Книги фарма 2 / Bertram G. Katzung-Basic & Clinical Pharmacology(9th Edition)

Approximately 30% of patients using sulfasalazine discontinue the drug because of toxicity. Common adverse effects include nausea, vomiting, headache, and rash. Hemolytic anemia and methemoglobinemia also occur, but rarely. Neutropenia occurs in 1.4–4.4% of patients, while thrombocytopenia is very rare. Pulmonary toxicity and positive double-stranded DNA are occasionally seen, but drug-induced lupus is rare. Reversible infertility occurs in men, but sulfasalazine does not affect fertility in women. The drug does not appear to be teratogenic.

TNF- Blocking Agents

Cytokines play a central role in the immune response (see Chapter 56: Immunopharmacology) and in rheumatoid arthritis. Although a wide range of cytokines are expressed in the joints of rheumatoid arthritis patients, TNF- appears to be at the heart of the inflammatory process.

TNF- effects cellular function via activation of specific membrane-bound TNF receptors (TNFR1, TNFR2). Administered soluble TNF receptors, by combining with soluble TNF- , can inhibit the effects of the endogenous cytokine. Monoclonal anti-TNF antibodies can, in theory, cross-link TNF receptors on the cell surface and inhibit T cell and macrophage function. Three drugs interfering with TNF- have been approved for the treatment of rheumatoid arthritis.

Adalimumab

Mechanism of Action

Adalimumab is a recombinant human anti-TNF monoclonal antibody. This compound complexes with soluble TNF- and prevents its interaction with p55 and p75 cell surface receptors. This results in down-regulation of macrophage and T cell function.

Pharmacokinetics

Adalimumab is given subcutaneously and has a half-life of 9–14 days. Its clearance is decreased by approximately 30% in the presence of methotrexate, and the formation of human antimonoclonal antibody is decreased from 12% to 4% when methotrexate is given at the same time.

Indications

The compound is indicated for the treatment of rheumatoid arthritis and decreases the rate of formation of new erosions. It is effective both as monotherapy and in combination with methotrexate. The usual dose is 40 mg every other week, though increased responses may be evident at higher dosages. Adalimumab is presently being tested in psoriasis, psoriatic arthritis, ankylosing spondylitis, and juvenile chronic arthritis.

Adverse Effects

In common with the other TNF- blocking agents, the risk of macrophage-dependent infection (including tuberculosis and other opportunistic infections) must be considered when using adalimumab, and screening for latent tuberculosis or active tuberculosis is recommended before starting adalimumab or other TNF- blocking agents. There is no evidence of an increased incidence of solid malignancies when adalimumab is used. It is not clear if the incidence of lymphomas is increased by adalimumab. A low incidence of newly formed double-stranded (ds) DNA antibodies and antinuclear antibodies (ANAs) has been documented when using adalimumab, but clinical lupus is extremely rare. Rare leukopenias and vasculitis, apparently associated with

adalimumab, have been documented.

Infliximab

Mechanism of Action

Infliximab is a chimeric (25% mouse, 75% human) monoclonal antibody that binds with high affinity to soluble and possibly membrane-bound TNF-. Its mechanism of action probably is the same as that of adalimumab.

Pharmacokinetics

Infliximab is given as an intravenous infusion at doses ranging from 3 mg/kg to 10 mg/kg, although the usual dose is 3–5 mg/kg. While most studies used an every-8-week regimen, a number of patients require dosing every 6–7 weeks. There is a relationship between serum concentration and effect, though individual clearances vary markedly. The terminal half-life is 9–12 days without accumulation after repeated dosing at the recommended interval of 8 weeks. After intermittent therapy, infliximab elicits up to a 62% incidence of human antichimeric antibodies. Concurrent therapy with methotrexate markedly decreases the prevalence of human antichimeric antibodies.

