Pharmacology_Katzung

Pharmacology_Katzung. The mechanism of action of 5-ASA is not certain. The primary action of salicylate and other NSAIDs is due to blockade of prostaglandin synthesis by inhibition of cyclooxygenase. However, the aminosalicylates have variable effects on prostaglandin production. It is thought that 5-ASA modulates inflammatory mediators derived from both the cyclooxygenase and lipoxygenase pathways. Other potential mechanisms of action of the 5-ASA drugs relate to their ability to interfere with the production of inflammatory cytokines. 5-ASA inhibits the activity of nuclear factor-κB (NF-κB), an important transcription factor for proinflammatory cytokines. 5-ASA may also inhibit cellular functions of natural killer cells, mucosal lymphocytes, and macrophages, and it may scavenge reactive oxygen metabolites.


Pharmacology_Katzung

Pharmacology_Katzung. 5-ASA drugs induce and maintain remission in ulcerative colitis and are considered to be the first-line agents for treatment of mild to moderate active ulcerative colitis. Their efficacy in Crohn’s disease is unproven, although many clinicians use 5-ASA agents as first-line therapy for mild to moderate disease involving the colon or distal ileum. The effectiveness of 5-ASA therapy depends in part on achieving high drug concentration at the site of active disease. Thus, 5-ASA suppositories or enemas are useful in patients with ulcerative colitis or Crohn’s disease confined to the rectum (proctitis) or distal colon (proctosigmoiditis). In patients with ulcerative colitis or Crohn’s colitis that extends to the proximal colon, both the azo compounds and mesalamine formulations are useful. For the treatment of Crohn’s disease involving the small bowel, mesalamine compounds, which release 5-ASA in the small intestine, have a theoretic advantage over the azo compounds.


Pharmacology_Katzung

Pharmacology_Katzung. Sulfasalazine has a high incidence of adverse effects, most of which are attributable to systemic effects of the sulfapyridine molecule. Slow acetylators of sulfapyridine have more frequent and more severe adverse effects than fast acetylators. Up to 40% of patients cannot tolerate therapeutic doses of sulfasalazine. The most common problems are dose-related and include nausea, gastrointestinal upset, headaches, arthralgias, myalgias, bone marrow suppression, and malaise. Hypersensitivity to sulfapyridine (or, rarely, 5-ASA) can result in fever, exfoliative dermatitis, pancreatitis, pneumonitis, hemolytic anemia, pericarditis, or hepatitis. Sulfasalazine has also been associated with oligospermia, which reverses upon discontinuation of the drug. Sulfasalazine impairs folate absorption and processing; hence, dietary supplementation with 1 mg/d folic acid is recommended.


Pharmacology_Katzung

Pharmacology_Katzung. In contrast to sulfasalazine, other aminosalicylate formulations are well tolerated. In most clinical trials, the frequency of drug adverse events is similar to that in patients treated with placebo. For unclear reasons, olsalazine may stimulate a secretory diarrhea—which should not be confused with active IBD—in 10% of patients. Rare hypersensitivity reactions may occur with all aminosalicylates but are much less common than with sulfasalazine. Careful studies have documented subtle changes indicative of renal tubular damage in patients receiving high doses of aminosalicylates. Rare cases of interstitial nephritis are reported, particularly in association with high doses of mesalamine formulations; this may be attributable to the higher serum 5-ASA levels attained with these drugs. Sulfasalazine and other aminosalicylates rarely cause worsening of colitis, which may be misinterpreted as refractory colitis.


Pharmacology_Katzung

Pharmacology_Katzung. In gastrointestinal practice, prednisone and prednisolone are the most commonly used oral glucocorticoids. These drugs have an intermediate duration of biologic activity allowing once-daily dosing. Hydrocortisone enemas, foam, or suppositories are used to maximize colonic tissue effects and minimize systemic absorption via topical treatment of active IBD in the rectum and sigmoid colon. Absorption of hydrocortisone is reduced with rectal administration, although 15–30% of the administered dosage is still absorbed.


Pharmacology_Katzung

Pharmacology_Katzung. Budesonide is a potent synthetic analog of prednisolone that has high affinity for the glucocorticoid receptor but is subject to rapid first-pass hepatic metabolism (in part by CYP3A4), resulting in low oral bioavailability. Two pH-controlled delayed-release oral formulations of budesonide are available that release the drug either in the distal ileum and colon (pH > 5.5, Entocort) or in the colon (pH > 7, Uceris), where it is absorbed. The bioavailability of controlled-release budesonide capsules is approximately 10%. As in other tissues, glucocorticoids inhibit production of inflammatory cytokines (tumor necrosis factor [TNF]-α, interleukin [IL]-1) and chemokines (IL-8); reduce expression of inflammatory cell adhesion molecules; and inhibit gene transcription of nitric oxide synthase, phospholipase A2, cyclooxygenase-2, and NF-κB.


Pharmacology_Katzung

Pharmacology_Katzung. Glucocorticoids are commonly used in the treatment of patients with moderate to severe active IBD. Active disease is commonly treated with an initial oral dosage of 40–60 mg/d of prednisone or prednisolone. Higher doses have not been shown to be more efficacious but have significantly greater adverse effects. Once a patient responds to initial therapy (usually within 1–2 weeks), the dosage is tapered to minimize development of adverse effects. In severely ill patients, the drugs are usually administered intravenously. For the treatment of IBD involving the rectum or sigmoid colon, rectally administered glucocorticoids are preferred because of their lower systemic absorption.


Pharmacology_Katzung

Pharmacology_Katzung. For the treatment of IBD involving the rectum or sigmoid colon, rectally administered glucocorticoids are preferred because of their lower systemic absorption. The oral controlled-release budesonide (9 mg/d) formulations described above are used in the treatment of mild to moderate Crohn’s disease involving the ileum and proximal colon (Entocort) and ulcerative colitis (Uceris). They are slightly less effective than prednisolone in achieving clinical remission but have significantly less adverse systemic effects. Corticosteroids are not useful for maintaining disease remission. Other medications such as aminosalicylates or immunosuppressive agents should be used for this purpose. Oral controlled-release budesonide formulations are metabolized extensively in the liver by CYP3A4. Potent inhibitors of CYP3A4 can increase budesonide plasma levels several-fold, increasing the likelihood of adverse effects. General adverse effects of glucocorticoids are reviewed in Chapter 39.


Pharmacology_Katzung

Pharmacology_Katzung. PURINE ANALOGS: AZATHIOPRINE & 6-MERCAPTOPURINE Azathioprine and 6-mercaptopurine (6-MP) are purine antimetabolites that have immunosuppressive properties (see Chapters 54 and 55). The bioavailability of azathioprine (80%) is superior to 6-MP (50%). After absorption, azathioprine is rapidly converted by a nonenzymatic process to 6-MP. 6-Mercaptopurine subsequently undergoes a complex biotransformation via competing catabolic enzymes (xanthine oxidase and thiopurine methyltransferase) that produce inactive metabolites and anabolic pathways that produce active thioguanine nucleotides. Azathioprine and 6-MP have a serum half-life of less than 2 hours; however, the active 6-thioguanine nucleotides are concentrated in cells resulting in a prolonged half-life of days. The prolonged kinetics of 6-thioguanine nucleotide results in a median delay of 17 weeks before onset of therapeutic benefit from oral azathioprine or 6-MP is observed in patients with IBD.


Pharmacology_Katzung

Pharmacology_Katzung. Azathioprine and 6-MP are important agents in the induction and maintenance of remission of ulcerative colitis and Crohn’s disease. Although the optimal dose is uncertain, most patients with normal thiopurine-S-methyltransferase (TPMT) activity (see below) are treated with 6-MP, 1–1.5 mg/kg/d, or azathioprine, 2–2.5 mg/kg/d. After 3–6 months of treatment, 50–60% of patients with active disease achieve remission. These agents help maintain remission in up to 80% of patients. Among patients who depend on long-term glucocorticoid therapy to control active disease, purine analogs allow dose reduction or elimination of steroids in the majority.


Pharmacology_Katzung

Pharmacology_Katzung. Dose-related toxicities of azathioprine or 6-MP include nausea, vomiting, bone marrow depression (leading to leukopenia, macrocytosis, anemia, or thrombocytopenia), and hepatic toxicity. Routine laboratory monitoring with complete blood count and liver function tests is required in all patients. Leukopenia or elevations in liver chemistries usually respond to medication dose reduction. Severe leukopenia may predispose to opportunistic infections; leukopenia may respond to therapy with granulocyte stimulating factor. Catabolism of 6-MP by TPMT is low in 11% and absent in 0.3% of the population, leading to increased production of active 6-thioguanine metabolites and increased risk of bone marrow depression. TPMT levels can be measured before initiating therapy. These drugs should not be administered to patients with no TPMT activity and should be initiated at lower doses in patients with intermediate activity. Hypersensitivity reactions to azathioprine or 6-MP occur in 5% of patients.


Pharmacology_Katzung

Pharmacology_Katzung. to patients with no TPMT activity and should be initiated at lower doses in patients with intermediate activity. Hypersensitivity reactions to azathioprine or 6-MP occur in 5% of patients. These include fever, rash, pancreatitis, diarrhea, and hepatitis.


Pharmacology_Katzung

Pharmacology_Katzung. As with transplant recipients receiving long-term 6-MP or azathioprine therapy, there appears to be an increased risk of lymphoma among patients with IBD, some of which may be related to Epstein-Barr virus infection. The drugs are also associated with an increased risk of nonmelanoma skin cancers. These drugs cross the placenta; however, there are many reports of successful pregnancies in women taking these agents, and the risk of teratogenicity appears to be small. Allopurinol markedly reduces xanthine oxide catabolism of the purine analogs, potentially increasing active 6-thioguanine nucleotides that may lead to severe leukopenia. Allopurinol should not be given to patients taking 6-MP or azathioprine except in carefully monitored situations.


Pharmacology_Katzung

Pharmacology_Katzung. Methotrexate is another antimetabolite that has beneficial effects in a number of chronic inflammatory diseases, including Crohn’s disease and rheumatoid arthritis (see Chapter 36), and in cancer (see Chapter 54). Methotrexate may be given orally, subcutaneously, or intramuscularly. Reported oral bioavailability is 50–90% at doses used in chronic inflammatory diseases. Intramuscular and subcutaneous methotrexate exhibit nearly complete bioavailability.


Pharmacology_Katzung

Pharmacology_Katzung. The principal mechanism of action is inhibition of dihydrofolate reductase, an enzyme important in the production of thymidine and purines. At the high doses used for chemotherapy, methotrexate inhibits cellular proliferation. However, at the low doses used in the treatment of IBD (12–25 mg/wk), the antiproliferative effects may not be evident. Methotrexate may interfere with the inflammatory actions of IL-1. It may also stimulate increased release of adenosine, an endogenous anti-inflammatory autacoid. Methotrexate may also stimulate apoptosis and death of activated T lymphocytes. Methotrexate is used to induce and maintain remission in patients with Crohn’s disease. Its efficacy in ulcerative colitis is uncertain. To induce remission, patients are treated with 15–25 mg of methotrexate once weekly by subcutaneous injection. If a satisfactory response is achieved within 8–12 weeks, the dose is reduced to 15 mg/wk.


