Anti- Inflammatory, Antiarthritis, and Related Agent Chapter 16

Salicylates Popular anti-inflammatory agents because of their ability to block the inflammatory response, and because of their antipyretic (fever blocking) and analgesic (pain blocking) properties Generally available without prescription and relatively non- toxic Aspirin: available OTC and most widely used drug for treating inflammatory conditions Others: balsalazide (Colazal); choline magnesium trisalicylate (Tricosal); diflunisal (generic); mesalamine (Pentasa); etc.

Salicylates Therapeutic Actions and Indications: inhibit the synthesis of prostaglandin, an important mediator of the inflammatory reaction Indicated for treatment of mild to moderate pain, fever, and numerous inflammatory conditions, including RA and OA. Pharmacokinetics: readily absorbed directly from the stomach, reaching peak levels within 5-30 minutes. Metabolized in the liver and excreted in the urine. Salicylates do cross the placenta and enter breast milk they are not indicated for use during pregnancy (associated with bleeding risk for mother)

Salicylates Contraindications and Cautions: presence of known allergy, bleeding abnormalities, impaired renal function, chickenpox or influenza, surgery or other procedures scheduled within one week, and pregnancy or lactation. Adverse effects: may be result of direct drug effects on the stomach nausea, dypepsi, heartburn, epigastric discomfort. Salicylism can occur with high levels of aspirin- dizziness, ringing in ears, nausea, vomiting, diarrhea, mental confusion. Salicylate toxicity: tachypnea, hemorrhage, excitement, confusion, pulmonary edema, convulsions (may occur in doses of 20-25g in adults and 4g in children)

Nonsteroidal anti-inflammatory and related agents NSAIDs: provide strong anti- inflammatory and analgesic effects without the adverse effects associated with the corticosteroids NSAIDs are a drug class that has become one of the most commonly used drug types in the US Black box warning on these drugs: Cardiovascular and gastrointestinal risks

NSAIDs Therapeutic actions and indications: anti-inflammatory, analgesic, and antipyretic effects of NSAIDs are largely related to inhibition of prostaglandin synthesis; NSAIDs block two enzymes know as COX-1 and COX-2 Pharmacokinetics: Rapidly absorbed in the GI tract reaching peak levels in 1-3 hours. They are metabolized in the liver and excreted in the urine. NSAIDs cross the placenta and cross into breast milk- therefore not recommended during pregnancy

NSAIDs Contraindications and Cautions: presence of allergy to any NSAID or salicylate; CV dysfunction; peptic ulcers or known GI bleeding; pregnancy. Caution should be used with renal or hepatic dysfunction. Adverse Effects: PT with NSAIDs often experience nausea, dyspepsia, GI pain, constipation, diarrhea, flatulence. Headache, dizziness, and fatigue also occur frequently and can be related to the effects the drug has on the CNS. Bleeding, platelet inhibition, HTN, and even bone marrow depression have been reported with chronic use.

Acetaminophen Acetaminophen (Tylenol) used to treat moderate to mild pain and fever and often is used in place of NSAIDs or salicylates. Most frequently used drug in management of pain and fever in children Widely available OTC and is found in combination products It can be extremely toxic and can cause severe liver toxicity and lead to death

Acetaminophen Therapeutic actions and indications: acetaminophen acts directly on the thermoregulatory cells in the hypothalamus to cause sweating and vasodilation; this in turn causes release of heat and lowers fever. Indicated for the treatment of pain and fever associated with a variety of conditions including influenza. Acetaminophen is also indicated for the relief of musculoskeletal pain associated with arthritis. Pharmacokinetics: Rapidly absorbed in the GI tract reaching peak levels in 0.5 to 2 hours. It is extensively metabolized in the liver and excreted in urine. (caution with hepatic and renal impairment)

Acetaminophen Contraindications and cautions: presence of allergy; pregnancy; hepatic dysfunction or chronic alcoholism Adverse effects: headache, hemolytic anemia, renal dysfunction, skin rash, and fever. Hepatotoxicity is a potentially fatal adverse effect that is usually associated with chronic use and overdose and is related to direct toxic effects on the liver.

