Part 2 book “Basic & clinical pharmacology” has contents: Agents used in dyslipidemia, drugs used in disorders of coagulation, hypothalamic & pituitary hormones, thyroid & antithyroid drugs, adrenocorticosteroids & adrenocortical antagonists, cancer chemotherapy, antimycobacterial drugs,… and other contents.
SECTION VI DRUGS USED TO TREAT DISEASES OF THE BLOOD, INFLAMMATION, & GOUT 33 C Agents Used in Cytopenias; Hematopoietic Growth Factors H A P T E R James L Zehnder, MD* C ASE STUDY A 25-year-old woman who has been on a strict vegan diet for the past years presents with increasing numbness and paresthesias in her extremities, generalized weakness, a sore tongue, and gastrointestinal discomfort Physical examination reveals a pale woman with diminished vibration sensation, diminished spinal reflexes, and extensor plantar reflexes (Babinski sign) Examination of her oral cavity reveals atrophic glossitis, in which the tongue appears deep red in color and abnormally smooth and shiny due to atrophy of the lingual papillae Laboratory testing reveals a macrocytic anemia based on a hematocrit of 30% (normal for Hematopoiesis, the production from undifferentiated stem cells of circulating erythrocytes, platelets, and leukocytes, is a remarkable process that produces more than 200 billion new * The author acknowledges contributions of the previous author of this chapter, Susan B Masters, PhD women, 37–48%), a hemoglobin concentration of 9.4 g/dL, an erythrocyte mean cell volume (MCV) of 123 fL (normal, 84–99 fL), an erythrocyte mean cell hemoglobin concentration (MCHC) of 34% (normal, 31–36%), and a low reticulocyte count Further laboratory testing reveals a normal serum folate concentration and a serum vitamin B12 (cobalamin) concentration of 98 pg/mL (normal, 250–1100 pg/mL) Once megaloblastic anemia was identified, why was it important to measure serum concentrations of both folic acid and cobalamin? Should this patient be treated with oral or parenteral vitamin B12? blood cells per day in the normal person and even greater numbers of cells in persons with conditions that cause loss or destruction of blood cells The hematopoietic machinery resides primarily in the bone marrow in adults and requires a constant supply of three essential nutrients—iron, vitamin B12, and folic acid—as well as the presence of hematopoietic growth factors, proteins 591 592 SECTION VI Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout that regulate the proliferation and differentiation of hematopoietic cells Inadequate supplies of either the essential nutrients or the growth factors result in deficiency of functional blood cells Anemia, a deficiency in oxygen-carrying erythrocytes, is the most common deficiency and several forms are easily treated Sickle cell anemia, a condition resulting from a genetic alteration in the hemoglobin molecule, is common but is not easily treated It is discussed in the Box: Sickle Cell Disease and Hydroxyurea Thrombocytopenia and neutropenia are not rare, and some forms are amenable to drug therapy In this chapter, we first consider treatment of anemia due to deficiency of iron, vitamin B12, or folic acid and then turn to the medical use of hematopoietic growth factors to combat anemia, thrombocytopenia, and neutropenia, and to support stem cell transplantation ■■ AGENTS USED IN ANEMIAS IRON Basic Pharmacology Iron deficiency is the most common cause of chronic anemia Like other forms of chronic anemia, iron deficiency anemia leads to pallor, fatigue, dizziness, exertional dyspnea, and other generalized symptoms of tissue hypoxia The cardiovascular adaptations to chronic anemia—tachycardia, increased cardiac output, vasodilation—can worsen the condition of patients with underlying cardiovascular disease Iron forms the nucleus of the iron-porphyrin heme ring, which together with globin chains forms hemoglobin Hemoglobin reversibly binds oxygen and provides the critical mechanism for oxygen delivery from the lungs to other tissues In the absence of adequate iron, small erythrocytes with insufficient hemoglobin are formed, giving rise to microcytic hypochromic anemia Ironcontaining heme is also an essential component of myoglobin, cytochromes, and other proteins with diverse biologic functions Pharmacokinetics Free inorganic iron is extremely toxic, but iron is required for essential proteins such as hemoglobin; therefore, evolution has provided an elaborate system for regulating iron absorption, transport, and storage (Figure 33–1) The system uses specialized transport, storage, ferrireductase, and ferroxidase proteins whose concentrations are controlled by the