Pharmacology_Katzung

Pharmacology_Katzung. Most persons experience a harmless cutaneous vasodilation and sensation of warmth after each dose when niacin is started or the dose increased. Taking 81–325 mg of aspirin 30 minutes beforehand blunts this prostaglandin-mediated effect. Naproxen, 220 mg once daily, also mitigates the flush. Tachyphylaxis to flushing usually occurs within a few days at doses above 1.5–3 g daily. Patients should be warned to expect the flush and understand that it is a harmless side effect. Pruritus, rashes, dry skin or mucous membranes, and acanthosis nigricans have been reported. The latter requires the discontinuance of niacin because of its association with insulin resistance. Some patients experience nausea and abdominal discomfort. Many can continue the drug at reduced dosage, with inhibitors of gastric acid secretion or with antacids not containing aluminum. Niacin should be avoided in patients with significant peptic disease.


Pharmacology_Katzung

Pharmacology_Katzung. Reversible elevations in aminotransferases up to twice normal may occur, usually not associated with liver toxicity. However, liver function should be monitored at baseline and at appropriate intervals. Rarely, true hepatotoxicity may occur, and the drug should be discontinued. The association of severe hepatic dysfunction, including acute necrosis, with the use of over-thecounter sustained-release preparations of niacin has been reported. This effect has not been noted to date with an extended-release preparation, Niaspan, given at bedtime in doses of 2 g or less. Carbohydrate tolerance may be moderately impaired, especially in obese patients. Niacin may be given to diabetics who are receiving insulin and to some receiving oral agents but it may increase insulin resistance. This can be addressed by increasing the dose of insulin or the oral agents. Hyperuricemia occurs in some patients and occasionally precipitates gout. Allopurinol can be given with niacin if needed. Red cell


Pharmacology_Katzung

Pharmacology_Katzung. be addressed by increasing the dose of insulin or the oral agents. Hyperuricemia occurs in some patients and occasionally precipitates gout. Allopurinol can be given with niacin if needed. Red cell macrocytosis can occur and is not an indication for discontinuing treatment. Significant platelet deficiency can occur rarely and is reversible on cessation of treatment. Rarely, niacin is associated with arrhythmias, mostly atrial, and with macular edema, both requiring cessation of treatment. Patients should be instructed to report blurring of distance vision. Niacin may potentiate the action of antihypertensive agents, requiring adjustment of their dosages. Birth defects have been reported in offspring of animals given very high doses.


Pharmacology_Katzung

Pharmacology_Katzung. Colestipol, cholestyramine, and colesevelam are useful only for isolated increases in LDL. In patients who also have hypertriglyceridemia, VLDL levels may be further increased during treatment with resins. The bile acid-binding agents are large polymeric cationic exchange resins that are insoluble in water. They bind bile acids in the intestinal lumen and prevent their reabsorption. The resin itself is not absorbed. Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. Bile acids, metabolites of cholesterol, are normally efficiently reabsorbed in the jejunum and ileum (Figure 35–2). Excretion is increased up to tenfold when resins are given, resulting in enhanced conversion of cholesterol to bile acids in liver via 7α-hydroxylation, which is normally controlled by negative feedback by bile acids. Decreased activation of the FXR receptor by bile acids may result in a modest increase in plasma triglycerides but can also improve glucose metabolism in patients with diabetes. The latter effect is due to increased secretion of the incretin glucagon-like peptide-1 from the intestine, thus increasing insulin secretion. Increased uptake of LDL and IDL from plasma results from upregulation of LDL receptors, particularly in liver. Therefore, the resins are without effect in patients with homozygous familial hypercholesterolemia who have no functioning receptors but may be useful in those with some residual receptor function and in patients with


Pharmacology_Katzung

Pharmacology_Katzung. are without effect in patients with homozygous familial hypercholesterolemia who have no functioning receptors but may be useful in those with some residual receptor function and in patients with receptor-defective combined heterozygous states.


Pharmacology_Katzung

Pharmacology_Katzung. The resins are used in treatment of patients with primary hypercholesterolemia, producing approximately 20% reduction in LDL cholesterol in maximal dosage. If resins are used to treat LDL elevations in persons with combined hyperlipidemia, they may cause an increase in VLDL, requiring the addition of a second agent such as a fibrate or niacin. Resins are also used in combination with other drugs to achieve further hypocholesterolemic effect (see below). They may be helpful in relieving pruritus in patients who have cholestasis and bile salt accumulation. Because the resins bind digitalis glycosides, they may be useful in digitalis toxicity.


Pharmacology_Katzung

Pharmacology_Katzung. Colestipol and cholestyramine are available as granular preparations. A gradual increase of dosage of granules from 4 or 5 g/d to 20 g/d is recommended. Total dosages of 30–32 g/d may be needed for maximum effect. The usual dosage for a child is 10–20 g/d. Granular resins are mixed with juice or water and allowed to hydrate for 1 minute. Colestipol is also available in 1-g tablets that must be swallowed whole, with a maximum dose of 16 g daily. Colesevelam is available in 625-mg tablets and as a suspension (1875-mg or 3750-mg packets). The maximum dose is six tablets or 3750 mg as suspension, daily. Resins should be taken in two or three doses with meals.


Pharmacology_Katzung

Pharmacology_Katzung. Common complaints are constipation and bloating, usually relieved by increasing dietary fiber. Resins should be avoided in patients with diverticulitis. Heartburn and diarrhea are occasionally reported. In patients who have preexisting bowel disease or cholestasis, steatorrhea may occur. Malabsorption of vitamin K occurs rarely, leading to hypoprothrombinemia. Prothrombin time should be measured frequently in patients who are taking resins and anticoagulants. Malabsorption of folic acid has been reported rarely. Increased formation of gallstones, particularly in obese persons, was an anticipated adverse effect but has rarely occurred in practice. Absorption of certain drugs, including those with neutral or cationic charge as well as anions, may be impaired by the resins. These include digitalis glycosides, thiazides, warfarin, tetracycline, thyroxine, iron salts, pravastatin, fluvastatin, ezetimibe, folic acid, phenylbutazone, aspirin, and ascorbic acid, among others.


Pharmacology_Katzung

Pharmacology_Katzung. In general, additional medication (except niacin) should be given 1 hour before or at least 2 hours after the resin to ensure adequate absorption. Colesevelam does not bind digoxin, warfarin, or reductase inhibitors. Ezetimibe inhibits intestinal absorption of phytosterols and cholesterol. Added to statin therapy, it provides an additional effect, decreasing LDL levels and further reducing the dimensions of atherosclerotic plaques. Ezetimibe is readily absorbed and conjugated in the intestine to an active glucuronide, reaching peak blood levels in 12–14 hours. It undergoes enterohepatic circulation, and its half-life is 22 hours. Approximately 80% of the drug is excreted in feces. Plasma concentrations are substantially increased when it is administered with fibrates and reduced when it is given with cholestyramine. Other resins may also decrease its absorption. There are no significant interactions with warfarin or digoxin. Mechanism of Action


Pharmacology_Katzung

Pharmacology_Katzung. Mechanism of Action Ezetimibe selectively inhibits intestinal absorption of cholesterol and phytosterols. A transport protein, NPC1L1, is the target of the drug. It is effective in the absence of dietary cholesterol because it also inhibits reabsorption of cholesterol excreted in the bile. The effect of ezetimibe on cholesterol absorption is constant over the dosage range of 5–20 mg/d. Therefore, a daily dose of 10 mg is used. Average reduction in LDL cholesterol with ezetimibe alone in patients with primary hypercholesterolemia is about 18%, with minimal increases in HDL cholesterol. It is also effective in patients with phytosterolemia. Ezetimibe is synergistic with reductase inhibitors, producing decrements as great as 25% in LDL cholesterol beyond that achieved with the reductase inhibitor alone.


Pharmacology_Katzung

Pharmacology_Katzung. Ezetimibe does not appear to be a substrate for cytochrome P450 enzymes. Experience to date reveals a low incidence of reversible impaired hepatic function with a small increase in incidence when given with a reductase inhibitor. Myositis has been reported rarely.


Pharmacology_Katzung

Pharmacology_Katzung. Microsomal triglyceride transfer protein (MTP) plays an essential role in the addition of triglycerides to nascent VLDL in liver, and to chylomicrons in the intestine. Its inhibition decreases VLDL secretion and consequently the accumulation of LDL in plasma. An MTP inhibitor, lomitapide, is available but is currently restricted to patients with homozygous familial hypercholesterolemia. It causes accumulation of triglycerides in the liver in some individuals. Elevations in transaminases can occur. Patients must maintain a low fat diet to avoid steatorrhea and should take steps to minimize deficiency of essential fat-soluble nutrients. Lomitapide is given orally in gradually increasing doses of 5-to 60-mg capsules once daily 2 hours after the evening meal. It is available only through a restricted (REMS) program for patients with homozygous familial hypercholesterolemia.


Pharmacology_Katzung

Pharmacology_Katzung. Mipomersen is an antisense oligonucleotide that targets apo B-100, mainly in the liver. It is important to note that the apo B-100 gene is also transcribed in the retina and in cardiomyocytes. Subcutaneous injections of mipomersen reduce levels of LDL and Lp(a). Mild to moderate injection site reactions and flu-like symptoms can occur. The drug is available only for use in homozygous familial hypercholesterolemia through a restricted (REMS) program.


Pharmacology_Katzung

Pharmacology_Katzung. Development of inhibitors of proprotein convertase subtilisin/ kexin type 9 (PCSK9) followed on the observation that loss of function mutations result in very low levels of LDL and no apparent morbidity. Therapeutic agents currently available in this class are humanized antibodies to PCSK9 (evolocumab, alirocumab). LDL reductions of up to 70% at the highest doses have been achieved with these agents when administered subcutaneously every two weeks. (Evolocumab can also be given monthly at a higher dose). Triglycerides and apo B-100 are reduced, and Lp(a) levels decrease by about 25%. Rarely, hypersensitivity reactions have occurred. Local reactions at the injection site, upper respiratory and flu-like symptoms have been observed more frequently. Use of these agents is restricted to patients who have familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease who require additional reduction of LDL. They are given with diet and maximal tolerated statin and/or


Pharmacology_Katzung

Pharmacology_Katzung. who have familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease who require additional reduction of LDL. They are given with diet and maximal tolerated statin and/or ezetimibe. Development of small molecules and antisense oligonucleotides to inhibit PCSK9 is underway. Studies of PCSK9 inhibition should be approached with caution because of its established role in normal cell biology. These agents are very expensive.


Pharmacology_Katzung

Pharmacology_Katzung. Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from mature, large diameter HDL particles to triglyceride-rich lipoproteins that ultimately deliver the esters to liver whence both cholesterol and bile acids can be eliminated into the intestine. Inhibition of CETP leads to accumulation of mature HDL particles and diminution of the transport of cholesteryl esters to liver. The accumulation of large HDL particles does not have the cardioprotective effect anticipated on the basis of epidemiologic studies. Some reduction of LDL-C can be achieved and cholesterol efflux capacity enhanced. Thus far no drug (eg, torcetrapib, anacetrapib) in this class has been approved.