Indications

Infliximab is effective in rheumatoid arthritis and ulcerative colitis and is being used in other diseases, including psoriasis, psoriatic arthritis, juvenile chronic arthritis, Wegener's granulomatosis, giant cell arteritis, and sarcoidosis. In rheumatoid arthritis, a regimen of infliximab plus methotrexate decreases the rate of formation of new erosions more than methotrexate alone over 52–104 weeks. While it is recommended that methotrexate be used in conjunction with infliximab, a number of other DMARDs, including antimalarials, azathioprine, and cyclosporine, can be used as background therapy for this drug.

Adverse Effects

Upper respiratory tract infections, nausea, headache, sinusitis, rash, and cough are common when using infliximab, although their incidence does not appear to be very different from that of methotrexate. As a potent macrophage inhibitor, infliximab can be associated with activation of latent tuberculosis, and screening for latent tuberculosis is recommended prior to starting this therapy. Other opportunistic infections have been documented, although rarely. There is no evidence for an increased incidence of solid malignancies or lymphoma, but as with adalimumab, lymphomas should be looked for. It is not clear whether there is an increased incidence of demyelinating syndromes associated with infliximab. Rare cases of leukopenia and vasculitis have been documented. The incidence of positive ANA and double-stranded DNA is increased, although clinical lupus erythematosus remains an extremely rare occurrence and the presence of ANA and dsDNA does not contraindicate the use of infliximab. Infusion site reactions occur in approximately 3–11% of patients, and the combined use of antihistamines and H2 blocking agents apparently prevents some of these reactions.

Etanercept

Mechanism of Action

Etanercept is a recombinant fusion protein consisting of two soluble TNF p75 receptor moieties

linked to the Fc portion of human IgG1; it binds TNF- molecules and also inhibits lymphotoxin-.

Pharmacokinetics

Etanercept is given subcutaneously in a dosage of 25 mg twice weekly. The drug is slowly absorbed, with peak concentration 72 hours after drug administration. Etanercept has a mean serum elimination half-life of 4.5 days. Fifty milligrams given once weekly gives the same area under the curve and minimum serum concentrations as 25 mg twice weekly.

Indications

Etanercept is approved for the treatment of rheumatoid arthritis, juvenile chronic arthritis, and psoriatic arthritis and ankylosing spondylitis. It is used both as monotherapy and with methotrexate background; over 70% of patients taking etanercept are also using methotrexate. Etanercept decreases the rate of formation of new erosions relative to methotrexate alone. While etanercept is ineffective for treatment of ulcerative colitis, it is being used in many rheumatic syndromes such as scleroderma, Wegener's granulomatosis, giant cell arteritis, and sarcoidosis.

Adverse Effects

The incidence of activation of latent tuberculosis in patients treated with etanercept may be lower than that caused by other TNF blocking agents, but this difference is not statistically significant and it is appropriate to screen patients for latent or active tuberculosis prior to starting this medication. Similarly, opportunistic infections can occur when using etanercept. The incidence of solid malignancies is not increased, but as with other TNF-blocking agents one must be alert for lymphomas (although their incidence may not be increased compared with other DMARDs or active rheumatoid arthritis itself). While positive ANAs and double-stranded DNAs may be found in patients receiving this drug, these findings do not contraindicate continued use if clinical lupus symptoms do not occur. Injection site reactions occur in 20–40% of patients, although they rarely result in discontinuation of therapy. Although antietanercept antibodies appear sporadically in up to 16% of patients, the presence of the antibodies does not appear to interfere with efficacy or to presage toxicity.

Leflunomide

Mechanism of Action

Leflunomide undergoes rapid conversion, both in the intestine and in the plasma, to its active metabolite, A77-1726. This metabolite inhibits dihydroorotate dehydrogenase, leading to a decrease in ribonucleotide synthesis and the arrest of stimulated cells in the G1 phase of cell growth. Consequently, leflunomide inhibits T cell proliferation and production of autoantibodies by B cells. Secondary effects include increases of interleukin-10 receptor mRNA, decreased interleukin-8 receptor type A mRNA, and decreased TNF--dependent NFB activation.

