Drugs for Pain, Inflammation, and Arthritic Disorders



Drugs for Pain, Inflammation, and Arthritic Disorders



Classification of Drugs for Pain, Inflammation, and Arthritic Disorders*





*Note that some drugs are listed more than once.


aAlso indomethacin (INDOCIN), sulindac (CLINORIL), ketorolac (TORADOL, ACUVAIL, SPRIX), piroxicam (FELDENE), nabumetone (RELAFEN), etodolac (LODINE), meloxicam (MOBIC), diclofenac (FLECTOR, VOLTAREN GEL, ZIPSOR), and combination formulations such as ibuprofen and famotidine (DUEXIS) and naproxen and esomeprazole (VIMOVO).


bAlso infliximab (REMICADE), adalimumab (HUMIRA), anakinra (KINERET), abatacept (ORENCIA), tocilizumab (ACTEMRA), certolizumab (CIMZIA), and golimumab (SIMPONI).





Rheumatoid Arthritis


RA is an autoimmune disorder of unknown cause. The hallmark symptom of RA is joint inflammation, and most patients with RA experience a chronic, fluctuating course of disease that, despite therapeutic measures, can result in progressive joint destruction, deformity, disability, and premature death. RA affects 2% to 3% of the U.S. population, making it the most common systemic inflammatory disease (Box 30-1). It is three times more common in women than in men. RA is characterized by symmetrical joint inflammation that most frequently affects the small joints of the hands, wrists, and feet, but also the joints of the ankles, elbows, hips, knees, and shoulders. Cardiopulmonary, neurologic, and ocular inflammation are also often found in patients with RA, and many patients develop rheumatoid nodules on the extensor surfaces of the elbows, forearms, and hands. In addition, many patients have extraarticular manifestations, such as vasculitis, lymphadenopathy, and splenomegaly.



Box 30-1   The Case of the Aching Arthritic




Case Discussion


RA is a common disease, affecting more than 2 million people in the United States; it is three times more likely to be found in women than in men. RA is an autoimmune disease that causes chronic, symmetrical inflammation of the joints. The disease can begin at any age but most often starts after age 40 and before age 60. There are two main classes of medications used in treating RA: the antiinflammatory agents, such as celecoxib, aspirin, and cortisone, used to reduce pain and inflammation; and the disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, leflunomide, hydroxychloroquine, and others, which promote disease remission and prevent progressive joint destruction. Newer immunomodulating DMARD agents are administered by the intravenous route and include infliximab, anakinra, adalimumab, and others. Methotrexate is the most common DMARD used to treat RA, and the use of the selective COX-2 inhibitor celecoxib is warranted given no stated history of cardiovascular disease in the patient.


As shown in Figure 30-1, RA is triggered by autoimmune mechanisms that lead to the destruction of synovial tissue and other connective tissue. Both humoral and cellular immune mechanisms are involved in the pathogenesis of the disease. These mechanisms include the cytokine-mediated activation of T and B lymphocytes and the recruitment and activation of macrophages. The inflammatory leukocytes then release a variety of prostaglandins, cytotoxic compounds, and free radicals that cause joint inflammation and destruction. Patients with RA show elevated levels of immunoglobulin G–rheumatoid factor (IgG-RF) complexes; extracorporeal filtering of these complexes using immunoabsorption apheresis has helped some patients.


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FIGURE 30-1 Pathogenesis of rheumatoid arthritis and sites of action of selected antirheumatic drugs. In this simplified view of the immune system, dendritic (antigen-presenting) cells phagocytose antigens and present them to T cells, thereby activating the T cells. Activated T cells stimulate the production of B and T cells. B cells produce plasma cells that form rheumatoid antibodies. Helper T cells activate macrophages and cytotoxic T cells. Together, T cells, macrophages, and cytotoxic T cells produce cytotoxic cytokines (tumor necrosis factor [TNF] α, interleukin (IL)-1, IL-6, and others) and prostaglandins that cause joint inflammation, synovial proliferation, and bone and cartilage destruction. Abatacept blocks the co-stimulation of T cells. Methotrexate and leflunomide inhibit the proliferation and activity of T cells and B cells. Etanercept, infliximab, adalimumab, golimumab, and certolizumab inactivate TNF–α. Anakinra blocks the action of IL-1, and tocilizumab inactivates IL-6. Not shown are the glucocorticoids that inhibit T-cell activation and IL-2 production by regulation of gene transcription. Glucocorticoids and nonsteroidal antiinflammatory drugs (NSAIDs) also inhibit the formation of prostaglandins. Immunoglobulin G–rheumatoid factor (IgG-RF) complexes are detected in the blood of patients with rheumatoid arthritis.