Pharmacology_Katzung

Pharmacology_Katzung. AMP-activated protein kinase acts as a sensor of energy status in cells. When increased ATP availability is required, AMP kinase increases fatty acid oxidation and insulin sensitivity, and inhibits cholesterol and triglyceride biosynthesis. Although the trials to date have been directed at decreasing LDL-C levels, AMP kinase activation may have merit for management of the metabolic syndrome and diabetes. An agent combining AMP kinase activation and ATP citrate lyase inhibition is in clinical trials. These are circular sugar polymers that can solubilize hydrophobic drugs for delivery and are approved for this purpose. They can also solubilize cholesterol from tissue sites such as arteriosclerotic plaque. Early stage animal studies on this potential therapeutic activity are in progress.


Pharmacology_Katzung

Pharmacology_Katzung. Combined drug therapy is useful (1) when VLDL levels are significantly increased during treatment of hypercholesterolemia with a resin; (2) when LDL and VLDL levels are both elevated initially; (3) when LDL or VLDL levels are not normalized with a single agent, or (4) when an elevated level of Lp(a) or an HDL deficiency coexists with other hyperlipidemias. The lowest effective doses should be used in combination therapy and the patient should be monitored more closely for evidence of toxicity. In combinations that include resins, the other agent (with the exception of niacin) should be separated temporally to ensure absorption. This combination is sometimes useful in treating patients with familial combined hyperlipidemia who are intolerant of niacin or statins. However, it may increase the risk of cholelithiasis.


Pharmacology_Katzung

Pharmacology_Katzung. This combination is sometimes useful in treating patients with familial combined hyperlipidemia who are intolerant of niacin or statins. However, it may increase the risk of cholelithiasis. This synergistic combination is useful in the treatment of familial hypercholesterolemia but may not control levels of VLDL in some patients with familial combined hyperlipoproteinemia. This combination effectively controls VLDL levels during resin therapy of familial combined hyperlipoproteinemia or other disorders involving both increased VLDL and LDL levels. When VLDL and LDL levels are both initially increased, doses of niacin as low as 1–3 g/d may be sufficient in combination with a resin. The niacin-resin combination is effective for treating heterozygous familial hypercholesterolemia.


Pharmacology_Katzung

Pharmacology_Katzung. If the maximum tolerated statin dose fails to achieve the LDL cholesterol goal in a patient with hypercholesterolemia, niacin may be helpful. This combination may be useful in the treatment of familial combined hyperlipoproteinemia. This combination is synergistic in treating primary hypercholesterolemia and may be of use in the treatment of patients with homozygous familial hypercholesterolemia who have some receptor function. Fenofibrate appears to be complementary with most statins in the treatment of familial combined hyperlipoproteinemia and other conditions involving elevations of both LDL and VLDL. The combination of fenofibrate with rosuvastatin appears to be especially well tolerated. Some other statins may interact unfavorably owing to effects on cytochrome P450 metabolism. In any case, particular vigilance for liver and muscle toxicity is indicated. COMBINATIONS OF RESINS, EZETIMIBE, NIACIN, & REDUCTASE INHIBITORS


Pharmacology_Katzung

Pharmacology_Katzung. COMBINATIONS OF RESINS, EZETIMIBE, NIACIN, & REDUCTASE INHIBITORS These agents act in a complementary fashion to normalize cholesterol in patients with severe disorders involving elevated LDL. The effects are sustained, and little compound toxicity has been observed. Effective doses of the individual drugs may be lower than when each is used alone; for example, as little as 1–2 g of niacin may substantially increase the effects of the other agents. These agents can be used together to achieve maximal reduction of LDL. Because of the need for parenteral administration of PCSK9 antibody and its expense, this therapy is reserved for patients with familial hypercholesterolemia or atherosclerotic vascular disease who do not respond adequately to other regimens.


Pharmacology_Katzung

Pharmacology_Katzung. • Atorvastatin, simvastatin, rosuvastatin, pitavastatin • Fluvastatin, pravastatin, lovastatin: Similar but somewhat less efficacious • Fenofibrate,gemfibrozil Peroxisome proliferator-activated receptor-alpha (PPAR-α) agonists Decrease secretion of very-low-density lipoproteins (VLDL)•increaselipoproteinlipaseactivity•increasehigh-density lipoproteins (HDL) Hypertriglyceridemia, low HDL Oral•duration3–24h•Toxicity: Myopathy, hepatic dysfunction FIBRATES Subclass, Drug Mechanism of Action Effects Clinical Applications Pharmacokinetics, Toxicities, Interactions • Cholestyramine, colesevelam: Similar to colestipol • EzetimibeBlocks sterol transporter NPC1L1 in intestine brush border Inhibits reabsorption of cholesterol excreted in bile •decreasesLDLandphytosterolsElevated LDL, phytosterolemia Oral•duration24h•Toxicity: Low incidence of hepatic dysfunction, myositis


Pharmacology_Katzung

Pharmacology_Katzung. Decreases catabolism of apoAI•reducesVLDLsecretion from liver IncreasesHDL•decreaseslipoprotein(a) [Lp(a)], LDL LowHDL•elevatedVLDL,Lp(a); elevated LDL in statin-unresponsive or intolerant patients Oral•largedoses•Toxicity: Gastric irritation, flushing, low incidence of hepatic toxicity •mayreduceglucosetolerance• Extended-release niacin: Similar to regular niacin • Sustained-release niacin (not the same as extended-release product): Should be avoided PCSK9 HUMANIZED MONOCLONAL ANTIBODIES Evolocumab Complexes PCSK9 Inhibits catabolism of LDL receptor Familial hypercholesterolemia not Parenteral•Cost~$14,000/year•Toxicity: injection site reactions, nasopharyngitis, responsive to oral therapy • Alirocumab Similar to evolucumab flu-like symptoms, rarely myalgia, neurocognitive and ophthalmologic events Atorvastatin Generic, Lipitor Cholestyramine Generic, Questran, Prevalite Colestipol Generic, Colestid Ezetimibe Generic, Zetia Fenofibrate Generic, Tricor, Antara, Lofibra


Pharmacology_Katzung

Pharmacology_Katzung. Atorvastatin Generic, Lipitor Cholestyramine Generic, Questran, Prevalite Colestipol Generic, Colestid Ezetimibe Generic, Zetia Fenofibrate Generic, Tricor, Antara, Lofibra Fluvastatin Generic, Lescol, Lescol XL Gemfibrozil Generic, Lopid Lovastatin Generic, Mevacor, Altoprev Niacin, nicotinic acid, vitamin B3 Generic only Pravastatin Generic, Pravachol Rosuvastatin Generic, Crestor Simvastatin Generic, Zocor Afshar M, Thanassoulis G: Lipoprotein(a): new insights from modern genomics. Curr Opin Lipidol 2017;28:170. Ballantyne CM et al: Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: Results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. J Am Coll Cardiol 2013;62:1154.


Pharmacology_Katzung

Pharmacology_Katzung. Boekholdt SM et al: Levels and changes of HDL cholesterol and apolipoprotein A-I in relation to risk of cardiovascular events among statin-treated patients: A meta-analysis. Circulation 2013;128:1504. Bonow RO, Yancy CW: High-intensity statins for secondary prevention. JAMA Cardiol 2017;2:55. Cannon CP et al: Ezetimibe added to statin therapy after acute coronary syndrome. N Engl J Med 2015;372:2387. Chou R et al: Statins for prevention of cardiovascular disease in adults: Evidence report and systematic review for the US Preventive Services Task Force. JAMA 2016;316:2008. Dron JS, Hegele RA: Complexity of mechanisms among human proprotein convertase subtilisin-kexin type 9 variants. Curr Opin Lipidol 2017;28:161. Elam M, Lovato E, Ginsberg H: The role of fibrates in cardiovascular disease prevention, The ACCORD–lipid perspective. Curr Opin Lipidol 2011;22:55.


Pharmacology_Katzung

Pharmacology_Katzung. Elam M, Lovato E, Ginsberg H: The role of fibrates in cardiovascular disease prevention, The ACCORD–lipid perspective. Curr Opin Lipidol 2011;22:55. Gaudet D et al: Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med 2015;373:438. Gouni-Berthold I et al: Systematic review of published phase 3 data on antiPCSK9 monoclonal antibodies in patients with hypercholesterolaemia. Br J Clin Pharmacol 2016;82:1412. International Atherosclerosis Society: IAS Position Paper: Global Recommendations for the Management of Dyslipidemia. Available at: www.athero.org/ IASPositionPaper.asp. Jacobson TA et al: On behalf of the NLA Expert Panel. National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 2. J Clin Lipidol 2015;9:S1. LaRosa JC et al: Safety and effect of very low levels of low density lipoprotein cholesterol on cardiovascular events. Am J Cardiol 2013;111:1221.


Pharmacology_Katzung

Pharmacology_Katzung. LaRosa JC et al: Safety and effect of very low levels of low density lipoprotein cholesterol on cardiovascular events. Am J Cardiol 2013;111:1221. Mampuya WM et al: Treatment strategies in patients with statin intolerance: The Cleveland Clinic experience. Am Heart J 2013;166:597. Nduka C et al: Impact of antiretroviral therapy on serum lipoprotein levels and dyslipidemias: a systematic review and meta-analysis. Int J Cardiol 2015;199:307. Perry CM: Lomitapide: A review of its use in adults with homozygous familial hypercholesterolemia. Am J Cardiovasc Drugs 2013;13:265. Raal FJ, Stein EA: The effects of mipomersen on inhibiting hepatic VLDL apolipoprotein B 100 and propensity for hepatic steatosis. Clin Chem 2016;62:1052. Reith C, Armitage J: Management of residual risk after statin therapy. Atherosclerosis 2016;245;161. Rodriguez F: Association between intensity of statin therapy and mortality in patients with atherosclerotic cardiovascular disease. JAMA Cardiol 2016;2:47.


Pharmacology_Katzung

Pharmacology_Katzung. Rodriguez F: Association between intensity of statin therapy and mortality in patients with atherosclerotic cardiovascular disease. JAMA Cardiol 2016;2:47. Silverman MG et al: Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: A systematic review and meta-analysis. JAMA Cardiol 2016;316:1289. Stone NJ et al: 2013 ACC/AHA guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. A report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation 2014; 129 (25 Suppl 2):S1. Erratum: Circulation 2015;132:e396. Swiger JK et al: Statins and cognition: A systematic review and meta-analysis of short and long term cognitive effects. Mayo Clin Proceed 2013;88:1213.


Pharmacology_Katzung

Pharmacology_Katzung. Swiger JK et al: Statins and cognition: A systematic review and meta-analysis of short and long term cognitive effects. Mayo Clin Proceed 2013;88:1213. Tsujita K et al: Impact of dual-lipid lowering with ezetimibe and atorvastatin on coronary plaque regression in patients with percutaneous coronary intervention. The randomized controlled PRECISE-IVUS trial. J Am Coll Cardiol 2015;66:495. Yahya R et al: Lomitapide effects HDL composition and function. Atherosclerosis 2016;251:15. Zimmer S et al: Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming. Sci Transl Med 2016;8:333ra50.