Pharmacology_Katzung

Pharmacology_Katzung. At higher dosage, methotrexate may cause bone marrow depression, megaloblastic anemia, alopecia, and mucositis. At the doses used in the treatment of IBD, these events are uncommon but warrant dose reduction if they do occur. Folate supplementation reduces the risk of these events without impairing the anti-inflammatory action. In patients with psoriasis treated with methotrexate, hepatic damage is common; however, among patients with IBD and rheumatoid arthritis, the risk is significantly lower. Renal insufficiency may increase risk of hepatic accumulation and toxicity.


Pharmacology_Katzung

Pharmacology_Katzung. A dysregulation of the helper T cell type 1 (Th1) response and regulatory T cells (Tregs) is present in IBD, especially Crohn’s disease. One of the key proinflammatory cytokines in IBD is tumor necrosis factor (TNF). TNF is produced by the innate immune system (eg, dendritic cells, macrophages), the adaptive immune system (especially Th1 cells), and nonimmune cells (fibroblasts, smooth muscle cells). TNF exists in two biologically active forms: soluble TNF and membrane-bound TNF. The biologic activity of soluble and membrane-bound TNF is mediated by binding to TNF receptors (TNFR) that are present on some cells (especially Th1 cells, innate immune cells, and fibroblasts). Binding of TNF to TNFR initially activates components including NF-κB that stimulate transcription, growth, and expansion. Biologic actions ascribed to TNFR activation include release of proinflammatory cytokines from macrophages, T-cell activation and proliferation, fibroblast collagen production, up-regulation of


Pharmacology_Katzung

Pharmacology_Katzung. Biologic actions ascribed to TNFR activation include release of proinflammatory cytokines from macrophages, T-cell activation and proliferation, fibroblast collagen production, up-regulation of endothelial adhesion molecules responsible for leukocyte migration, and stimulation of hepatic acute phase reactants. Activation of TNFR may later lead to apoptosis (programmed cell death) of activated cells.


Pharmacology_Katzung

Pharmacology_Katzung. Four monoclonal antibodies to human TNF are approved for the treatment of IBD: infliximab, adalimumab, golimumab, and certolizumab (Table 62–3). Infliximab, adalimumab, and golimumab are antibodies of the IgG1 subclass. Certolizumab is a recombinant antibody that contains an Fab fragment that is conjugated to polyethylene glycol (PEG) but lacks an Fc portion. The Fab portion of infliximab is a chimeric mouse-human antibody, but adalimumab, certolizumab, and golimumab are fully humanized. Infliximab is administered as an intravenous infusion. At therapeutic doses of 5–10 mg/kg, the half-life of infliximab is approximately 8–10 days, resulting in plasma disappearance of antibodies over 8–12 weeks. Adalimumab, golimumab, and certolizumab are administered by subcutaneous injection. Their half-lives are approximately 2 weeks.


Pharmacology_Katzung

Pharmacology_Katzung. All four agents bind to soluble and membrane-bound TNF with high affinity, preventing the cytokine from binding to its receptors. Binding of all three antibodies to membrane-bound TNF also causes reverse signaling that suppresses cytokine release. When infliximab, adalimumab, or golimumab bind to membrane-bound TNF, the Fc portion of the human IgG1 region promotes antibody-mediated apoptosis, complement activation, and cellular cytotoxicity of activated T lymphocytes and macrophages. Certolizumab, without an Fc portion, lacks these properties. TABLE 62–3 Anti-TNF antibodies used in inflammatory bowel disease. TNF, tumor necrosis factor.


Pharmacology_Katzung

Pharmacology_Katzung. Infliximab, adalimumab, and certolizumab are approved for the acute and chronic treatment of patients with moderate to severe Crohn’s disease who have had an inadequate response to conventional therapies. Infliximab, adalimumab, and golimumab are approved for the acute and chronic treatment of moderate to severe ulcerative colitis. With induction therapy, these approved agents lead to symptomatic improvement in 60% and disease remission in 30% of patients with moderate to severe Crohn’s disease, including patients who have been dependent on glucocorticoids or who have not responded to 6-MP or methotrexate. The median time to clinical response is 2 weeks. Induction therapy is generally given as follows: infliximab 5 mg/kg intravenous infusion at 0, 2, and 6 weeks; adalimumab 160 mg (in divided doses) initially and 80 mg subcutaneous injection at 2 weeks; and certolizumab 400 mg subcutaneous injection at 0, 2, and 4 weeks. Patients who respond may be treated with chronic maintenance


Pharmacology_Katzung

Pharmacology_Katzung. divided doses) initially and 80 mg subcutaneous injection at 2 weeks; and certolizumab 400 mg subcutaneous injection at 0, 2, and 4 weeks. Patients who respond may be treated with chronic maintenance therapy, as follows: infliximab 5 mg/kg intravenous infusion every 8 weeks; adalimumab 40 mg subcutaneous injection every 2 weeks; certolizumab 400 mg subcutaneous injection every 4 weeks. With chronic, regularly scheduled therapy, clinical response is maintained in more than 60% of patients and disease remission in 40%. However, one-third of patients eventually lose response despite higher doses or more frequent injections. Loss of response in many patients may be due to the development of antibodies to the TNF antibody or to other mechanisms.


Pharmacology_Katzung

Pharmacology_Katzung. Infliximab is approved for the treatment of patients with moderate to severe ulcerative colitis who have had inadequate response to mesalamine or corticosteroids. After induction therapy of 5–10 mg/wk at 0, 2, and 6 weeks, 70% of patients have a clinical response and one third achieve a clinical remission. With continued maintenance infusions every 8 weeks, approximately 50% of patients have continued clinical response. Adalimumab and golimumab also are approved for the treatment of moderate to severe ulcerative colitis but appear to be less effective than intravenous infliximab. After induction therapy, less than 55% of patients have a clinical response and less than 20% achieve remission. The reason why subcutaneous anti-TNF formulations are less effective than intravenous infliximab is uncertain.


Pharmacology_Katzung

Pharmacology_Katzung. Serious adverse events occur in up to 6% of patients with anti-TNF therapy. The most important adverse effect of these drugs is infection due to suppression of the Th1 inflammatory response. This may lead to serious infections such as bacterial sepsis, tuberculosis, invasive fungal organisms, reactivation of hepatitis B, listeriosis, and other opportunistic infections. Reactivation of latent tuberculosis, with dissemination, has occurred. Before administering anti-TNF therapy, all patients must undergo testing with tuberculin skin tests or interferon gamma release assays. Prophylactic therapy for tuberculosis is warranted for patients with positive test results before beginning anti-TNF therapy. More common but usually less serious infections include upper respiratory infections (sinusitis, bronchitis, and pneumonia) and cellulitis. The risk of serious infections is increased markedly in patients taking concomitant corticosteroids.


Pharmacology_Katzung

Pharmacology_Katzung. Antibodies to the antibody (ATA) may develop with all four agents. These antibodies may attenuate or eliminate the clinical response and increase the likelihood of developing acute or delayed infusion or injection reactions. Antibody formation is much more likely in patients given episodic anti-TNF therapy than regular scheduled injections. In patients on chronic maintenance therapy, the prevalence of ATA with infliximab is 10%, with certolizumab 8%, and with adalimumab or golimumab 3%. Antibody development also is less likely in patients who receive concomitant therapy with immunomodulators (ie, 6-MP or methotrexate). Concomitant treatment with anti-TNF agents and immunomodulators may increase the risk of lymphoma.


Pharmacology_Katzung

Pharmacology_Katzung. Infliximab intravenous infusions result in acute adverse infusion reactions in up to 10% of patients, but discontinuation of the infusion for severe reactions is required in less than 2%. Infusion reactions are more common with the second or subsequent infusions than with the first. Early mild reactions include fever, headache, dizziness, urticaria, or mild cardiopulmonary symptoms that include chest pain, dyspnea, or hemodynamic instability. Reactions to subsequent infusions may be reduced with prophylactic administration of acetaminophen, diphenhydramine, or corticosteroids. Severe acute reactions include significant hypotension, shortness of breath, muscle spasms, and chest discomfort; such reactions may require treatment with oxygen, epinephrine, and corticosteroids.


Pharmacology_Katzung

Pharmacology_Katzung. A delayed serum sickness-like reaction may occur 1–2 weeks after anti-TNF therapy in 1% of patients. These reactions consist of myalgia, arthralgia, jaw tightness, fever, rash, urticaria, and edema and usually require discontinuation of that agent. Positive antinuclear antibodies and anti-double-stranded DNA develop in a small number of patients. Development of a lupus-like syndrome is rare and resolves after discontinuation of the drug. Rare but serious adverse effects of all anti-TNF agents also include severe hepatic reactions leading to acute hepatic failure, demyelinating disorders, hematologic reactions, and new or worsened congestive heart failure in patients with underlying heart disease. Anti-TNF agents may cause a variety of psoriatic skin rashes, which usually resolve after drug discontinuation.


Pharmacology_Katzung

Pharmacology_Katzung. Lymphoma appears to be increased in patients with untreated IBD. Anti-TNF agents may further increase the risk of lymphoma in this population, although the relative risk is uncertain. An increased number of cases of hepatosplenic T-cell lymphoma, a rare but usually fatal disease, have been noted in children and young adults, virtually all of whom have been on combined therapy with immunomodulators, anti-TNF agents, or corticosteroids. Anti-TNF agents may also be associated with an increased risk of nonmelanoma skin cancers.


Pharmacology_Katzung

Pharmacology_Katzung. Integrins are a family of adhesion molecules on the surface of leukocytes that may interact with another class of adhesion molecules on the surface of the vascular endothelium known as selectins, allowing circulating leukocytes to adhere to the vascular endothelium and subsequently move through the vessel wall into the tissue. Integrins consist of heterodimers that contain two subunits, alpha and beta. Two monoclonal antibodies directed against integrins are available for the treatment of inflammatory bowel disease: natalizumab and vedolizumab. Both are administered intravenously. Natalizumab is a humanized IgG4 monoclonal antibody targeted only against the α4 subunit; thus, it blocks several integrins on circulating inflammatory cells and prevents binding to the vascular adhesion molecules and subsequent migration into surrounding tissues, including the bowel and central nervous system. Unfortunately, patients treated with natalizumab may develop progressive multifocal


Pharmacology_Katzung

Pharmacology_Katzung. molecules and subsequent migration into surrounding tissues, including the bowel and central nervous system. Unfortunately, patients treated with natalizumab may develop progressive multifocal leukoencephalopathy (PML) due to central nervous system reactivation of a human polyomavirus (JC virus), which is present in latent form in over 80% of adults. Patients who are positive for JC virus antibody have a mean risk of PML of 3.9 per 1000 patients; however, the risk is markedly increased in patients treated for more than 24 months or receiving other immunosuppressants.