Pharmacokinetics

Leflunomide is completely absorbed and has a mean plasma half-life of 19 days. A77-1726 is subject to enterohepatic recirculation and is efficiently reabsorbed. Cholestyramine can enhance leflunomide excretion and increases total clearance by approximately 50%.

Indications

Leflunomide is as effective as methotrexate in rheumatoid arthritis, including inhibition of bony damage. In one study, combined treatment with methotrexate and leflunomide resulted in a 46.2% ACR20 response compared with 19.5% in patients receiving methotrexate alone.

Adverse Effects

Diarrhea or loose bowels occur in approximately 25% of patients given leflunomide, although only about 3–5% discontinue drug because of this effect. Elevation in liver enzymes also occurs. Both effects can be reduced by decreasing the dose of leflunomide. Other adverse effects associated with leflunomide are mild alopecia, weight gain, and increased blood pressure. Leukopenia and thrombocytopenia occur rarely. This drug is contraindicated in pregnancy.

Combination Therapy with DMARDs

In a 1998 study, approximately half of North American rheumatologists treated moderately aggressive rheumatoid arthritis with combination therapy. Combinations of DMARDs can be designed rationally on the basis of complementary mechanisms of action, nonoverlapping pharmacokinetics, and nonoverlapping toxicity.

When added to methotrexate background therapy, cyclosporine, chloroquine, leflunomide, infliximab, adalimumab, and etanercept have all shown improved efficacy. In contrast, azathioprine, auranofin, or sulfasalazine plus methotrexate results in no additional therapeutic benefit. Other combinations have occasionally been used, including the combination of intramuscular gold with hydroxychloroquine. A triple-therapy regimen (methotrexate, sulfasalazine, and hydroxychloroquine) was recently tested and compared with methotrexate plus sulfasalazine or methotrexate plus hydroxychloroquine. Seventy-eight percent of the triple therapy group achieved an ACR20 response at 2 years, compared with 60% of those treated with methotrexate plus hydroxychloroquine and 49% of those treated with methotrexate plus sulfasalazine.

While it might be anticipated that combination therapy might result in more toxicity, this is often not the case. Combination therapy for patients not responding adequately to monotherapy is becoming the rule in the treatment of rheumatoid arthritis.

Immunoabsorption Apheresis

Extracorporeal immunoabsorption of plasma over columns containing an inert silica matrix and covalently attached highly purified staphylococcal protein A (Prosorba column) involves apheresis of about 1200 mL plasma weekly for 3 months.

Mechanism of Action

Although this treatment has been available for idiopathic thrombocytopenic purpura for several years, its mechanism of action is not understood. Removal of IgG and IgG-containing immune complexes does not explain its effects in rheumatoid arthritis. The most recent hypothesis for this treatment's mechanism of action is down-regulation of B cell function through the release of small amounts of staphylococcal protein A complexed with immunoglobulins.

Indications

This treatment has generally been used in patients who have failed numerous other therapies, so its low efficacy in rheumatoid arthritis is better than it appears. The study establishing efficacy in rheumatoid arthritis showed a 41.7% ACR20 response among Prosorba-treated patients compared with 15.6% in the sham-treated group. Further testing is clearly indicated.

Adverse Effects

Common adverse events include joint pain, joint swelling, and hypotension. Central intravenous line usage may be associated with pulmonary emboli and sepsis. Other events, such as nausea, rash, pruritus, flushing, and fever occurred in 1–6% of treatments in both sham and treatment groups in the double-blind trial. Rare leukocytoclastic vasculitis has been documented.

Glucocorticoid Drugs

The general pharmacology of corticosteroids, including mechanism of action, pharmacokinetics, and other applications, is discussed in Chapter 39: Adrenocorticosteroids & Adrenocortical Antagonists.

Indications

Corticosteroids have been used in 60–70% of rheumatoid arthritis patients. Their effects are prompt and dramatic, and they are capable of slowing the appearance of new bone erosions. Corticosteroids may be administered for certain serious extra-articular manifestations such as pericarditis or eye involvement or during periods of exacerbation. When prednisone is required for long-term therapy, the dosage should not exceed 7.5 mg daily, and gradual reduction of the dose should be encouraged. Alternate-day corticosteroid therapy is usually unsuccessful in rheumatoid arthritis.