Antiarthritis Agents Antiarthritis drugs include the gold compounds, which are used to prevent and suppress arthritis in selected patients with RA. The other antiarthritis drugs are specifically used to block the inflammation and tissue damage of RA Gold Compounds: used for RA patients who don’t respond to other antiarthritis medications. This is a treatment with “gold salts” also known as chrysotherapy which is gold taken up by macrophages, which then inhibit phagocytosis; this is reserved for patients who are unresponsive to conventional therapy.

Gold Compounds Therapeutic actions and indications: Chrysotherapy results in inhibition of phagocytosis. Because phagocytosis is blocked, the release of lysosomal enzymes is inhibited and tissue destruction is decreased. This action allows gold salts to suppress and prevent some arthritis and synovitis. Gold salts are indicate to treat selected cased of RA and juvenile RA in patients whose disease has been unresponsive to standard therapy. These drugs do not repair damage; they prevent further damage and so are most effective if used early in disease.

Gold compounds Pharmacokinetics: absorbed at varying rates, depending on their route of administration. They are widely distributed throughout the body but seem to concentrate in the HPA system and in the adrenal and renal cortices. Gold salts are excreted in urine and feces; these drugs cross the placenta and go into breast milk Barrier contraceptives should be recommended to women of childbearing age, and another method of feeding the baby should be used if gold salts are needed in a lactating woman.

Gold Compounds Contraindications and Cautions: gold salts can be quit toxic and are contraindicated in the presence of any know allergy to gold, diabetes, CHF, severe debilitation, renal or hepatic impairment, HTN, pregnancy or lactation. Adverse effects: a variety of adverse effects are common with use of gold salts, stomatitis, gingivitis, glossitis, pharyngitis, laryngitis, colitis, diarrhea and other GI inflammation. Bone marrow depression, nephrotic syndromes, dermatitis, pruritus, and exfoliative dermatitis. Allergic reactions ranging from flushing, fainting, and dizziness to anaphylactic shock.

Disease- Modifying Antirheumatic Drugs Available for treatment arthritis and aggressively affect the process of inflammation. Many rheumatologists are selecting DMARDs early in the diagnosis, before damage to the joints has occurred. Adverse effects of these drugs can be severe and life- threatening because they alter the ability of the body to initiate or carry on an inflammatory reaction. Drugs include: anakinra (Kineret), etanercept (Enbrel, Leflunomide (Arava), and penicillamine (Depen)

DMARDs Therapeutic actions and indications: -Anakinra: blocks the increased interleukin-1, which is responsible for the degradation of cartilage in rheumatoid arthritis. (may be given by subcutaneous injection) -Etanercept: contains genetically engineered tumor necrosis factor receptors derived from Chinese hamster ovary cells. -Hyaluronidase derivatives: injected directly into the joint of patients with severe RA of the knee. They seem to cushion and lubricate the joint and relieve the pain associated with degenerative arthritis. -Leflunomide: directly inhibits an enzyme dihydroorotate dehydrogenase that is active in the autoimmune process that leads to RA, relieving signs and sx of inflammation and blocking the structural damage this inflamation can cause. -Penicillamine: lower immunoglobulin rheumatoid factor levels in patients with acute RA

DMARDs Contraindications and Cautions: presence of allergy or to animal products from which they were derived, pregnancy and lactation, acute infection and liver or renal impairment. Adverse effects: variety of adverse effects are common including local irritation at injection sites, pain with injection and increased risk of infection. Leflunomide is associated with potentially fatal myasthenic syndrome, bone marrow depression, and assorted hypersensitivity reactions. Etanercept is associated with severe bone marrow suppression, and a warning has been issued statin that the drug has been associated with development of serious CNS problems including multiple sclerosis. Leflunomide has been associated with severe hepatic toxicity, and the patients liver function needs to be monitored closely.

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