Pharmacology_Katzung

Pharmacology_Katzung. Vedolizumab is a monoclonal antibody with activity directed specifically against the α4/β7 integrin, thereby blocking interaction of leukocytes with gut vascular endothelial cell adhesion molecules. Because lymphocytes trafficking to the brain are unaffected, the risk of reactivation of JC virus and PML is believed to be extremely low. With the advent of vedolizumab, natalizumab is almost never used for the treatment of IBD. Vedolizumab is increasingly used as a second-line treatment for patients with moderate to severe ulcerative colitis or Crohn’s disease who cannot take anti-TNF agents due to side effects, lack of efficacy, or loss of response. After intravenous induction therapy of 300 mg at 0, 2, and 6 weeks, patients with a clinical response are treated with intravenous maintenance therapy every 8 weeks. Vedolizumab appears to have a very low incidence of serious side effects. Neutralizing antibodies may develop in 2–10% of patients.


Pharmacology_Katzung

Pharmacology_Katzung. Exocrine pancreatic insufficiency is most commonly caused by cystic fibrosis, chronic pancreatitis, or pancreatic resection. When secretion of pancreatic enzymes falls below 10% of normal, fat and protein digestion is impaired and can lead to steatorrhea, azotorrhea, vitamin malabsorption, and weight loss. Pancreatic enzyme supplements, which contain a mixture of amylase, lipase, and proteases, are the mainstay of treatment for pancreatic enzyme insufficiency. Two major types of preparations in use are pancreatin and pancrelipase. Pancreatin is an alcohol-derived extract of hog pancreas with relatively low concentrations of lipase and proteolytic enzymes, whereas pancrelipase is an enriched preparation. On a per-weight basis, pancrelipase has approximately 12 times the lipolytic activity and more than 4 times the proteolytic activity of pancreatin. Consequently, pancreatin is no longer in common clinical use. Only pancrelipase is discussed here.


Pharmacology_Katzung

Pharmacology_Katzung. Pancrelipase is available worldwide in both non-enteric-coated and enteric-coated preparations. Formulations are available in sizes containing varying amounts of lipase, amylase, and protease. However, manufacturers’ listings of enzyme content do not always reflect true enzymatic activity. Pancrelipase enzymes are rapidly and permanently inactivated by gastric acids. Viokace is a non-enteric-coated tablet that should be given concomitantly with acid suppression therapy (PPI or H2 antagonist) to reduce acid-mediated destruction within the stomach. Enteric-coated formulations are more commonly used because they do not require concomitant acid suppression therapy. At present, five enteric-coasted, delayed-release formulations are approved for use (Creon, Pancreaze, Zenpep, Ultresa, and Pertyze).


Pharmacology_Katzung

Pharmacology_Katzung. Pancrelipase preparations are administered with each meal and snack. Enzyme activity may be listed in international units (IU) or USP units. One IU is equal to 2–3 USP units. Dosing should be individualized according to the age and weight of the patient, the degree of pancreatic insufficiency, and the amount of dietary fat intake. Therapy is initiated at a dose that provides 60,000–90,000 USP units (20,000–30,000 IU) of lipase activity in the prandial and postprandial period—a level that is sufficient to reduce steatorrhea to a clinically insignificant level in most cases. Suboptimal response to enteric-coated formulations may be due to poor mixing of granules with food or slow dissolution and release of enzymes. Gradual increase of dose, change to a different formulation, or addition of acid suppression therapy may improve response. For patients with feeding tubes, microspheres may be mixed with enteral feeding prior to administration.


Pharmacology_Katzung

Pharmacology_Katzung. Pancreatic enzyme supplements are well tolerated. The capsules should be swallowed, not chewed, because pancreatic enzymes may cause oropharyngeal mucositis. Excessive doses may cause diarrhea and abdominal pain. The high purine content of pancreas extracts may lead to hyperuricosuria and renal stones. Several cases of colonic strictures were reported in patients with cystic fibrosis who received high doses of pancrelipase with high lipase activity. These high-dose formulations have since been removed from the market.


Pharmacology_Katzung

Pharmacology_Katzung. Extensive surgical resection or disease of the small intestine may result in short-bowel syndrome with malabsorption of nutrients and fluids. Patients with less than 200 cm of small intestine (with or without colon resection) usually are dependent on partial or complete parenteral nutritional support to maintain hydration and nutrition. Teduglutide is a glucagon-like peptide 2 analog that binds to enteric neurons and endocrine cells, stimulating release of a number of trophic hormones (including insulin-like growth factor) that stimulate mucosal epithelial growth and enhance fluid absorption. In clinical trials, 54% of patients treated with teduglutide (0.05 mg/kg once daily by subcutaneous injection) reduced their need for parenteral support by at least 1 day/ wk compared with 23% treated with placebo. Teduglutide may be associated with an increased risk of neoplasia, including colorectal polyps.


Pharmacology_Katzung

Pharmacology_Katzung. Ursodiol (ursodeoxycholic acid) is a naturally occurring bile acid that makes up less than 5% of the circulating bile salt pool in humans and a much higher percentage in bears. After oral administration, it is absorbed, conjugated in the liver with glycine Drugs Used in the Treatment of Gastrointestinal Diseases 1113 or taurine, and excreted in the bile. Conjugated ursodiol undergoes extensive enterohepatic recirculation. The serum half-life is approximately 100 hours. With long-term daily administration, ursodiol constitutes 30–50% of the circulating bile acid pool. A small amount of unabsorbed conjugated or unconjugated ursodiol passes into the colon, where it is either excreted or undergoes dehydroxylation by colonic bacteria to lithocholic acid, a substance with potential hepatic toxicity.


Pharmacology_Katzung

Pharmacology_Katzung. The solubility of cholesterol in bile is determined by the relative proportions of bile acids, lecithin, and cholesterol. Although prolonged ursodiol therapy expands the bile acid pool, this does not appear to be the principal mechanism of action for dissolution of gallstones. Ursodiol decreases the cholesterol content of bile by reducing hepatic cholesterol secretion. Ursodiol also appears to stabilize hepatocyte canalicular membranes, possibly through a reduction in the concentration of other endogenous bile acids or through inhibition of immune-mediated hepatocyte destruction.


Pharmacology_Katzung

Pharmacology_Katzung. Ursodiol is used for dissolution of small cholesterol gallstones in patients with symptomatic gallbladder disease who refuse cholecystectomy or who are poor surgical candidates. At a dosage of 10 mg/kg/d orally for 12–24 months, dissolution occurs in up to 50% of patients with small (<5–10 mm) noncalcified gallstones. It is also effective for the prevention of gallstones in obese patients undergoing rapid weight loss therapy. Ursodiol is also the first-line agent used for the treatment of early primary biliary cirrhosis (PBC). As a nontoxic bile acid, ursodiol is believed to reduce liver injury by replacement of more toxic endogenous bile acids and through anti-inflammatory effects. At a dose of 13–15 mg/kg/d, ursodiol improves liver biochemical abnormalities, slows the rate of clinical and histologic progression, reduces the need for liver transplantation, and improves long-term survival. Approximately 35% of patients with PBC do not respond to ursodiol.


Pharmacology_Katzung

Pharmacology_Katzung. Ursodiol is practically free of serious adverse effects. Bile salt-induced diarrhea is uncommon. Unlike its predecessor, chenodeoxycholate, ursodiol has not been associated with hepatotoxicity.


Pharmacology_Katzung

Pharmacology_Katzung. Obeticholic acid is a synthetic derivative of the naturally occurring bile acid chenodeoxycholate. Like ursodiol, it is a nontoxic bile acid and is believed to reduce liver injury by decreasing hepatic concentrations of more toxic endogenous bile acids. It also is a ligand for the nuclear farnesoid X receptor, which modulates hepatic inflammation, fibrosis, gluconeogenesis, lipid synthesis, and insulin sensitivity. Obeticholic acid was recently approved for the treatment of PBC at a dose of 5–10 mg/d orally in combination with ursodiol in patients who have had an inadequate response to ursodiol monotherapy. In a randomized, double-blind, placebo-controlled, 12-month trial, almost 50% of patients treated with combination therapy had a clinical response compared with 10% treated with ursodiol alone. Obeticholic acid causes severe pruritus in up to 25% of patients (especially at the 10 mg dose), leading to discontinuation in up to 10% of patients.


Pharmacology_Katzung

Pharmacology_Katzung. Portal hypertension most commonly occurs as a consequence of chronic liver disease. Portal hypertension is caused by increased blood flow within the portal venous system and increased resistance to portal flow within the liver. Splanchnic blood flow is increased in patients with cirrhosis due to low arteriolar resistance that is mediated by increased circulating vasodilators and decreased vascular sensitivity to vasoconstrictors. Intrahepatic vascular resistance is increased in cirrhosis due to fixed fibrosis within the spaces of Disse and hepatic veins as well as reversible vasoconstriction of hepatic sinusoids and venules. Among the consequences of portal hypertension are ascites, hepatic encephalopathy, and the development of portosystemic collaterals—especially gastric or esophageal varices. Varices can rupture, leading to massive upper gastrointestinal bleeding.


Pharmacology_Katzung

Pharmacology_Katzung. Several drugs are available that reduce portal pressures. These may be used in the short term for the treatment of active variceal hemorrhage or long term to reduce the risk of hemorrhage. The pharmacology of octreotide is discussed above under Antidiarrheal Agents. In patients with cirrhosis and portal hypertension, intravenous somatostatin (250 mcg/h) or octreotide (50 mcg/h) reduces portal blood flow and variceal pressures; the mechanism by which they do so is poorly understood. They do not appear to induce direct contraction of vascular smooth muscle. Their activity may be mediated through inhibition of release of glucagon and other gut peptides that alter mesenteric blood flow. Although data from clinical trials are conflicting, these agents are probably effective in promoting initial hemostasis from bleeding esophageal varices. They are generally administered for 3–5 days.


Pharmacology_Katzung

Pharmacology_Katzung. Vasopressin (antidiuretic hormone) is a polypeptide hormone secreted by the hypothalamus and stored in the posterior pituitary. Its pharmacology is discussed in Chapters 17 and 37. Although its primary physiologic role is to maintain serum osmolality, it is also a potent arterial vasoconstrictor. When administered intravenously by continuous infusion, vasopressin causes splanchnic arterial vasoconstriction that leads to reduced splanchnic perfusion and lowered portal venous pressures. Before the advent of octreotide, vasopressin was commonly used to treat acute variceal hemorrhage. However, because of its high adverse-effect profile, it is no longer used for this purpose. In contrast, for patients with acute gastrointestinal bleeding from small bowel or large bowel vascular ectasias or diverticulosis, vasopressin may be infused—to promote vasospasm—into one of the branches of the superior or inferior mesenteric artery through an angiographically placed catheter. Adverse effects with


Pharmacology_Katzung

Pharmacology_Katzung. vasopressin may be infused—to promote vasospasm—into one of the branches of the superior or inferior mesenteric artery through an angiographically placed catheter. Adverse effects with systemic vasopressin are common. Systemic and peripheral vasoconstriction can lead to hypertension, myocardial ischemia or infarction, or mesenteric infarction. These effects may be reduced by coadministration of nitroglycerin, which may further reduce portal venous pressures (by reducing portohepatic vascular resistance) and may also reduce the coronary and peripheral vascular vasospasm caused by vasopressin. Other common adverse effects are nausea, abdominal cramps, and diarrhea (due to intestinal hyperactivity). Furthermore, the antidiuretic effects of vasopressin promote retention of free water, which can lead to hyponatremia, fluid retention, and pulmonary edema.