Other rheumatic diseases in which the corticosteroids' potent anti-inflammatory effects may be useful include vasculitis, systemic lupus erythematosus, Wegener's granulomatosis, psoriatic arthritis, giant cell arteritis, sarcoidosis, and even gout.

Intra-articular corticosteroids are often helpful to alleviate painful symptoms and, when successful, are preferable to increasing the dosage of systemic medication.

Adverse Effects

Prolonged use of these drugs leads to serious and disabling toxic effects as described in Chapter 39: Adrenocorticosteroids & Adrenocortical Antagonists. There is controversy over whether many of these side effects occur at doses below 7.5 mg prednisone equivalent daily, although many experts believe that even 5 mg/d can cause these effects in susceptible individuals.

Dietary Manipulation of Inflammation

Arachidonic acid is an eicosatetraenoic acid that is metabolized by the cyclooxygenase and lipoxygenase pathways, yielding several mediators (see Chapter 18: The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds). These mediators have potent effects on many systems, including the immune system. It has been demonstrated that dietary manipulation which substitutes unsaturated fatty acids (such as eicosapentaenoic acid, found in marine fish) causes the alternative fatty acids to be metabolized, changing the final prostaglandin and leukotriene products of the process. The products of eicosapentaenoic acid metabolism are less potent than the corresponding mediators derived from arachidonic acid (sometimes by several

orders of magnitude), and they diminish the activities of the eicosatetraenoic mediators by competing with them for shared target-cell receptors.

The results of clinical studies suggest that therapy with dietary eicosapentaenoic acid decreases both morning stiffness and the number of tender joints in patients with rheumatoid arthritis and erythema associated with psoriasis. The efficacy of dietary eicosapentaenoic acid approximates that of the NSAIDs. These preliminary results and the near absence of significant adverse effects suggest that dietary alteration or supplementation to provide 1–4 g/d of eicosapentaenoic acid may be a beneficial addition to conventional treatment of rheumatoid arthritis.

Katzung PHARMACOLOGY, 9e > Section VI. Drugs Used to Treat Disease of the Blood, Inflammation, & Gout > Chapter 36. Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout >

Other Analgesics

Acetaminophen is one of the most important drugs used for the treatment of mild to moderate pain when an anti-inflammatory effect is not necessary. Phenacetin, a prodrug that is metabolized to acetaminophen, is more toxic than its active metabolite and has no rational indications.

Acetaminophen

Acetaminophen is the active metabolite of phenacetin and is responsible for its analgesic effect. It is a weak COX-1 and COX-2 inhibitor in peripheral tissues and possesses no significant antiinflammatory effects. Recent evidence suggests that acetaminophen may inhibit a third enzyme, COX-3, in the central nervous system. COX-3 appears to be a splice variant product of the COX-1 gene.

Pharmacokinetics

Acetaminophen is administered orally. Absorption is related to the rate of gastric emptying, and peak blood concentrations are usually reached in 30–60 minutes. Acetaminophen is slightly bound to plasma proteins and is partially metabolized by hepatic microsomal enzymes and converted to acetaminophen sulfate and glucuronide, which are pharmacologically inactive (Figure 4–4). Less than 5% is excreted unchanged. A minor but highly active metabolite (N-acetyl-p-benzoquinone) is important in large doses because of its toxicity to both liver and kidney. The half-life of acetaminophen is 2–3 hours and is relatively unaffected by renal function. With toxic doses or liver disease, the half-life may be increased twofold or more.