In patients with RA, NSAIDs are used to relieve pain and inflammation, and DMARDs are used to suppress the underlying disease process and slow the progression of joint destruction. The sites of action of selected antirheumatic drugs are depicted in Figure 30-1 and discussed later.



Osteoarthritis


OA, also called degenerative joint disease, is the most common joint disease in the world. It affects about 10% of persons over 60 years of age, and radiographic evidence of OA can be found in most persons over 65. However, the disease is not simply associated with the aging process. Other factors that increase the risk for OA include obesity, osteoporosis, smoking, heredity, repetitive use of joints through work or leisure activities, and joint trauma.


OA primarily affects weight-bearing joints and causes deformity, limitation of motion, and progressive disability. The cartilage undergoes thickening, inflammation, splitting, and thinning. Eventually the cartilaginous layer is completely destroyed, leading to erosion and microfractures in the underlying bone. The major symptoms of OA are pain, stiffness, and muscle weakness around affected joints.


Nonpharmacologic measures for treating OA include joint protection and splinting, physiotherapy, orthotic prostheses to support the feet, and joint replacement surgery. Pharmacologic measures include NSAIDs, local glucocorticoid injections, and experimental chondroprotective drugs (e.g., chondroitin sulfate and glucosamine). Recently, sodium hyaluronate (SUPARTZ) was approved for intraarticular injection as a type of joint fluid replacement in the treatment of OA. It is a sterile, viscoelastic solution prepared from chicken combs (the fleshy growths on top of chicken heads). The antidepressant duloxetine (see Chapter 22) is also indicated for the management of persistent musculoskeletal pain caused by chronic OA and chronic low back pain.



Gout


Gout is an arthritic syndrome caused by an inflammatory response to crystals of monosodium urate monohydrate in joints, renal tubules, and other tissues. The deposition of these crystals occurs as a consequence of hyperuricemia, which can result from overproduction or underexcretion of uric acid. Risk factors for gout include obesity, alcohol consumption, and hypertension. Cancer chemotherapy can also increase plasma uric acid by cell death and lysis, releasing purines into the plasma; the purines are subsequently catabolized to uric acid.


Acute gout is treated with an NSAID or colchicine to relieve joint inflammation. Subsequent attacks of gout can be prevented by long-term therapy with a drug that either increases uric acid excretion or inhibits uric acid formation and thereby reduces the serum level of uric acid as discussed later.



Nonsteroidal Antiinflammatory Drugs


Mechanism of Action


The NSAIDs make up a large family of weak acidic drugs whose pharmacologic effects result primarily from the inhibition of cyclooxygenase (COX), an enzyme that catalyzes the first step in the synthesis of prostaglandins from arachidonic acid and other precursor fatty acids (see Chapter 26). COX is a microsomal enzyme, existing as a dimer (two molecules linked to form a functional unit) in the lumen and membrane of the endoplasmic reticulum. NSAIDs decrease COX activity primarily by competitive inhibition; however, aspirin forms a covalent, irreversible inhibition of COX (Fig. 30-2). The net effect of NSAID administration is a decrease in the production of prostaglandins and other autacoids.


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FIGURE 30-2 Mechanism of action for aspirin. A, The cyclooxygenase (COX) enzyme exists as a homodimer with two interlocking identical molecules, each providing an active channel for its substrates. Aspirin is chemically known as acetylsalicylic acid. B, Aspirin molecules enter the active channel of COX and add an acetyl group to an amino acid R-group in the active site of COX. The acetyl group is attached to serine at the 530 position in COX-1 and to serine at the 516 position in COX-2. This produces irreversible or noncompetitive inhibition. C, The aspirin molecule without the acetyl group is called salicylic acid or salicylate, which is a competitive inhibitor of COX.