Pharmacology_Katzung

Pharmacology_Katzung. The patient’s history of muscle symptoms should be care-fully evaluated. The genotype at the SLCO1B1 locus might be obtained to determine whether myositis is due to impaired metabolism of statins. If you agree that her muscle symptoms were clearly associated with statin use but were not particu-larly severe and not associated with creatine kinase elevations significantly greater than normal, you could prescribe any one the agents she tried in the past or select a different statin. The starting dose should be low and the drug given on alter-nate days, increasing the dose and frequency to achieve the LDL-C goal. If this is not tolerated or the goal is not reached, alternate drugs can be used, including a bile acid binding resin, intestinal sterol absorption inhibitor, or niacin (monitoring uric acid, glucose, and liver enzymes). These can be used in combinations with each other or with a low dose statin. If all else fails, use of a PCSK9 monoclonal antibody should be con-sidered. Her


Pharmacology_Katzung

Pharmacology_Katzung. uric acid, glucose, and liver enzymes). These can be used in combinations with each other or with a low dose statin. If all else fails, use of a PCSK9 monoclonal antibody should be con-sidered. Her homocysteine level should be measured because of the synergy between that amino acid and Lp(a) with respect to thrombotic risk. Also, because of her elevated Lp(a), she should be evaluated for aortic stenosis.


Pharmacology_Katzung

Pharmacology_Katzung. Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout


Pharmacology_Katzung

Pharmacology_Katzung. Ahmed A. Negm, MD, & Daniel E. Furst, MD twice daily. His symptoms are reduced at this dosage, but he com-plains of significant heartburn that is not controlled by antacids. He is then switched to celecoxib, 200 mg twice daily, and on this regimen his joint symptoms and heartburn resolve. Two years later, he returns with increased joint symptoms. His hands, wrists, elbows, feet, and knees are all now involved and appear swollen, warm, and tender. What therapeutic options should be considered at this time? What are the possible complications? A 48-year-old man presents with complaints of bilateral morning stiffness in his wrists and knees and pain in these joints on exercise. On physical examination, the joints are slightly swollen. The rest of the examination is unremarkable. His laboratory findings are also negative except for slight anemia, elevated erythrocyte sedi-mentation rate, and positive rheumatoid factor. With the diagnosis of rheumatoid arthritis, he is started on a regimen


Pharmacology_Katzung

Pharmacology_Katzung. findings are also negative except for slight anemia, elevated erythrocyte sedi-mentation rate, and positive rheumatoid factor. With the diagnosis of rheumatoid arthritis, he is started on a regimen of naproxen, 220 mg twice daily. After 1 week, the dosage is increased to 440 mg


Pharmacology_Katzung

Pharmacology_Katzung. The immune response occurs when immunologically competent cells are activated in response to foreign organisms or antigenic substances liberated during the acute or chronic inflammatory response. The outcome of the immune response for the host may be deleterious if it leads to chronic inflammation without resolution of the underlying injurious process (see Chapter 55). Chronic inflammation involves the release of multiple cytokines and chemokines plus a very complex interplay of immunoactive cells. The whole range of autoimmune diseases (eg, RA, vasculitis, SLE) and inflammatory conditions (eg, gout) derive from abnormalities in this cascade.


Pharmacology_Katzung

Pharmacology_Katzung. The cell damage associated with inflammation acts on cell membranes to release leukocyte lysosomal enzymes; arachidonic acid is then liberated from precursor compounds, and various eicosanoids are synthesized (see Chapter 18). The lipoxygenase pathway of arachidonate metabolism yields leukotrienes, which have a powerful chemotactic effect on eosinophils, neutrophils, and macrophages and promote bronchoconstriction and alterations in vascular permeability. During inflammation, stimulation of the neutrophil membranes produces oxygen-derived free radicals and other reactive molecules such as hydrogen peroxide and hydroxyl radicals. The interaction of these substances with arachidonic acid results in the generation of chemotactic substances, thus perpetuating the inflammatory process.


Pharmacology_Katzung

Pharmacology_Katzung. The treatment of patients with inflammation involves two primary goals: first, the relief of symptoms and the maintenance of function, which are usually the major continuing complaints of the patient; and second, the slowing or arrest of the tissue-damaging process. In RA, several validated combined indices are used to define response (eg, Disease Activity Score28 [DAS28], American College of Rheumatology Response Index [ACR Response], Clinical Disease Activity Score [CDAI], Simplified Disease Activity Index [SDAI]). These indices often combine joint tenderness and swelling, patient response, and laboratory data. Reduction of inflammation with NSAIDs often results in relief of pain for significant periods. Furthermore, most of the nonopioid analgesics (aspirin, etc) have anti-inflammatory effects, so they are appropriate for the treatment of both acute and chronic inflammatory conditions.


Pharmacology_Katzung

Pharmacology_Katzung. The glucocorticoids also have powerful anti-inflammatory effects and when first introduced were considered to be the ultimate answer to the treatment of inflammatory arthritis. Although there are data indicating that low-dose corticosteroids have disease-modifying properties, particularly in the early phase of RA, their toxicity makes them less favored than other medications, when it is possible to use the others. However, the glucocorticoids continue to have a significant role in the long-term treatment of arthritis. Another important group of agents are characterized as disease-modifying anti-rheumatic drugs (DMARDs) including biologics (a subset of the DMARDs). They decrease inflammation, improve symptoms, and slow the bone damage associated with RA. They affect more basic inflammatory mechanisms than do glucocorticoids or the NSAIDs. They may also be more toxic than those alternative medications.


Pharmacology_Katzung

Pharmacology_Katzung. Salicylates and other similar agents used to treat rheumatic disease share the capacity to suppress the signs and symptoms of inflammation including pain. These drugs also exert antipyretic effects. Since aspirin, the original NSAID, has a number of adverse effects, many other NSAIDs have been developed in attempts to improve upon aspirin’s efficacy and decrease its toxicity. The NSAIDs are grouped in several chemical classes, as shown in Figure 36–1. This chemical diversity yields a broad range of pharmacokinetic characteristics (Table 36–1). Although there are many differences in the kinetics of NSAIDs, they have some general properties in common. All but one of the NSAIDs are weak organic acids as given; the exception, nabumetone, is a ketone prodrug that is metabolized to the acidic active drug.


Pharmacology_Katzung

Pharmacology_Katzung. Most of these drugs are well absorbed, and food does not substantially change their bioavailability. Most of the NSAIDs are highly metabolized, some by phase I followed by phase II mechanisms and others by direct glucuronidation (phase II) alone. NSAID metabolism proceeds, in large part, by way of the CYP3A or CYP2C families of P450 enzymes in the liver (see Chapter 4). While renal excretion is the most important route for final elimination, nearly all undergo varying degrees of biliary excretion and reabsorption (enterohepatic circulation). In fact, the degree of lower gastrointestinal (GI) tract irritation correlates with the amount of enterohepatic circulation. Most of the NSAIDs are highly protein-bound (~ 98%), usually to albumin. Most of the NSAIDs (eg, ibuprofen, ketoprofen) are racemic mixtures, while one, naproxen, is provided as a single enantiomer and a few have no chiral center (eg, diclofenac).


Pharmacology_Katzung

Pharmacology_Katzung. All NSAIDs can be found in synovial fluid after repeated dosing. Drugs with short half-lives remain in the joints longer than would be predicted from their half-lives, while drugs with longer half-lives disappear from the synovial fluid at a rate proportionate to their half-lives. NSAID anti-inflammatory activity is mediated chiefly through inhibition of prostaglandin biosynthesis (Figure 36–2). Various NSAIDs have additional possible mechanisms of action, including inhibition of chemotaxis, down-regulation of IL-1 production, decreased production of free radicals and superoxide, and interference with calcium-mediated intracellular events. Aspirin irreversibly acetylates and blocks platelet COX, while the nonCOX-selective NSAIDs are reversible inhibitors. FIGURE 36–1 Chemical structures of some NSAIDs.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 36–1 Chemical structures of some NSAIDs. Selectivity for COX-1 versus COX-2 is variable and incomplete for the older NSAIDs, but selective COX-2 inhibitors have been synthesized. The selective COX-2 inhibitors do not affect platelet function at their usual doses. The efficacy of COX-2-selective drugs equals that of the older NSAIDs, while GI safety may be improved. On the other hand, selective COX-2 inhibitors increase the incidence of edema, hypertension, and possibly, myocardial infarction. As of August 2011, celecoxib and the less selective meloxicam were the only COX-2 inhibitors marketed in the USA. Celecoxib has a


Pharmacology_Katzung

Pharmacology_Katzung. U.S Food and Drug Administration (FDA) “black box” warning concerning cardiovascular risks. It has been recommended that all NSAID product labels be revised to mention cardiovascular risks. In July 2015 the FDA strengthened the warning that NSAIDs can cause heart attacks or strokes. A study found that NSAID use was associated with increased risk of serious bleeding and cardiovascular events after myocardial infarction. The risk is higher among users of celecoxib and diclofenac, and lower among users of ibuprofen and naproxen.


Pharmacology_Katzung

Pharmacology_Katzung. The NSAIDs decrease the sensitivity of vessels to bradykinin and histamine, affect lymphokine production from T lymphocytes, and reverse the vasodilation of inflammation. To varying degrees, all newer NSAIDs are analgesic, anti-inflammatory, and antipyretic, and all (except the COX-2–selective agents and the nonacetylated salicylates) inhibit platelet aggregation. NSAIDs are all gastric irritants and can be associated with GI ulcers and bleeds as well, although as a group the newer agents tend to cause less GI irritation than aspirin. Nephrotoxicity, reported for all NSAIDs, is due, in part, to interference with the autoregulation of renal blood flow, which is modulated by prostaglandins. Hepatotoxicity also can occur with any NSAID. Although these drugs effectively inhibit inflammation, there is no evidence that—in contrast to drugs such as methotrexate, biologics, and other DMARDs—they alter the course of any arthritic disorder.


