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P A R T 3  Drugs acting on the immune system

of inflammation. Because they alter the course of the inflammatory process, many rheumatologists are select- ing to use DMARDs early in the diagnosis, before damage to the joints has occurred. Adverse effects asso- ciated with these drugs (see Adverse effects) can be severe to life-threatening because they alter the ability of the body to initiate or carry on an inflammatory reaction. DMARDs discussed in this chapter include drugs used when people do not respond to conventional therapy—anakinra ( Kineret ), etanercept ( Enbrel ), leflunomide ( Arava ) and penicillamine ( D-Penamine )— and drugs used to directly decrease pain in joints affected by arthritis, including hyaluronidase derivative ( Hyalase ) and sodium hyaluronate ( Fermathron ). Additional drugs also used to modify the disease process in rheumatoid arthritis include the antineoplas- tic drug methotrexate (see Chapter 14), the monoclonal antibodies infliximab ( Remicade ), golimumab ( Simponi ) and adalimumab ( Humira ) (see Chapter 17), the T cell suppressor abatacept ( Orencia ) (see Chapter 17), certain antimalarial drugs (see Chapter 12), some additional antineoplastic drugs such as cyclophosphamide (see Chapter 14) and the immune modulators cyclosporin A and azathioprine (see Chapter 17). Therapeutic actions and indications Anakinra is one of the newest of the antiarthritis drugs. This drug is an interleukin-1 receptor antagonist. It blocks the increased interleukin-1, which is responsible for the degradation of cartilage in rheumatoid arth­ ritis. This drug must be given each day by subcutaneous injection and is often used in combination with other antiarthritis drugs. Etanercept contains genetically-engineered tumour necrosis factor (TNF) receptors derived from Chinese hamster ovary cells. These receptors react with free- floating TNF released by active leucocytes in auto- immune inflammatory disease to prevent the damage caused by TNF. See Table 16.3 for usual indications. Hyaluronidase derivatives, such as hylan G-F 20 and sodium hyaluronate, have elastic and viscous properties. These drugs are injected directly into the joints of people with severe rheumatoid arthritis of the knee. They seem to cushion and lubricate the joint and relieve the pain associated with degenerative arthritis. They are given weekly for 3 to 5 weeks. Leflunomide directly inhibits an enzyme, dihydro- orotate dehydrogenase (DHODH), which is active in the autoimmune process that leads to rheumatoid arthri- tis, relieving signs and symptoms of inflammation and blocking the structural damage this inflammation can cause, slowing disease progression. Penicillamine lowers the immunoglobulin M (IgM) rheumatoid factor levels in people with acute rheum­ atoid arthritis, relieving the signs and symptoms of

inflammation. It may take 2 to 3 months of therapy before a response is noted. Pharmacokinetics Anakinra is slowly absorbed from the subcutaneous tissue, reaching peak levels in 3 to 7 hours. It is meta­ bolised in the tissues and excreted in the urine. It has a half-life of 4 to 6 hours. Etanercept is very slowly absorbed after subcutaneous injection, reaching peak levels in 72 hours. It is metabolised and destroyed in the tissues with a half-life of 115 hours. The hyaluronidase derivatives are not absorbed systemically. Leflunomide is slowly absorbed from the GI tract, reaching peak levels in 6 to 12 hours. It undergoes hepatic metabolism and excretion in the urine. The half-life of leflunomide is 14 to 18 days. Penicillamine is an oral drug that reaches peak levels in 1 to 3 hours after administration. It is extensively metabolised in the liver and excreted in the urine with a half-life of 2 to 3 hours. Contraindications and cautions These drugs are contraindicated in the presence of allergy to the drugs or to the animal products fromwhich they were derived (Chinese hamster products in etaner­ cept; chicken products in hylan G-F 20 and sodium hyaluronate); pregnancy or breastfeeding because of the potential for adverse effects on the fetus or neonate ; acute infection because of the blocking of normal inflammatory pathways ; and liver or renal impairment, which could be exacerbated by these drugs. Adverse effects A variety of adverse effects are common with the use of these drugs, including local irritation at injection sites (anakinra, etanercept, hyaluronidase derivatives and sodium hyaluronate), pain with injection and increased risk of infection. Leflunomide is associatedwith potentially fatal hepatic toxicity and rashes. Penicillamine is associ- ated with a potentially fatal myasthenic syndrome, bone marrow depression and assorted hypersensitivity reac- tions. Etanercept is associated with severe bone marrow suppression, and a warning has been issued stating that the drug has been associated with the development of serious CNS problems, including multiple sclerosis. It can also cause severe myelosuppression and increased risk of infections and cancer development. People who use this drug need to be monitored very closely. Leflunomide has been associated with severe hepatic toxicity, and the person’s liver function needs to be monitored closely. Clinically important drug–drug interactions Hyaluronidase derivatives such as sodium hyaluro- nate should not be injected at the same time as local anaesthetics.