Pharmacology_Katzung

Pharmacology_Katzung. Terlipressin is a vasopressin analog that appears to have similar efficacy to vasopressin with fewer adverse effects. Although this agent is available in other countries, it has never been approved for use in the USA.


Pharmacology_Katzung

Pharmacology_Katzung. The pharmacology of β-receptor-blocking agents is discussed in Chapter 10. Beta-receptor antagonists reduce portal venous pressures via a decrease in portal venous inflow. This decrease is due to a decrease in cardiac output (β1 blockade) and to splanchnic vasoconstriction (β2 blockade) caused by the unopposed effect of systemic catecholamines on α receptors. Thus, nonselective β blockers such as propranolol and nadolol are more effective than selective β1 blockers in reducing portal pressures. Among patients with cirrhosis and esophageal varices who have not previously had an episode of variceal hemorrhage, the incidence of bleeding among patients treated with nonselective β blockers is 15% compared with 25% in control groups. Among patients with a history of variceal hemorrhage, the likelihood of recurrent hemorrhage is 80% within 2 years. Nonselective β blockers significantly reduce the rate of recurrent bleeding, although a reduction in mortality is unproved.


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Pharmacology_Katzung. H2-receptor blockers, eg, cimetidine: Effective reduction of nocturnal acid but less effective against stimulated secretion; very safe, available over the counter (OTC). Cimetidine, but not other H2 blockers, is a weak antiandrogenic agent and a potent CYP enzyme inhibitor Sucralfate: Polymerizes at site of tissue damage (ulcer bed) and protects against further damage; very insoluble with no systemic effects; must be given four times daily Antacids: Popular OTC medication for symptomatic relief of heartburn; not as useful as PPI and H2 blockers in peptic diseases Domperidone: Like metoclopramide, but less CNS effect; not available in USA Cholinomimetics: Neostigmine often used for colonic pseudo-obstruction in hospitalized patients Macrolides: Erythromycin useful in diabetic gastroparesis but tolerance develops


Pharmacology_Katzung

Pharmacology_Katzung. Cholinomimetics: Neostigmine often used for colonic pseudo-obstruction in hospitalized patients Macrolides: Erythromycin useful in diabetic gastroparesis but tolerance develops DRUGS STIMULATING MOTILITY •MetoclopramideD2-receptorblocker•removesinhibition of acetylcholine neurons in enteric nervous system Increases gastric emptying and intestinal motility Gastric paresis (eg, in diabetes)•antiemetic(see below) Parkinsonian symptoms due to block of central nervous system (CNS) D2 receptors hydroxide, other nonabsorbable salts and sugars Osmotic agents increase water content of stool Usually causes evacuation within 4–6 h, sooner in large doses Simple constipation; Bulk-forming laxatives: Methylcellulose, psyllium, etc: increase volume of colon contents, stimulate evacuation Stimulants: senna, cascara; stimulate activity; may cause cramping Stool surfactants: Docusate, mineral oil; lubricate stool, ease passage


Pharmacology_Katzung

Pharmacology_Katzung. Stimulants: senna, cascara; stimulate activity; may cause cramping Stool surfactants: Docusate, mineral oil; lubricate stool, ease passage Chloride channel activators: Lubiprostone, prostanoic acid derivative, stimulates chloride secretion into intestine, increasing fluid content; linaclotide, guanylyl cyclase-C agonist, stimulates chloride secretion by CFTR Opioid receptor antagonists: Alvimopan, methylnaltrexone; block intestinal μ-opioid receptors but do not enter CNS, so analgesia is maintained Colloidal bismuth compounds: Subsalicylate and citrate salts available. OTC preparations popular and have some value in travelers’ diarrhea due to adsorption of toxins Kaolin + pectin: Adsorbent compounds available OTC in some countries Anticholinergics: Nonselective action on gut activity, usually associated with typical antimuscarinic toxicity


Pharmacology_Katzung

Pharmacology_Katzung. Kaolin + pectin: Adsorbent compounds available OTC in some countries Anticholinergics: Nonselective action on gut activity, usually associated with typical antimuscarinic toxicity Chloride channel activator: Lubiprostone (see above); useful in constipation-predominant IBS in women; linaclotide (see above): useful in adults with constipation-predominant IBS Corticosteroids: Mechanism not known but useful in antiemetic IV cocktails Antimuscarinics (scopolamine): Effective in emesis due to motion sickness; not other types Antihistaminics: Moderate efficacy in motion sickness and chemotherapy-induced emesis Phenothiazines: Act primarily through block of D2 and muscarinic receptors Cannabinoids: Dronabinol is available for use in chemotherapy-induced nausea and vomiting, but is associated with CNS marijuana effects • Corticosteroids: Generalized anti-inflammatory effect; see Chapter 39


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Pharmacology_Katzung. PANCREATIC SUPPLEMENTS •PancrelipaseReplacement enzymes from animal pancreatic extracts Improves digestion of dietary fat, protein, and carbohydrate Pancreatic insufficiency due to cystic fibrosis, pancreatitis, pancreatectomy Takenwitheverymeal•mayincreaseincidence of gout •Pancreatin: Similar pancreatic extracts but much lower potency; rarely used Aluminum hydroxide gel * Generic, AlternaGEL, others Calcium carbonate*Generic, Tums, others Famotidine Generic, Maalox, Mylanta, Gaviscon, Gelusil, others Generic, Pepcid, Pepcid AC, * Pepcid Complete * Nizatidine Generic, Axid, Axid AR* Ranitidine Generic, Zantac, Zantac 75 * Dicyclomine Generic, Bentyl, others Glycopyrrolate Generic, Robinul Hyoscyamine Anaspaz, Levsin, others Scopolamine Generic, Transderm Scop Omeprazole Generic, Prilosec, Prilosec OTC* Lansoprazole Generic, Prevacid * Pantoprazole Generic, Protonix Granisetron Generic, Kytril Ondansetron Generic, Zofran Dronabinol Generic, Marinol


Pharmacology_Katzung

Pharmacology_Katzung. Omeprazole Generic, Prilosec, Prilosec OTC* Lansoprazole Generic, Prevacid * Pantoprazole Generic, Protonix Granisetron Generic, Kytril Ondansetron Generic, Zofran Dronabinol Generic, Marinol Fosaprepitant Emend, Emend IV Metoclopramide Generic, Reglan, others Netupitant/palonosetron Akynzeo Prochlorperazine Generic, Compazine Promethazine Generic, Phenergan, others Trimethobenzamide Generic, Tigan, others Budesonide Entocort, Uceris Hydrocortisone Cortenema, Cortifoam, Proctofoam–HC Rectal: Rowasa, Canasa Sulfasalazine Generic, Azulfidine Diphenoxylate Generic, Lomotil, others Methylcellulose Generic, Citrucel Bisacodyl *Generic, Dulcolax, others Docusate*Generic, Colace, others Lactulose Generic, Chronulac, Cephulac, others Magnesium hydroxide (milk of magnesia, Epsom Salt) *Generic Polycarbophil*Equalactin, Mitrolan, FiberCon, Fiber–Lax Polyethylene glycol electrolyte Co–Lyte, GoLYTELY, HalfLytely, solution Moviprep, others Senna *Senokot, ExoLax, others


Pharmacology_Katzung

Pharmacology_Katzung. Polycarbophil*Equalactin, Mitrolan, FiberCon, Fiber–Lax Polyethylene glycol electrolyte Co–Lyte, GoLYTELY, HalfLytely, solution Moviprep, others Senna *Senokot, ExoLax, others Sodium Phosphate Fleets Phospho-soda, OsmoPrep, Visicol Ursodiol Generic, Actigall, URSO *Over-the-counter formulations. Alshamsi F et al: Efficacy and safety of proton pump inhibitors for stress ulcer prophylaxis in critically ill patients: A systematic review and meta-analysis of randomized trials. Crit Care 2016;20:120. Barletta JF et al: Stress ulcer prophylaxis. Crit Care Med 2016;44:1395. Bredenoord AJ et al: Gastro-oesophageal reflux disease. Lancet 2013; 381(9881):1933. Fallone CA et al: The Toronto Consensus for the treatment of Helicobacter pylori infection in adults. Gastroenterology 2016;151:51. Ford AC et al: Eradication therapy for peptic ulcer disease in Helicobacter pylori-positive people. Cochrane Database Syst Rev 2016;4:CD003840.


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Pharmacology_Katzung. Ford AC et al: Eradication therapy for peptic ulcer disease in Helicobacter pylori-positive people. Cochrane Database Syst Rev 2016;4:CD003840. Gerson L: Proton pump inhibitors and potential interactions with clopidogrel: An update. Curr Gastroenterol Rep 2013;15:329. Gomm W et al: Association of proton pump inhibitors with risk of dementia. JAMA Neurol 2016;73:410. Katz PO et al: Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol 2013;108:308. Lazarus B et al: Proton pump inhibitor use and the risk of chronic kidney disease. JAMA Intern Med 2016;176:238. Malfertheiner P et al: Management of Helicobacter pylori infection—the Maastricht IV/Florence Consensus report. Gut 2012;61:646. Medlock S et al: Co-prescription of gastroprotective agents and their efficacy in elderly patients taking nonsteroidal anti-inflammatory drugs: A systematic review of observational studies. Clin Gastroenterol Hepatol 2013;11:1259.


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Pharmacology_Katzung. Scheiman JM: The use of proton pump inhibitors in treating and preventing NSAID-induced mucosal damage. Arthritis Res Ther 2013;15(Suppl 3):S5. Schubert ML: Gastric secretion. Curr Opin Gastroenterol 2014;30:578. Sigterman KE et al: Short-term treatment with proton pump inhibitors, H2-receptor antagonists, and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease. Cochrane Database Syst Rev 2013;5:CD002095. Camilleri M et al: Clinical guideline: Management of gastroparesis. Am J Gastroenterol 2013;108:18. Enweluzo C et al: Gastroparesis: A review of current and emerging treatment options. Clin Exp Gastroenterol 2013;6:161. Farmer AD: Diabetic gastroparesis: Pathophysiology, evaluation and management. Br J Hosp Med 2012;73:451. Bharucha AE et al: American Gastroenterological Association Medical Position Statement on constipation. Gastroenterology 2013;144:211.


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Pharmacology_Katzung. Bharucha AE et al: American Gastroenterological Association Medical Position Statement on constipation. Gastroenterology 2013;144:211. Brenner DM et al: Chronic constipation. Gastroenterol Clin North Am 2016;45:205. Brock C et al: Opioid-induced bowel dysfunction: Pathophysiology and management. Drugs 2012;72:1847. Ford AC et al: Laxatives for chronic constipation in adults. BMJ 2012;345:e6168. Johnson DA et al: Optimizing adequacy of bowel cleansing for colonoscopy: Recommendations from the US Multisociety Task Force on Colorectal Cancer. Gastroenterology 2014;147:903. Kilgore TW et al: Bowel preparation with split-dose polyethylene glycol before colonoscopy: A meta-analysis of randomized controlled trials. Gastrointest Endosc 2011;73:1240. Linaclotide (Linzess) for constipation. Med Lett Drugs Ther 2012;54:91. Schey R et al: Lubiprostone for the treatment of adults with constipation and irritable bowel syndrome. Dig Dis Sci 2011;56:1619.


