Pharmacology_Katzung

Pharmacology_Katzung. 1. Mechanism of Action: Tofacitinib is a targeted synthetic small molecule (tsDMARD) that selectively inhibits all members of the Janus kinase (JAK; see Chapter 2) family to varying degrees. At therapeutic doses, tofacitinib exerts its effect mainly by inhibiting JAK3, and to a lesser extent JAK1, hence interrupting the JAK-STAT signaling pathway. This pathway plays a major role in the pathogenesis of autoimmune diseases including RA. The JAK3/JAK1 complex is responsible for signal transduction from the common γ-chain receptor (IL2RG) for IL-2, -4, -7, -9, -15, and -21, which subsequently influences transcription of several genes that are crucial for the differentiation, proliferation, and function of NK cells and T and B lymphocytes. In addition, JAK1 (in combination with other JAKs) controls signal transduction from IL-6 and interferon receptors. RA patients receiving tofacitinib rapidly reduce C-reactive protein. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Pharmacokinetics: The recommended dose of tofacitinib in the treatment of RA is 5 mg twice daily; there is a clear trend to increased response (and increased toxicity) at double this dose. In 2016, the FDA approved extended-release (XR) tofacitinib citrate 11 mg tablets for once-daily treatment. Tofacitinib has an absolute oral bioavailability of 74%, high-fat meals do not affect the AUC, and the elimination half-life is about 3 hours. Metabolism (of 70%) occurs in the liver, mainly by CYP3A4 and to a lesser extent by CYP2C19. The remaining 30% is excreted unchanged by the kidneys. Patients taking CYP enzyme inhibitors and those with moderate hepatic or renal impairment require dose reduction to 5 mg once daily. It should not be given to patients with severe hepatic disease. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Indications: Tofacitinib was originally developed to prevent solid organ allograft rejection. It has also been tested for the treatment of inflammatory bowel disease, spondyloarthritis, psoriasis, and dry eyes. To date, tofacitinib is approved in the United States for the treatment of adult patients with moderately to severely active RA who have failed or are intolerant to methotrexate. It is not approved in Europe for this indication. It can be used as a monotherapy or in combination with other csDMARDs, including methotrexate. Ongoing studies are evaluating its role in other rheumatic diseases such as PsA, psoriasis, and JIA. 4.


Pharmacology_Katzung

Pharmacology_Katzung. Adverse Effects: Tofacitinib slightly increases the risk of infection, and it has thus far not been used with potent immunosuppressants (eg, azathioprine, cyclosporine) or biologic bDMARDs because additive immunosuppression is feared, although it has not been tested in combinations. Upper respiratory tract infection and urinary tract infection represent the most common infections. More serious infections are also reported, including pneumonia, cellulitis, esophageal candidiasis, and other opportunistic infections. All patients should be screened for latent or active tuberculosis before the initiation of treatment. Lymphoma and other malignancies such as lung and breast cancer have been reported in patients taking tofacitinib, although some studies discuss the potential use of JAK inhibitors to treat certain lymphomas. Dose-dependent increases in the levels of low-density lipoprotein (LDL), high-density lipoprotein (HDL), and total cholesterol have been found in patients receiving


Pharmacology_Katzung

Pharmacology_Katzung. to treat certain lymphomas. Dose-dependent increases in the levels of low-density lipoprotein (LDL), high-density lipoprotein (HDL), and total cholesterol have been found in patients receiving tofacitinib, often beginning about 6 weeks after starting treatment; therefore, lipid levels should be monitored. Although tofacitinib causes a dose-dependent increase in CD19 B cells and CD4 T cells plus a reduction in CD16/CD56 NK cells, the clinical significance of these changes remains unclear. Drug-related neutropenia and anemia occur, requiring drug discontinuation. Headache, diarrhea, elevation of liver enzymes, and gastrointestinal perforation are among the other reported effects of tofacitinib.


Pharmacology_Katzung

Pharmacology_Katzung. IL-1α plays a major role in the pathogenesis of several inflammatory and autoimmune diseases including RA. IL-1α, IL-1β, and IL-1 receptor antagonist (IL-1RA) are other members of the IL-1 family. All three bind to IL-1 receptors in the same manner. However, IL1RA does not initiate the intracellular signaling pathway and thus acts as a competitive inhibitor of the proinflammatory IL-1α and IL-1β. 1. Mechanism of Action: Anakinra is the oldest drug in this family but is now rarely used for RA. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Mechanism of Action: Anakinra is the oldest drug in this family but is now rarely used for RA. 2. Pharmacokinetics: Anakinra is administered subcutaneously and reaches a maximum plasma concentration after 3–7 hours. The absolute bioavailability of anakinra is 95%, and it has a 4to 6-hour terminal half-life. The recommended dose in the treatment of RA is 100 mg daily. The dose of anakinra depends on the body weight in the treatment of cryopyrin-associated periodic syndrome (CAPS), starting with 1–2 mg/kg per day to a maximum of 8 mg/kg per day. Reduction in the frequency of administering anakinra to every other day is recommended in patients with renal insufficiency. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Indications: Anakinra is approved for the treatment of moderately to severely active RA in adult patients, but it is rarely used for this indication. However, anakinra is the drug of choice for CAPS, particularly the neonatal-onset multisystem inflammatory disease (NOMID) subtype. Anakinra is effective in gout (see below) and is used for other diseases including Behçet’s disease and adult onset JIA. Its use for giant cell arteritis is controversial. 1. Mechanism of Action: Canakinumab is a human IgG1/κ monoclonal antibody against IL-1β. It forms a complex with IL-1β, preventing its binding to IL-1 receptors. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Mechanism of Action: Canakinumab is a human IgG1/κ monoclonal antibody against IL-1β. It forms a complex with IL-1β, preventing its binding to IL-1 receptors. 2. Pharmacokinetics: Canakinumab is given by subcutaneous injection. It reaches peak serum concentrations 7 days after a single subcutaneous injection. Canakinumab has an absolute bioavailability of 66% and a 26-day mean terminal half-life. The recommended dose for patients with SJIA who weigh more than 7.5 kg is 4 mg/kg every 4 weeks. There is a weight-adjusted algorithm for treating CAPS. 3. Indications: Canakinumab is indicated for active SJIA in children 2 years or older. As noted, it is also used to treat CAPS, particularly the familial cold autoinflammatory syndrome and Muckle-Wells syndrome subtypes for adults and children 4 years or older. Canakinumab is also used to treat gout (see below).


Pharmacology_Katzung

Pharmacology_Katzung. 1. Mechanism of Action: Rilonacept is the ligand-binding domain of the IL-1 receptor. It binds mainly to IL-1β and binds with lower affinity to IL-1α and IL-1RA. Rilonacept neutralizes IL-1β and prevents its attachment to IL-1 receptors. 2. Pharmacokinetics: The subcutaneous dose of rilonacept for CAPS is age-dependent. In patients 12–17 years of age, 4.4 mg/kg (maximum of 320 mg) is the loading dose, with a maintenance dose of 2.2 mg/kg (maximum of 160 mg) weekly. Those 18 years and older receive 320 mg as a loading dose and 160 mg weekly thereafter. The steady-state plasma concentration is reached after 6 weeks. 3. Indications: Rilonacept is approved to treat CAPS subtypes: familial cold autoinflammatory syndrome and Muckle-Wells syndrome in patients 12 years or older. Rilonacept is also used to treat gout (see below). Adverse Effects of Interleukin-1 Inhibitors


Pharmacology_Katzung

Pharmacology_Katzung. Adverse Effects of Interleukin-1 Inhibitors The most common adverse effects are injection site reactions (up to 40%) and upper respiratory tract infections. Serious infections occur rarely in patients given IL-1 inhibitors. Headache, abdominal pain, nausea, diarrhea, arthralgia, and flu-like illness all have been reported, as have hypersensitivity reactions. Patients taking IL-1 inhibitors may experience transient neutropenia, which requires regular monitoring of neutrophil counts. Belimumab is an antibody that specifically inhibits B-lymphocyte stimulator (BLyS). It is administered as an intravenous infusion. The recommended dose is 10 mg/kg at weeks 0, 2, and 4, and every 4 weeks thereafter. Belimumab has a distribution half-life of 1.75 days and a terminal half-life of 19.4 days.


Pharmacology_Katzung

Pharmacology_Katzung. Belimumab is approved only for the treatment of adult patients with active, seropositive SLE who are receiving standard treatment. The drug was approved after a protracted series of clinical trials, and its place in the SLE armamentarium is not clear. Belimumab should not be used in patients with active renal or neurological manifestations of SLE, as there are no data for these conditions. In addition, the efficacy of belimumab has not been tested in combination with other bDMARDs or cyclophosphamide.


Pharmacology_Katzung

Pharmacology_Katzung. The most common adverse effects of belimumab are nausea, diarrhea, and respiratory tract infection. As with other bDMARDs, there is a slight increase in the risk of infection including serious infections. Cases of depression and suicide have been reported in patients receiving belimumab, although these patients may have had neurologic SLE, thus confounding the causal relationship. Infusion reactions including anaphylaxis are among the other adverse effects. A very small percentage of patients develop antibodies toward belimumab; their clinical significance is not clear. In a 1998 survey, approximately half of North American rheumatologists treated moderately aggressive RA with combination therapy, and the use of drug combinations is probably much higher now. Combinations of DMARDs can be designed rationally on the basis of complementary mechanisms of action, nonoverlapping pharmacokinetics, and nonoverlapping toxicities.


Pharmacology_Katzung

Pharmacology_Katzung. When added to methotrexate background therapy, cyclosporine, chloroquine, hydroxychloroquine, leflunomide, infliximab, adalimumab, rituximab, and etanercept have all shown improved efficacy. Triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine appears to be as effective as etanercept and methotrexate. In contrast, azathioprine or sulfasalazine plus methotrexate results in no additional therapeutic benefit. Other combinations have occasionally been used. While it might be anticipated that combination therapy could result in more toxicity, this is often not the case. Combination therapy for patients not responding adequately to monotherapy is now the rule in the treatment of RA. The general pharmacology of corticosteroids, including mechanism of action, pharmacokinetics, and other applications, is discussed in Chapter 39.


Pharmacology_Katzung

Pharmacology_Katzung. The general pharmacology of corticosteroids, including mechanism of action, pharmacokinetics, and other applications, is discussed in Chapter 39. Corticosteroids have been used in 60–70% of RA patients. Their effects are prompt and dramatic, and they are capable of slowing the appearance of new bone erosions. Corticosteroids may be administered for certain serious extra-articular manifestations of RA such as pericarditis or eye involvement or during periods of exacerbation. When prednisone is required for long-term therapy, the dosage should not exceed 7.5 mg daily, and gradual reduction of the dose should be encouraged. Alternate-day corticosteroid therapy is usually unsuccessful in RA.


Pharmacology_Katzung

Pharmacology_Katzung. Other rheumatic diseases in which the corticosteroids’ potent anti-inflammatory effects may be useful include vasculitis, SLE, Wegener’s granulomatosis, PA, giant cell arteritis, sarcoidosis, and gout. Intra-articular corticosteroids are often helpful to alleviate painful symptoms and, when successful, are preferable to increasing the dosage of systemic medication.