Prostaglandin Effects


Prostaglandins play an important role in the development of pain, inflammation, and fever. Prostaglandins are released from cells in response to chemical stimuli or physical trauma. They sensitize sensory nerve endings to nociceptive stimuli and thereby amplify the generation of pain impulses. They also promote tissue inflammation by stimulating inflammatory cell chemotaxis, causing vasodilation and increasing capillary permeability and edema.


Fever, defined as the elevation of body temperature to a level above 37° C (98.6° F), often results from an alteration of hypothalamic thermoregulatory mechanisms. Bacterial toxins and other pyrogens stimulate the production of cytokines by leukocytes, and these cytokines increase prostaglandin synthesis in the preoptic area of the hypothalamus. The prostaglandins then act to reset the body’s thermostat to a new point above 37° C. This in turn activates temperature-raising mechanisms, such as a reduction in heat loss via cutaneous vasodilation, and causes the temperature to rise. All NSAIDs relieve fever by inhibiting prostaglandin synthesis in the hypothalamus, but these drugs are not capable of reducing body temperature below normal.



Cyclooxygenase Isozymes


COX is now known to occur in two major isoforms: COX-1 and COX-2. COX-1 is a constitutive or housekeeping enzyme that is found in relatively constant levels in various tissues. COX-1 participates in the synthesis of prostaglandins that have a cytoprotective effect on the gastrointestinal (GI) tract. It also catalyzes the formation of thromboxane A2 in platelets, leading to platelet aggregation and hemostasis. In contrast, COX-2 is an inducible enzyme. Its levels are normally very low in most tissues but are rapidly up-regulated during the inflammatory process by proinflammatory substances (e.g., cytokines, endotoxins, and tumor promoters). Both COX-1 and COX-2 appear to participate in renal homeostasis.


Most of the NSAIDs available today are nonselective inhibitors of COX-1 and COX-2. The discovery of COX isozymes led to the development of selective COX-2 inhibitors, the first one being celecoxib. These selective inhibitors are effective antiinflammatory drugs, and they produce less GI bleeding and ulcers than do the nonselective COX inhibitors.


A third COX isozyme (COX-3), which was recently discovered, appears to be an alternative splice variant of COX-1. Acetaminophen potently inhibits COX-3, and this finding likely explains the reason that acetaminophen has little antiinflammatory action.



Specific Agents


Nonselective Cyclooxygenase Inhibitors


Among the nonselective COX inhibitors are many well-known NSAIDs that are available without a prescription, including aspirin, ibuprofen, ketoprofen, and naproxen. Acetaminophen is a weak antiinflammatory agent, but it is also included in this class of drugs because it exerts analgesic and antipyretic effects via inhibition of COX. As shown in Table 30-1, NSAIDs vary greatly in potency and half-life, but most of them are administered two to four times a day with food.



Lower doses of NSAIDs are usually sufficient to treat mild to moderate pain and counteract fever, whereas higher doses are generally needed to relieve inflammation associated with arthritic disorders and injuries. NSAIDs are particularly effective in relieving pain caused by tissue inflammation or bone or joint trauma, and they can be combined with opioid analgesics to obtain a greater analgesic effect and reduce the need for higher doses of opioids. For example, NSAIDs are widely used in the treatment of postoperative pain, either alone or in combination with an opioid.


Although NSAIDs are effective in relieving the pain of chronic disorders, their long-term use is associated with a number of adverse effects, including GI bleeding, peptic ulcers, and renal and hepatic dysfunction. Acetaminophen produces fewer GI problems than do other nonselective COX inhibitors, but it also lacks significant antiplatelet and antiinflammatory activity. Although acetaminophen can be used concurrently with another NSAID for supplemental analgesia, alternative combinations of two NSAIDs should generally be avoided, not only because they increase the risk of GI and other side effects but also because they sometimes have adverse interactions. For example, aspirin and other salicylates displace some NSAIDs (e.g., ketorolac) from plasma proteins and thereby increase their serum levels significantly.