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Pharmacology_Katzung. Schey R et al: Lubiprostone for the treatment of adults with constipation and irritable bowel syndrome. Dig Dis Sci 2011;56:1619. Wald A: Constipation: Advances in diagnosis and treatment. JAMA 2016;315:185. Camilleri M: Bile acid diarrhea: Prevalence, pathogenesis, and therapy. Gut Liver 2015;9:332. Kent AJ: Pharmacologic management of diarrhea. Gastroenterol Clin N Am 2010; 39:496. Li Z et al: Treatment of chronic diarrhea. Best Pract Clin Gastroenterol 2012; 26:677. Chang L et al: 2015 James W. Freston Topic Conference: A renaissance in the understanding and management of irritable bowel syndrome. Clin Gastroenterol Hepatol 2016;14:e77. Chey WD et al: Linaclotide for irritable bowel syndrome with constipation: A 26-week randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety. Am J Gastroenterol 2012;107:1702.


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Pharmacology_Katzung. Ford AC et al: American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol 2014;109(Suppl 1):S2. Lembo AJ et al: Eluxadoline for irritable bowel syndrome with diarrhea. N Engl J Med 2016;374(3):242. Vazquez RM et al: Linaclotide, a synthetic guanylate cyclase C agonist, for the treatment of functional gastrointestinal disorders associated with constipation. Exp Rev Gastroenterol Hepatol 2011;5:301. Basch E et al: Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline update. J Clin Oncol 2011;29:4189. Ettinger DS et al: Antiemesis. J Natl Canc Comp Netw 2012;10:456. Jordan K et al: Recent developments in the prevention of chemotherapy-induced nausea and vomiting (CINV): A comprehensive review. Ann Oncol 2015; 26:1081. Navarri R et al: Antiemetic prophylaxis for chemotherapy-induced nausea and vomiting. N Engl J Med 2016;374:1356.


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Pharmacology_Katzung. Navarri R et al: Antiemetic prophylaxis for chemotherapy-induced nausea and vomiting. N Engl J Med 2016;374:1356. Navarri R et al: Olanzapine for the prevention of chemotherapy-induced nausea and vomiting. N Engl J Med 2016;375:134. Bloomgren G et al: Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012;366:20. Bressler B et al: Clinical guidelines for the medical management of nonhospitalized ulcerative colitis: The Toronto consensus. Gastroenterology 2015;148:1035. Casteelle N et al: Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology 2015;148:1320. Cheifetz AS et al: Management of active Crohn disease. JAMA 2013;309:2150. Ford AC et al: Efficacy of biological therapies in inflammatory bowel disease: A systematic review and meta-analysis. Am J Gastroenterol 2011;106:644.


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Pharmacology_Katzung. Ford AC et al: Efficacy of biological therapies in inflammatory bowel disease: A systematic review and meta-analysis. Am J Gastroenterol 2011;106:644. Ford A et al: Efficacy of oral vs. topical, or combined oral and topical 5-aminosalicylates in ulcerative colitis: A systematic review and meta-analysis. Am J Gastroenterol 2012;107:167. Ford A et al: Ulcerative colitis. BMJ 2013;346:f432. Kotlyar DS et al: Risk of lymphoma in patients with inflammatory bowel disease treated with azathioprine and 6-mercaptopurine: A meta-analysis. Clin Gastroenterol Hepatol 2015;13:847. Mosli MH et al: Vedolizumab for induction and maintenance of remission in ulcerative colitis: A Cochrane systematic review and meta-analysis. Inflamm Bowel Dis 2015;21:1151. Ordas I: Ulcerative colitis. Lancet 2012;380:1606. Pola S et al: Strategies for the care of adults hospitalized for active ulcerative colitis. Clin Gastroenterol Hepatol 2012;10:1315.


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Pharmacology_Katzung. Ordas I: Ulcerative colitis. Lancet 2012;380:1606. Pola S et al: Strategies for the care of adults hospitalized for active ulcerative colitis. Clin Gastroenterol Hepatol 2012;10:1315. Sandborn WJ et al: Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2012;142:257. Sandborn WJ et al: Subcutaneous golimumab induces clinical response and remission in patients with moderate to severe ulcerative colitis. Gastroenterology 2014;146:85. Sandborn WJ et al: Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2014;146:96. Sandborn WJ et al: Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2013;369:711.


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Pharmacology_Katzung. Crohn’s disease. N Engl J Med 2013;369:711. Terdiman JP et al: American Gastroenterological Association Institute guide on the use of thiopurines, methotrexate, and anti-TNF-alpha biologic drugs for the induction and maintenance of remission in inflammatory Crohn’s disease. Gastroenterology 2013;145:1459. Forsmark C: Management of chronic pancreatitis. Gastroenterology 2013; 144:1282. Whitcomb DC et al: Pancrelipase delayed-release capsules (CREON) for exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatic surgery: A double-blind randomized trial. Am J Gastroenterol 2010;105:2276. Wier HA et al: Pancreatic enzyme supplementation. Curr Opin Pediatr 2011;23:541. Hempfling W, Dilger K, Beuers U: Systematic review: Ursodeoxycholic acid— Adverse effects and drug interactions. Aliment Pharmacol Ther 2003;18:963.


Pharmacology_Katzung

Pharmacology_Katzung. Hempfling W, Dilger K, Beuers U: Systematic review: Ursodeoxycholic acid— Adverse effects and drug interactions. Aliment Pharmacol Ther 2003;18:963. Hirschfield GM et al: Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 2015;148:751. Ahmed ME: Treatment of portal hypertension. World J Gastroenterol 2012; 18:1166. Garcia-Tsao G et al: Management of varices and variceal hemorrhage in cirrhosis. N Engl J Med 2010;362:823. Buchman AL: Teduglutide and short bowel syndrome: Every night without parenteral fluids is a good night. Gastroenterology 2012;143:1416. Jeppesen PB et al: Teduglutide reduces need for parenteral support among patients with short bowel syndrome with intestinal failure. Gastroenterology 2012;143:1473.


Pharmacology_Katzung

Pharmacology_Katzung. The immediate goals of therapy are to improve this young woman’s symptoms of abdominal pain, diarrhea, weight loss, and fatigue. Equally important goals are to reduce the intestinal inflammation in hopes of preventing progression to intestinal stenosis, fistulization, and need for surgery. One option now is to step up her therapy by giving her a slow, tapering course of systemic corticosteroids (eg, prednisone) for 8–12 weeks in order to quickly bring her symptoms and inflammation under control while also initiating therapy with an immunomodulator (eg, azathioprine or mercap-topurine) in hopes of achieving long-term disease remis-sion. If satisfactory disease control is not achieved within 3–6 months, therapy with an anti-TNF agent would then be recommended. Alternatively, patients with moderate-to-severe Crohn’s disease who have failed mesalamine may be treated upfront with both an anti-TNF agent and immu-nomodulators, which achieves higher remission rates than either agent alone and


Pharmacology_Katzung

Pharmacology_Katzung. Crohn’s disease who have failed mesalamine may be treated upfront with both an anti-TNF agent and immu-nomodulators, which achieves higher remission rates than either agent alone and may improve long-term outcomes.


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Pharmacology_Katzung. Therapeutic & Toxic Potential of Over-the-Counter Agents Valerie B. Clinard, PharmD, & Robin L. Corelli, PharmD


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Pharmacology_Katzung. Her social history is significant for alcohol use (three to four glasses of wine/night). Her vital signs include the following: temperature 99.8°F, blood pressure 132/64 mm Hg, pulse 78 bpm, and respiratory rate 15/min. On physical examination, she had left upper abdominal tenderness with evidence of hepatomegaly and mild scleral icterus. Laboratory data revealed the following: alanine aminotransferase, 527 IU/L (normal 10–35 IU/L); aspartate aminotransferase, 425 IU/L (normal < 35 IU/L); and bilirubin, 2.9 mg/dL (normal 0.1–0.3 mg/dL). What medications do OTC cold and flu preparations typically contain? Which of the OTC medications might have contrib-uted to the patient’s current symptoms? KH, a 55-year-old woman, presents to the emergency department with nausea, vomiting, and complaints of new-onset flu symptoms over the past several days. Her past medical history is significant for allergic rhinitis and chronic lower back pain secondary to a work-related fall 2 years ago. Her


Pharmacology_Katzung

Pharmacology_Katzung. of new-onset flu symptoms over the past several days. Her past medical history is significant for allergic rhinitis and chronic lower back pain secondary to a work-related fall 2 years ago. Her current medications include Norco 5/325 (hydrocodone 5 mg/ acetaminophen 325 mg per tablet; two tablets four times daily for pain) and loratadine (10 mg daily). The patient also reported recent use of several over-the-counter (OTC) medications over the past 3 days to treat the new-onset flu symptoms, including Alka-Seltzer Plus Severe Cold + Flu (two tablets every 4 hours during the day) and Tylenol PM (two tablets at bedtime).


Pharmacology_Katzung

Pharmacology_Katzung. In the USA, medications are divided by law into two classes: those restricted to sale by prescription only and those for which directions for safe use by the public can be written. The latter category constitutes the nonprescription, or over-the-counter (OTC), medications. This category does not include supplements (vitamins, minerals, herbals, and botanicals), which are subject to different regulatory requirements (see Chapter 64, Dietary Supplements & Herbal Medications). In 2016, the American public spent approximately $34 billion on OTC products to self-manage a wide variety of acute and chronic medical conditions.


Pharmacology_Katzung

Pharmacology_Katzung. It is apparent that many OTC medications are comparable products advertised to consumers in ways that suggest significant differences between them. For example, there are over 100 different systemic analgesic products, almost all of which contain aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, or a combination of these agents as primary ingredients. They are made different from one another by the addition of questionable ingredients such as caffeine or antihistamines; by brand names chosen to suggest a specific use or strength (eg, “women’s,” “migraine,” “arthritis,” “maximum”); or by special dosage formulations (eg, enteric-coated tablets, gel tabs, liquids, orally disintegrating strips and tablets, sustained-release products, powders, seltzers). Generally, a price is attached to all of these features, and in most cases, a less expensive generic product can be equally effective. It is probably safe to assume that the public is generally


Pharmacology_Katzung

Pharmacology_Katzung. Generally, a price is attached to all of these features, and in most cases, a less expensive generic product can be equally effective. It is probably safe to assume that the public is generally overwhelmed and confused by the wide array of products presented and will likely use those that are most heavily advertised.