Pharmacology_Katzung

Pharmacology_Katzung. Several NSAIDs (including aspirin) reduce the incidence of colon cancer when taken chronically. Several large epidemiologic studies have shown a 50% reduction in relative risk for this neoplasm when the drugs are taken for 5 years or longer. The mechanism for this protective effect is unclear. Although not all NSAIDs are approved by the FDA for the whole range of rheumatic diseases, most are probably effective in RA, seronegative spondyloarthropathies (SpA, eg, PsA and arthritis associated with inflammatory bowel disease), OA, localized musculoskeletal syndromes (eg, sprains and strains, low back pain), and gout (except tolmetin, which appears to be ineffective in gout). TABLE 36–1 Properties of aspirin and some other nonsteroidal anti-inflammatory drugs.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 36–1 Properties of aspirin and some other nonsteroidal anti-inflammatory drugs. 1Major anti-inflammatory metabolite of aspirin. 2Salicylate is usually given in the form of aspirin. 3Total urinary excretion including metabolites. 4Nabumetone is a prodrug; the half-life and urinary excretion are for its active metabolite. 5A single daily dose is sufficient because of the long half-life. Adverse effects are generally quite similar for all of the NSAIDs: 1. Central nervous system: Headaches, tinnitus, dizziness, and rarely, aseptic meningitis. 2. Cardiovascular: Fluid retention, hypertension, edema, and rarely, myocardial infarction and congestive heart failure (CHF). 3. Gastrointestinal: Abdominal pain, dyspepsia, nausea, vomiting, and rarely, ulcers or bleeding. 4. Hematologic: Rare thrombocytopenia, neutropenia, or even aplastic anemia. 5. Hepatic: Abnormal liver function test results and rare liver failure. 6. Pulmonary: Asthma. 7.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Hematologic: Rare thrombocytopenia, neutropenia, or even aplastic anemia. 5. Hepatic: Abnormal liver function test results and rare liver failure. 6. Pulmonary: Asthma. 7. Skin: Rashes, all types, pruritus. 8. Renal: Renal insufficiency, renal failure, hyperkalemia, and proteinuria. Aspirin’s long use and availability without prescription diminishes its glamour compared with that of the newer NSAIDs. Aspirin is now rarely used as an anti-inflammatory medication and will be reviewed only in terms of its antiplatelet effects (ie, doses of 81–325 mg once daily). 1.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Pharmacokinetics: Salicylic acid is a simple organic acid with a pKa of 3.0. Aspirin (acetylsalicylic acid; ASA) has a pKa of 3.5 (see Table 1–3). Aspirin is absorbed as such and is rapidly hydrolyzed (serum half-life 15 minutes) to acetic acid and salicylate by esterases in tissue and blood (Figure 36–3). Salicylate is nonlinearly bound to albumin. Alkalinization of the urine increases the rate of excretion of free salicylate and its water-soluble conjugates. 2. Mechanisms of Action: Aspirin irreversibly inhibits platelet COX so that aspirin’s antiplatelet effect lasts 8–10 days (the life of the platelet). In other tissues, synthesis of new COX replaces the inactivated enzyme so that ordinary doses have a duration of action of 6–12 hours. 3. Clinical Uses: Aspirin decreases the incidence of transient ischemic attacks, unstable angina, coronary artery thrombosis with myocardial infarction, and thrombosis after coronary artery bypass grafting (see Chapter 34). 4.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Epidemiologic studies suggest that long-term use of aspirin at low dosage is associated with a lower incidence of colon cancer, possibly related to its COX-inhibiting effects. 5. Adverse Effects: In addition to the common side effects listed above, aspirin’s main adverse effects at antithrombotic doses are gastric upset (intolerance) and gastric and duodenal ulcers. Hepatotoxicity, asthma, rashes, GI bleeding, and renal toxicity rarely if ever occur at antithrombotic doses. 6. The antiplatelet action of aspirin contraindicates its use by patients with hemophilia. Although previously not recommended during pregnancy, aspirin may be valuable in treating preeclampsia-eclampsia.


Pharmacology_Katzung

Pharmacology_Katzung. These drugs include magnesium choline salicylate, sodium salicylate, and salicyl salicylate. All nonacetylated salicylates are effective anti-inflammatory drugs, and they do not inhibit platelet aggregation. They may be preferable when COX inhibition is undesirable such as in patients with asthma, those with bleeding tendencies, and even (under close supervision) those with renal dysfunction. The nonacetylated salicylates are administered in doses up to 3–4 g of salicylate a day and can be monitored using serum salicylate measurements.


Pharmacology_Katzung

Pharmacology_Katzung. COX-2 selective inhibitors, or coxibs, were developed in an attempt to inhibit prostaglandin synthesis by the COX-2 isozyme induced at sites of inflammation without affecting the action of the constitutively active “housekeeping” COX-1 isozyme found in the GI tract, kidneys, and platelets. COX-2 inhibitors at usual doses have no impact on platelet aggregation, which is mediated by thromboxane produced by the COX-1 isozyme. In contrast, they do inhibit COX-2-mediated prostacyclin synthesis in the vascular endothelium. As a result, COX-2 inhibitors do not offer –––––Disturbance of cell membranes Stimulus Phospholipids Arachidonic acid PhospholipaseLipoxygenaseLeukotrienes LTC4/D4/E4 Alteration of vascular permeability, bronchial constriction, increased secretion Bronchospasm, congestion, mucous plugging LTB4 Phagocyte attraction, activation Inflammation Prostaglandins Thromboxane Prostacyclin CyclooxygenaseLeukocyte modulation Inflammation Phospholipase inhibitors Corticosteroids Fatty


Pharmacology_Katzung

Pharmacology_Katzung. plugging LTB4 Phagocyte attraction, activation Inflammation Prostaglandins Thromboxane Prostacyclin CyclooxygenaseLeukocyte modulation Inflammation Phospholipase inhibitors Corticosteroids Fatty acid substitution (diet) Lipoxygenase inhibitors Receptor antagonists Colchicine NSAID, ASA


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 36–2 Prostanoid mediators derived from arachidonic acid and sites of drug action. ASA, acetylsalicylic acid (aspirin); LT, leukotriene; NSAID, nonsteroidal anti-inflammatory drug. Conjugation with Conjugation Oxidationglucuronic acid FIGURE 36–3 Structure and metabolism of the salicylates. (Reproduced, with permission, from Meyers FH, Jawetz E, Goldfien A: Review of Medical Pharmacology, 7th ed. McGraw-Hill, 1980. Copyright © The McGraw-Hill Companies, Inc.) the cardioprotective effects of traditional nonselective NSAIDs. Recommended doses of COX-2 inhibitors cause renal toxicities similar to those associated with traditional NSAIDs. Clinical data suggested a higher incidence of cardiovascular thrombotic events associated with COX-2 inhibitors such as rofecoxib and valdecoxib, resulting in their withdrawal from the market.


Pharmacology_Katzung

Pharmacology_Katzung. Celecoxib is a selective COX-2 inhibitor—about 10–20 times more selective for COX-2 than for COX-1. Pharmacokinetic and dosage considerations are given in Table 36–1. Celecoxib is associated with fewer endoscopic ulcers than most other NSAIDs. Probably because it is a sulfonamide, celecoxib may cause rashes. It does not affect platelet aggregation at usual doses. It interacts occasionally with warfarin—as would be expected of a drug metabolized via CYP2C9. Adverse effects are the common toxicities listed above.


Pharmacology_Katzung

Pharmacology_Katzung. Meloxicam is an enolcarboxamide related to piroxicam that preferentially inhibits COX-2 over COX-1, particularly at its lowest therapeutic dose of 7.5 mg/d. It is not as selective as celecoxib and may be considered “preferentially” selective rather than “highly” selective. It is associated with fewer clinical GI symptoms and complications than piroxicam, diclofenac, and naproxen. Similarly, while meloxicam is known to inhibit synthesis of thromboxane A2, even at supratherapeutic doses, its blockade of thromboxane A2 does not reach levels that result in decreased in vivo platelet function (see common adverse effects above). Diclofenac is a phenylacetic acid derivative that is relatively nonselective as a COX inhibitor. Pharmacokinetic and dosage characteristics are set forth in Table 36–1.


Pharmacology_Katzung

Pharmacology_Katzung. Diclofenac is a phenylacetic acid derivative that is relatively nonselective as a COX inhibitor. Pharmacokinetic and dosage characteristics are set forth in Table 36–1. Gastrointestinal ulceration may occur less frequently than with some other NSAIDs. A preparation combining diclofenac and misoprostol decreases upper gastrointestinal ulceration but may result in diarrhea. Another combination of diclofenac and * Listed alphabetically. omeprazole was also effective with respect to the prevention of recurrent bleeding, but renal adverse effects were common in high-risk patients. Diclofenac, 150 mg/d, appears to impair renal blood flow and glomerular filtration rate. Elevation of serum aminotransferases occurs more commonly with this drug than with other NSAIDs.


Pharmacology_Katzung

Pharmacology_Katzung. A 0.1% ophthalmic preparation is promoted for prevention of postoperative ophthalmic inflammation and can be used after intraocular lens implantation and strabismus surgery. A topical gel containing 3% diclofenac is effective for solar keratoses. Diclofenac in rectal suppository form can be considered for preemptive analgesia and postoperative nausea. In Europe, diclofenac is also available as an oral mouthwash and for intramuscular administration. Although diflunisal is derived from salicylic acid, it is not metabolized to salicylic acid or salicylate. It undergoes an enterohepatic cycle with reabsorption of its glucuronide metabolite followed by cleavage of the glucuronide to again release the active moiety. Diflunisal is subject to capacity-limited metabolism, with serum half-lives at various dosages approximating that of salicylates (Table 36–1). In RA the recommended dose is 500–1000 mg daily in two divided doses. It is rarely used today.


Pharmacology_Katzung

Pharmacology_Katzung. Etodolac is a racemic acetic acid derivative with an intermediate half-life (Table 36–1). The analgesic dosage of etodolac is 200– 400 mg three to four times daily. The recommended dose in OA and RA is 300 mg twice or three times a day up to 500 mg twice a day initially followed by a maintenance of 600 mg/d. Flurbiprofen is a propionic acid derivative with a possibly more complex mechanism of action than other NSAIDs. Its (S)(–) enantiomer inhibits COX nonselectively, but it has been shown in rat tissue to also affect tumor necrosis factor α (TNF-α) and nitric oxide synthesis. Hepatic metabolism is extensive; its (R)(+) and (S)(–) enantiomers are metabolized differently, and it does not undergo chiral conversion. It does demonstrate enterohepatic circulation.


Pharmacology_Katzung

Pharmacology_Katzung. Flurbiprofen is also available in a topical ophthalmic formulation for inhibition of intraoperative miosis. Flurbiprofen intravenously is effective for perioperative analgesia in minor ear, neck, and nose surgery and in lozenge form for sore throat. Although its adverse effect profile is similar to that of other NSAIDs in most ways, flurbiprofen is also rarely associated with cogwheel rigidity, ataxia, tremor, and myoclonus. Ibuprofen is a simple derivative of phenylpropionic acid (Figure 36–1). In doses of about 2400 mg daily, ibuprofen is equivalent to 4 g of aspirin in anti-inflammatory effect. Pharmacokinetic characteristics are given in Table 36–1. Oral ibuprofen is often prescribed in lower doses (<1600 mg/d), at which it is analgesic but not anti-inflammatory. It is available over the counter in low-dose forms.


Pharmacology_Katzung

Pharmacology_Katzung. Oral ibuprofen is often prescribed in lower doses (<1600 mg/d), at which it is analgesic but not anti-inflammatory. It is available over the counter in low-dose forms. Ibuprofen oral and IV is effective in closing patent ductus arteriosus in preterm infants, with much the same efficacy and safety as indomethacin. A topical cream preparation appears to be absorbed into fascia and muscle; ibuprofen cream was more effective than placebo cream in the treatment of primary knee OA. A liquid gel preparation of ibuprofen, 400 mg, provides prompt relief and good overall efficacy in postsurgical dental pain.