Pharmacology_Katzung

Pharmacology_Katzung. Some of the symptoms of RA, especially morning stiffness and joint pain, follow a circadian rhythm, probably due to an increase in proinflammatory cytokines in the early morning. A recent approach uses delayed-release prednisone for the treatment of early morning stiffness and pain in RA. The tablet contains an inactive outer layer and a core of the active drug. The outer layer dissolves over 4–6 hours, releasing the prednisone. Taking the drug at 9–10 pm results in a small pulse of prednisone at 2–4 am, decreasing the circadian inflammatory cytokines. At low doses of 3–5 mg prednisone, the adrenal-pituitary axis does not seem to be impacted. Prolonged use of corticosteroids leads to serious and disabling toxic effects as described in Chapter 39. Many of these adverse effects occur at doses below 7.5 mg prednisone equivalent daily and many experts believe that even 3–5 mg/d can cause adverse effects in susceptible individuals when this class of drugs is used over prolonged periods.


Pharmacology_Katzung

Pharmacology_Katzung. Acetaminophen is one of the most important drugs used in the treatment of mild to moderate pain when an anti-inflammatory effect is not necessary. Phenacetin, a prodrug that is metabolized to acetaminophen, is more toxic and should not be used. Acetaminophen is the active metabolite of phenacetin and is responsible for its analgesic effect. It is a weak COX-1 and COX-2 inhibitor in peripheral tissues and possesses no significant anti-inflammatory effects. 1.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Pharmacokinetics: Acetaminophen is administered orally. Peak blood concentrations are usually reached in 30–60 minutes. Acetaminophen is poorly bound to plasma proteins and is partially metabolized by hepatic microsomal enzymes to the inactive sulfate and glucuronide (see Figure 4–5). Less than 5% is excreted unchanged. In large doses, a minor but highly reactive metabolite (N-acetyl-p-benzoquinone) is important because it is toxic to both liver and kidney (see Chapter 4). The half-life of acetaminophen is 2–3 hours and is relatively unaffected by renal function. With toxic doses or liver disease, the half-life may be increased twofold or more. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Indications: Although said to be equivalent to aspirin as an analgesic and antipyretic agent, acetaminophen lacks anti-inflammatory properties. It does not affect uric acid levels and lacks platelet-inhibiting effects. The drug is useful in mild to moderate pain such as headache, myalgia, postpartum pain, and other circumstances in which aspirin is an effective analgesic. Acetaminophen alone is inadequate therapy for inflammatory conditions such as RA. For mild analgesia, acetaminophen is the preferred drug in patients allergic to aspirin, when salicylates are poorly tolerated. It is preferable to aspirin in patients with hemophilia, in those with a history of peptic ulcer, and in those in whom bronchospasm is precipitated by aspirin. Unlike aspirin, acetaminophen does not antagonize the effects of uricosuric agents. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Adverse Effects: In therapeutic doses, a mild reversible increase in hepatic enzymes may occasionally occur. With larger doses, dizziness, excitement, and disorientation may occur. Ingestion of 15 g of acetaminophen may be fatal, death being caused by severe hepatotoxicity with centrilobular necrosis, sometimes associated with acute renal tubular necrosis (see Chapters 4 and 58). 4.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Present data indicate that even 4 g acetaminophen is associated with increased liver function test abnormalities. Doses greater than 4 g/d are not usually recommended, and a history of alcoholism contraindicates even this dose. Early symptoms of hepatic damage include nausea, vomiting, diarrhea, and abdominal pain. Cases of renal damage without hepatic damage have occurred, even after usual doses of acetaminophen. Therapy for overdose is much less satisfactory than that for aspirin overdose. In addition to supportive therapy, one should provide sulfhydryl groups in the form of acetylcysteine to neutralize the toxic metabolites (see Chapter 58). 5. Hemolytic anemia and methemoglobinemia are very rare adverse events. Interstitial nephritis and papillary necrosis— serious complications of phenacetin—have not occurred, and GI bleeding also has not occurred. Caution is necessary in patients with any type of liver disease. 6.


Pharmacology_Katzung

Pharmacology_Katzung. 6. Dosage: Acute pain and fever may be effectively treated with 325–500 mg four times daily and proportionately less for children. Dosing in adults is now recommended not to exceed 4 g/d, in most cases. Ketorolac is an NSAID promoted for systemic use mainly as a short-term analgesic (not longer than 1 week), not as an anti-inflammatory drug (although it has typical NSAID properties). Pharmacokinetics are presented in Table 36–1. The drug is an effective analgesic and has been used successfully to replace morphine in some situations involving mild to moderate postsurgical pain. It is most often given intramuscularly or intravenously, but an oral formulation is available. When used with an opioid, it may decrease the opioid requirement by 25–50%. Toxicities are similar to those of other NSAIDs (see page 645), although renal toxicity is more common with chronic use.


Pharmacology_Katzung

Pharmacology_Katzung. Tramadol is a centrally acting synthetic analgesic, structurally related to opioids. Since naloxone, an opioid receptor blocker, inhibits only 30% of the analgesic effect of tramadol, the mechanism of action of this drug must involve both nonopioid and opioid receptors. Tramadol does not have significant anti-inflammatory effects. The drug may exert part of its analgesic effect by enhancing 5-hydroxytryptamine (5-HT) release and inhibiting the reuptake of norepinephrine and 5-HT (see Chapter 31).


Pharmacology_Katzung

Pharmacology_Katzung. Gout is a metabolic disease characterized by recurrent episodes of acute arthritis due to deposits of monosodium urate in joints and cartilage. Uric acid renal calculi, tophi, and interstitial nephritis may also occur. Adverse cardiovascular outcomes are becoming more clear as well. Gout is usually associated with a high serum uric acid level (hyperuricemia), a poorly soluble substance that is the major end product of purine metabolism. In most mammals, uricase converts uric acid to the more soluble allantoin; this enzyme is absent in humans. While clinical gouty episodes are associated with hyperuricemia, most individuals with hyperuricemia may never develop a clinical event from urate crystal deposition.


Pharmacology_Katzung

Pharmacology_Katzung. The treatment of gout aims to relieve acute gouty attacks and prevent recurrent gouty episodes and urate lithiasis. Therapies for acute gout are based on our current understanding of the pathophysiologic events that occur in this disease (Figure 36–5). Clinical gout is dependent on a macromolecular complex of proteins, called NLRP3, which regulates the activation of IL-1. Urate crystals activate NLRP3, resulting in release of prostaglandins and lysosomal enzymes by synoviocytes. Attracted by these chemotactic mediators, polymorphonuclear leukocytes migrate into the joint space and amplify the ongoing inflammatory process. In the later phases of the attack, increased numbers of mononuclear phagocytes (macrophages) appear, ingest the urate crystals, and release more inflammatory mediators.


Pharmacology_Katzung

Pharmacology_Katzung. Before starting chronic urate-lowering therapy for gout, patients in whom hyperuricemia is associated with gout and urate lithiasis must be clearly distinguished from individuals with only hyperuricemia. The efficacy of long-term drug treatment in an asymptomatic hyperuricemic person is unproved. Although there are data suggesting a clear relationship between the degree of uric acid elevation and the likelihood of clinical gout, in some individuals, uric acid levels may be elevated up to 2 standard deviations above the mean for a lifetime without adverse consequences. Many different agents have been used for the treatment of acute and chronic gout. However, non-adherence to these drugs is exceedingly common; adherence has been documented to be 18–26% in younger patients. Providers should be aware of compliance as an important issue. MNPMNPPMNColchicineSynoviocytesUratecrystalPGLTB4Indomethacin,phenylbutazonePGPGEnzymesMNPIL-1IL-1–––


Pharmacology_Katzung

Pharmacology_Katzung. MNPMNPPMNColchicineSynoviocytesUratecrystalPGLTB4Indomethacin,phenylbutazonePGPGEnzymesMNPIL-1IL-1––– FIGURE 36–5 Pathophysiologic events in a gouty joint. Synoviocytes phagocytose urate crystals and then secrete inflammatory mediators, which attract and activate polymorphonuclear leukocytes (PMN) and mononuclear phagocytes (MNP) (macrophages). Drugs active in gout inhibit crystal phagocytosis and polymorphonuclear leukocyte and macrophage release of inflammatory mediators. PG, prostaglandin; IL-1, interleukin-1; LTB4, leukotriene B4. Although NSAIDs, corticosteroids, or colchicine are now first-line drugs for acute gout, colchicine was the primary treatment for many years. Colchicine is an alkaloid isolated from the autumn crocus, Colchicum autumnale. Its structure is shown in Figure 36–6. 1.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Pharmacokinetics: Colchicine is absorbed readily after oral administration, reaches peak plasma levels within 2 hours, and is eliminated with a serum half-life of 9 hours. Metabolites are excreted in the intestinal tract and urine. 2. Pharmacodynamics: Colchicine relieves the pain and inflammation of gouty arthritis in 12–24 hours without altering the metabolism or excretion of urates and without other analgesic effects. Colchicine produces its anti-inflammatory effects by binding to the intracellular protein tubulin, thereby preventing its polymerization into microtubules and leading to the inhibition of leukocyte migration and phagocytosis. It also inhibits the formation of leukotriene B4 and IL-1β. Several of colchicine’s adverse effects are produced by its inhibition of tubulin polymerization and cell mitosis. 3. Indications: Colchicine is indicated for gout and is also used between attacks (the “intercritical period”) for prolonged


Pharmacology_Katzung

Pharmacology_Katzung. 3. Indications: Colchicine is indicated for gout and is also used between attacks (the “intercritical period”) for prolonged FIGURE 36–6 Colchicine and uricosuric drugs. prophylaxis (at low doses). It prevents attacks of acute Mediterranean fever and may have a mild beneficial effect in sarcoid arthritis and in hepatic cirrhosis. Colchicine is also used to treat and prevent pericarditis, pleurisy, and coronary artery disease, probably due to its anti-inflammatory effect. Although it has been given intravenously, this route is no longer approved by the FDA (2009). 4.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Adverse Effects: Colchicine often causes diarrhea and may occasionally cause nausea, vomiting, and abdominal pain. Hepatic necrosis, acute renal failure, disseminated intravascular coagulation, and seizures have also been observed. Colchicine may rarely cause hair loss and bone marrow depression, as well as peripheral neuritis, myopathy, and, in some cases, death. The more severe adverse events have been associated with the intravenous administration of colchicine. 5. Dosage: In prophylaxis (the most common use), the dosage of colchicine is 0.6 mg one to three times daily. For terminating a gouty attack, a regimen of 1.2 mg followed by a single 0.6-mg oral dose was as effective as higher dose regimens, and adverse events were less frequent. In 2008, the FDA requested that intravenous preparations containing colchicine be discontinued in the United States because of their potential life-threatening adverse effects. Therefore, intravenous colchicine is no longer available.


Pharmacology_Katzung

Pharmacology_Katzung. In 2009, the FDA approved a new oral formulation of colchicine for the treatment of gout, allowing Colcrys (a branded colchicine) marketing exclusivity in the United States. Generic colchicine rather than Colcrys is available throughout the rest of the world. In addition to inhibiting prostaglandin synthase, NSAIDs inhibit urate crystal phagocytosis. Aspirin is not used because it causes renal retention of uric acid at low doses (≤2.6 g/d). It is uricosuric at doses greater than 3.6 g/d. Indomethacin is commonly used in the initial treatment of gout as a replacement for colchicine. For acute gout, 50 mg is given three times daily; when a response occurs, the dosage is reduced to 25 mg three times daily for 5–7 days. All other NSAIDs except aspirin, salicylates, and tolmetin have been successfully used to treat acute gouty episodes. Oxaprozin, which lowers serum uric acid, is theoretically a good choice. These agents appear to be as effective and safe as the older drugs.