Pharmacology_Katzung

Pharmacology_Katzung. Since 1972, the US Food and Drug Administration (FDA) has been engaged in a methodical review of OTC ingredients for both safety and efficacy. There have been two major outcomes of this review: (1) Ingredients designated as ineffective or unsafe for their claimed therapeutic use are being eliminated from OTC product formulations (eg, antimuscarinic agents have been eliminated from OTC sleep aids; attapulgite and polycarbophil can no longer be marketed as OTC antidiarrheal products); and (2) agents previously available by prescription only have been made available for OTC use because they were judged by the review panel to be generally safe and effective for consumer use without medical supervision (Table 63–1). The prescription-to-OTC switch process has significantly enhanced and expanded self-care options for US consumers. More than 100 OTC active ingredients or dosages are on the market today that were previously available only by prescription. Other OTC ingredients previously


Pharmacology_Katzung

Pharmacology_Katzung. self-care options for US consumers. More than 100 OTC active ingredients or dosages are on the market today that were previously available only by prescription. Other OTC ingredients previously available in low doses only are now available in original prescription strength formulations (eg, ranitidine 150 mg, famotidine 20 mg). Examples of other prescription medications with the potential for future OTC reclassification include oral contraceptives, nicotine replacement therapy (oral inhaler, nasal spray) for smoking cessation, proton-pump inhibitors (pantoprazole) for heartburn, and second-generation nonsedating antihistamines (desloratadine) for relief of allergy and cold symptoms. The prescription-to-OTC reclassification process is both costly and rigorous, and only select prescription medications are appropriate candidates for a switch (eg, a consumer can self-diagnose and safely treat the condition). For example, the cholesterol-lowering agents lovastatin and pravastatin were


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Pharmacology_Katzung. medications are appropriate candidates for a switch (eg, a consumer can self-diagnose and safely treat the condition). For example, the cholesterol-lowering agents lovastatin and pravastatin were denied OTC status on the basis that these agents could not be used safely and effectively in an OTC setting. The nonprescription drug advisory committee believed that diagnosis and ongoing management by a health care professional was necessary for the management of hyperlipidemia, a chronic, asymptomatic condition with potentially life-threatening consequences. In a similar recommendation, oral acyclovir for OTC use in the treatment of recurrent genital herpes was not approved because of concerns about misdiagnosis and inappropriate use leading to increased viral resistance.


Pharmacology_Katzung

Pharmacology_Katzung. There are three reasons why it is essential for clinicians to be familiar with the OTC class of products. First, many OTC medications are effective in treating common ailments, and it is important to be able to help the patient select a safe, effective product. Because health care insurance practices encourage clinicians to reduce costs, many providers will recommend effective OTC treatments, since these medications are rarely paid for by health plans. Second, many of the active ingredients contained in OTC medications may worsen existing medical conditions or interact with prescription medications (see Chapter 66, Important Drug Interactions & Their Mechanisms). Finally, the misuse or abuse of OTC products may actually produce significant medical complications. Phenylpropanolamine, for example, a sympathomimetic previously found in many cold, allergy, and weight control products, was withdrawn from the US market by the FDA based on reports that the drug increased the risk of


Pharmacology_Katzung

Pharmacology_Katzung. for example, a sympathomimetic previously found in many cold, allergy, and weight control products, was withdrawn from the US market by the FDA based on reports that the drug increased the risk of hemorrhagic stroke. Dextromethorphan, an antitussive found in many cough and cold preparations, has been increasingly abused in high doses (eg, >5–10 times the recommended antitussive dose) by adolescents as a hallucinogen. Although severe complications associated with dextromethorphan as a single agent in overdose are uncommon, many dextromethorphan-containing products


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Pharmacology_Katzung. TABLE 63–1 Selected agents switched from prescription to over-the-counter status by the US Food and Drug Administration (2006–2017). are formulated with other ingredients (acetaminophen, antihistamines, and sympathomimetics) that can be fatal in overdose. Loperamide is sometimes used in large doses to create an opioid-like high or to self-treat opioid withdrawal symptoms. In large doses, loperamide may cross the blood-brain barrier and cause altered mental status and respiratory depression; additionally, loperamide may induce ventricular arrhythmias in supratherapeutic doses. Pseudoephedrine, a decongestant contained in numerous OTC cold preparations, has been used in the illicit manufacture of methamphetamine. A general awareness of these products and their formulations will enable clinicians to more fully appreciate the potential for OTC medication-related problems in their patients.


Pharmacology_Katzung

Pharmacology_Katzung. Table 63–2 lists examples of OTC products that may be used effectively to treat common medical problems. The selection of one ingredient over another may be important in patients with certain medical conditions or in patients taking other medications. These are discussed in detail in other chapters. TABLE 63–2 Ingredients of known efficacy for selected over-the-counter (OTC) classes. Ranitidine (Zantac 75, Zantac 150) Fexofenadine (Allegra 12 hour, Allegra 24 hour) Loratadine (Alavert, Claritin) Relief and prevention of heartburn associated with acid indigestion. Treatment of frequent heartburn (occurs 2 or more days a week). Temporary relief of the following symptoms due to hay fever or upper respiratory allergies: sneezing, runny nose, itchy, watery eyes, itching of nose or throat.


Pharmacology_Katzung

Pharmacology_Katzung. Temporary relief of the following symptoms due to hay fever or upper respiratory allergies: sneezing, runny nose, itchy, watery eyes, itching of nose or throat. Avoid use: in children <12 years of age; if patient has trouble or pain swallowing food, vomiting with blood, or bloody or black stools; with other acid reducers; if symptoms include heartburn with lightheadedness, sweating, dizziness, or chest pain; for treatment durations >14 days. Adverse effects include: nausea, agitation, headache, dizziness, agitation, and gynecomastia (cimetidine; rare). Avoid use: in children <18 years of age; if patient has trouble or pain swallowing food, vomiting with blood, or bloody or black stools; if symptoms include heartburn with lightheadedness, sweating, dizziness, or chest pain; for treatment durations >14 days. Adverse effects include: headache, abdominal pain, nausea, diarrhea, and flatulence.


Pharmacology_Katzung

Pharmacology_Katzung. Adverse effects include: headache, abdominal pain, nausea, diarrhea, and flatulence. Avoid use: in children <2 years of age; in combination with other sedatives and alcohol as sedative effects may be potentiated. Use caution when driving or operating machinery. Adverse effects include: drowsiness, dizziness, fatigue, nausea, and urinary retention. Antihistamines are contained in many OTC preparations in combination with analgesics, decongestants, and expectorants. See the warnings section for each formulation. To prevent symptoms, take 30–60 minutes before consuming food or beverages that cause heartburn. Cimetidine may increase the serum concentrations of theophylline, warfarin, and phenytoin. Not intended for immediate relief (products take 1–4 days for full effect). Take with water before eating in the morning. Patients may repeat a 2-week course of therapy every 4 months. PPI therapy can increase risk of Clostridium difficile-associated diarrhea and risk of fracture.


Pharmacology_Katzung

Pharmacology_Katzung. Patients may repeat a 2-week course of therapy every 4 months. PPI therapy can increase risk of Clostridium difficile-associated diarrhea and risk of fracture. Esomeprazole, lansoprazole, and omeprazole may interact with warfarin, clopidogrel, cilostazol, antifungal medications, diazepam, digoxin, tacrolimus, and HIV antiretrovirals. Diphenhydramine is the most sedating antihistamine. Consult product labeling before use in children ages 2–11 years. First-generation antihistamines (chlorpheniramine, clemastine, diphenhydramine) may cause excitability in children. Second-generation antihistamines (cetirizine, fexofenadine, levocetirizine, loratadine) have minimal anticholinergic effects and are associated with lower chances of sedation. TABLE 63–2 Ingredients of known efficacy for selected over-the-counter (OTC) classes. (Continued)


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 63–2 Ingredients of known efficacy for selected over-the-counter (OTC) classes. (Continued) Temporary relief of upset stomach with heartburn, acid indigestion, and sour stomach. Products containing simethicone are used for relief of bloating, pressure, or gas symptoms. To control symptoms of diarrhea (including traveler’s diarrhea). Bismuth-containing products are also used to relieve upset stomach symptoms (indigestion, heartburn, nausea, gas, belching). Avoid use in patients with: severe renal impairment (aluminumand sodium-containing products); heart failure or high blood pressure (sodium-containing products). Adverse effects include: diarrhea (magnesium preparations) and constipation (aluminum preparations). Avoid use in patients: taking salicylate products; with allergies to aspirin; with bleeding disorders; with peptic ulcer disease; with bloody or black stool; in children or teenagers with chickenpox or flu-like symptoms due to an increased risk of Reye’s syndrome.


Pharmacology_Katzung

Pharmacology_Katzung. Combinations of magnesium and aluminum hydroxide are less likely to cause constipation or diarrhea and offer high neutralizing capacity. With prolonged use, antacids may cause “acid rebound” (paradoxical acid hyper-secretory state associated with increased gastrin levels). Antacids can significantly reduce the absorption of many prescription drugs. Antidiarrheal agents should not be used if diarrhea occurs with fever >100°F or if blood or mucus present in stool. Bismuth-containing products may be used as part of combination therapy for Helicobacter pylori eradication therapy. Loperamide, a synthetic opioid, is not considered a controlled substance but is sometimes abused in high doses for euphoric opioid-like effects. TABLE 63–2 Ingredients of known efficacy for selected over-the-counter (OTC) classes. (Continued) Miconazole (Desenex, Lotrimin AF) Miconazole (Monistat-1, Monistat-3, Monistat-7, Vagistat-3) Tioconazole (Monistat-1 1-Day, Vagistat-1)


Pharmacology_Katzung

Pharmacology_Katzung. Miconazole (Desenex, Lotrimin AF) Miconazole (Monistat-1, Monistat-3, Monistat-7, Vagistat-3) Tioconazole (Monistat-1 1-Day, Vagistat-1) Dextromethorphan (Delsym, Robitussin Cough, Vicks 44) Relieves itching, burning, scaling, chafing, and discomfort associated with tinea pedis (athlete’s foot), tinea cruris (jock itch), and tinea corporis (ringworm). Treatment of vaginal yeast (candidiasis) infections and for the relief of external vulvar itching and irritation associated with vaginal yeast infections. Temporary relief of cough due to minor throat and bronchial irritation with the common cold or inhaled irritants. For external use only. Avoid contact with eyes, nose, mouth, or other mucous membranes. Avoid use: in children <2 years of age (clotrimazole, miconazole, tolnaftate) or children <12 years of age (butenafine, terbinafine). Adverse effects include: erythema, irritation, itching, and burning.


Pharmacology_Katzung

Pharmacology_Katzung. Adverse effects include: erythema, irritation, itching, and burning. For vaginal use only. Avoid use: in children <12 years of age; if patient has lower abdominal, back, or shoulder pain, or fever, chills, nausea, vomiting, or foul-smelling vaginal discharge; in combination with tampons, douches, spermicides, or other vaginal products. Adverse effects include: vaginal itching, burning, vaginal soreness, and swelling. Avoid use: in patients taking a monoamine oxidase inhibitor (MAOI), or for 2 weeks after discontinuation of an MAOI. Use with caution in patients with a chronic cough that occurs with smoking, asthma, and emphysema and in patients with cough with production of mucus. Adverse effects include: confusion, excitement, irritability, nervousness, and serotonin syndrome (uncommon). For treatment of athlete’s foot, apply product to spaces between toes and change shoes and socks daily.