Pharmacology_Katzung

Pharmacology_Katzung. In comparison with indomethacin, ibuprofen decreases urine output less and also causes less fluid retention. The drug is relatively contraindicated in individuals with nasal polyps, angioedema, and bronchospastic reactivity to aspirin. Aseptic meningitis (particularly in patients with SLE), and fluid retention have been reported. The concomitant administration of ibuprofen and aspirin antagonizes the irreversible platelet inhibition induced by aspirin. Thus, treatment with ibuprofen in patients with increased cardiovascular risk may limit the cardioprotective effects of aspirin. Furthermore, the use of ibuprofen concomitantly with aspirin may decrease the total anti-inflammatory effect. Common adverse effects are listed on page 645 rare hematologic effects include agranulocytosis and aplastic anemia.


Pharmacology_Katzung

Pharmacology_Katzung. Indomethacin, introduced in 1963, is an indole derivative (Figure 36–1). It is a potent nonselective COX inhibitor and may also inhibit phospholipase A and C, reduce neutrophil migration, and decrease T-cell and B-cell proliferation. Indomethacin differs somewhat from other NSAIDs in its indications and toxicities. It has been used to accelerate closure of patent ductus arteriosus. Indomethacin has been tried in numerous small or uncontrolled trials for many other conditions, including Sweet’s syndrome, juvenile RA, pleurisy, nephrotic syndrome, diabetes insipidus, urticarial vasculitis, postepisiotomy pain, and prophylaxis of heterotopic ossification in arthroplasty.


Pharmacology_Katzung

Pharmacology_Katzung. An ophthalmic preparation is efficacious for conjunctival inflammation and to reduce pain after traumatic corneal abrasion. Gingival inflammation is reduced after administration of indomethacin oral rinse. Epidural injections produce a degree of pain relief similar to that achieved with methylprednisolone in postlaminectomy syndrome. At usual doses, indomethacin has the common side effects listed above. The GI effects may include pancreatitis. Headache is experienced by 15–25% of patients and may be associated with dizziness, confusion, and depression. Renal papillary necrosis has also been observed. A number of interactions with other drugs have been reported (see Chapter 66). Ketoprofen is a propionic acid derivative that inhibits both COX (nonselectively) and lipoxygenase. Its pharmacokinetic characteristics are given in Table 36–1. Concurrent administration of probenecid elevates ketoprofen levels and prolongs its plasma half-life.


Pharmacology_Katzung

Pharmacology_Katzung. The effectiveness of ketoprofen at dosages of 100–300 mg/d is equivalent to that of other NSAIDs. Its major adverse effects are on the GI tract and the central nervous system (see common adverse effects above). Nabumetone is the only nonacid NSAID in current use; it is given as a ketone prodrug (Figure 36–1) and resembles naproxen in structure. Its half-life of more than 24 hours (Table 36–1) permits once-daily dosing, and the drug does not appear to undergo enterohepatic circulation. Renal impairment results in a doubling of its half-life and a 30% increase in the area under the curve. Its properties are very similar to those of other NSAIDs, though it may be less damaging to the stomach. Unfortunately, higher dosages (eg, 1500–2000 mg/d) are often needed, and this is a very expensive NSAID.


Pharmacology_Katzung

Pharmacology_Katzung. Naproxen is a naphthylpropionic acid derivative. It is the only NSAID presently marketed as a single enantiomer. Naproxen’s free fraction is significantly higher in women than in men, but half-life is similar in both sexes (Table 36–1). Naproxen is effective for the usual rheumatologic indications and is available in a slow-release formulation, as an oral suspension, and over the counter. A topical preparation and an ophthalmic solution are also available. The incidence of upper GI bleeding in over-the-counter use is low but still double that of over-the-counter ibuprofen (perhaps due to a dose effect). Rare cases of allergic pneumonitis, leukocytoclastic vasculitis, and pseudoporphyria as well as the common NSAID-associated adverse effects have been noted.


Pharmacology_Katzung

Pharmacology_Katzung. Oxaprozin is another propionic acid derivative NSAID. As noted in Table 36–1, its major difference from the other members of this subgroup is a very long half-life (50–60 hours), although oxaprozin does not undergo enterohepatic circulation. It is mildly uricosuric. Otherwise, the drug has the same benefits and risks that are associated with other NSAIDs. Piroxicam, an oxicam (Figure 36–1), is a nonselective COX inhibitor that at high concentrations also inhibits polymorphonuclear leukocyte migration, decreases oxygen radical production, and inhibits lymphocyte function. Its long half-life (Table 36–1) permits once-daily dosing. Piroxicam can be used for the usual rheumatic indications. When piroxicam is used in dosages higher than 20 mg/d, an increased incidence of peptic ulcer and bleeding (relative risk up to 9.5) is encountered (see common adverse effects above).


Pharmacology_Katzung

Pharmacology_Katzung. Sulindac is a sulfoxide prodrug. It is reversibly metabolized to the active sulfide metabolite and has enterohepatic cycling; this prolongs the duration of action to 12–16 hours. In addition to its rheumatic disease indications, sulindac suppresses familial intestinal polyposis and it may inhibit the development of colon, breast, and prostate cancer in humans. Among the more severe adverse reactions, Stevens-Johnson epidermal necrolysis syndrome, thrombocytopenia, agranulocytosis, and nephrotic syndrome; all have been observed. It is sometimes associated with cholestatic liver damage. Tolmetin is a nonselective COX inhibitor with a short half-life (1–2 hours) and is not often used. It is ineffective (for unknown reasons) in the treatment of gout. Azapropazone, carprofen, meclofenamate, and tenoxicam are rarely used and are not reviewed here.


Pharmacology_Katzung

Pharmacology_Katzung. Azapropazone, carprofen, meclofenamate, and tenoxicam are rarely used and are not reviewed here. All NSAIDs, including aspirin, are about equally efficacious with a few exceptions—tolmetin seems not to be effective for gout, and aspirin is less effective than other NSAIDs (eg, indomethacin) for AS. Thus, NSAIDs tend to be differentiated on the basis of toxicity and cost-effectiveness. For example, the GI and renal side effects of ketorolac limit its use. Some surveys suggest that indomethacin and tolmetin are the NSAIDs associated with the greatest toxicity, while salsalate, aspirin, and ibuprofen are least toxic. The selective COX-2 inhibitors were not included in these analyses.


Pharmacology_Katzung

Pharmacology_Katzung. For patients with renal insufficiency, nonacetylated salicylates may be best. Diclofenac and sulindac are associated with more liver function test abnormalities than other NSAIDs. The relatively expensive, selective COX-2 inhibitor celecoxib is probably safest for patients at high risk for GI bleeding but may have a higher risk of cardiovascular toxicity. Celecoxib or a nonselective NSAID plus omeprazole or misoprostol may be appropriate in patients at highest risk for GI bleeding; in this subpopulation of patients, they are cost-effective despite their high acquisition costs. The choice of an NSAID thus requires a balance of efficacy, cost-effectiveness, safety, and numerous personal factors (eg, other drugs also being used, concurrent illness, compliance, medical insurance coverage), so that there is no best NSAID for all patients. There may, however, be one or two best NSAIDs for a specific person.


Pharmacology_Katzung

Pharmacology_Katzung. RA is a progressive immunologic disease that causes significant systemic effects, shortens life, and reduces mobility and quality of life. Interest has centered on finding treatments that might arrest—or at least slow—this progression by modifying the disease itself. The effects of disease-modifying therapies may take 2 weeks to 6 months to become clinically evident.


Pharmacology_Katzung

Pharmacology_Katzung. These therapies include conventional synthetic (cs) and biologic (b) disease-modifying antirheumatic drugs (recently designated csDMARDs and bDMARDs, respectively). The conventional synthetic agents include small molecule drugs such as methotrexate, azathioprine, chloroquine and hydroxy-chloroquine, cyclophosphamide, cyclosporine, leflunomide, mycophenolate mofetil, and sulfasalazine. Tofacitinib, though marketed as a biologic, is actually a targeted synthetic DMARD (tsDMARD). Gold salts, which were once extensively used, are no longer recommended because of their significant toxicities and questionable efficacy. Nevertheless, they have found limited use for RA in Canada. Biologics are large-molecule therapeutic agents, usually proteins, which are often produced by recombinant DNA technology. The bDMARDs approved for RA include a T-cell–modulating biologic (abatacept), a B-cell cytotoxic agent (rituximab), an anti–IL-6 receptor antibody (tocilizumab), IL-1–inhibiting agents (anakinra,


Pharmacology_Katzung

Pharmacology_Katzung. The bDMARDs approved for RA include a T-cell–modulating biologic (abatacept), a B-cell cytotoxic agent (rituximab), an anti–IL-6 receptor antibody (tocilizumab), IL-1–inhibiting agents (anakinra, rilonacept, canakinumab), and the TNF-α–blocking agents (five drugs); bDMARDs are further divided into biological original (or legacy) products and biosimilar DMARDs (boDMARDs and bsDMARDs, respectively).


Pharmacology_Katzung

Pharmacology_Katzung. The small-molecule DMARDs and biologics are discussed alphabetically, independent of origin. 1. Mechanism of action: Abatacept is a co-stimulation modulator biologic that inhibits the activation of T cells (see also Chapter 55). After a T cell has engaged an antigen-presenting cell (APC), a second signal is produced by CD28 on the T cell that interacts with CD80 or CD86 on the APC, leading to T-cell activation. Abatacept (which contains the endogenous ligand CTLA-4) binds to CD80 and 86, thereby inhibiting the binding to CD28 and preventing the activation of T cells. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Pharmacokinetics: The recommended dose of abatacept for the treatment of adult patients with RA is three intravenous infusion “induction” doses (day 0, week 2, and week 4), followed by monthly infusions. The dose is based on body weight; patients weighing less than 60 kg receiving 500 mg, those 60–100 kg receiving 750 mg, and those more than 100 kg receiving 1000 mg. Abatacept is also available as a subcutaneous formulation and is given as 125 mg subcutaneously once weekly. JIA can also be treated with abatacept with an induction schedule at day 0, week 2, and week 4, followed by intravenous infusion every 4 weeks. The recommended dose for patients 6–17 years of age and weighing less than 75 kg is 10 mg/kg, while those weighing 75 kg or more follow the adult intravenous doses to a maximum not to exceed 1000 mg. The terminal serum half-life is 13–16 days. Co-administration with methotrexate, NSAIDs, and corticosteroids does not influence abatacept clearance.


Pharmacology_Katzung

Pharmacology_Katzung. Most patients respond to abatacept within 12–16 weeks after the initiation of the treatment; however, some patients can respond in as few as 2–4 weeks. A study showed equivalence between adalimumab (see TNF-α Blocking Agents) and abatacept. 3.