Pharmacology_Katzung

Pharmacology_Katzung. Probenecid and sulfinpyrazone are uricosuric drugs employed to decrease the body pool of urate in patients with tophaceous gout or in those with increasingly frequent gouty attacks. In a patient who excretes large amounts of uric acid, the uricosuric agents should not be used. Lesinurad (RDEA594) is a promising new uricosuric agent that is currently in phase 3 trials. 1. Chemistry and Pharmacokinetics: Uricosuric drugs are organic acids (Figure 36–6) and, as such, act at the anion transport sites of the renal tubule (see Chapter 15). Probenecid is completely reabsorbed by the renal tubules and is metabolized slowly with a terminal serum half-life of 5–8 hours. Sulfinpyrazone or its active hydroxylated derivative is excreted by the kidneys. Even so, the duration of its effect after oral administration is almost as long as that of probenecid, which is given once or twice daily. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Pharmacodynamics: Uricosuric drugs—probenecid, sulfinpyrazone, as well as fenofibrate, and losartan—inhibit active transport sites for reabsorption and secretion in the proximal renal tubule so that net reabsorption of uric acid in the proximal tubule is decreased. Because aspirin in doses of less than 2.6 g daily causes net retention of uric acid by inhibiting the secretory transporter, it should not be used for analgesia in patients with gout. The secretion of other weak acids (eg, penicillin) is also reduced by uricosuric agents. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. As the urinary excretion of uric acid increases, the size of the urate pool decreases, although the plasma concentration may not be greatly reduced. In patients who respond favorably, tophaceous deposits of urate are reabsorbed, with relief of arthritis and remineralization of bone. With the ensuing increase in uric acid excretion, a predisposition to the formation of renal stones is augmented rather than decreased; therefore, the urine volume should be maintained at a high level, and at least early in treatment, the urine pH should be kept above 6.0 by the administration of alkali. 4. Indications: Uricosuric therapy should be initiated in gouty patients with underexcretion of uric acid when allopurinol or febuxostat is contraindicated or when tophi are present. Therapy should not be started until 2–3 weeks after an acute attack. 5.


Pharmacology_Katzung

Pharmacology_Katzung. 5. Adverse Effects: Both of these organic acids cause equivalent GI irritation, but sulfinpyrazone is more active in this regard. A rash may appear after the use of either compound. Nephrotic syndrome has occurred after the use of probenecid. Both sulfinpyrazone and probenecid may rarely cause aplastic anemia. 6. Contraindications and Cautions: It is essential to maintain a large urine volume to minimize the possibility of stone formation. 7. Dosage: Probenecid is usually started at a dosage of 0.5 g orally daily in divided doses, progressing to 1 g daily after 1 week. Sulfinpyrazone is started at a dosage of 200 mg orally daily, progressing to 400–800 mg daily. It should be given in divided doses with food to reduce adverse GI effects. The preferred and standard-of-care therapy for gout during the period between acute episodes is allopurinol, which reduces total uric acid body burden by inhibiting xanthine oxidase.


Pharmacology_Katzung

Pharmacology_Katzung. The preferred and standard-of-care therapy for gout during the period between acute episodes is allopurinol, which reduces total uric acid body burden by inhibiting xanthine oxidase. 1. Chemistry and Pharmacokinetics: The structure of allopurinol, an isomer of hypoxanthine, is shown in Figure 36–7. Allopurinol is approximately 80% absorbed after oral administration and has a terminal serum half-life of 1–2 hours. FIGURE 36–7 Inhibition of uric acid synthesis by allopurinol occurs because allopurinol and alloxanthine inhibit xanthine oxidase. (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.) Like uric acid, allopurinol is metabolized by xanthine oxidase, but the resulting compound, alloxanthine, retains the capacity to inhibit xanthine oxidase and has a long enough duration of action so that allopurinol is given only once a day. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Pharmacodynamics: Dietary purines are not an important source of uric acid. Quantitatively important amounts of purine are formed from amino acids, formate, and carbon dioxide in the body. Those purine ribonucleotides not incorporated into nucleic acids and derived from nucleic acid degradation are converted to xanthine or hypoxanthine and oxidized to uric acid (Figure 36–7). Allopurinol inhibits this last step, resulting in a fall in the plasma urate level and a decrease in the overall urate burden. The more soluble xanthine and hypoxanthine are increased. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Indications: Allopurinol is often the first-line agent for the treatment of chronic gout in the period between attacks and it tends to prolong the intercritical period. As with uricosuric agents, the therapy is begun with the expectation that it will be continued for years if not for life. When initiating allopurinol, colchicine or NSAID should be used until steady-state serum uric acid is normalized or decreased to less than 6 mg/dL and they should be continued for 6 months or longer. Thereafter, colchicine or the NSAID can be cautiously stopped while continuing allopurinol therapy. 4.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Adverse Effects: In addition to precipitating gout (the reason to use concomitant colchicine or NSAID), GI intolerance (including nausea, vomiting, and diarrhea), peripheral neuritis and necrotizing vasculitis, bone marrow suppression, and aplastic anemia may rarely occur. Hepatic toxicity and interstitial nephritis have been reported. An allergic skin reaction characterized by pruritic maculopapular lesions occurs in 3% of patients. Isolated cases of exfoliative dermatitis have been reported. In very rare cases, allopurinol has become bound to the lens, resulting in cataracts. 5.


Pharmacology_Katzung

Pharmacology_Katzung. 5. Interactions and Cautions: When chemotherapeutic purines (eg, azathioprine) are given concomitantly with allopurinol, their dosage must be reduced by about 75%. Allopurinol may also increase the effect of cyclophosphamide. Allopurinol inhibits the metabolism of probenecid and oral anticoagulants and may increase hepatic iron concentration. Safety in children and during pregnancy has not been established. 6. Dosage: The initial dosage of allopurinol is 50–100 mg/d. It should be titrated upward until serum uric acid is below 6 mg/ dL; this level is commonly achieved at 300–400 mg/d but is not restricted to this dose; doses as high as 800 mg/d may be needed. As noted above, colchicine or an NSAID should be given during the first months of allopurinol therapy to prevent the gouty arthritis episodes that sometimes occur. Febuxostat is a non-purine xanthine oxidase inhibitor that was approved by the FDA in 2009. 1.


Pharmacology_Katzung

Pharmacology_Katzung. Febuxostat is a non-purine xanthine oxidase inhibitor that was approved by the FDA in 2009. 1. Pharmacokinetics: Febuxostat is more than 80% absorbed following oral administration. With maximum concentration achieved in approximately 1 hour and a half-life of 4–18 hours, once-daily dosing is effective. Febuxostat is extensively metabolized in the liver. All of the drug and its inactive metabolites appear in the urine, although less than 5% appears as unchanged drug. 2. Pharmacodynamics: Febuxostat is a potent and selective inhibitor of xanthine oxidase, thereby reducing the formation of xanthine and uric acid without affecting other enzymes in the purine or pyrimidine metabolic pathway. In clinical trials, Febuxostat at daily dosing of 80 mg or 120 mg was more effective in lowering serum urate levels than was allopurinol at a standard 300-mg daily dose. The urate-lowering effect was comparable regardless of the pathogenic cause of hyperuricemia— overproduction or underexcretion.


Pharmacology_Katzung

Pharmacology_Katzung. 3. Indications: Febuxostat is approved at doses of 40 or 80 mg for the treatment of chronic hyperuricemia in gout patients. Although it appeared to be more effective then allopurinol as urate-lowering therapy, the allopurinol dosing was limited to 300 mg/d, thus not reflecting the actual dosing regimens used in clinical practice. At this time, the dose equivalence of allopurinol and febuxostat is unknown. 4. Adverse Effects: As with allopurinol, prophylactic treatment with colchicine or NSAIDs should be started at the beginning of therapy to avoid gout flares. The most frequent treatment-related adverse events are liver function abnormalities, diarrhea, headache, and nausea. Febuxostat is well tolerated in patients with a history of allopurinol intolerance. There does not appear to be an increased risk of cardiovascular events. 5.


Pharmacology_Katzung

Pharmacology_Katzung. 5. Dosage: The recommended starting dose of febuxostat is 40 mg daily. Because there was concern for cardiovascular events in the original phase 3 trials, the FDA approved only 40-mg and 80-mg dosing. No dose adjustment is necessary for patients with renal impairment since it is highly metabolized into an inactive metabolite by the liver. Pegloticase is the newest urate-lowering therapy to be approved for the treatment of refractory chronic gout. 1. Chemistry: Pegloticase is a recombinant mammalian uricase that is covalently attached to methoxy polyethylene glycol (mPEG) to prolong the circulating half-life and diminish immunogenic response. 2.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Pharmacokinetics and Dosage: The recommended dose for pegloticase is 8 mg every 2 weeks administered as an intravenous infusion. It is a rapidly acting drug, achieving a peak decline in uric acid level within 24–72 hours. The serum half-life ranges from 6 to 14 days. Several studies have shown earlier clearance of PEG-uricase (mean of 11 days) due to antibody response when compared to PEG-uricase antibody-negative subjects (mean of 16.1 days). 3. Pharmacodynamics: Urate oxidase enzyme, absent in humans and some higher primates, converts uric acid to allantoin. This product is highly soluble and can be easily eliminated by the kidney. Pegloticase has been shown to maintain low urate levels for up to 21 days after a single dose at doses of 4–12 mg, allowing for IV dosing every 2 weeks. Pegloticase should not be used for asymptomatic hyperuricemia.


Pharmacology_Katzung

Pharmacology_Katzung. 4. Adverse Effects: Gout flare can occur during treatment with pegloticase, especially during the first 3–6 months of treatment, requiring prophylaxis with NSAIDs or colchicine. Large numbers of patients show immune responses to pegloticase. The presence of antipegloticase antibodies is associated with shortened circulating half-life, loss of response leading to a rise in plasma urate levels, and a higher rate of infusion reactions and anaphylaxis. Anaphylaxis occurs in more than 6–15% of patients receiving pegloticase. Monitoring of plasma uric acid level, with rising level as an indicator of antibody production, allows for safer administration and monitoring of efficacy. In addition, other oral urate-lowering agents should be avoided in order not to mask the loss of pegloticase efficacy. Nephrolithiasis, arthralgia, muscle spasm, headache, anemia, and nausea may occur. Other less frequent side effects noted include upper respiratory tract infection, peripheral edema, urinary tract


Pharmacology_Katzung

Pharmacology_Katzung. Nephrolithiasis, arthralgia, muscle spasm, headache, anemia, and nausea may occur. Other less frequent side effects noted include upper respiratory tract infection, peripheral edema, urinary tract infection, and diarrhea. There is some concern for hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency because of the formation of hydrogen peroxide by uricase; therefore, pegloticase should be avoided in these patients.