Pharmacology_Katzung

Pharmacology_Katzung. For treatment of athlete’s foot, apply product to spaces between toes and change shoes and socks daily. Topical vaginal antifungals should only be used for treatment of recurrent vulvovaginal candidiasis in healthy, nonpregnant women who were previously diagnosed by a clinician. Therapy should be discontinued if symptoms do not improve within 3 days or if symptoms persist after 7 days of treatment. Vaginal products (7-day therapy preferred) can be used for treatment in pregnant women. Products with similar brand names may contain different antifungal products; read labels and instructions for use carefully. Condoms and diaphragms may be damaged by the products and fail to prevent pregnancy or sexually transmitted disease. Dextromethorphan is a nonopioid congener of levorphanol without analgesic or addictive properties. Health care providers should be alert for problems of abuse or misuse. Often used with antihistamines, decongestants, and expectorants in combination products.


Pharmacology_Katzung

Pharmacology_Katzung. Often used with antihistamines, decongestants, and expectorants in combination products. Notify provider if symptoms do not improve in 7 days or are accompanied by fever, rash, or persistent headache. TABLE 63–2 Ingredients of known efficacy for selected over-the-counter (OTC) classes. (Continued) Decongestants, Phenylephrine systemic (Sudafed PE) Polycarbophil, psyllium, and methylcellulose preparations (Citrucel, Fibercon, Metamucil) Temporary relief of sinus congestion and pressure. Temporarily relieves nasal congestion due to the common cold, hay fever, or other upper respiratory allergies. To prevent pregnancy following unprotected intercourse or possible contraceptive failure. Used to help loosen phlegm (mucus) and thin bronchial secretions to make cough more productive. Temporary relief of occasional constipation and irregularity.


Pharmacology_Katzung

Pharmacology_Katzung. Used to help loosen phlegm (mucus) and thin bronchial secretions to make cough more productive. Temporary relief of occasional constipation and irregularity. Avoid use: in patients taking an MAOI or for 2 weeks after stopping the MAOI. Use with caution in patients with heart disease; high blood pressure; diabetes; thyroid disease; trouble urinating due to an enlarged prostate gland. Adverse effects include: arrhythmias, tachycardia, high blood pressure, anxiety, headache, dizziness, tremor, and insomnia. Avoid use in the case of known or suspected pregnancy. Adverse effects include: heavier menstrual bleeding, nausea, lower abdominal pain, fatigue, headache, dizziness, and breast tenderness. Avoid use in children <2 years of age. Adverse effects include: nausea, vomiting, stomach pain, and dizziness. Avoid use in patients with difficulty swallowing. Avoid use in patients with kidney disease.


Pharmacology_Katzung

Pharmacology_Katzung. Adverse effects include: nausea, vomiting, stomach pain, and dizziness. Avoid use in patients with difficulty swallowing. Avoid use in patients with kidney disease. May be found in combination with antihistamine, antitussives, expectorants, and analgesic products. Extended-release pseudoephedrine products should not be used in children <12 years of age. Federal regulations established to discourage the illicit manufacture of methamphetamine specify that all drug products containing pseudoephedrine must be stored in locked cabinets or behind the pharmacy counter and can only be sold in limited quantities to consumers after they provide photo identification and are entered into a registry. Available only by prescription for women <17 years of age. Should be taken as soon as possible within 72 hours after unprotected intercourse. If vomiting occurs within 2 hours of taking the tablet, the dose may need to be repeated.


Pharmacology_Katzung

Pharmacology_Katzung. Should be taken as soon as possible within 72 hours after unprotected intercourse. If vomiting occurs within 2 hours of taking the tablet, the dose may need to be repeated. Use backup contraceptive after administration. Patients taking oral contraceptives regularly should also use backup contraception, such as condom, until next period cycle starts. The only OTC expectorant recognized as safe and effective by the FDA. Often used with antihistamines, decongestants, and antitussives in combination products. Administer with a large quantity of fluids for best results. When used for self-care, do not use extended-release tablets in children <12 years of age. The safest laxatives for chronic use include bulk formers and stool softeners. The bulk formers in powder formulation must be taken with adequate fluid for optimal effect and to avoid choking. TABLE 63–2 Ingredients of known efficacy for selected over-the-counter (OTC) classes. (Continued)


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Pharmacology_Katzung. TABLE 63–2 Ingredients of known efficacy for selected over-the-counter (OTC) classes. (Continued) Pyrethrins combined with piperonyl butoxide (RID) Treatment of overactive bladder for women with symptoms of urge incontinence and urinary urgency and frequency for at least 3 months. Treatment of head lice (permethrincontaining products); and pubic and body lice (piperonyl butoxidecontaining products). Avoid use in: men; women <18 years of age; patients with symptoms of a urinary tract infection (pain or burning when urinating, blood in urine, unexplained lower back pain, urine that is cloudy or foul smelling). Adverse effects include: sleepiness, dizziness, confusion, dry mouth, constipation, and blurred vision. For external use only. Avoid use: if allergic to ragweed; in children <2 years of age; near the eyes; inside the nose, mouth, or vagina; on lice in eyebrows or eyelashes. Adverse effects include: itching and redness at the application sites.


Pharmacology_Katzung

Pharmacology_Katzung. Adverse effects include: itching and redness at the application sites. Women should consult with their physician about symptoms before using this product. Women who only experience accidental urine loss when coughing, sneezing, or laughing may have stress incontinence; this product is not effective for this condition. The OTC patch formulation contains the same dosage as the prescription product. One patch should be applied to abdomen, hips, or buttocks every 4 days; alternating sites. Proper use requires careful inspection and thorough application of the products (10 minutes) to the affected areas. Following application, lice and nits (eggs) should be removed with a fine-tooth comb. Kills live lice (neurotoxic), but is not effective for eggs (nits). Therefore, repeat process in 7-10 days to kill newly hatched nits.


Pharmacology_Katzung

Pharmacology_Katzung. Kills live lice (neurotoxic), but is not effective for eggs (nits). Therefore, repeat process in 7-10 days to kill newly hatched nits. Clothing, bed linens, and other items that the infested person wore or used during the 2 days before treatment should be washed using the hot water (130°F) cycle and dried using the high heat cycle. CHAPTER 63 Therapeutic & Toxic Potential of Over-the-Counter Agents 1127 TABLE 63–2 Ingredients of known efficacy for selected over-the-counter (OTC) classes. (Continued) The recommendations listed in Table 63–2 are based on the efficacy of the ingredients and on the principles set forth in the following paragraphs. 1.


Pharmacology_Katzung

Pharmacology_Katzung. The recommendations listed in Table 63–2 are based on the efficacy of the ingredients and on the principles set forth in the following paragraphs. 1. Select the product that is simplest in formulation; in general, single-ingredient products are preferred. Combination products may contain effective doses of some ingredients and subtherapeutic doses of others. Furthermore, there may be differing durations of action among the ingredients, and there is always a possibility that the clinician or patient is unaware of the presence of certain active ingredients in the product. 2. Select a product that contains a therapeutically effective dose. 3.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Select a product that contains a therapeutically effective dose. 3. Consumers and providers should carefully read the “Drug Facts” label (Figure 63–1) to determine which ingredients are appropriate based on the patient’s symptoms, underlying health conditions, and whatever is known about the medications the patient is already taking. Many products with the same brand name contain different ingredients that are labeled for different uses. For example, multiple products (with different active ingredients) carry the Allegra name, including Allegra Allergy (fexofenadine), Allegra-D (fexofenadine and pseudoephedrine), and Allegra Anti-Itch Cream (allantoin and diphenhydramine). 4. Recommend a generic product if one is available. 5. Be wary of claims of specific superiority over similar products. 6. For children, the dose, dosage form, and palatability of the product are prime considerations.


Pharmacology_Katzung

Pharmacology_Katzung. Certain ingredients in OTC products should be avoided or used with caution in selected patients because they may exacerbate existing medical problems or interact with other medications the patient is taking. The presence of many of the more potent OTC ingredients may be unexpectedly hidden in products (Table 63–3). Although OTC medications have standardized label formatting and content requirements (Figure 63–1), many consumers do not carefully read or comprehend this information. Lack of awareness of the ingredients in OTC products and the belief by many patients and providers that OTC products are ineffective and harmless may cause diagnostic confusion and compromise therapeutic management. For example, innumerable OTC products, including analgesics and allergy, cough, and cold preparations, contain sympathomimetics. These agents should be avoided or used cautiously by patients with type 1 diabetes and patients with hypertension, angina, or hyperthyroidism. Aspirin should not be


Pharmacology_Katzung

Pharmacology_Katzung. contain sympathomimetics. These agents should be avoided or used cautiously by patients with type 1 diabetes and patients with hypertension, angina, or hyperthyroidism. Aspirin should not be used in children and adolescents for viral infections (with or without fever) because of an increased risk of Reye’s syndrome. Aspirin and other NSAIDs should be avoided by individuals with active peptic ulcer disease, certain platelet disorders and patients taking oral anticoagulants. Cimetidine, an H2 antagonist, is a well-known inhibitor of hepatic drug metabolism and can increase the blood levels and toxicity of agents such as phenytoin, theophylline, and warfarin.


Pharmacology_Katzung

Pharmacology_Katzung. Overuse or misuse of OTC products may cause significant medical problems. A prime example is rhinitis medicamentosa or “rebound rhinitis,” a condition that manifests as nasal congestion without rhinorrhea, associated with the regular use of topical decongestant nasal sprays for more than 3 days. The improper and long-term use of some antacids (eg, aluminum hydroxide) may cause constipation and even impaction in the elderly, as well as hypophosphatemia. Long-term laxative use can result in abdominal cramping and fluid and electrolyte disturbances. A condition known as laxative abuse syndrome is often observed in women with anorexia nervosa. Insomnia, nervousness, and restlessness can result from the use of sympathomimetics or caffeine present in many OTC products (Table 63–3). The long-term use of analgesics containing caffeine may trigger rebound headaches upon discontinuation. OTC products containing aspirin, other salicylates, acetaminophen, ibuprofen, or naproxen may increase the


Pharmacology_Katzung

Pharmacology_Katzung. use of analgesics containing caffeine may trigger rebound headaches upon discontinuation. OTC products containing aspirin, other salicylates, acetaminophen, ibuprofen, or naproxen may increase the risk of hepatotoxicity and gastrointestinal hemorrhage in individuals who consume three or more alcoholic drinks daily, and long-term use of these products has been associated with interstitial nephritis. Acute ingestion of large amounts of


Pharmacology_Katzung

Pharmacology_Katzung. Chlorpheniramine maleate 2 mg . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Antihistamine Uses temporarily relieves these symptoms due to hay fever or other upper respiratory allergies: Sneezing Runny nose Itchy, watery eyes Itchy throat A breathing problem such as emphysema or chronic bronchitis Trouble urinating due to an enlarged prostate gland Ask a doctor or pharmacist before use if you are taking tranquilizers or sedatives Avoid alcoholic drinks Alcohol, sedatives, and tranquilizers may increase drowsiness Be careful when driving a motor vehicle or operating machinery Excitability may occur, especially in children If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. Inactive ingredients D&C yellow no. 10, lactose, magnesium stearate, microcrystalline cellulose, pregelatinized starch


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 63–1 Typical FDA-required labeling for an over-the-counter antihistamine. The label must contain, in the following order: active ingredient(s), including the amount in each dosage unit; purpose of product (pharmacologic action); use(s) for product (indication); specific warnings, including when the product should not be used and pregnancy information; when the patient should seek care of a health care provider; side effects and substances or activities to avoid; dosage instructions (when, how, and how often to take medication); and inactive ingredients. Additional requirements include, but are not limited to, the following: type size must be large enough to be easily read, >6-point font type for information in drug facts section; bullets must be solid square or circle 5-point type; and directions in table format for dosage instructions when presented for three or more age groups or populations. Image from http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ ucm143551.htm


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Pharmacology_Katzung. TABLE 63–3 Hidden ingredients in over-the-counter (OTC) products. acetaminophen by adults or children can cause serious, and often fatal, hepatotoxicity (see Chapter 4). Antihistamines may cause sedation or drowsiness, especially when taken concurrently with sedative-hypnotics, tranquilizers, alcohol, or other central nervous system depressants.