The NSAIDs can interact with a large number of other drugs through pharmacokinetic and pharmacodynamic mechanisms. Most NSAIDs inhibit the renal excretion of lithium and can increase lithium serum levels and toxicity. NSAIDs can reduce the clearance of methotrexate and aminoglycoside drugs. NSAIDs can also interfere to varying degrees with the antihypertensive effect of diuretics, β-adrenoceptor antagonists, angiotensin inhibitors, and other antihypertensive drugs. When given with potassium-sparing diuretics, NSAIDs can cause potassium retention and lead to hyperkalemia. Some drug interactions are associated with only a particular NSAID. For example, high doses of salicylates exert a hypoglycemic effect that can alter the effects of antidiabetic drugs. Indomethacin reduces the natriuretic effect of diuretics and can cause nephrotoxicity when given with triamterene.


Low doses of acetaminophen can be safely used for analgesia and antipyresis during pregnancy. The use of other NSAIDs during the second half of pregnancy is generally not recommended, however, because of potential adverse effects on the fetus. These effects result from prostaglandin inhibition and include GI bleeding, platelet inhibition, renal dysfunction, and premature closure of the ductus arteriosus.



Aspirin and Other Salicylates


The therapeutic value of salicylates was originally recognized when they were identified as the active ingredients of willow bark and other plant materials used in folk medicine to relieve pain and fever. Aspirin was synthesized in 1899 during a search for a salicylate derivative that would be less irritating to the stomach than salicylic acid. Aspirin soon became widely used around the world as an analgesic, antipyretic, and antiinflammatory drug.


Salicylic acid derivatives include aspirin (acetylsalicylic acid [ASA]) and several nonacetylated drugs, such as salsalate, choline magnesium salicylate, and methyl salicylate (oil of wintergreen).



Pharmacologic Effects and Indications

In adults, the salicylates can be used in the management of pain, fever, and inflammation, as well as in the prophylaxis of myocardial infarction, stroke, and other thromboembolic disorders. In children, the use of salicylates should be avoided, because the risk of Reye syndrome appears to be increased in virus-infected children who are treated with these drugs.


The analgesic, antipyretic, and antiinflammatory effect of aspirin and other salicylates result from nonspecific inhibition of COX in peripheral tissues and the CNS. Aspirin irreversibly acetylates platelet COX and has a longer-lasting effect on thromboxane synthesis than do other salicylates. The antiplatelet effect of aspirin persists for about 14 days, whereas that of most other NSAIDs is much shorter. The effect is long-lived because platelets lack a nucleus and do not make new COX enzyme.


The salicylates are usually administered orally, but formulations are also available for topical and rectal administration. The oral dosage of aspirin that is needed to inhibit platelet aggregation is somewhat lower than the oral dosage needed to obtain analgesic and antipyretic effects, and it is much lower than the oral dosage needed to relieve inflammation caused by arthritic and other inflammatory disorders. Figure 30-3 shows the relationship between the dosage of aspirin and the pharmacologic and toxic effects of the drug.


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FIGURE 30-3 Relationship between the dosage of aspirin and the pharmacologic and toxic effects of the drug.


Pharmacokinetics

Aspirin is well absorbed from the gut. Although its concurrent administration with antacids may slow its absorption rate, it does not significantly reduce its bioavailability. Aspirin is rapidly hydrolyzed to salicylic acid (salicylate) by plasma esterase, and this accounts for its short plasma half-life (about 15 minutes). Most of the pharmacologic effects of aspirin are attributed to its salicylate metabolite, which has a half-life of about 2 hours. Aspirin itself, however, is responsible for irreversible inhibition of platelet COX and platelet aggregation.


Most of the salicylic acid formed from aspirin and other salicylate drugs is conjugated with glycine to form salicyluric acid. This substance is then excreted in the urine, along with about 10% of free salicylate and a similar amount of glucuronide conjugates. The rate of excretion of salicylate is affected by urine pH. For this reason, alkalinization of the urine by administration of sodium bicarbonate has been used to increase the ionization and elimination of salicylic acid in cases of drug overdose (see Chapter 2).


When a therapeutic dose of aspirin or other salicylate drug is ingested, the rate of metabolism and the rate of excretion of salicylate are proportional to the drug’s plasma concentration (first-order elimination). When an excessive dose is taken, the elimination pathways become saturated, giving rise to zero-order elimination. For this reason, larger doses can rapidly elevate plasma salicylate concentrations to toxic levels, especially in the elderly, who are at greatest risk of aspirin toxicity.

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Jul 23, 2016 | Posted by in PHARMACY | Comments Off on Drugs for Pain, Inflammation, and Arthritic Disorders

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