Pharmacology_Katzung

Pharmacology_Katzung. Corticosteroids are sometimes used in the treatment of severe symptomatic gout, by intra-articular, systemic, or subcutaneous routes, depending on the degree of pain and inflammation. The most commonly used oral corticosteroid is prednisone. The recommended oral dose is 30–50 mg/d for 1–2 days, tapered over 7–10 days. Intra-articular injection of 10 mg (small joints), 30 mg (wrist, ankle, elbow), and 40 mg (knee) of triamcinolone acetonide can be given if the patient is unable to take oral medications.


Pharmacology_Katzung

Pharmacology_Katzung. Drugs targeting the IL-1 pathway, such as anakinra, canakinumab, and rilonacept, are used for the treatment of gout. Although the data are limited, these agents may provide a promising treatment option for acute gout in patients with contraindications to, or who are refractory to, traditional therapies like NSAIDs or colchicine. A recent study suggests that canakinumab, a fully human antiIL-1β monoclonal antibody, can provide rapid and sustained pain relief at a dose of 150 mg subcutaneously. These medications are also being evaluated as therapies for prevention of gout flares while initiating urate-lowering therapy.


Pharmacology_Katzung

Pharmacology_Katzung. GENERIC NAME AVAILABLE AS NONSTEROIDAL ANTI-INFLAMMATORY DRUGS Aspirin, acetylsalicylic acid Generic, Easprin, others Bromfenac Prolensa, Bromday Celecoxib Celebrex Choline salicylate Various Diclofenac Generic, Cataflam, Voltaren Diflunisal Generic, Dolobid Etodolac Generic, Lodine Fenoprofen Generic, Nalfon Flurbiprofen Generic, Ansaid, Ocufen (ophthalmic) Ibuprofen Generic, Motrin, Rufen, Advil (OTC), Nuprin (OTC), others Indomethacin Generic, Indocin Ketoprofen Generic, Orudis Magnesium salicylate Doan’s Pills, Magan, Mobidin Meclofenamate sodium Generic Mefenamic acid Generic, Ponstel Meloxicam Generic, Mobic Nabumetone Generic Naproxen Generic (OTC), Naprosyn, Anaprox, Aleve (OTC) Oxaprozin Generic, Daypro Piroxicam Generic, Feldene Salsalate, salicylsalicylic acid Generic, Disalcid Sodium salicylate Generic Sodium thiosalicylate Generic, Rexolate Sulindac Generic, Clinoril Suprofen Profenal (Ophthalmic) Tolmetin Generic, Tolectin DISEASE-MODIFYING ANTIRHEUMATIC DRUGS Abatacept


Pharmacology_Katzung

Pharmacology_Katzung. Sodium salicylate Generic Sodium thiosalicylate Generic, Rexolate Sulindac Generic, Clinoril Suprofen Profenal (Ophthalmic) Tolmetin Generic, Tolectin DISEASE-MODIFYING ANTIRHEUMATIC DRUGS Abatacept Orencia Adalimumab Humira ACETAMINOPHEN AND OTHER ANALGESICS Acetaminophen Generic, Tylenol, Tempra, Panadol, Acephen, others Tramadol Ultram DRUGS USED IN GOUT GENERIC NAME AVAILABLE AS Anakinra Kineret Auranofin Ridaura Aurothioglucose Solganal Belimumab Benlysta Canakinumab Ilaris Certolizumab Cimzia Cyclophosphamide Generic, Cytoxan Cyclosporine Generic, Sandimmune Etanercept Enbrel Gold sodium thiomalate Generic, Aurolate Golimumab Simponi Infliximab Remicade Leflunomide Generic, Arava Methotrexate Generic, Rheumatrex Mycophenolate mofetil Generic, Cellcept Penicillamine Cuprimine, Depen Rilonacept Arcalyst Rituximab Rituxan Sulfasalazine Generic, Azulfidine Tocilizumab Actemra Tofacitinib Xeljanz Ketorolac tromethamine Generic, Toradol Allopurinol Generic, Zyloprim Colchicine


Pharmacology_Katzung

Pharmacology_Katzung. Depen Rilonacept Arcalyst Rituximab Rituxan Sulfasalazine Generic, Azulfidine Tocilizumab Actemra Tofacitinib Xeljanz Ketorolac tromethamine Generic, Toradol Allopurinol Generic, Zyloprim Colchicine Generic*, Colchrys Febuxostat Uloric Pegloticase Krystexxa Probenecid Generic Sulfinpyrazone Generic, Anturane PREP AR A TIONS A V AIL ABLE *Outside the United States.


Pharmacology_Katzung

Pharmacology_Katzung. Hatemi G et al: EULAR recommendations for the management of Behçet disease. Ann Rheum Dis 2008;67:1656. Hellman DB, Imboden JB Jr: Rheumatologic, immunologic, and allergic disorders. In: Papadakis MA, McPhee ST (editors). Current Medical Diagnosis & Treatment, 2017. McGraw-Hill Education, 2017. Chan FK et al: Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med 2002;347:2104. Clevers H: Colon cancer—Understanding how NSAIDs work. N Engl J Med 2006;354:761. Deeks JJ, Smith LA, Bradley MD: Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: Systematic review of randomised controlled trials. BMJ 2002;325:619. Furst DE et al: Dose response and safety study of meloxicam up to 22.5 mg daily in rheumatoid arthritis: A 12 week multi-center, double blind, dose response study versus placebo and diclofenac. J Rheumatol 2002;29:436.


Pharmacology_Katzung

Pharmacology_Katzung. Knijff-Dutmer EA et al: Platelet function is inhibited by non-selective non-steroidal anti-inflammatory drugs but not by cyclooxygenase-2-selective inhibitors in patients with rheumatoid arthritis. Rheumatology (Oxford) 2002;41:458. Lago P et al: Safety and efficacy of ibuprofen versus indomethacin in preterm infants treated for patent ductus arteriosus: A randomized controlled trial. Eur J Pediatr 2002;161:202. Laine L et al: Serious lower gastrointestinal clinical events with non-selective NSAID or coxib use. Gastroenterology 2003;124:288. Moran EM: Epidemiological and clinical aspects of nonsteroidal anti-inflammatory drugs and cancer risks. J Environ Pathol Toxicol Oncol 2002;21:193. Niccoli L, Bellino S, Cantini F: Renal tolerability of three commonly employed non-steroidal anti-inflammatory drugs in elderly patients with osteoarthritis. Clin Exp Rheumatol 2002;20:201.


Pharmacology_Katzung

Pharmacology_Katzung. Niccoli L, Bellino S, Cantini F: Renal tolerability of three commonly employed non-steroidal anti-inflammatory drugs in elderly patients with osteoarthritis. Clin Exp Rheumatol 2002;20:201. Olsen AMS et al: Association of NSAID use with risk of bleeding and cardiovascular events in patients receiving antithrombotic therapy after myocardial infarction. JAMA 2015;313:805. Ray WA et al: COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease. Lancet 2002;360:1071. Rovensky J et al: Treatment of knee osteoarthritis with a topical nonsteroidal anti-inflammatory drug. Results of a randomized, double-blind, placebo-controlled study on the efficacy and safety of a 5% ibuprofen cream. Drugs Exp Clin Res 2001;27:209. Slawson D: NSAID Use associated with increased risk of serious bleeding and CV events after MI. Am Fam Physician 2015;92;60.


Pharmacology_Katzung

Pharmacology_Katzung. Slawson D: NSAID Use associated with increased risk of serious bleeding and CV events after MI. Am Fam Physician 2015;92;60. U.S. Food and Drug Administration: FDA Drug Safety Communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes. Available at: www.fda.gov/ Drugs/DrugSafety/ucm451800.htm. Vane J, Botting R: Inflammation and the mechanism of action of anti-inflammatory drugs. FASEB J 1987;1:89. http://www.rheumatology. org/I-Am-A/Patient-Caregiver/Treatments/NSAIDs. Atzeni F et al: Potential target of infliximab in autoimmune and inflammatory diseases. Autoimmun Rev 2007;6:8. Bannwarth B, Kostine M, Poursac N: A pharmacokinetic and clinical assessment of tofacitinib for the treatment of rheumatoid arthritis. Expert Opin Drug Metab Toxicol 2013;9:6.


Pharmacology_Katzung

Pharmacology_Katzung. Bannwarth B, Kostine M, Poursac N: A pharmacokinetic and clinical assessment of tofacitinib for the treatment of rheumatoid arthritis. Expert Opin Drug Metab Toxicol 2013;9:6. Besada E, Koldingsnes W, Nossent J: Characteristics of late onset neutropenia in rheumatologic patients treated with rituximab: A case review analysis from a single center. QJM 2012;105:6. Bongartz T et al: Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies. JAMA 2006;295:2275. Bosello S et al: B cell depletion in diffuse progressive systemic sclerosis: safety, skin score modification and IL-6 modulation in an up to thirty-six months follow-up open-label trial. Arthritis Res Ther 2010;12:R54. Conklyn M et al: The JAK3 inhibitor CP-690550 selectively reduces NK and CD8+ cell numbers in cynomolgus monkey blood following chronic oral dosing. J Leukoc Biol 2004;76:6.


Pharmacology_Katzung

Pharmacology_Katzung. Conklyn M et al: The JAK3 inhibitor CP-690550 selectively reduces NK and CD8+ cell numbers in cynomolgus monkey blood following chronic oral dosing. J Leukoc Biol 2004;76:6. Cronstein B: How does methotrexate suppress inflammation? Clin Exp Rheumatol 2010:28(Suppl 61):S21. De Lauretis A et al: Serum interleukin 6 is predictive of early functional decline and mortality in interstitial lung disease associated with systemic sclerosis. J Rheumatol 2013;40:435. Dinarello CA, Simon A, van der Meer JW: Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov 2012;11:8. Emery P et al: Golimumab, a human anti-tumor necrosis factor α monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naïve patients with active rheumatoid arthritis. Arthritis Rheum 2009;60:2272.


Pharmacology_Katzung

Pharmacology_Katzung. Emery P et al: IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomized placebo-controlled trial. Ann Rheum Dis 2008;67:1516. Emery P et al: The impact of T-cell co-stimulation modulation in patients with undifferentiated inflammatory arthritis or very early rheumatoid arthritis: a clinical and imaging study of abatacept. Ann Rheum Dis 2010;69:510. Feagan BG et al: The effects of infliximab therapy on health-related quality of life in ulcerative colitis patients. Am J Gastroenterol 2007;102:4. Fleischmann R et al: Review of head-to-head study designs in rheumatoid arthritis. Semin Arthritis Rheum 2016;46:279. Furst DE: Rational use of disease-modifying antirheumatic drugs. Drugs 1990;39:19. Furst DE et al: Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2012. Ann Rheum Dis 2013;72.


Pharmacology_Katzung

Pharmacology_Katzung. Furst DE et al: Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2012. Ann Rheum Dis 2013;72. Gabay C et al: Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): A randomised, double-blind, controlled phase 4 trial. Lancet 2013;4:381. Genovese MC et al: Abatacept for rheumatoid arthritis refractory to tumor necrosis factor α inhibition. N Engl J Med 2005;353:1114. Genovese MC et al: Subcutaneous abatacept versus intravenous abatacept: A phase IIIb noninferiority study in patients with an inadequate response to methotrexate. Arthritis Rheum 2011;63:10. Griffiths CE et al: Comparison of ustekinumab and etanercept for moderate-tosevere psoriasis. N Engl J Med 2010;362:118. Keystone E et al: Improvement in patient-reported outcomes in a rituximab trial in patients with severe rheumatoid arthritis refractory to anti-tumor necrosis factor therapy. Arthritis Rheum 2008;59:785.