Pharmacology_Katzung

Pharmacology_Katzung. Indications: Abatacept can be used as monotherapy or in combination with methotrexate or other DMARDs in patients with moderate to severe RA or severe PJIA. It has been tested in combination with methotrexate in early rapidly progressing RA and methotrexate-naïve patients. The combination was superior to methotrexate in achieving minimal disease activity as early as 2 months, significantly inhibiting radiographic progression at 1 year and improving patients’ physical function and symptoms. Such improvement is sustained or improved during the second year. Another trial (ADJUST) tested the effectiveness of abatacept in preventing progression to defined RA in patients with undifferentiated inflammatory arthritis. The results showed that numerically, RA developed in more patients treated with placebo than in those treated with abatacept over 1 year. Abatacept has been tested in other rheumatic diseases like SLE, primary Sjögren’s syndrome, type 1 diabetes, inflammatory bowel disease, and


Pharmacology_Katzung

Pharmacology_Katzung. placebo than in those treated with abatacept over 1 year. Abatacept has been tested in other rheumatic diseases like SLE, primary Sjögren’s syndrome, type 1 diabetes, inflammatory bowel disease, and psoriasis vulgaris, but the most beneficial effects were seen in psoriatic arthritis (PsA) patients.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Adverse Effects: There is a slightly increased risk of infection (as with other biologic DMARDs), predominantly of the upper respiratory or urinary tracts. Concomitant use with TNF-α antagonists or other biologics is not recommended due to the increased incidence of serious infection. All patients should be screened for latent tuberculosis and viral hepatitis before starting this medication. Live vaccines should be avoided in patients while taking abatacept and up to 3 months after discontinuation. Infusion-related reactions and hypersensitivity reactions, including anaphylaxis, have been reported but are rare. Antiabatacept antibody formation is infrequent (<5%) and has no effect on clinical outcomes. There is a possible increase in lymphomas but not other malignancies when using abatacept. 1.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Mechanism of Action: Azathioprine is a csDMARD that acts through its major metabolite, 6-thioguanine. 6-Thioguanine suppresses inosinic acid synthesis, B-cell and T-cell function, immunoglobulin production, and IL-2 secretion (see Chapter 55). 2. Pharmacokinetics: Azathioprine can be given orally or parenterally. Its metabolism is bimodal in humans, with rapid metabolizers clearing the drug four times faster than slow metabolizers. Production of 6-thioguanine is dependent on thiopurine methyltransferase (TPMT), and patients with low or absent TPMT activity (0.3% of the population) are at particularly high risk of myelosuppression by excess concentrations of the parent drug, if dosage is not adjusted. 3. Indications: Azathioprine is approved for use in RA at 2 mg/kg per day. It is also used for the prevention of kidney transplant rejection in combination with other immune suppressants.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Indications: Azathioprine is approved for use in RA at 2 mg/kg per day. It is also used for the prevention of kidney transplant rejection in combination with other immune suppressants. Controlled trials show efficacy in PA, reactive arthritis, polymyositis, SLE, maintenance of remission in vasculitis, and Behçet’s disease. Azathioprine is also used in scleroderma; however, in one study, it was found to be less effective than cyclophosphamide in controlling the progression of scleroderma lung disease. Another registry study indicated possible usefulness in scleroderma lung disease. Thus it is not clear what place, if any, azathioprine has for treating scleroderma. 4. Adverse Effects: Azathioprine’s toxicity includes bone marrow suppression, GI disturbances, and some increase in infection risk. As noted in Chapter 55, lymphomas may be increased with azathioprine use. Rarely, fever, rash, and hepatotoxicity signal acute allergic reactions. 1.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Mechanism of Action: Chloroquine and hydroxychloroquine are nonbiologic drugs mainly used for malaria (see Chapter 52) and in the rheumatic diseases as csDMARDs. The following mechanisms have been proposed: suppression of T-lymphocyte responses to mitogens, inhibition of leukocyte chemotaxis, stabilization of lysosomal enzymes, processing through the Fc-receptor, inhibition of DNA and RNA synthesis, and the trapping of free radicals. 2. Pharmacokinetics: Antimalarials are rapidly absorbed and 50% protein-bound in the plasma. They are very extensively tissue-bound, particularly in melanin-containing tissues such as the eyes. The drugs are deaminated in the liver and have blood elimination half-lives of up to 45 days. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Indications: Antimalarials are approved for RA, but they are not considered very effective DMARDs. Dose-loading may increase rate of response. There is no evidence that these compounds alter bony damage in RA at their usual dosages (up to 6.4 mg/kg per day for hydroxychloroquine or 200 mg/d for chloroquine). It usually takes 3–6 months to obtain a response. Antimalarials are used very commonly in SLE because they decrease mortality and the skin manifestations, serositis, and joint pains of this disease. They have also been used in Sjögren’s syndrome. 4. Adverse Effects: Although ocular toxicity (see Chapter 52) may occur at dosages greater than 250 mg/d for chloroquine and greater than 6.4 mg/kg/d for hydroxychloroquine, it rarely occurs at lower doses. Nevertheless, ophthalmologic monitoring every 12 months is advised. Other toxicities include dyspepsia, nausea, vomiting, abdominal pain, rashes, and nightmares. These drugs appear to be relatively safe in pregnancy.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Mechanism of Action: Cyclophosphamide is a csDMARD. Its major active metabolite is phosphoramide mustard, which cross-links DNA to prevent cell replication. It suppresses T-cell and B-cell function by 30–40%; T-cell suppression correlates with clinical response in the rheumatic diseases. Its pharmacokinetics and toxicities are discussed in Chapter 54. 2. Indications: Cyclophosphamide is used regularly at 2 mg/ kg per day to treat SLE, vasculitis, Wegener’s granulomatosis, and other severe rheumatic diseases although mycophenolate is now often used for SLE and rituximab is often used for some forms of vasculitis (see below). 1. Mechanism of Action: Cyclosporine is a peptide antibiotic but is considered a csDMARD. Through regulation of gene transcription, it inhibits IL-1 and IL-2 receptor production and secondarily inhibits macrophage–T-cell interaction and T-cell responsiveness (see Chapter 55). T-cell–dependent B-cell function is also affected. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Pharmacokinetics: Cyclosporine absorption is incomplete and somewhat erratic, although a microemulsion formulation improves its consistency and provides 20–30% bioavailability. Grapefruit juice increases cyclosporine bioavailability by as much as 62%. Cyclosporine is metabolized by CYP3A and consequently is subject to a large number of drug interactions (see Chapters 55 and 66). 3. Indications: Cyclosporine is approved for use in RA and retards the appearance of new bony erosions. Its usual dosage is 3–5 mg/kg per day divided into two doses. Anecdotal reports suggest that it may be useful in SLE, polymyositis and dermatomyositis, Wegener’s granulomatosis, juvenile chronic arthritis, and refractory eye involvement in Behçet disease. 4.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Adverse Effects: Leukopenia, thrombocytopenia, and, to a lesser extent, anemia are predictable. High doses can be cardiotoxic and neurotoxic, and sterility may occur after chronic dosing at antirheumatic doses, especially in women. Bladder cancer is very rare but must be looked for, even 5 years after cessation of use. 1. Mechanism of Action: Leflunomide, another csDMARD, 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 reduces production of autoantibodies by B cells. Secondary effects include increases of IL-10 receptor mRNA, decreased IL-8 receptor type A mRNA, and decreased TNF-α–dependent nuclear factor kappa B (NF-κB) activation. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Pharmacokinetics: Leflunomide is completely absorbed from the gut and has a mean plasma half-life of 19 days. Its active metabolite, A77-1726, has approximately the same half-life and is subject to enterohepatic recirculation. Cholestyramine can enhance leflunomide excretion and increases total clearance by approximately 50%. 3. Indications: Leflunomide is as effective as methotrexate in RA, 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. 4.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Adverse Effects: Diarrhea occurs in approximately 25% of patients given leflunomide, although only about 3–5% of patients discontinue the drug because of this side effect. Elevation in liver enzymes can occur. 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. Methotrexate, a synthetic nonbiologic antimetabolite, is the first-line csDMARD for treating RA and is used in 50–70% of patients. It is active in this condition at much lower doses than those needed in cancer chemotherapy (see Chapter 54). 1.


Pharmacology_Katzung

Pharmacology_Katzung. Mechanism of Action: Methotrexate’s principal mechanism of action at the low doses used in the rheumatic diseases probably relates to inhibition of amino-imidazolecarboxamide ribonucleotide (AICAR) transformylase and thymidylate synthetase. AICAR, which accumulates intracellularly, competitively inhibits AMP deaminase, leading to an accumulation of AMP. The AMP is released and converted extracellularly to adenosine, which is a potent inhibitor of inflammation. As a result, the inflammatory functions of neutrophils, macrophages, dendritic cells, and lymphocytes are suppressed. Methotrexate has secondary effects on polymorphonuclear chemotaxis. There is some effect on dihydrofolate reductase and this affects lymphocyte and macrophage function, but this is not its principal mechanism of action. Methotrexate has direct inhibitory effects on proliferation and stimulates apoptosis in immune-inflammatory cells. Additionally, it inhibits proinflammatory cytokines linked to rheumatoid