Indications

Although equivalent to aspirin as an effective analgesic and antipyretic agent, acetaminophen differs in that it lacks anti-inflammatory properties. It does not affect uric acid levels and lacks

platelet-inhibiting properties. The drug is useful in mild to moderate pain such as headache, myalgia, postpartum pain, and other circumstances in which aspirin is an effective analgesic. Acetaminophen alone is inadequate therapy for inflammatory conditions such as rheumatoid arthritis, though it may be used as an analgesic adjunct to anti-inflammatory therapy. For mild analgesia, acetaminophen is the preferred drug in patients allergic to aspirin or when salicylates are poorly tolerated. It is preferable to aspirin in patients with hemophilia or a history of peptic ulcer and in those in whom bronchospasm is precipitated by aspirin. Unlike aspirin, acetaminophen does not antagonize the effects of uricosuric agents; it may be used concomitantly with probenecid in the treatment of gout. It is preferred to aspirin in children with viral infections.

Adverse Effects

In therapeutic doses, a mild increase in hepatic enzymes may occasionally occur in the absence of jaundice; this is reversible when the drug is withdrawn. With larger doses, dizziness, excitement, and disorientation are seen. Ingestion of 15 g of acetaminophen may be fatal, death being caused by severe hepatotoxicity with centrilobular necrosis, sometimes associated with acute renal tubular necrosis (see Chapter 4: Drug Biotransformation and Chapter 59: Management of the Poisoned Patient). Early symptoms of hepatic damage include nausea, vomiting, diarrhea, and abdominal pain. Recent data also implicate acetaminophen in rare cases of renal damage without hepatic damage. This damage has occurred even after usual doses of acetaminophen. Therapy is much less satisfactory than for aspirin overdose. In addition to supportive therapy, the measure that has proved most useful is the provision of sulfhydryl groups in the form of acetylcysteine to neutralize the toxic metabolites (see Chapter 59: Management of the Poisoned Patient).

Hemolytic anemia and methemoglobinemia, reported with the use of phenacetin, are rarely noted with acetaminophen. Interstitial nephritis and papillary necrosis—serious complications of phenacetin—although anticipated with widespread chronic use of acetaminophen, have not occurred. Gastrointestinal bleeding does not occur. Caution should be exercised in patients with liver disease.

Dosage

Acute pain and fever may be effectively treated with 325–500 mg four times daily and proportionately less for children. Steady state conditions are attained within a day.

Phenacetin

Phenacetin is no longer prescribed in the USA and has been removed from many over-the-counter analgesic combinations. However, it is still present in a number of proprietary analgesics in this country and is in common use in many other parts of the world. The association between the excessive use of analgesic combinations—especially those that contain phenacetin—and the development of renal failure has been recognized for almost 30 years.

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Drugs Used in Gout

Gout is a familial metabolic disease characterized by recurrent episodes of acute arthritis due to deposits of monosodium urate in joints and cartilage. Formation of uric acid calculi in the kidneys

may also occur. Gout is usually associated with high serum levels of uric acid, a poorly soluble substance that is the major end product of purine metabolism. In most mammals, uricase converts uric acid to the more soluble allantoin; this enzyme is absent in humans.

The treatment of gout is aimed at relieving the acute gouty attack and preventing recurrent gouty episodes and urate lithiasis. Therapy for an attack of acute gouty arthritis is based on our current understanding of the pathophysiologic events that occur in this disease (Figure 36–5). Urate crystals are initially phagocytosed by synoviocytes, which then release prostaglandins, lysosomal enzymes, and interleukin-1. Attracted by these chemotactic mediators, polymorphonuclear leukocytes migrate into the joint space and amplify the ongoing inflammatory process. In the later phases of the attack, increased numbers of mononuclear phagocytes (macrophages) appear, ingest the urate crystals, and release more inflammatory mediators. This sequence of events suggests that the most effective agents for the management of acute urate crystal-induced inflammation are those that suppress different phases of leukocyte activation.

Figure 36–5.

Pathophysiologic events in a gouty joint. Synoviocytes phagocytose urate crystals and then secrete inflammatory mediators, which attract and activate polymorphonuclear leukocytes (PMN) and mononuclear phagocytes (MNP) (macrophages). Drugs active in gout inhibit crystal phagocytosis and polymorphonuclear leukocyte and macrophage release of inflammatory mediators. (PG, prostaglandin; IL-1, interleukin-1; LTB4, leukotriene B4.)