Pharmacology_Katzung

Pharmacology_Katzung. Khanna D et al: Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet 2016;387:2630. Kobayashi K et al: Leukoencephalopathy with cognitive impairment following tocilizumab for the treatment of rheumatoid arthritis (RA). Intern Med 2009;48:15. Kremer J: Toward a better understanding of methotrexate. Arthritis Rheum 2004;50:1370. Landewé R et al: Efficacy of certolizumab pegol on signs and symptoms of axial spondyloarthritis including ankylosing spondylitis: 24-week results of a double-blind randomised placebo-controlled Phase 3 study. Ann Rheum Dis 2014;73:1. Maurizio Cutolo: The kinase inhibitor tofacitinib in patients with rheumatoid arthritis: Latest findings and clinical potential. Ther Adv Musculoskelet Dis 2013;5:1.


Pharmacology_Katzung

Pharmacology_Katzung. Maurizio Cutolo: The kinase inhibitor tofacitinib in patients with rheumatoid arthritis: Latest findings and clinical potential. Ther Adv Musculoskelet Dis 2013;5:1. Mease P et al: Abatacept in the treatment of patients with psoriatic arthritis: results of a double-blind, randomized, placebo-controlled phase 2 trial. Arthritis Rheum 2011;63:939. Mease PJ et al: Effect of certolizumab pegol on signs and symptoms in patients with psoriatic arthritis: 24-week results of a Phase 3 double-blind randomised placebo-controlled study (RAPID-PsA). Ann Rheum Dis 2014;73:1. Nadashkevich O et al: A randomized unblinded trial of cyclophosphamide versus azathioprine in the treatment of systemic sclerosis. Clin Rheumatol 2006;25. Ørum M et al: Beneficial effect of infliximab on refractory sarcoidosis. Dan Med J 2012;59:12. Papoutsaki M et al: Infliximab in psoriasis and psoriatic arthritis. BioDrugs 2013;27(Suppl 1):13.


Pharmacology_Katzung

Pharmacology_Katzung. Ørum M et al: Beneficial effect of infliximab on refractory sarcoidosis. Dan Med J 2012;59:12. Papoutsaki M et al: Infliximab in psoriasis and psoriatic arthritis. BioDrugs 2013;27(Suppl 1):13. Plosker G, Croom K: Sulfasalazine: A review of its use in the management of rheumatoid arthritis. Drugs 2006;65:1825. Riese RJ, Krishnaswami S, Kremer J: Inhibition of JAK kinases in patients with rheumatoid arthritis: Scientific rationale and clinical outcomes. Best Pract Res Clin Rheumatol 2010;24:4. Ruperto N et al: Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial. Lancet 2008; 2:372. Scott DL, Kingsley GH: Tumor necrosis factor inhibitors for rheumatoid arthritis. N Engl J Med 2006;355:704. Shima Y et al: The skin of patients with systemic sclerosis softened during the treatment with anti-IL-6 receptor antibody tocilizumab. Rheumatology (Oxford) 2010;49:2408.


Pharmacology_Katzung

Pharmacology_Katzung. Shima Y et al: The skin of patients with systemic sclerosis softened during the treatment with anti-IL-6 receptor antibody tocilizumab. Rheumatology (Oxford) 2010;49:2408. Smolen J et al: Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomized controlled trial. Ann Rheum Dis 2009;68:797. Spies CM et al: Prednisone chronotherapy. Clin Exp Rheumatol 2011; 29(Suppl 68):5. Strober B et al: Effect of tofacitinib, a Janus kinase inhibitor, on haematological parameters during 12 weeks of psoriasis treatment. Br J Dermatol 2013;169:5. Tanaka T, Ogata A, Narazaki M: Tocilizumab for the treatment of rheumatoid arthritis. Expert Rev Clin Immunol 2010;6:6. Teng GG, Turkiewicz AM, Moreland LW: Abatacept: A costimulatory inhibitor for treatment of rheumatoid arthritis. Expert Opin Biol Ther 2005;5:1245.


Pharmacology_Katzung

Pharmacology_Katzung. Teng GG, Turkiewicz AM, Moreland LW: Abatacept: A costimulatory inhibitor for treatment of rheumatoid arthritis. Expert Opin Biol Ther 2005;5:1245. Turner D: Severe acute ulcerative colitis: the pediatric perspective. Dig Dis 2009;27:3 van Gurp EA et al: The effect of the JAK inhibitor CP-690,550 on peripheral immune parameters in stable kidney allograft patients. Transplantation 2009;87:1. Weinblatt M et al: Adalimumab, a fully human anti-tumor necrosis factor α monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate. Arthritis Rheum 2003;48:35. Weinblatt ME et al: Head-to-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: Findings of a phase IIIb, multinational, prospective, randomized study. Arthritis Rheum 2013;65:1.


Pharmacology_Katzung

Pharmacology_Katzung. Westhovens R et al: Clinical efficacy and safety of abatacept in methotrexate-naïve patients with early rheumatoid arthritis and poor prognostic factors. Ann Rheum Dis 2009;68:1870. Westhovens R et al: Disease remission is achieved within two years in over half of methotrexate naive patients with early erosive rheumatoid arthritis (RA) treated with abatacept plus MTX: results from the AGREE trial (abstract 638). Arthritis Rheum 2009;60:S239. Yokota S, Kishimoto T: Tocilizumab: Molecular intervention therapy in children with systemic juvenile idiopathic arthritis. Expert Rev Clin Immunol 2010;6:5. Zouali M, Uy EA: Belimumab therapy in systemic lupus erythematosus. BioDrugs 2013;27:3. Chandrasekharan NV et al: COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression. Proc Natl Acad Sci USA 2002;99:13926.


Pharmacology_Katzung

Pharmacology_Katzung. Lee CR, McTavish D, Sorkin EM: Tramadol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs 1993;46:2. Becker MA et al: Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005;353:2450. Getting SJ et al: Activation of melanocortin type 3 receptor as a molecular mechanism for adrenocorticotropic hormone efficacy in gouty arthritis. Arthritis Rheum 2002;46:2765. Schumacher HR: Febuxostat: A non-purine, selective inhibitor of xanthine oxidase for the management of hyperuricaemia in patients with gout. Expert Opin Investig Drugs 2005;14:893. So A et al: A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther 2007;9:R28.


Pharmacology_Katzung

Pharmacology_Katzung. So A et al: A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther 2007;9:R28. U.S. Food and Drug Administration: Questions and Answers About FDA’s Enforcement Action Against Unapproved Injectable Colchicine Products. Available at: www.fda.gov/drugs/guidancecomplianceregulatoryinformation/ enforcementactivitiesbyfda/selectedenforcementactionsonunapproveddrugs/ ucm119642.htm Wallace SL, Singer JZ: Systemic toxicity associated with intravenous administration of colchicine—Guidelines for use. J Rheumatol 1988;15:495.


Pharmacology_Katzung

Pharmacology_Katzung. This patient had good control of his symptoms for 1 year but now has a prolonged flare, probably denoting worsen-ing disease (not just a temporary flare). In addition to physical findings and measurement of acute-phase reac-tants such as sedimentation rate or C-reactive protein, it would be wise to get hand and feet radiographs to docu-ment whether he has developed joint damage. Assuming such damage is found, the appropriate approach would be either a combination of nonbiologic DMARDs (eg, adding sulfasalazine and hydroxychloroquine) or adding a biologic medication, usually a TNF inhibitor. Follow-up should be every 1–3 months to gauge response and toxicity. Adverse events requiring caution are an increased risk of infection, possible appearance of lymphoma and rare liver function test or hematologic abnormalities. Importantly, close follow-up should ensue, including changing medications every 3–6 months until full disease control is achieved. Roger K. Long, MD, & Hakan Cakmak, MD


Pharmacology_Katzung

Pharmacology_Katzung. A 4-year-old boy (height 90 cm, –3 standard deviations [SD]; weight 14.5 kg, approximately 15th percentile) presents with short stature. Review of the past history and growth chart demonstrates normal birth weight and birth length, but a progressive decrease in height per-centiles relative to age-matched normal ranges starting at 6 months of age, and orthostasis with febrile illnesses. Physical examination demonstrates short stature and mild generalized obesity. Genital examination reveals descended but small testes and a phallic length of –2 SD. Laboratory evaluations demonstrate growth hormone (GH) deficiency and a delayed bone age of 18 months. The patient is started on replacement with recombinant human GH at a dose of 40 mcg/kg per day subcutaneously. After 1 year of treatment, his height velocity has increased from 5 cm/y to 11 cm/y. How does GH stimulate growth in children? What other hormone deficiencies are sug-gested by the patient’s history and physical examination? What


Pharmacology_Katzung

Pharmacology_Katzung. height velocity has increased from 5 cm/y to 11 cm/y. How does GH stimulate growth in children? What other hormone deficiencies are sug-gested by the patient’s history and physical examination? What other hormone replacements is this patient likely to require?


Pharmacology_Katzung

Pharmacology_Katzung. The control of metabolism, growth, and reproduction is mediated by a combination of neural and endocrine systems located in the hypothalamus and pituitary gland. The pituitary weighs about 0.6 g and rests at the base of the brain in the bony sella turcica near the optic chiasm and the cavernous sinuses. The pituitary consists of an anterior lobe (adenohypophysis) and a posterior lobe (neurohypophysis) (Figure 37–1). It is connected to the overlying hypothalamus by a stalk of neurosecretory fibers and blood vessels, including a portal venous system that drains the hypothalamus and perfuses the anterior pituitary. The portal venous system carries small regulatory hormones (Figure 37–1, Table 37–1) from the hypothalamus to the anterior pituitary. The posterior lobe hormones are synthesized in the hypothalamus and transported via the neurosecretory fibers in the stalk of the pituitary to the posterior lobe; from there they are released into the circulation.


Pharmacology_Katzung

Pharmacology_Katzung. DA Posterior pituitary Endocrine glands, liver, bone, & other tissues Portal venous system Anterior pituitary +–HypothalamusSST Oxytocin ADH PRL GHRH TRH CRH GnRH GH TSH ACTH LH FSH


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 37–1 The hypothalamic-pituitary endocrine system. Hormones released from the anterior pituitary stimulate the production of hormones by a peripheral endocrine gland, the liver, or other tissues, or act directly on target tissues. Prolactin and the hormones released from the posterior pituitary (vasopressin and oxytocin) act directly on target tissues. Hypothalamic factors regulate the release of anterior pituitary hormones. ACTH, adrenocorticotropin; ADH, antidiuretic hormone [vasopressin]; CRH, corticotropin-releasing hormone; DA, dopamine; FSH, follicle-stimulating hormone; GH, growth hormone; GHRH, growth hormone-releasing hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; PRL, prolactin; SST, somatostatin; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone.