Pharmacology_Katzung

Pharmacology_Katzung. of action. Methotrexate has direct inhibitory effects on proliferation and stimulates apoptosis in immune-inflammatory cells. Additionally, it inhibits proinflammatory cytokines linked to rheumatoid synovitis.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Pharmacokinetics: Methotrexate can be administered either orally or parentally (SC or IM). The drug is approximately 70% absorbed after oral administration (see Chapter 54). Although variable, bioavailability decreased further in one study when more than 25 mg weekly MTX was used. MTX is metabolized to a less active hydroxylated product. Both the parent compound and the metabolite are polyglutamated within cells where they stay for prolonged periods. Methotrexate’s serum half-life is usually only 6–9 hours. Hydroxychloroquine can reduce the clearance or increase the tubular reabsorption of methotrexate. Methotrexate is excreted principally in the urine, but up to 30% may be excreted in bile. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Dosage and Indications: It is recommended to start treatment with 7.5 mg weekly. According to patient response, methotrexate is increased to the most common dosing regimen for the treatment of RA, which is 15–25 mg weekly. Notably there is an increased effect up to 30–35 mg weekly, although with increased toxicity. The drug decreases the rate of appearance of new erosions. Evidence supports its use in juvenile chronic arthritis, and it has been used in psoriasis, PA, AS, polymyositis, dermatomyositis, Wegener’s granulomatosis, giant cell arteritis, SLE, and vasculitis. 4.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Adverse Effects: Nausea and mucosal ulcers are the most common toxicities. Additionally, many other side effects such as leukopenia, anemia, stomatitis, GI ulcerations, and alopecia are probably the result of inhibiting cellular proliferation. Progressive dose-related hepatotoxicity in the form of enzyme elevation occurs frequently, but cirrhosis is rare (<1%). Liver toxicity is not related to serum methotrexate concentrations. A rare hypersensitivity-like lung reaction with acute shortness of breath has been documented, as have pseudo-lymphomatous reactions. The incidence of GI and liver function test abnormalities can be reduced by the use of leucovorin 24 hours after each weekly dose or by the use of folic acid, although this may decrease the efficacy of the methotrexate by about 10%. This drug is contraindicated in pregnancy. 1.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Mechanism of Action: Mycophenolate mofetil (MMF), a csD-MARD, is converted to mycophenolic acid, the active form of the drug. The active product inhibits inosine monophosphate dehydrogenase, leading to suppression of Tand B-lymphocyte proliferation. Downstream, it interferes with leukocyte adhesion to endothelial cells through inhibition of E-selectin, P-selectin, and intercellular adhesion molecule 1. MMF’s pharmacokinetics and toxicities are discussed in Chapter 55. 2. Indications: MMF is effective for the treatment of renal disease due to SLE and may be useful in vasculitis and Wegener’s granulomatosis. Although MMF is occasionally used at a dosage of 2 g/d to treat RA, there are no well-controlled data regarding its efficacy in this disease. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Adverse Effects: MMF is associated with nausea, dyspepsia, and abdominal pain. Like azathioprine, it can cause hepatotoxicity. MMF can also cause leukopenia, thrombocytopenia, and anemia. MMF is associated with an increased incidence of infections. It is only rarely associated with malignancy. 1. Mechanism of Action: Rituximab is a chimeric monoclonal antibody biologic agent that targets CD20 B lymphocytes (see Chapter 55). Depletion of these cells takes place through cell-mediated and complement-dependent cytotoxicity and stimulation of cell apoptosis. Depletion of B lymphocytes reduces inflammation by decreasing the presentation of antigens to T lymphocytes and inhibiting the secretion of proinflammatory cytokines. Rituximab rapidly depletes peripheral B cells, although this depletion correlates neither with efficacy nor with toxicity. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Pharmacokinetics: Rituximab is given as two intravenous infusions of 1000 mg, separated by 2 weeks. It may be repeated every 6–9 months, as needed. Repeated courses remain effective. Pretreatment with acetaminophen, an antihistamine, and intravenous glucocorticoids (usually 100 mg of methylprednisolone) given 30 minutes prior to infusion decreases the incidence and severity of infusion reactions. 3. Indications: Rituximab is indicated for the treatment of moderately to severely active RA in combination with methotrexate in patients with an inadequate response to one or more TNF-α antagonists. Rituximab in combination with glucocorticoids is also approved for the treatment of adult patients with granulomatosis with polyangiitis (previously known as Wegener’s granulomatosis) and microscopic polyangiitis and is used in other forms of vasculitis as well (see Chapter 54 for its use in lymphomas and leukemias). 4.


Pharmacology_Katzung

Pharmacology_Katzung. Adverse Effects: About 30% of patients develop rash with the first 1000-mg treatment; this incidence decreases to about 10% with the second infusion and progressively decreases with each course of therapy thereafter. These rashes do not usually require discontinuation of therapy, although an urticarial or anaphylactoid reaction precludes further therapy. Immunoglobulins (particularly IgG and IgM) may decrease with repeated courses of therapy and infections can occur, although they do not seem directly associated with the decreases in immunoglobulins. Serious, and sometimes fatal, bacterial, fungal, and viral infections are reported for up to 1 year of the last dose of rituximab, and patients with severe and active infections should not receive rituximab. Rituximab is associated with reactivation of hepatitis B virus (HBV) infection, which requires monitoring before and several months after the initiation of the treatment. Rituximab has not been associated with either activation of


Pharmacology_Katzung

Pharmacology_Katzung. of hepatitis B virus (HBV) infection, which requires monitoring before and several months after the initiation of the treatment. Rituximab has not been associated with either activation of tuberculosis or the occurrence of lymphomas or other tumors (see Chapter 55). Fatal mucocutaneous reactions have been reported in patients receiving rituximab. Different cytopenias can occur, which require complete blood cell monitoring every 2–4 months in RA patients. Other adverse effects, such as cardiovascular events, are rare.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Mechanism of Action: Sulfasalazine, a csDMARD, is metabolized to sulfapyridine and 5-aminosalicylic acid. The sulfapyridine is probably the active moiety when treating RA (unlike inflammatory bowel disease; see Chapter 62). Some authorities believe that the parent compound, sulfasalazine, also has an effect. Suppression of T-cell responses to concanavalin and inhibition of in vitro B-cell proliferation are documented. In vitro, sulfasalazine or its metabolites inhibit the release of inflammatory cytokines produced by monocytes or macrophages—eg, IL-1, -6, and -12, and TNF-α. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Pharmacokinetics: Only 10–20% of orally administered sulfasalazine is absorbed, although a fraction undergoes enterohepatic recirculation into the bowel where it is reduced by intestinal bacteria to liberate sulfapyridine and 5-aminosalicylic acid (see Figure 62–8). Sulfapyridine is well absorbed while 5-aminosalicylic acid remains unabsorbed. Some sulfasalazine is excreted unchanged in the urine whereas sulfapyridine is excreted after hepatic acetylation and hydroxylation. Sulfasalazine’s half-life is 6–17 hours. 3. Indications: Sulfasalazine is effective in RA and reduces radiologic disease progression. It has also been used in juvenile chronic arthritis, PsA, inflammatory bowel disease, AS, and spondyloarthropathy-associated uveitis. The usual regimen is 2–3 g/d. 4.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Adverse Effects: 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 1–5% of patients, while thrombocytopenia is very rare. Pulmonary toxicity and positive double-stranded DNA (dsDNA) 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. 1.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Mechanism of Action: Tocilizumab, a newer biologic humanized antibody, binds to soluble and membrane-bound IL-6 receptors, and inhibits the IL-6-mediated signaling via these receptors. IL-6 is a proinflammatory cytokine produced by different cell types including T cells, B cells, monocytes, fibroblasts, and synovial and endothelial cells. IL-6 is involved in a variety of physiologic processes such as T-cell activation, hepatic acute-phase protein synthesis, and stimulation of the inflammatory processes involved in diseases such as RA and systemic sclerosis (SSc). In a phase 4 superiority study, tocilizumab monotherapy was superior to adalimumab monotherapy for reduction of signs and symptoms of rheumatoid arthritis in patients with incomplete response to MTX. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Pharmacokinetics: The half-life of tocilizumab is dose-dependent, approximately 11 days for the 4-mg/kg dose and 13 days for the 8-mg/kg dose. IL-6 can suppress several CYP450 isoenzymes; thus, inhibiting IL-6 may restore CYP450 activities to higher levels. This may be clinically relevant for drugs that are CYP450 substrates and have a narrow therapeutic window (eg, cyclosporine or warfarin), and dosage adjustment of these medications may be needed. Tocilizumab can be used in combination with nonbiologic DMARDs or as monotherapy. In the United States the recommended starting dose for RA is 4 mg/kg intravenously every 4 weeks followed by an increase to 8 mg/kg (not exceeding 800 mg/infusion) dependent on clinical response.


Pharmacology_Katzung

Pharmacology_Katzung. In Europe, the starting dose of tocilizumab is 8 mg/kg up to 800 mg. Tocilizumab dosage in SJIA or PJIA follows an algorithm that accounts for body weight. Additionally, dosage modifications are recommended on the basis of certain laboratory changes such as elevated liver enzymes, neutropenia, and thrombocytopenia. 3. Indications: Tocilizumab is a bDMARD indicated for adult patients with moderately to severely active RA who have had an inadequate response to one or more DMARDs. It is also indicated in patients who are older than 2 years with active SJIA or active PJIA. A recent study showed that it is slightly more effective than adalimumab. There is an ongoing phase 3 study to test its use in SSc. 4.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Adverse Effects: Serious infections including tuberculosis, fungal, viral, and other opportunistic infections have occurred. Screening for tuberculosis should be done prior to beginning tocilizumab. The most common adverse reactions are upper respiratory tract infections, headache, hypertension, and elevated liver enzymes.


Pharmacology_Katzung

Pharmacology_Katzung. Neutropenia and reduction in platelet counts occur occasionally, and lipids (eg, cholesterol, triglycerides, LDL, and HDL) should be monitored. GI perforation has been reported when using tocilizumab in patients with diverticulitis and in those using corticosteroids, although it is not clear that this adverse effect is more common than with TNF-α–blocking agents. Demyelinating disorders including multiple sclerosis are rarely associated with tocilizumab use. Fewer than 1% of the patients taking tocilizumab develop anaphylactic reaction. Anti-tocilizumab antibodies develop in 2% of the patients, and these can be associated with hypersensitivity reactions requiring discontinuation. Cytokines play a central role in the immune response (see Chapter 55) and in RA. Although a wide range of cytokines are expressed in the joints of RA patients, TNF-α appears to be particularly important in the inflammatory process.


Pharmacology_Katzung

Pharmacology_Katzung. TNF-α affects cellular function via activation of specific membrane-bound TNF receptors (TNFR1, TNFR2). Five “legacy” bDMARDs interfering with TNF-α have been approved for the treatment of RA and other rheumatic diseases (Figure 36–4). Biosimilar biologics (bsDMARDs) with lower costs are available in some countries and are being tested in other countries. Thus far, the efficacy, toxicity, and immunogenicity of the biosimilars are equivalent to the legacy compounds. These drugs have many adverse effects in common (see below). 1. Mechanism of Action: Adalimumab is a fully human IgG1 anti-TNF monoclonal antibody. This compound complexes with soluble TNF-α and prevents its interaction with p55 and p75 cell surface receptors. This results in down-regulation of macrophage and T-cell function. FC region of human IgG1 FC region of human IgG1CH3 Extracellular domain VL of human p75 receptor CH2 FC region of human IgG1 CH3


Pharmacology_Katzung

Pharmacology_Katzung. FC region of human IgG1 FC region of human IgG1CH3 Extracellular domain VL of human p75 receptor CH2 FC region of human IgG1 CH3 FIGURE 36–4 Structures of TNF-α antagonists used in rheumatoid arthritis. CH, constant heavy chain; CL, constant light chain; Fc, complex immunoglobulin region; VH, variable heavy chain; VL, variable light chain. Red regions, human derived; blue regions, mouse derived; green regions, polyethylene glycol (PEG).