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Pharmacology_Katzung. Finally, use of OTC cough and cold preparations in the pediatric population has been under scrutiny by the FDA based on a lack of efficacy data in children less than 12 years of age and reports of serious toxicity in children. Following a thorough review, the FDA recommends that OTC cough and cold agents (eg, products containing antitussives, expectorants, decongestants, and antihistamines) not be used in infants and children younger than 2 years old due to serious and potentially life-threatening adverse events associated with accidental overdose including arrhythmias, hallucinations, and encephalopathy. Drug information sources for OTC products include the Handbook of Nonprescription Drugs, the most comprehensive resource for OTC medications. It evaluates ingredients contained in major OTC drug classes and lists the ingredients included in many OTC products. Facts and Comparisons eAnswers is an online reference that is updated monthly; it provides detailed OTC product information


Pharmacology_Katzung

Pharmacology_Katzung. OTC drug classes and lists the ingredients included in many OTC products. Facts and Comparisons eAnswers is an online reference that is updated monthly; it provides detailed OTC product information and patient counseling instructions. Any health care provider who seeks more specific information regarding OTC products may find useful the references listed below.


Pharmacology_Katzung

Pharmacology_Katzung. US Food and Drug Administration: Drug applications for over-the-counter drugs. http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm143551. Consumer Healthcare Products Association website: http://www.chpa.org/. htm. Handbook of Nonprescription Drugs, 18th ed. American Pharmacists Association, US National Library of Medicine: DailyMed. https://dailymed.nlm.nih.gov/ 2015. dailymed/index.cfm. Facts and Comparisons eAnswers (online). Wolters Kluwer Health, 2017.


Pharmacology_Katzung

Pharmacology_Katzung. Combination OTC “cold and flu” medications typically contain analgesics (eg, acetaminophen, aspirin), antihistamines (eg, chlorpheniramine, diphenhydramine), antitussives (eg, dextromethorphan), expectorants (eg, guaifenesin), and nasal decongestants (eg, phenylephrine, pseudoephedrine). KH’s chronic prescription medications include a narcotic analgesic combination product that provides 2600 mg of acetamino-phen and 40 mg of hydrocodone. Over the past few days, KH has added two different OTC acetaminophen-containing products including Alka-Seltzer Plus Severe Cold + Flu (650 mg acetaminophen/2 tablets) every 4 hours and Tylenol PM (1000 mg acetaminophen/2 tablets) at bedtime. The clini-cian should obtain a detailed medication history to determine the actual total dose of acetaminophen consumed, but it is likely that KH has ingested more than 6 g of acetaminophen daily over the past 72 hours. This cumulative dosage, coupled with KH’s chronic ethanol consumption (three to four glasses


Pharmacology_Katzung

Pharmacology_Katzung. but it is likely that KH has ingested more than 6 g of acetaminophen daily over the past 72 hours. This cumulative dosage, coupled with KH’s chronic ethanol consumption (three to four glasses of wine daily), significantly potentiates the risk for acet-aminophen hepatotoxicity. In the USA, unintentional acet-aminophen overdose is a leading cause of acute liver failure. The warnings section on all OTC acetaminophen-containing products clearly state that severe liver damage may occur when consumers: (1) take dosages >4000 mg in 24 hours; (2) use acetaminophen in combination with other drugs containing acetaminophen; or (3) take acetaminophen and drink three or more alcoholic beverages daily. Unfortunately, many consum-ers do not carefully read OTC medication labels, and many do not appreciate the amount of acetaminophen “hidden” in combination prescription and OTC products.


Pharmacology_Katzung

Pharmacology_Katzung. Cathi E. Dennehy, PharmD, & Candy Tsourounis, PharmD


Pharmacology_Katzung

Pharmacology_Katzung. A 53-year-old woman with a history of knee osteoarthritis, high cholesterol, type 2 diabetes, and hypertension presents with new onset of hot flashes and a question about a dietary supplement. She is obese (body mass index [BMI] 33), does not exercise, and spends a good portion of her work day in a seated position. She eats a low-sugar diet and regularly eats packaged frozen meals for dinner because she doesn’t have time to cook regularly. Her most recent laboratory values include a low-density lipoprotein (LDL) cholesterol that is above goal at 160 mg/dL (goal < 100 mg/dL) and a hemo-globin A1c that is well controlled at 6%. Her blood pressure is high at 160/100 mm Hg. Her prescription medications include simvastatin, metformin, and benazepril. She also takes over-the-counter ibuprofen for occasional knee pain and a multivitamin supplement once daily. She has heard good things about natural products and asks you if taking a garlic supplement daily could help to bring her blood


Pharmacology_Katzung

Pharmacology_Katzung. for occasional knee pain and a multivitamin supplement once daily. She has heard good things about natural products and asks you if taking a garlic supplement daily could help to bring her blood pres-sure and cholesterol under control. She’s also very interested in St. John’s wort after a friend told her that it helped allevi-ate her hot flashes and could also help improve mood. How should you advise her? Are there any supplements that could increase bleeding risk if taken with ibuprofen?


Pharmacology_Katzung

Pharmacology_Katzung. The medical use of plants in their natural and unprocessed form undoubtedly began when the first intelligent animals noticed that certain food plants altered particular body functions. While there is a great deal of historical information about the use of plant-based supplements, there is also much unreliable information as a result of unknown or poor-quality natural product formulations, poorly designed clinical studies that do not account for randomization errors, confounders, and—most importantly—a placebo effect that can contribute 30–50% of the observed response. Since the literature surrounding dietary supplements is evolving, reputable evidence-based resources should be used to evaluate claims and guide treatment decisions. An unbiased and regularly updated compendium of basic and clinical information regarding botanicals is Natural Medicines by Therapeutic Research Center (see References), which includes content review by an international, * The US Food and Drug Administration


Pharmacology_Katzung

Pharmacology_Katzung. information regarding botanicals is Natural Medicines by Therapeutic Research Center (see References), which includes content review by an international, * The US Food and Drug Administration (FDA) recognizes “herbal medication” and “botanical medication” as “dietary supplements.” For the purposes of this chapter, they are identical.


Pharmacology_Katzung

Pharmacology_Katzung. multidisciplinary, collaborative review committee of experts. The recommendations in this database are limited by the quality of the existing research and the quality of the dietary supplement used at the time of the report. As a result, all statements regarding positive benefits should be regarded as preliminary, and conclusions regarding safety should be considered tentative at this time.


Pharmacology_Katzung

Pharmacology_Katzung. For legal purposes, “dietary supplements” are distinguished from “prescription drugs” derived from plants (morphine, digitalis, atropine, etc) by virtue of being available without a prescription and, unlike “over-the-counter medications,” are legally considered dietary supplements rather than drugs. This distinction eliminates the need for proof of efficacy and safety prior to marketing and also places the burden of proof on the FDA to prove that a supplement is harmful before it can be removed from the market or its use can be restricted. Furthermore, marketed dietary supplements are not tested for dose-response relationships or toxicity, and there is a lack of adequate testing for mutagenicity, carcinogenicity, and teratogenicity. Although manufacturers are prohibited from marketing unsafe or ineffective products, the FDA has met significant challenges from the supplement industry largely due to the strong lobbying effort by supplement manufacturers and the variability in


Pharmacology_Katzung

Pharmacology_Katzung. unsafe or ineffective products, the FDA has met significant challenges from the supplement industry largely due to the strong lobbying effort by supplement manufacturers and the variability in interpretation of the Dietary Supplement Health and Education Act (DSHEA). The DSHEA defines dietary supplements as vitamins, minerals, herbs or other botanicals, amino acids or dietary supplements used to supplement the diet by increasing dietary intake, or concentrates, metabolites, constituents, extracts, or any combination of these ingredients. For the purposes of this chapter, plant-based substances and certain synthetic purified chemicals will be referred to as dietary supplements. Among the purified chemicals, glucosamine, coenzyme Q10, and melatonin are of significant pharmacologic interest. Ephedrine, the active principle in Ma-huang, is discussed in Chapter 9.


Pharmacology_Katzung

Pharmacology_Katzung. This chapter provides some historical perspective and describes the evidence provided by randomized, double-blind, placebo-controlled trials, meta-analyses, and systematic reviews involving several of the most commonly used agents in this class. Health care providers should adhere to the principles of “do no harm” but also, because patients are strongly influenced by popular opinion and media reports, be open to therapies that support “integrative health” safely and responsibly. Unproven therapies that are marketed as “alternatives” to conventional medicine should be viewed with caution, but therapies that are supported by evidence-based medicine and have been assessed for benefits and risks when used in combination with conventional medicine can be viewed favorably, especially if a patient expresses an interest in, and a desire to utilize, dual treatment approaches.


Pharmacology_Katzung

Pharmacology_Katzung. Under the DSHEA, dietary supplements are not considered overthe-counter drugs in the USA but rather food supplements used for health maintenance. Legally, dietary supplements are intended to supplement the diet, but consumers may use them in the same fashion as drugs and even use them in place of drugs or in combination with drugs.


Pharmacology_Katzung

Pharmacology_Katzung. In 1994, the US Congress, influenced by growing “consumerism” as well as strong manufacturer lobbying efforts, passed the DSHEA. The DSHEA required the establishment of Good Manufacturing Practice (GMP) standards for the supplement industry; however, it was not until 2007 that the FDA issued a final rule on the proposed GMP standards. This 13-year delay allowed supplement manufacturers to self-regulate the manufacturing process and resulted in many instances of adulteration, misbranding, and contamination. For example, a study using DNA barcoding to confirm botanical content evaluated 44 botanicals containing 30 plant species and found product substitutions in 32% of samples (see Newmaster reference). Therefore, much of the criticism regarding the dietary supplement industry involves problems with botanical misidentification, a lack of product purity, and variations in potency and purification, which continue to be problematic even with GMP standards in place. When the new GMP