body’s demand for hemoglobin synthesis and adequate iron stores (Table 33–1) A peptide called hepcidin, produced primarily by liver cells, serves as a key central regulator of the system Nearly all of the iron used to support hematopoiesis is reclaimed from catalysis of the hemoglobin in senescent or damaged erythrocytes Normally, only a small amount of iron is lost from the body each day, so dietary requirements are small and easily fulfilled by the iron available in a wide variety of foods However, in special populations with Sickle Cell Disease and Hydroxyurea Sickle cell disease is an important genetic cause of hemolytic anemia, a form of anemia due to increased erythrocyte destruction, instead of the reduced mature erythrocyte production seen with iron, folic acid, and vitamin B12 deficiency Patients with sickle cell disease are homozygous for the aberrant β-hemoglobin S (HbS) allele (substitution of valine for glutamic acid at amino acid of β-globin) or heterozygous for HbS and a second mutated β-hemoglobin gene such as hemoglobin C (HbC) or β-thalassemia Sickle cell disease has an increased prevalence in individuals of African descent because the heterozygous trait confers resistance to malaria In the majority of patients with sickle cell disease, anemia is not the major problem; the anemia is generally well compensated even though such individuals have a chronically low hematocrit (20–30%), a low serum hemoglobin level (7–10 g/dL), and an elevated reticulocyte count Instead, the primary problem is that deoxygenated HbS chains form polymeric structures that dramatically change erythrocyte shape, reduce deformability, and elicit membrane permeability changes that further promote hemoglobin polymerization Abnormal erythrocytes aggregate in the microvasculature—where oxygen tension is low and hemoglobin is deoxygenated—and cause veno-occlusive damage In the musculoskeletal system, this results in characteristic, extremely severe bone and joint pain In the cerebral vascular system, it causes ischemic stroke Damage to the spleen increases the risk of infection, particularly by encapsulated bacteria such as Streptococcus pneumoniae In the pulmonary system, there is an increased risk of infection and, in adults, an increase in embolism and pulmonary hypertension Supportive treatment includes analgesics, antibiotics, pneumococcal vaccination, and blood transfusions In addition, the cancer chemotherapeutic drug hydroxyurea (hydroxycarbamide) reduces veno-occlusive events It is approved in the United States for treatment of adults with recurrent sickle cell crises and approved in Europe in adults and children with recurrent vaso-occlusive events As an anticancer drug used in the treatment of chronic and acute myelogenous leukemia, hydroxyurea inhibits ribonucleotide reductase and thereby depletes deoxynucleoside triphosphate and arrests cells in the S phase of the cell cycle (see Chapter 54) In the treatment of sickle cell disease, hydroxyurea acts through poorly defined pathways to increase the production of fetal hemoglobin γ (HbF), which interferes with the polymerization of HbS Clinical trials have shown that hydroxyurea decreases painful crises in adults and children with severe sickle cell disease Its adverse effects include hematopoietic depression, gastrointestinal effects, and teratogenicity in pregnant women CHAPTER 33 Agents Used in Cytopenias; Hematopoietic Growth Factors 593 Spleen, other tissues macrophage Blood Senescent RBC Gut lumen Intestinal epithelial cells Hgb F Hgb Hgb Tf HCP1 FP F DB Fe3+ FP – Hepcidin FP Fe2+ DMT1 – – – Erythroferrone Hepcidin TfR F Heme RBC production Fe Bone marrow erythrocyte precursor TfR Hepatocyte FIGURE 33–1 Absorption, transport, and storage of iron Intestinal epithelial cells actively absorb inorganic iron via the divalent metal transporter (DMT1) and heme iron via the heme carrier protein (HCP1) Iron that is absorbed or released from absorbed heme iron in the intestine (1) is actively transported into the blood by ferroportin (FP) and stored as ferritin (F) In the blood, iron is transported by transferrin (Tf ) to erythroid precursors in the bone marrow for synthesis of hemoglobin (Hgb) in red blood cells (RBC); (2) or to hepatocytes for storage as ferritin (3) The transferrin-iron complex binds to transferrin receptors (TfR) in erythroid precursors and hepatocytes and is internalized After release of iron, the TfR-Tf complex is recycled to the plasma membrane and Tf is released Macrophages that phagocytize senescent erythrocytes (RBC) reclaim the iron from the RBC hemoglobin and either export it or store it as ferritin (4) Hepatocytes use several mechanisms to take up iron and store the iron as ferritin High hepatic iron stores increase hepcidin synthesis, and hepcidin inhibits ferroportin; low hepatocyte iron and increased erythroferrone inhibits hepcidin and enhances iron absorption via ferroportin Ferrous iron (Fe2+), blue diamonds, squares; ferric iron (Fe3+), red; DB, duodenal cytochrome B; F, ferritin; (Modified and reproduced, with permission, from Trevor A et al: Pharmacology Examination & Board Review, 9th ed McGraw-Hill, 2010 Copyright © The McGraw-Hill Companies, Inc.) either increased iron requirements (eg, growing children, pregnant women) or increased losses of iron (eg, menstruating women), iron requirements can exceed normal dietary supplies, and iron deficiency can develop A Absorption The average American diet contains 10–15 mg of elemental iron daily A normal individual absorbs 5–10% of this iron, or about 0.5–1 mg daily Iron is absorbed in the duodenum and proximal jejunum, although the more distal small intestine can absorb iron if necessary Iron absorption increases in response to low iron stores or increased iron requirements Total iron absorption increases to 1–2 mg/d in menstruating women and may be as high as 3–4 mg/d in pregnant women Iron is available in a wide variety of foods but is especially abundant in meat The iron in meat protein can be efficiently absorbed, because heme iron in meat hemoglobin and myoglobin can be absorbed intact without first having to be dissociated into elemental iron (Figure 33–1) Iron in other foods, especially vegetables and grains, is often tightly bound to organic compounds and is much less available for absorption Nonheme iron in foods and iron in inorganic iron salts and complexes must be reduced by a ferrireductase to ferrous iron (Fe2+) before it can be absorbed by intestinal mucosal cells Iron crosses the luminal membrane of the intestinal mucosal cell by two mechanisms: active transport of ferrous iron by the divalent metal transporter DMT1, and absorption of iron complexed with heme (Figure 33–1) Together with iron split 594 SECTION VI Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout TABLE 33–1 Iron distribution in normal adults.1 Iron Content (mg) Hemoglobin Myoglobin Enzymes Transport (transferrin) Storage (ferritin and other forms) Total Men Women 3050 1700 430 300 10 8 750 300 4248 2314 Values are based on data from various sources and assume that normal men weigh 80 kg and have a hemoglobin level of 16 g/dL and that normal women weigh 55 kg and have a hemoglobin level of 14 g/dL Adapted, with permission, from Kushner JP: Hypochromic anemias In: Wyngaarden JB, Smith LH (editors) Cecil Textbook of Medicine, 18th ed Saunders, 1988 Copyright Elsevier from absorbed heme, the newly absorbed iron can be actively transported into the blood across the basolateral membrane by a transporter known as ferroportin and oxidized to ferric iron (Fe3+) by the ferroxidase hephaestin The liver-derived hepcidin inhibits intestinal cell iron release by binding to ferroportin and triggering its internalization and destruction Excess iron is stored in intestinal epithelial cells as ferritin, a water-soluble complex consisting of a core of ferric hydroxide covered by a shell of a specialized storage protein called apoferritin B Transport Iron is transported in the plasma bound to transferrin, a β-globulin that can bind two molecules of ferric iron (Figure 33–1) The transferrin-iron complex enters maturing erythroid cells by a specific receptor mechanism Transferrin receptors—integral membrane glycoproteins present in large numbers on proliferating erythroid cells—bind and internalize the transferrin-iron complex through the process of receptor-mediated endocytosis In endosomes, the ferric iron is released, reduced to ferrous iron, and transported by DMT1 into the cytoplasm, where it is funneled into hemoglobin synthesis or stored as ferritin The transferrintransferrin receptor complex is recycled to the cell membrane, where the transferrin dissociates and returns to the plasma This process provides an efficient mechanism for supplying the iron required by developing red blood cells Increased erythropoiesis is associated with an increase in the number of transferrin receptors on developing erythroid cells and a reduction in hepatic hepcidin release Iron store depletion and iron deficiency anemia are associated with an increased concentration of serum transferrin C Storage In addition to the storage of iron in intestinal mucosal cells, iron is also stored, primarily as ferritin, in macrophages in the liver, spleen, and bone, and in