Pharmacology_Katzung

Pharmacology_Katzung. Drugs that mimic or block the effects of hypothalamic and pituitary hormones have pharmacologic applications in three primary areas: (1) as replacement therapy for hormone deficiency states; (2) as antagonists for diseases caused by excess production of pituitary hormones; and (3) as diagnostic tools for identifying several endocrine abnormalities. All the hormones produced by the anterior pituitary except prolactin are key participants in hormonal systems in which they regulate the production of hormones and autocrine-paracrine factors by endocrine glands and other peripheral tissues. In these systems, the secretion of the pituitary hormone is under the control of one or more hypothalamic hormones. Each hypothalamic-pituitary-endocrine gland system or axis provides multiple opportunities for complex neuroendocrine regulation of growth and development, metabolism, and reproductive function.


Pharmacology_Katzung

Pharmacology_Katzung. The anterior pituitary hormones can be classified according to hormone structure and the types of receptors that they activate. Growth hormone (GH) and prolactin (PRL), single-chain protein hormones with significant homology, form one group. Both hormones activate receptors of the JAK/STAT superfamily (see Chapter 2). Three pituitary hormones—thyroid-stimulating hormone (TSH, thyrotropin), follicle-stimulating hormone (FSH), and luteinizing hormone (LH)— are dimeric proteins that activate G protein-coupled receptors (see Chapter 2). TSH, FSH, and LH share a common α subunit. Their β subunits, though somewhat similar to each other, differ enough to confer receptor specificity. Finally, adrenocorticotropic hormone (ACTH), a peptide cleaved from a larger precursor, proopiomelanocortin (POMC) represents a third category. POMC can be cleaved into various other biologically active peptides like α-melanocyte-stimulating hormone (MSH) and β-endorphin


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 37–1 Links between hypothalamic, anterior pituitary, and target organ hormone or mediator.1 1All of these hormones act through G protein-coupled receptors except GH and PRL, which act through JAK/STAT receptors. 2Endogenous GnRH, which is released in pulses, stimulates LH and FSH release. When administered continuously as a drug, GnRH and its analogs inhibit LH and FSH release through down-regulation of GnRH receptors. (+), stimulant; (−), inhibitor. (see Chapter 31). Like TSH, LH, and FSH, ACTH acts through a G protein–coupled receptor. A unique feature of the ACTH receptor (also known as the melanocortin 2 receptor) is that a transmembrane protein, melanocortin 2 receptor accessory protein, is essential for normal ACTH receptor trafficking and signaling.


Pharmacology_Katzung

Pharmacology_Katzung. TSH, FSH, LH, and ACTH share similarities in the regulation of their release from the pituitary. Each is under the control of a distinctive hypothalamic peptide that stimulates their production by acting on G protein-coupled receptors (Table 37–1). TSH release is regulated by thyrotropin-releasing hormone (TRH), whereas the release of LH and FSH (known collectively as gonadotropins) is stimulated by pulses of gonadotropinreleasing hormone (GnRH). ACTH release is stimulated by corticotropin-releasing hormone (CRH). An important regulatory feature shared by these four structurally related hormones is that they and their hypothalamic releasing factors are subject to feedback inhibitory regulation by the hormones whose production they control. TSH and TRH production are inhibited by the two key thyroid hormones, thyroxine and triiodothyronine (see Chapter 38). Gonadotropin and GnRH production is inhibited in women by estrogen and progesterone, and in men by testosterone and other


Pharmacology_Katzung

Pharmacology_Katzung. two key thyroid hormones, thyroxine and triiodothyronine (see Chapter 38). Gonadotropin and GnRH production is inhibited in women by estrogen and progesterone, and in men by testosterone and other androgens. ACTH and CRH production are inhibited by cortisol. Feedback regulation is critical to the physiologic control of thyroid, adrenal cortical, and gonadal function and is also important in pharmacologic treatments that affect these systems.


Pharmacology_Katzung

Pharmacology_Katzung. The hypothalamic hormonal control of GH and prolactin differs from the regulatory systems for TSH, FSH, LH, and ACTH. The hypothalamus secretes two hormones that regulate GH; growth hormone-releasing hormone (GHRH) stimulates GH production, whereas the peptide somatostatin (SST) inhibits GH production. GH and its primary peripheral mediator, insulin-like growth factor-I (IGF-I), also provide feedback to inhibit GH release. Prolactin production is inhibited by the catecholamine dopamine acting through the D2 subtype of dopamine receptors. The hypothalamus does not produce a hormone that specifically stimulates prolactin secretion, although TRH can stimulate prolactin release, particularly when TRH concentrations are high in the setting of primary hypothyroidism.


Pharmacology_Katzung

Pharmacology_Katzung. Whereas all the pituitary and hypothalamic hormones described previously are available for use in humans, only a few are of major clinical importance. Because of the greater ease of administration of target endocrine gland hormones or their synthetic analogs, the related hypothalamic and pituitary hormones are used infrequently as treatments. However, many of them (TRH, TSH, CRH, ACTH, GnRH, GHRH) are used for specialized diagnostic testing. These agents are described in Tables 37–2 and 37–3 and are not discussed further in this chapter. In contrast, GH, SST, TABLE 37–2 Clinical uses of hypothalamic hormones and their analogs. Growth hormone-Used rarely as a diagnostic test for GH and releasing hormone GHRH sufficiency (GHRH) Thyrotropin-May be used to diagnose TRH or TSH releasinghormone deficiencies; not currently available for (TRH, protirelin) clinical use in United States


Pharmacology_Katzung

Pharmacology_Katzung. Thyrotropin-May be used to diagnose TRH or TSH releasinghormone deficiencies; not currently available for (TRH, protirelin) clinical use in United States Corticotropin-releasing Used rarely to distinguish Cushing’s disease hormone (CRH) from ectopic ACTH secretion Gonadotropin-May be used in a single dose to assess releasing hormone initiation of puberty (pubertal gonadotropin (GnRH) response) May be used in pulses to treat infertility caused by GnRH deficiency Analogs used in long-acting formulations to inhibit gonadal function in children with precocious puberty, in some transgender/ gender variant early pubertal adolescents (to block endogenous puberty), in men with prostate cancer and women undergoing assisted reproductive technology (ART) or women who require ovarian suppression for a gynecologic disorder Dopamine Dopamine agonists (eg, bromocriptine, cabergoline) used for treatment of hyperprolactinemia


Pharmacology_Katzung

Pharmacology_Katzung. Dopamine Dopamine agonists (eg, bromocriptine, cabergoline) used for treatment of hyperprolactinemia LH, FSH, GnRH, and dopamine or analogs of these hormones are commonly used and are described in the following text. Growth hormone, an anterior pituitary hormone, is required during childhood and adolescence for attainment of normal adult size and has important effects throughout postnatal life on lipid and carbohydrate metabolism, and on lean body mass and bone density. Its growth-promoting effects are primarily mediated via IGF-I (also known as somatomedin C). Individuals with congenital or acquired deficiency of GH during childhood or adolescence fail to reach their midparental target adult height and have disproportionately increased body fat and decreased muscle mass. Adults with GH deficiency also have disproportionately low lean body mass. A. Structure


Pharmacology_Katzung

Pharmacology_Katzung. A. Structure Growth hormone is a 191-amino-acid peptide with two sulfhydryl bridges. Its structure closely resembles that of prolactin. In the past, medicinal GH was isolated from the pituitaries of human cadavers. However, this form of GH was found to be contaminated with prions that could cause Creutzfeldt-Jakob disease. For this reason, it is no longer used. Somatropin, the recombinant form of GH, has a 191-amino-acid sequence that is identical with the predominant native form of human GH. B. Absorption, Metabolism, and Excretion Circulating endogenous GH has a half-life of approximately 20 minutes and is predominantly cleared by the liver. Recombinant human GH (rhGH) is administered subcutaneously 6–7 times per week. Peak levels occur in 2–4 hours, and active blood levels persist for approximately 36 hours.


Pharmacology_Katzung

Pharmacology_Katzung. Growth hormone mediates its effects via cell surface receptors of the JAK/STAT cytokine receptor superfamily. The hormone has two distinct GH receptor binding sites. Dimerization of two GH receptors is stimulated by a single GH molecule and activates TABLE 37–3 Diagnostic uses of thyroid-stimulating hormone and adrenocorticotropin.


Pharmacology_Katzung

Pharmacology_Katzung. signaling cascades mediated by receptor-associated JAK tyrosine kinases and STATs (see Chapter 2). The hormone has complex effects on growth, body composition, and carbohydrate, protein, and lipid metabolism. The growth-promoting effects are mediated principally, but not solely, through an increase in the production of IGF-I. Much of the circulating IGF-I is produced by the liver. Growth hormone also stimulates production of IGF-I in bone, cartilage, muscle, kidney, and other tissues, where it has autocrine or paracrine roles. It stimulates longitudinal bone growth until the epiphyseal plates fuse—near the end of puberty. In both children and adults, GH has anabolic effects in muscle and catabolic effects in adipose cells that shift the balance of body mass to an increase in muscle mass and a reduction in adiposity. The direct and indirect effects of GH on carbohydrate metabolism are mixed, in part because GH and IGF-I have opposite effects on insulin sensitivity. Growth hormone


Pharmacology_Katzung

Pharmacology_Katzung. and a reduction in adiposity. The direct and indirect effects of GH on carbohydrate metabolism are mixed, in part because GH and IGF-I have opposite effects on insulin sensitivity. Growth hormone reduces insulin sensitivity, which results in mild hyperinsulinemia and increased blood glucose levels, whereas IGF-I has insulin-like effects on glucose transport. In patients who are unable to respond to growth hormone because of severe resistance (caused by GH receptor mutations, post-receptor signaling mutations, or GH antibodies), the administration of recombinant human IGF-I may cause hypoglycemia because of its insulin-like effects.


Pharmacology_Katzung

A. Growth Hormone Deficiency

Pharmacology_Katzung. A. Growth Hormone Deficiency


Pharmacology_Katzung

Pharmacology_Katzung. Growth hormone deficiency can have a genetic basis, be associated with midline developmental defect syndromes (eg, septo-optic dysplasia), or be acquired as a result of damage to the pituitary or hypothalamus by a traumatic event (including breech or traumatic delivery), intracranial tumors, infection, infiltrative or hemorrhagic processes, or irradiation. Neonates with isolated GH deficiency are typically of normal size at birth because prenatal growth is not GH-dependent. In contrast, IGF-I is essential for normal prenatal and postnatal growth. Through poorly understood mechanisms, IGF-I expression and postnatal growth become GH-dependent during the first year of life. In childhood, GH deficiency typically presents as short stature, often with mild adiposity. Another early sign of GH deficiency is hypoglycemia due to the loss of a counter-regulatory hormonal response of GH to hypoglycemia; young children are at risk for this condition due to high sensitivity to insulin. Criteria for


Pharmacology_Katzung

Pharmacology_Katzung. is hypoglycemia due to the loss of a counter-regulatory hormonal response of GH to hypoglycemia; young children are at risk for this condition due to high sensitivity to insulin. Criteria for diagnosis of GH deficiency usually include (1) a subnormal height velocity for age and (2) a subnormal serum GH response following provocative testing with at least two GH secretagogues. Clonidine (α2-adrenergic agonist), levodopa (dopaminergic agonist), and exercise are factors that increase GHRH levels. Arginine and insulin-induced hypoglycemia cause diminished SST, which increases GH release. The prevalence of GH deficiency is approximately 1:5000. If therapy with rhGH is initiated at an early age, many children with short stature due to GH deficiency will achieve an adult height within their midparental target height range.