Before starting chronic therapy for gout, patients in whom hyperuricemia is associated with gout and urate lithiasis must be clearly distinguished from those who have only hyperuricemia. In an asymptomatic person with hyperuricemia, the efficacy of long-term drug treatment is unproved. In some individuals, uric acid levels may be elevated up to 2 SD above the mean for a lifetime without adverse consequences.

Colchicine

Colchicine is an alkaloid isolated from the autumn crocus, Colchicum autumnale. Its structure is shown in Figure 36–6.

Figure 36–6.

Colchicine and uricosuric drugs.

Pharmacokinetics

Colchicine is absorbed readily after oral administration and reaches peak plasma levels within 2 hours. Metabolites of the drug are excreted in the intestinal tract and urine.

Pharmacodynamics

Colchicine dramatically relieves the pain and inflammation of gouty arthritis in 12–24 hours without altering the metabolism or excretion of urates and without other analgesic effects. Colchicine produces its anti-inflammatory effects by binding to the intracellular protein tubulin, thereby preventing its polymerization into microtubules and leading to the inhibition of leukocyte migration and phagocytosis. It also inhibits the formation of leukotriene B4. Several of colchicine's

adverse effects are produced by its inhibition of tubulin polymerization and cell mitosis.

Indications

Colchicine was the traditional drug used for alleviating the inflammation of acute gouty arthritis. Although colchicine is more specific in gout than the NSAIDs, other agents (eg, indomethacin and other NSAIDs [except aspirin]) have replaced it in the treatment of acute gout because of the troublesome diarrhea associated with colchicine therapy. Colchicine is now used for the prophylaxis of recurrent episodes of gouty arthritis, is effective in preventing attacks of acute Mediterranean fever, and may have a mild beneficial effect in sarcoid arthritis and in hepatic cirrhosis.

Adverse Effects

Colchicine often causes diarrhea and may occasionally cause nausea, vomiting, and abdominal pain. Colchicine may rarely cause hair loss and bone marrow depression as well as peripheral neuritis and myopathy.

Acute intoxication after ingestion of large (nontherapeutic) doses of the alkaloid is characterized by burning throat pain, bloody diarrhea, shock, hematuria, and oliguria. Fatal ascending central nervous system depression has been reported. Treatment is supportive.

Dosage

The prophylactic dose of colchicine is 0.6 mg one to three times daily. For terminating an attack of gout, the traditional initial dose of colchicine is usually 0.6 or 1.2 mg, followed by 0.6 mg every 2 hours until pain is relieved or nausea and diarrhea appear. The total dose can be given intravenously if necessary, but it should be remembered that as little as 8 mg in 24 hours may be fatal.

NSAIDs in Gout

In addition to inhibiting prostaglandin synthase, indomethacin and other NSAIDs also inhibit urate crystal phagocytosis. Indomethacin is commonly used as initial treatment of gout as the replacement for colchicine. Three or four doses of 50 mg every 6 hours are given; when a response occurs, the dosage is reduced to 25 mg three or four times daily for about 5 days.

All other NSAIDs except aspirin, salicylates, and tolmetin have been successfully used to treat acute gouty episodes. Oxaprozin, which lowers serum uric acid, is theoretically a good NSAID though it should not be given to patients with uric acid stones because it increases uric acid excretion in the urine. These agents appear to be as effective and safe as the older drugs.

Uricosuric Agents

Probenecid and sulfinpyrazone are uricosuric drugs employed to decrease the body pool of urate in patients with tophaceous gout or in those with increasingly frequent gouty attacks. In a patient who excretes large amounts of uric acid, the uricosuric agents should be avoided so as not to precipitate the formation of uric acid calculi.

Chemistry

Uricosuric drugs are organic acids (Figure 36–6) and, as such, act at the anionic transport sites of the renal tubule (see Chapter 15: Diuretic Agents). Sulfinpyrazone is a metabolite of an analog of