parenchymal liver cells (Figure 33–1) The mobilization of iron from macrophages and hepatocytes is primarily controlled by hepcidin regulation of ferroportin activity Low hepcidin concentrations result in iron release from these storage sites; high hepcidin concentrations inhibit iron release Ferritin is detectable in serum Since the ferritin present in serum is in equilibrium with storage ferritin in reticuloendothelial tissues, the serum ferritin level can be used to estimate total body iron stores D Elimination There is no mechanism for excretion of iron Small amounts are lost in the feces by exfoliation of intestinal mucosal cells, and trace amounts are excreted in bile, urine, and sweat These losses account for no more than mg of iron per day Because the body’s ability to excrete iron is so limited, regulation of iron balance must be achieved by changing intestinal absorption and storage of iron in response to the body’s needs As noted below, impaired regulation of iron absorption leads to serious pathology Clinical Pharmacology A Indications for the Use of Iron The only clinical indication for the use of iron preparations is the treatment or prevention of iron deficiency anemia This manifests as a hypochromic, microcytic anemia in which the erythrocyte mean cell volume (MCV) and the mean cell hemoglobin concentration are low (Table 33–2) Iron deficiency is commonly seen in populations with increased iron requirements These include infants, especially premature infants; children during rapid growth periods; pregnant and lactating women; and patients with chronic kidney disease who lose erythrocytes at a relatively high rate during hemodialysis and also form them at a high rate as a result of treatment with the erythrocyte growth factor erythropoietin (see below) Inadequate iron absorption also can cause iron deficiency This is seen after gastrectomy and in patients with severe small bowel disease that results in generalized malabsorption TABLE 33–2 Distinguishing features of the nutritional anemias Nutritional Deficiency Type of Anemia Laboratory Abnormalities Iron Microcytic, hypochromic with MCV < 80 fL and MCHC < 30% Low SI < 30 mcg/dL with increased TIBC, resulting in a % transferrin saturation (SI/TIBC) of 3.6 μmol/mol creatinine) methylmalonic acid MCV, mean cell volume; MCHC, mean cell hemoglobin concentration; SI, serum iron; TIBC, transferrin iron-binding capacity CHAPTER 33 Agents Used in Cytopenias; Hematopoietic Growth Factors 595 The most common cause of iron deficiency in adults is blood loss Menstruating women lose about 30 mg of iron with each menstrual period; women with heavy menstrual bleeding may lose much more Thus, many premenopausal women have low iron stores or even iron deficiency In men and postmenopausal women, the most common site of blood loss is the gastrointestinal tract Patients with unexplained iron deficiency anemia should be evaluated for occult gastrointestinal bleeding B Treatment Iron deficiency anemia is treated with oral or parenteral iron preparations Oral iron corrects the anemia just as rapidly and completely as parenteral iron in most cases if iron absorption from the gastrointestinal tract is normal An exception is the high requirement for iron of patients with advanced chronic kidney disease who are undergoing hemodialysis and treatment with erythropoietin; for these patients, parenteral iron administration is preferred Oral iron therapy—A wide variety of oral iron preparations is available Because ferrous iron is most efficiently absorbed, ferrous salts should be used Ferrous sulfate, ferrous gluconate, and ferrous fumarate are all effective and inexpensive and are recommended for the treatment of most patients Different iron salts provide different amounts of elemental iron, as shown in Table 33–3 In an iron-deficient individual, about 50–100 mg of iron can be incorporated into hemoglobin daily, and about 25% of oral iron given as ferrous salt can be absorbed Therefore, 200–400 mg of elemental iron should be given daily to correct iron deficiency most rapidly Patients unable to tolerate such large doses of iron can be given lower daily doses of iron, which results in slower but still complete correction of iron deficiency Treatment with oral iron should be continued for 3–6 months after correction of the cause of the iron loss This corrects the anemia and replenishes iron stores Common adverse effects of oral iron therapy include nausea, epigastric discomfort, abdominal cramps, constipation, and diarrhea These effects are usually dose-related and often can be overcome by lowering the daily dose of iron or by taking the