Pharmacology_Katzung

Pharmacology_Katzung. In the past, it was believed that adults with GH deficiency do not exhibit a significant syndrome. However, more detailed studies suggest that adults with GH deficiency often have generalized obesity, reduced muscle mass, asthenia, diminished bone mineral density, dyslipidemia, and reduced cardiac output. Growth hormone-deficient adults who have been treated with GH experience reversal of many of these manifestations. B. Growth Hormone Treatment of Pediatric Patients with Short Stature


Pharmacology_Katzung

Pharmacology_Katzung. B. Growth Hormone Treatment of Pediatric Patients with Short Stature Although the greatest improvement in growth occurs in patients with GH deficiency, exogenous GH has some effect on height in children with short stature caused by conditions other than GH deficiency. Growth hormone has been approved for several conditions (Table 37–4) and has been used experimentally or off-label in many others. Prader-Willi syndrome is an autosomal dominant genetic disease associated with growth failure, obesity, and carbohydrate intolerance. In children with Prader-Willi syndrome and growth failure, GH treatment decreases body fat and increases lean body mass, linear growth, and energy expenditure.


Pharmacology_Katzung

Pharmacology_Katzung. Growth hormone treatment has also been shown to have a strong beneficial effect on final height of girls with Turner syndrome (45 X karyotype and variants). In clinical trials, GH treatment has been shown to increase final height in girls with Turner syndrome by 10–15 cm (4–6 inches). Because girls with Turner syndrome also have either absent or rudimentary ovaries, GH must be judiciously combined with gonadal steroids to achieve maximal height. Other conditions of pediatric growth failure for which GH treatment is approved include chronic renal insufficiency pre-transplant and small-for-gestational-age at birth TABLE 37–4 Clinical uses of recombinant human growth hormone. in which the child’s height remains more than 2 standard deviations below normal at 2 years of age.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 37–4 Clinical uses of recombinant human growth hormone. in which the child’s height remains more than 2 standard deviations below normal at 2 years of age. A controversial but approved use of GH is for children with idiopathic short stature (ISS). This is a heterogeneous population that has in common no identifiable cause of the short stature. Some have arbitrarily defined ISS clinically as having a height at least 2.25 standard deviations below normal for children of the same age and a predicted adult height that is less than 2.25 standard deviations below normal. In this group of children, many years of GH therapy result in an average increase in adult height of 4–7 cm (1.57–2.76 inches) at a cost of $5000–$40,000 per year. The complex issues involved in the cost-risk-benefit relationship of this use of GH are important because an estimated 400,000 children in the United States fit the diagnostic criteria for ISS.


Pharmacology_Katzung

Pharmacology_Katzung. Treatment of children with short stature should be carried out by specialists experienced in GH administration. Dose requirements vary with the condition being treated, with GH-deficient children typically being most responsive. Children must be observed closely for slowing of growth velocity, which could indicate a need to increase the dosage or the possibility of epiphyseal plate fusion or intercurrent problems such as hypothyroidism or malnutrition. Other Uses of Growth Hormone


Pharmacology_Katzung

Pharmacology_Katzung. Growth hormone affects many organ systems and also has a net anabolic effect. It has been tested in a number of conditions that are associated with a severe catabolic state and is approved for the treatment of wasting in patients with AIDS. In 2004, GH was approved for treatment of patients with short bowel syndrome who are dependent on total parenteral nutrition (TPN). After intestinal resection or bypass, the remaining functional intestine in many patients undergoes extensive adaptation that allows it to adequately absorb nutrients. However, other patients fail to adequately adapt and develop a malabsorption syndrome. Growth hormone has been shown to increase intestinal growth and improve its function in experimental animals. Benefits of GH treatment for patients with short bowel syndrome and dependence on TPN have mostly been short-lived in the clinical studies that have been published to date. Growth hormone is administered with glutamine, which also has trophic effects on the


Pharmacology_Katzung

Pharmacology_Katzung. and dependence on TPN have mostly been short-lived in the clinical studies that have been published to date. Growth hormone is administered with glutamine, which also has trophic effects on the intestinal mucosa.


Pharmacology_Katzung

Pharmacology_Katzung. Growth hormone is a popular component of “anti-aging” programs. Serum levels of GH normally decline with aging; anti-aging programs claim that injection of GH or administration of drugs purported to increase GH release are effective anti-aging remedies. These claims are largely unsubstantiated. In contrast, studies in mice and the nematode Caenorhabditis elegans have clearly demonstrated that analogs of human GH and IGF-I consistently shorten life span and that loss-of-function mutations in the signaling pathways for the GH and IGF-I analogs lengthen life span. Another use of GH is by athletes for a purported increase in muscle mass and athletic performance. Growth hormone is one of the drugs banned by the International Olympic Committee.


Pharmacology_Katzung

Pharmacology_Katzung. In 1993, the FDA approved the use of recombinant bovine growth hormone (rbGH) in dairy cattle to increase milk production. Although milk and meat from rbGH-treated cows appear to be safe, these cows have a higher incidence of mastitis, which could increase antibiotic use and result in greater antibiotic residues in milk and meat.


Pharmacology_Katzung

Pharmacology_Katzung. Children generally tolerate growth hormone treatment well. Adverse events are relatively rare and include pseudotumor cerebri, slipped capital femoral epiphysis, progression of scoliosis, edema, hyperglycemia, and increased risk of asphyxiation in severely obese patients with Prader-Willi syndrome and upper airway obstruction or sleep apnea. Patients with Turner syndrome have an increased risk of otitis media while taking GH. In children with GH deficiency, periodic evaluation of the other anterior pituitary hormones may reveal concurrent deficiencies, which also require treatment (ie, with hydrocortisone, levothyroxine, or gonadal hormones). Pancreatitis, gynecomastia, and nevus growth have occurred in patients receiving GH. Adults tend to have more adverse effects from GH therapy. Peripheral edema, myalgias, and arthralgias (especially in the hands and wrists) occur commonly but remit with dosage reduction. Carpal tunnel syndrome can occur. Growth hormone treatment increases the


Pharmacology_Katzung

Pharmacology_Katzung. edema, myalgias, and arthralgias (especially in the hands and wrists) occur commonly but remit with dosage reduction. Carpal tunnel syndrome can occur. Growth hormone treatment increases the activity of cytochrome P450 isoforms, which may reduce the serum levels of drugs metabolized by that enzyme system (see Chapter 4). There has been no increased incidence of malignancy among patients receiving GH therapy, but such treatment is contraindicated in a patient with a known active malignancy. Proliferative retinopathy may rarely occur. Growth hormone treatment of critically ill patients appears to increase mortality. The long-term health effects of GH treatment in childhood are unknown. The results from the Safety and Appropriateness of GH in Europe (SAGHE) study are variable. A higher all-cause mortality (mostly due to cardiovascular disease) was found in the GH treatment group in the French arm of the study, but no long-term risks of GH treatment were observed in the study arm from


Pharmacology_Katzung

Pharmacology_Katzung. mortality (mostly due to cardiovascular disease) was found in the GH treatment group in the French arm of the study, but no long-term risks of GH treatment were observed in the study arm from another region of Europe.


Pharmacology_Katzung

Pharmacology_Katzung. A small number of children with growth failure have severe IGF-I deficiency that is not responsive to exogenous GH. Causes include mutations in the GH receptor and in the GH receptor signaling pathway, neutralizing antibodies to GH, and IGF-I gene defects. In 2005, the FDA approved two forms of recombinant human IGF-I (rhIGF-I) for treatment of severe IGF-I deficiency that is not responsive to GH: mecasermin and mecasermin rinfabate. Mecasermin is rhIGF-I alone, while mecasermin rinfabate is a complex of rhIGF-I and recombinant human insulin-like growth factor–binding protein-3 (rhIGFBP-3). This binding protein significantly increases the circulating half-life of rhIGF-I. Normally, the great majority of the circulating IGF-I is bound to IGFBP-3, which is produced principally by the liver under the control of GH. Due to a patent settlement, mecasermin rinfabate is not available for short stature-related indications. Mecasermin is administered subcutaneously twice daily at a recommended


Pharmacology_Katzung

Pharmacology_Katzung. the control of GH. Due to a patent settlement, mecasermin rinfabate is not available for short stature-related indications. Mecasermin is administered subcutaneously twice daily at a recommended starting dosage of 0.04–0.08 mg/kg per dose and increased weekly up to a maximum twice-daily dosage of 0.12 mg/kg per dose.


Pharmacology_Katzung

Pharmacology_Katzung. The most important adverse effect observed with mecasermin is hypoglycemia. To avoid hypoglycemia, the prescribing instructions require consumption of a carbohydrate-containing meal or snack 20 minutes before or after mecasermin administration. Several patients have experienced intracranial hypertension, adenotonsillar hypertrophy, and asymptomatic elevation of liver enzymes.


Pharmacology_Katzung

Pharmacology_Katzung. Antagonists of GH are used to reverse the effects of GH-producing cells (somatotrophs) in the anterior pituitary that tend to form GH-secreting tumors. Hormone-secreting pituitary adenomas occur most commonly in adults. In adults, GH-secreting adenomas cause acromegaly, which is characterized by abnormal growth of cartilage and bone tissue, and many organs including skin, muscle, heart, liver, and the gastrointestinal tract. When a GH-secreting adenoma occurs before the long bone epiphyses close, it leads to a rare condition, gigantism. Larger pituitary adenomas produce greater amounts of GH and also can impair visual and central nervous system function by encroaching on nearby brain structures. The initial therapy of choice for GH-secreting adenomas is endoscopic transsphenoidal surgery. Medical therapy with GH antagonists is introduced if GH hypersecretion persists after surgery. These agents include somatostatin analogs and dopamine receptor agonists, which reduce the production of


Pharmacology_Katzung

Pharmacology_Katzung. Medical therapy with GH antagonists is introduced if GH hypersecretion persists after surgery. These agents include somatostatin analogs and dopamine receptor agonists, which reduce the production of GH, and the novel GH receptor antagonist pegvisomant, which prevents GH from activating GH signaling pathways. Radiation therapy is reserved for patients with inadequate response to surgical and medical therapies.


Pharmacology_Katzung

Pharmacology_Katzung. Somatostatin, a 14-amino-acid peptide (Figure 37–2), is found in the hypothalamus, other parts of the central nervous system, the pancreas, and other sites in the gastrointestinal tract. It functions primarily as an inhibitory paracrine factor and inhibits the release of GH, TSH, glucagon, insulin, and gastrin. Somatostatin is rapidly cleared from the circulation, with a half-life of 1–3 minutes. Phe7Phe68Asn510LysLysThrPheCysCysThr-olAcetateD-PheD-Trp411Cys312Gly213AlaCys114TrpThr9LysPheThrSerSSSSSomatostatinOctreotideFIGURE 37–2 Above: Amino acid sequence of somatostatin. Below: Sequence of the synthetic analog, octreotide. The kidney appears to play an important role in its metabolism and excretion.


