cyclosporin should be discontinued. The dose should be reduced if there is a 30% increase in the creatinine level, and cyclosporin should be ceased if the creatinine rises by 50%. Co-administration with fish oil can reduce the nephrotoxicity and hypertension.

Cyclophosphamide has both antimitotic and immunosuppressive properties. It has a cytotoxic effect on lymphocytes. It is a nitrogen mustard analogue which is converted to the active metabolite in the body.

The dose in rheumatoid vasculitis is 1 to 3 mg/kg/day orally. In some other conditions (such as systemic lupus erythematosus—SLE), it can be administered as an intravenous pulse.

The usefulness of cyclophosphamide is limited by its toxicity. The most common, and potentially serious, adverse effect with use of cyclophosphamide is bone marrow suppression, particularly neutropenia. Even if patients tolerate cyclophosphamide well for several months, there is usually a gradual decline in the white blood cell count that eventually requires dose adjustment.

Accumulation of active metabolites can lead to haemorrhagic cystitis. Strategies for preventing haemorrhagic cystitis include adequate hydration (intake of 3 litres of water per day), taking oral doses in the morning with plenty of water, and the use of mesna at the time of intravenous administration of cyclophosphamide (see Treatment regimens for systemic vasculitis).

Other adverse effects include nausea, vomiting, malaise and alopecia. There is an increased risk of bladder cancer with long-term use. Secondary bone marrow disorders including secondary leukaemia have been reported.

Pneumocystis jiroveci (carinii) pneumonia prophylaxis (eg with sulphamethoxazole+trimethoprim) should be considered for all patients unless contraindicated by allergy. Sulphamethoxazole+trimethoprim can also contribute to marrow suppression (see Pneumocystis jiroveci (carinii) pneumonia in Antibiotic guidelines).

A protocol for full blood count monitoring (at least every 2 weeks) should be established before initiating therapy. Patients with borderline cell counts may need more frequent monitoring.Urine analysis should be performed monthly, and patients advised to report dysuria. Cystoscopy should be performed if cystitis is suspected either because of symptoms, or asymptomatic abnormality on urine analysis. If cystitis is confirmed, it is a contraindication to further use of cyclophosphamide.