tablets immediately after or with meals Some patients have less severe TABLE 33–3 Some commonly used oral iron preparations Usual Adult Dosage for Treatment of Iron Deficiency (Tablets per Day) Tablet Size Elemental Iron per Tablet Ferrous sulfate, hydrated 325 mg 65 mg 2–4 Ferrous sulfate, desiccated 200 mg 65 mg 2–4 Ferrous gluconate 325 mg 36 mg 3–4 Ferrous fumarate 325 mg 106 mg 2–3 Preparation gastrointestinal adverse effects with one iron salt than another and benefit from changing preparations Patients taking oral iron develop black stools; this has no clinical significance in itself but may obscure the diagnosis of continued gastrointestinal blood loss Parenteral iron therapy—Parenteral therapy should be reserved for patients with documented iron deficiency who are unable to tolerate or absorb oral iron and for patients with extensive chronic anemia who cannot be maintained with oral iron alone This includes patients with advanced chronic renal disease requiring hemodialysis and treatment with erythropoietin, various postgastrectomy conditions and previous small bowel resection, inflammatory bowel disease involving the proximal small bowel, and malabsorption syndromes The challenge with parenteral iron therapy is that parenteral administration of inorganic free ferric iron produces serious dosedependent toxicity, which severely limits the dose that can be administered However, when the ferric iron is formulated as a colloid containing particles with a core of iron oxyhydroxide surrounded by a core of carbohydrate, bioactive iron is released slowly from the stable colloid particles In the United States, the three traditional forms of parenteral iron are iron dextran, sodium ferric gluconate complex, and iron sucrose Two newer preparations are available (see below) Iron dextran is a stable complex of ferric oxyhydroxide and dextran polymers containing 50 mg of elemental iron per milliliter of solution It can be given by deep intramuscular injection or by intravenous infusion, although the intravenous route is used most commonly Intravenous administration eliminates the local pain and tissue staining that often occur with the intramuscular route and allows delivery of the entire dose of iron necessary to correct the iron deficiency at one time Adverse effects of intravenous iron dextran therapy include headache, light-headedness, fever, arthralgias, nausea and vomiting, back pain, flushing, urticaria, bronchospasm, and, rarely, anaphylaxis and death Owing to the risk of a hypersensitivity reaction, a small test dose of iron dextran should always be given before full intramuscular or intravenous doses are given Patients with a strong history of allergy and patients who have previously received parenteral iron dextran are more likely to have hypersensitivity reactions after treatment with parenteral iron dextran The iron dextran formulations used clinically are distinguishable as high-molecular-weight and low-molecular-weight forms In the United States, the INFeD preparation is a low-molecular-weight form while Dexferrum is a high-molecular-weight form Clinical data—primarily from observational studies—indicate that the risk of anaphylaxis is largely associated with high-molecular-weight formulations Sodium ferric gluconate complex and iron-sucrose complex are alternative parenteral iron preparations Ferric carboxymaltose is a colloidal iron preparation embedded within a carbohydrate polymer Ferumoxytol is a superparamagnetic iron oxide nanoparticle coated with carbohydrate The carbohydrate shell is removed in the reticuloendothelial system, allowing the iron to be stored as ferritin, or released to transferrin Ferumoxytol may interfere with magnetic resonance imaging (MRI) studies Thus if 596 SECTION VI Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout imaging is needed, MRI should be performed prior to ferumoxytol therapy or alternative imaging modality used if needed soon after dosing The U.S Food and Drug Administration (FDA) has issued a black box warning about risk of potentially fatal allergic reactions associated with the use of ferumoxytol For patients treated chronically with parenteral iron, it is important to monitor iron storage levels to avoid the serious toxicity associated with iron overload Unlike oral iron therapy, which is subject to the regulatory mechanism provided by the intestinal uptake system, parenteral administration—which bypasses this regulatory system—can deliver more iron than can be safely stored Iron stores can be estimated on the basis of serum concentrations of ferritin and the transferrin saturation, which is the ratio of the