Pharmacology_Katzung

Pharmacology_Katzung. The kidney appears to play an important role in its metabolism and excretion. Somatostatin has limited therapeutic usefulness because of its short duration of action and multiple effects in many secretory systems. A series of longer-acting somatostatin analogs that retain biologic activity have been developed. Octreotide, the most widely used somatostatin analog (Figure 37–2), is 45 times more potent than somatostatin in inhibiting GH release but only twice as potent in reducing insulin secretion. Because of this relatively reduced effect on pancreatic beta cells, hyperglycemia rarely occurs during treatment. The plasma elimination half-life of octreotide is about 80 minutes, 30 times longer than that of somatostatin.


Pharmacology_Katzung

Pharmacology_Katzung. Octreotide, 50–200 mcg given subcutaneously every 8 hours, reduces symptoms caused by a variety of hormone-secreting tumors: acromegaly, carcinoid syndrome, gastrinoma, glucagonoma, insulinoma, VIPoma, and ACTH-secreting tumor. Other therapeutic use indications include diarrhea—secretory, HIV associated, diabetic, chemotherapy, or radiation induced—and portal hypertension. Somatostatin receptor scintigraphy, using radiolabeled octreotide, is useful in localizing neuroendocrine tumors having somatostatin receptors and helps predict the response to octreotide therapy. Octreotide is also useful for the acute control of bleeding from esophageal varices. Octreotide acetate injectable long-acting suspension is a slow-release microsphere formulation. It may be instituted after a brief course of shorter-acting octreotide has been demonstrated to be effective and tolerated. Injections into alternate gluteal muscles are repeated at 4-week intervals in doses of 10–40 mg.


Pharmacology_Katzung

Pharmacology_Katzung. Adverse effects of octreotide therapy include nausea, vomiting, abdominal cramps, flatulence, and steatorrhea with bulky bowel movements. Biliary sludge and gallstones may occur after 6 months of use in 20–30% of patients. However, the yearly incidence of symptomatic gallstones is about 1%. Cardiac effects include sinus bradycardia (25%) and conduction disturbances (10%). Pain at the site of injection is common, especially with the long-acting octreotide suspension. Vitamin B12 deficiency may occur with long-term use of octreotide. A long-acting formulation of lanreotide, another octapeptide somatostatin analog, is approved for treatment of acromegaly. Lanreotide appears to have effects comparable to those of octreotide in reducing GH levels and normalizing IGF-I concentrations.


Pharmacology_Katzung

Pharmacology_Katzung. Pegvisomant is a GH receptor antagonist used to treat acromegaly. It is the polyethylene glycol (PEG) derivative of a mutant GH, B2036. Pegylation reduces its clearance and improves its overall clinical effectiveness. Like native GH, pegvisomant has two GH receptor binding sites. However, one of its GH receptor binding sites has increased affinity for the GH receptor, whereas its second GH receptor binding site has reduced affinity. This differential receptor affinity allows the initial step (GH receptor dimerization) but blocks the conformational changes required for signal transduction. In clinical trials, pegvisomant was administered subcutaneously to patients with acromegaly; daily treatment for 12 months or more reduced serum levels of IGF-I into the normal range in 97%. Pegvisomant does not inhibit GH secretion and may lead to increased GH levels and possible adenoma growth. No serious problems have been observed; however, increases in liver enzymes without liver failure have


Pharmacology_Katzung

Pharmacology_Katzung. does not inhibit GH secretion and may lead to increased GH levels and possible adenoma growth. No serious problems have been observed; however, increases in liver enzymes without liver failure have been reported.


Pharmacology_Katzung

Pharmacology_Katzung. The gonadotropins are produced by gonadotroph cells, which comprise 7–15% of the cells in the pituitary. These hormones serve complementary functions in the reproductive process. In women, the principal function of FSH is to stimulate ovarian follicle development. Both FSH and LH are needed for ovarian steroidogenesis. In the ovary, LH stimulates androgen production by theca cells in the follicular stage of the menstrual cycle, whereas FSH stimulates the conversion of androgens to estrogens by granulosa cells. In the luteal phase of the menstrual cycle, estrogen and progesterone production is primarily under the control first of LH and then, if pregnancy occurs, under the control of human chorionic gonadotropin (hCG). Human chorionic gonadotropin is a placental glycoprotein nearly identical with LH; its actions are mediated through LH receptors.


Pharmacology_Katzung

Pharmacology_Katzung. In men, FSH is the primary regulator of spermatogenesis, whereas LH is the main stimulus for testosterone synthesis in Leydig cells. FSH helps maintain high local androgen concentrations in the vicinity of developing sperm by stimulating the production of androgen-binding protein in Sertoli cells. FSH also stimulates the conversion by Sertoli cells of testosterone to estrogen that is also required for spermatogenesis. FSH, LH, and hCG are available in several pharmaceutical forms. They are used in states of infertility to stimulate spermatogenesis in men and to induce follicle development and ovulation in women. Their most common clinical use is for the controlled ovarian stimulation that is the cornerstone of assisted reproductive technologies such as in vitro fertilization (IVF, see below).


Pharmacology_Katzung

Pharmacology_Katzung. All three hormones—FSH, LH, and hCG—are heterodimers that share an identical α subunit in addition to a distinct β subunit that confers receptor specificity. The β subunits of hCG and LH are nearly identical, and these two hormones are used interchangeably. All the gonadotropin preparations are administered by subcutaneous or intramuscular injection, usually on a daily basis. Half-lives vary by preparation and route of injection from 10 to 40 hours. A. Menotropins


Pharmacology_Katzung

Pharmacology_Katzung. A. Menotropins The first commercial gonadotropin product containing both FSH and LH was extracted from the urine of postmenopausal women. This purified extract of FSH and LH is known as menotropins, or human menopausal gonadotropins (hMG). From the early 1960s, these preparations were used for the stimulation of follicle development in women. The early extraction techniques were very crude, requiring around 30 L of urine to manufacture enough hMG needed for a single treatment cycle. These initial preparations were also contaminated with other proteins; less than 5% of the proteins present were bioactive. The FSH-to-LH bioactivity ratio of these early preparations was 1:1. As purity improved, it was necessary to add hCG in order to maintain this ratio of bioactivity. B. Follicle-Stimulating Hormone


Pharmacology_Katzung

Pharmacology_Katzung. Three forms of purified FSH are available. Urofollitropin, also known as uFSH, is a purified preparation of human FSH extracted from the urine of postmenopausal women. Virtually all the LH activity has been removed through a form of immuno-affinity chromatography that uses anti-hCG antibodies. Urofollitropin was withdrawn from the US market in 2015. Two recombinant forms of FSH (rFSH) are also available: follitropin alfa and follitropin beta. The amino acid sequences of these two products are identical to that of human FSH. They differ from each other and urofollitropin in the composition of carbohydrate side chains. The rFSH preparations have a shorter half-life than preparations derived from human urine but stimulate estrogen secretion at least as efficiently and, in some studies, more efficiently. Compared with urine derived gonadotropins, rFSH preparations have little protein contamination, much less batch-to-batch variability, and may cause less local tissue reaction. The rFSH


Pharmacology_Katzung

Pharmacology_Katzung. efficiently. Compared with urine derived gonadotropins, rFSH preparations have little protein contamination, much less batch-to-batch variability, and may cause less local tissue reaction. The rFSH preparations are considerably more expensive.


Pharmacology_Katzung

Pharmacology_Katzung. C. Luteinizing Hormone Lutropin alfa, the first and only recombinant form of human LH, was introduced in the United States in 2004 but withdrawn in 2012. When given by subcutaneous injection, it has a half-life of about 10 hours. Lutropin has only been approved for use in combination with follitropin alfa for stimulation of follicular development in infertile hypogonadotropic hypogonadal women with profound LH deficiency (<1.2 IU/L). Lutropin alfa with follitropin alfa may also be of benefit in certain subgroups of normogonadotropic women (eg, those with an inadequate response to prior follitropin alfa monotherapy). It has not been approved for use with the other preparations of FSH or for induction of ovulation. D. Human Chorionic Gonadotropin


Pharmacology_Katzung

Pharmacology_Katzung. D. Human Chorionic Gonadotropin Human chorionic gonadotropin is produced by the human placenta and excreted into the urine, whence it can be extracted and purified. It is a glycoprotein consisting of a 92-amino-acid α subunit virtually identical to that of FSH, LH, and TSH, and a β subunit of 145 amino acids that resembles that of LH except for the presence of a carboxyl terminal sequence of 30 amino acids not present in LH. Choriogonadotropin alfa (rhCG) is a recombinant form of hCG. Because of its greater consistency in biologic activity, rhCG is packaged and dosed on the basis of weight rather than units of activity. All of the other gonadotropins, including rFSH, are packaged and dosed on the basis of units of activity. Both the hCG preparation that is purified from human urine and rhCG can be administered by subcutaneous or intramuscular injection.


Pharmacology_Katzung

Pharmacology_Katzung. The gonadotropins and hCG exert their effects through G protein-coupled receptors. LH and FSH have complex effects on reproductive tissues in both sexes. In women, these effects change over the time course of a menstrual cycle as a result of a complex interplay among concentration-dependent effects of the gonadotropins, cross-talk of LH, FSH, and gonadal steroids, and the influence of other ovarian hormones. A coordinated pattern of FSH and LH secretion during the menstrual cycle (see Figure 40–1) is required for normal follicle development, ovulation, and pregnancy.


Pharmacology_Katzung

Pharmacology_Katzung. During the first 8 weeks of pregnancy, the progesterone and estrogen required to maintain pregnancy are produced by the ovarian corpus luteum. For the first few days after ovulation, the corpus luteum is maintained by maternal LH. However, as maternal LH concentration falls owing to increasing concentrations of progesterone and estrogen, the corpus luteum will continue to function only if the role of maternal LH is taken over by hCG produced by syncytiotrophoblast cells in the placenta. A. Ovulation Induction


Pharmacology_Katzung

Pharmacology_Katzung. A. Ovulation Induction The gonadotropins are used to induce follicle development and ovulation in women with anovulation that is secondary to hypogonadotropic hypogonadism, polycystic ovary syndrome, and other causes. Because of the high cost of gonadotropins and the need for close monitoring during their administration, they are generally reserved for anovulatory women who fail to respond to other less complicated forms of treatment (eg, clomiphene; see Chapter 40). Gonadotropins are also used for controlled ovarian stimulation in assisted reproductive technology procedures. Currently, a number of different protocols use gonadotropins in ovulation induction and controlled ovulation stimulation, and new protocols are continually being developed to improve the rates of success and to decrease the two primary risks of ovulation induction: multiple pregnancies and the ovarian hyperstimulation syndrome (OHSS; see below).


Pharmacology_Katzung

Pharmacology_Katzung. Although the details differ, all of these protocols are based on the complex physiology that underlies a normal menstrual cycle. Like a menstrual cycle, controlled ovulation stimulation is discussed in relation to a cycle that begins on the first day of a menstrual bleed (Figure 37–3). Shortly after the first day (usually on day 2), daily injections with one of the FSH preparations (hMG, urofollitropin, or rFSH) are begun and continued for approximately 8–12 days. In women with hypogonadotropic hypogonadism, follicle development requires treatment with a combination of FSH and LH because these women do not produce the basal level of LH that is required for normal follicle development. The dose and duration of gonadotropin treatment are based on the response as measured by the serum estradiol concentration and by ultrasound evaluation of ovarian follicle