Pharmacology_Katzung

Pharmacology_Katzung. 2. Pharmacokinetics: Adalimumab is given subcutaneously and has a half-life of 10–20 days. Its clearance is decreased by more than 40% in the presence of methotrexate, and the formation of human anti-monoclonal antibody is decreased when methotrexate is given at the same time. The usual dose in RA is 40 mg every other week, but dosing is frequently increased to 40 mg weekly. In psoriasis, 80 mg is given at week 0, 40 mg at week 1, and then 40 mg every other week thereafter. The initial dose in inflammatory bowel disease is higher; patients receive 160 mg at week 0, and 80 mg 2 weeks later, followed by a 40-mg maintenance dose every other week. Patients with ulcerative colitis should continue maintenance treatment beyond 8 weeks if they show evidence of remission by that time. Adalimumab dose depends on the body weight in patients with JIA: 20 mg every other week for patients weighing 15–30 kg, and 40 mg every other week in patients weighing 30 kg or more.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Indications: The compound is approved for RA, AS, PsA, JIA, plaque psoriasis, Crohn’s disease, and ulcerative colitis. It decreases the rate of formation of new erosions. It is effective both as monotherapy and in combination with methotrexate and other nonbiologic csDMARDs. Based only on case reports and case series, adalimumab has also been found to be effective in the treatment of Behçet’s disease, sarcoidosis, and notably, noninfectious uveitis. 1. Mechanism of Action: Certolizumab is a recombinant, humanized antibody Fab fragment conjugated to a polyethylene glycol (PEG) with specificity for human TNF-α. Certolizumab neutralizes membrane-bound and soluble TNF-α in a dose-dependent manner. Additionally, certolizumab does not contain an Fc region, found on a complete antibody, and does not fix complement or cause antibody-dependent cell-mediated cytotoxicity in vitro. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Pharmacokinetics: Certolizumab is given subcutaneously and has a half-life of 14 days. Methotrexate decreases the appearance of anti-certolizumab antibodies. The usual dose for RA is 400 mg initially and at weeks 2 and 4, followed by 200 mg every other week, or 400 mg every 4 weeks. 3. Indications: Certolizumab is indicated for the treatment of adults with moderately to severely active RA. It can be used as monotherapy or in combination with nonbiologic DMARDs. Additionally, certolizumab is approved in adult patients with Crohn’s disease, active PsA, and active AS. The certolizumab head-to-head TNFi trial, Exxelerate (NCT01500278), was a multicenter, single-blind, 24-month, randomized, parallel-group trial in moderate to severe MTX-incomplete-responder RA patients, comparing adalimumab + MTX to certolizumab


Pharmacology_Katzung

Pharmacology_Katzung. MTX. ACR20 responses at 3 months and achievement of low disease activity at 2 years were numerically comparable for both protocols. Although putatively a 24-month trial, patients could switch from one regimen to the other at 3 months, confounding comparability beyond that time frame. Not surprisingly, given this confounding, the primary goal of certolizumab MTX superiority was not met. Patients were switched without washout so blood levels of TNFis as a group could be expected to be very high during the switchover. Interestingly, no serious infectious events occurred during the switch-over period. 1. 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 (Figure 36–4); it binds TNF-α molecules and also inhibits lymphotoxin α. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Pharmacokinetics: Etanercept is given subcutaneously as 25 mg twice weekly or 50 mg weekly. In psoriasis, 50 mg is given twice weekly for 12 weeks and then is followed by 50 mg 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. A recent study demonstrated a reduction of radiographic progression with the use of 50 mg of etanercept weekly. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Indications: Etanercept is approved for the treatment of RA, juvenile chronic arthritis, psoriasis, PsA, and AS. It can be used as monotherapy, although over 70% of patients taking etanercept are also using methotrexate. Etanercept decreases the rate of formation of new erosions relative to methotrexate alone. It is also being used in other rheumatic syndromes such as scleroderma, granulomatosis with polyangiitis (Wegener’s granulomatosis), giant cell arteritis, Behçet’s disease, uveitis, and sarcoidosis. However, a comparative study of ustekinumab (an IL-12 and IL-23 blocker) and etanercept concluded that ustekinumab at a dose of 45 or 90 mg was superior to high-dose etanercept (50 mg twice weekly) over a 12-week period in patients with psoriasis. 1. Mechanism of Action: Golimumab is a human monoclonal antibody with a high affinity for soluble and membrane-bound TNF-α. Golimumab effectively neutralizes the inflammatory effects produced by TNF-α seen in diseases such as RA. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Pharmacokinetics: Golimumab is administered subcutaneously and has a half-life of approximately 14 days. Concomitant use with methotrexate increases golimumab serum levels and decreases anti-golimumab antibodies. The recommended dose for the treatment of RA, PsA, and AS is 50 mg given every 4 weeks. A higher dose of golimumab is used for the treatment of ulcerative colitis as follows: 200 mg initially at week 0 followed by 100 mg at week 2 and every 4 weeks thereafter. 3. Indications: Golimumab with methotrexate is indicated for the treatment of moderately to severely active RA in adult patients. It is also indicated for the treatment of PsA and AS and moderate to severe ulcerative colitis. 1. Mechanism of Action: Infliximab (Figure 36–4) is a chimeric (25% mouse, 75% human) IgG1 monoclonal antibody that binds with high affinity to soluble and possibly membrane-bound TNF-α. Its mechanism of action probably is the same as that of adalimumab. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Pharmacokinetics: Infliximab is given as an intravenous infusion with “induction” at 0, 2, and 6 weeks and maintenance every 8 weeks thereafter. Dosing is 3–10 mg/kg, and the usual dose is 3–5 mg/kg every 8 weeks. There is a relationship between serum concentration and effect, although 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 human antichimeric antibodies in up to 62% of patients. Concurrent therapy with methotrexate markedly decreases the prevalence of human antichimeric antibodies. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Indications: Infliximab is approved for use in RA, AS, PsA, Crohn’s disease, ulcerative colitis, pediatric inflammatory bowel disease, and psoriasis. It is being used off-label in other diseases, including granulomatosis with polyangiitis (Wegener’s granulomatosis), giant cell arteritis, Behçet’s disease, uveitis, and sarcoidosis. In RA, infliximab plus methotrexate decreases the rate of formation of new erosions. Although it is recommended that methotrexate be used in conjunction with infliximab, a number of other nonbiologic csDMARDs, including antimalarials, azathioprine, leflunomide, and cyclosporine, can be used as background therapy for this drug. Infliximab is also used as monotherapy. Adverse Effects of TNF-`-Blocking Agents


Pharmacology_Katzung

Pharmacology_Katzung. Adverse Effects of TNF-`-Blocking Agents TNF-α–blocking agents have multiple adverse effects in common. The risk of bacterial infections and macrophage-dependent infection (including tuberculosis, fungal, and other opportunistic infections) is increased, although it remains very low. Activation of latent tuberculosis is lower with etanercept than with other TNF-α–blocking agents. Nevertheless, all patients should be screened for latent or active tuberculosis before starting TNF-α– blocking agents. The use of TNF-α–blocking agents is also associated with increased risk of HBV reactivation; screening for HBV is important before starting the treatment.


Pharmacology_Katzung

Pharmacology_Katzung. TNF-α–blocking agents increase the risk of skin cancers— including melanoma—which necessitates periodic skin examination, especially in high-risk patients. On the other hand, there is no clear evidence of increased risk of solid malignancies or lymphomas with TNF-α–blocking agents, and their incidence may not be different compared with other bDMARDs or active RA itself.


Pharmacology_Katzung

Pharmacology_Katzung. A low incidence of newly formed dsDNA antibodies and antinuclear antibodies (ANAs) has been documented when using TNF-α–blocking agents, but clinical lupus is extremely rare and the presence of ANA and dsDNA antibodies per se does not contraindicate the use of TNF-α–blocking agents. In patients with borderline or overt heart failure (HF), TNF-α–blocking agents can exacerbate HF. TNF-α–blocking agents can induce the immune system to develop antidrug antibodies in about 17% of cases. These antibodies may interfere with drug efficacy and correlate with infusion site reactions. Injection site reactions occur in 20–40% of patients, although they rarely result in discontinuation of therapy. Cases of alopecia areata, hypertrichosis, and erosive lichen planus have been reported. Cutaneous pseudo-lymphomas are reported rarely with TNF-α–blocking agents, especially infliximab. TNF-α–blocking agents may increase the risk of gastrointestinal ulcers and large bowel perforation including


Pharmacology_Katzung

Pharmacology_Katzung. pseudo-lymphomas are reported rarely with TNF-α–blocking agents, especially infliximab. TNF-α–blocking agents may increase the risk of gastrointestinal ulcers and large bowel perforation including diverticular and appendiceal perforation.


Pharmacology_Katzung

Pharmacology_Katzung. Nonspecific interstitial pneumonia, psoriasis, and sarcoidosislike syndrome are among the rare reported toxicities associated with TNF-α blockers. Rare cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia have also been reported. The precipitating drug should be discontinued in such cases. 1. Mechanism of Action: Ustekinumab is an IL-12 and IL-23 antagonist. It is a fully human IgG monoclonal antibody to the p40 protein subunit, which is part of both IL-12 and IL-23. These two cytokines are important contributors to the chronic inflammation in psoriasis plaques, PsA, and Crohn’s disease. Ustekinumab prevents the binding of the p40 subunit of both IL-12 and IL-23 to the IL-12 receptor b1 found on the surface of CD4 T cells and NK cells. This interruption interferes with IL-12 and IL-23 signal transduction and suppresses the formation of proinflammatory TH1 and TH17 cells. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Pharmacokinetics: Ustekinumab is available as a 45and 90-mg SC injection for PsA and plaque psoriasis. Its bioavailability is 57% following SC injection; time to peak plasma concentration is 7–13.5 days and elimination half-life is 10–126 days. For adults with PsA, a loading dose at 0 and 4 weeks is followed by maintenance doses once every 12 weeks. IV infusion as a 130 mg dose is available for Crohn’s disease. 3. Indications: Ustekinumab is indicated for treatment of adult patients with PsA. It can be used as monotherapy or in combination with methotrexate. Other indications include plaque psoriasis and Crohn’s disease. 4. Adverse Effects: Upper respiratory tract infection is the most common side effect, but rare severe infection, malignancy, and reversible posterior leukoencephalopathy syndrome have been reported. Ustekinumab should be discontinued at least 15 weeks before live vaccines are administered and can be resumed at least 2 weeks after. 1.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Mechanism of Action: Secukinumab is a human IgG1 monoclonal antibody that selectively binds to the IL-17A cytokine, inhibiting its interaction with the IL-17A receptor. IL-17A is involved in normal inflammatory and immune responses. Elevated concentrations of IL-17A are found in psoriatic plaques and PsA. 2. Pharmakokinetics: Secukinumab is available as a SC injection or lyophilized powder for injection. Its peak plasma concentration is 13.7 mcg/mL (150 mg dose) and 27.3 mcg/mL (300 mg dose); elimination half-life is 22–31 days. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Indications and Dosage: Secukinumab is indicated for moderate to severe plaque psoriasis in patients who are candidates for systemic therapy or phototherapy. Initial loading dose is 300 mg SC at weeks 0, 1, 2, 3, and 4, followed by monthly maintenance (300 mg SC or 150 mg SC monthly). For adults with active PsA and moderate to severe plaque psoriasis, the same recommendations are followed. For patients with psoriatic arthritis as well as AS, administer with or without a loading dosage by SC injection; 150 mg SC every 4 weeks with or without MTX is recommended. 4. Adverse Effects: As for any of these biologics, infection is a common side effect (28.7%). Nasopharyngitis occurs in about 12%. TB status should be evaluated prior to therapy. Secukinumab may exacerbate Crohn’s disease.