total serum iron concentration to the total iron-binding capacity (TIBC) Vitamin B12 (cobalamin) serves as a cofactor for several essential biochemical reactions in humans Deficiency of vitamin B12 leads to megaloblastic anemia (Table 33–2), gastrointestinal symptoms, and neurologic abnormalities Although deficiency of vitamin B12 due to an inadequate supply in the diet is unusual, deficiency of B12 in adults—especially older adults—due to inadequate absorption of dietary vitamin B12 is a relatively common and easily treated disorder Clinical Toxicity Chemistry A Acute Iron Toxicity Acute iron toxicity is seen almost exclusively in young children who accidentally ingest iron tablets As few as 10 tablets of any of the commonly available oral iron preparations can be lethal in young children Adult patients taking oral iron preparations should be instructed to store tablets in child-proof containers out of the reach of children Children who are poisoned with oral iron experience necrotizing gastroenteritis with vomiting, abdominal pain, and bloody diarrhea followed by shock, lethargy, and dyspnea Subsequently, improvement is often noted, but this may be followed by severe metabolic acidosis, coma, and death Urgent treatment is necessary Whole bowel irrigation (see Chapter 58) should be performed to flush out unabsorbed pills Deferoxamine, a potent iron-chelating compound, can be given intravenously to bind iron that has already been absorbed and to promote its excretion in urine and feces Activated charcoal, a highly effective adsorbent for most toxins, does not bind iron and thus is ineffective Appropriate supportive therapy for gastrointestinal bleeding, metabolic acidosis, and shock must also be provided B Chronic Iron Toxicity Chronic iron toxicity (iron overload), also known as hemochromatosis, results when excess iron is deposited in the heart, liver, pancreas, and other organs It can lead to organ failure and death It most commonly occurs in patients with inherited hemochromatosis, a disorder characterized by excessive iron absorption, and in patients who receive many red cell transfusions over a long period of time (eg, individuals with β-thalassemia) Chronic iron overload in the absence of anemia is most efficiently treated by intermittent phlebotomy One unit of blood can be removed every week or so until all of the excess iron is removed Iron chelation therapy using parenteral deferoxamine or the oral iron chelators deferasirox or deferiprone (see Chapter 57) is less efficient as well as more complicated, expensive, and hazardous, but it may be the only option for iron overload that cannot be managed by phlebotomy, as is the case for many individuals with inherited and acquired causes of refractory anemia such as thalassemia major, sickle cell anemia, aplastic anemia, etc Deferiprone rarely has been associated with agranulocytosis; thus weekly monitoring of the CBC is required for patients treated with this drug VITAMIN B12 Vitamin B12 consists of a porphyrin-like ring with a central cobalt atom attached to a nucleotide Various organic groups may be covalently bound to the cobalt atom, forming different cobalamins Deoxyadenosylcobalamin and methylcobalamin are the active forms of the vitamin in humans Cyanocobalamin and hydroxocobalamin (both available for therapeutic use) and other cobalamins found in food sources are converted to the active forms The ultimate source of vitamin B12 is from microbial synthesis; the vitamin is not synthesized by animals or plants The chief dietary source of vitamin B12 is microbially derived vitamin B12 in meat (especially liver), eggs, and dairy products Vitamin B12 is sometimes called extrinsic factor to differentiate it from intrinsic factor, a protein secreted by the stomach that is required for gastrointestinal uptake of dietary vitamin B12 Pharmacokinetics The average American diet contains 5–30 mcg of vitamin B12 daily, 1–5 mcg of which is usually absorbed The vitamin is avidly stored, primarily in the liver, with an average adult having a total vitamin B12 storage pool of 3000–5000 mcg Only trace amounts of vitamin B12 are normally lost in urine and stool Because the normal daily requirements of vitamin B12 are only about mcg, it would take about years for all of the stored vitamin B12 to be exhausted and for megaloblastic anemia to develop if B12 absorption were stopped Vitamin B12 is absorbed after it complexes with intrinsic factor, a glycoprotein secreted by the parietal cells of the gastric mucosa Intrinsic factor combines with the vitamin B12 that is liberated from dietary sources in the stomach and duodenum, and the intrinsic factor–vitamin B12 complex is subsequently absorbed in the distal ileum by a highly selective receptor-mediated transport system Vitamin B12 deficiency in humans most often results from malabsorption of vitamin B12 due either to lack of intrinsic factor or to loss or malfunction of the absorptive mechanism in the distal ileum Nutritional deficiency is rare but may be seen in strict vegetarians after many years without meat, eggs, or dairy products Once absorbed, vitamin B12 is transported to the various cells of the body bound to a family of specialized glycoproteins, transcobalamin I, II, and III Excess vitamin B12 is stored in the liver CHAPTER 33 Agents Used in Cytopenias; Hematopoietic Growth Factors 597 Pharmacodynamics Two essential enzymatic reactions in humans require vitamin B12 (Figure 33–2) In one, methylcobalamin serves as an intermediate in the transfer of a methyl group from N 5-methyltetrahydrofolate to homocysteine, forming methionine (Figure 33–2A; Figure 33–3, section 1) Without vitamin B12, conversion of the major dietary and storage folate—N 5-methyltetrahydrofolate—to tetrahydrofolate, the precursor of folate cofactors, cannot occur As a result, vitamin B12 deficiency leads to deficiency of folate cofactors necessary for several biochemical reactions involving the transfer of one-carbon groups In particular, the depletion of tetrahydrofolate prevents synthesis of adequate supplies of the deoxythymidylate (dTMP) and purines required for DNA synthesis in rapidly dividing cells, as shown in Figure 33–3, section The accumulation of folate as N 5-methyltetrahydrofolate and the associated depletion of tetrahydrofolate cofactors in vitamin B12 deficiency have been referred to as the “methylfolate trap.” This is the biochemical step whereby vitamin B12 and folic acid metabolism are linked, and it explains why the megaloblastic anemia of vitamin B12 deficiency can be partially corrected by ingestion of large amounts of folic acid Folic acid can be reduced to dihydrofolate by the enzyme dihydrofolate A Methyl transfer N 5-Methyltetrahydrofolate Tetrahydrofolate Cobalamin Methylcobalamin Homocysteine Methionine B Isomerization of L-Methylmalonyl-CoA Methylmalonyl-CoA mutase L-Methylmalonyl-CoA Succinyl-CoA Deoxyadenosylcobalamin FIGURE 33–2 Enzymatic reactions that use vitamin B12 Purines N 5, N10-Methylenetetrahydrofolate dUMP Thymidylate synthase dTMP Glycine Serine transhydroxymethylase DNA synthesis Serine Tetrahydrofolate Dihydrofolate Folate reductase Methylcobalamin Homocysteine Folate reductase Folic acid Cobalamin Methionine N 5-Methyltetrahydrofolate Dietary folates FIGURE 33–3 Enzymatic reactions that use folates Section shows the vitamin B12–dependent reaction that allows most dietary folates to enter the tetrahydrofolate cofactor pool and becomes the “folate trap” in vitamin B12 deficiency Section shows the deoxythymidine monophosphate (dTMP) cycle Section shows the pathway by which folic acid enters the tetrahydrofolate cofactor pool Double arrows indicate pathways with more than one intermediate step dUMP, deoxyuridine monophosphate 598 SECTION VI Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout reductase (Figure 33–3, section 3) and thereby serve as a source of the tetrahydrofolate required for synthesis of the purines and dTMP required for DNA synthesis Vitamin B12 deficiency causes the accumulation of homocysteine due to reduced formation of methylcobalamin, which is required for the conversion of homocysteine to methionine (Figure 33–3, section 1) The increase in serum homocysteine can be used to help establish a diagnosis of vitamin B12 deficiency (Table 33–2) There is evidence from observational studies that elevated serum homocysteine increases the risk of atherosclerotic cardiovascular disease However, randomized clinical trials have not shown a definitive reduction in cardiovascular events (myocardial infarction, stroke) in patients receiving vitamin supplementation that lowers serum homocysteine The other reaction that requires vitamin B12 is isomerization of methylmalonyl-CoA to succinyl-CoA by the enzyme methylmalonyl-CoA mutase (Figure 33–2B) In vitamin B12 deficiency, this conversion cannot take place and the substrate, methylmalonyl-CoA, as well as methylmalonic acid accumulate The increase in serum and urine concentrations of methylmalonic acid can be used to support a diagnosis of vitamin B12 deficiency (Table 33–2) In the past, it was thought that abnormal accumulation of methylmalonyl-CoA causes the neurologic manifestations of vitamin B12 deficiency However, newer evidence implicates the disruption of the methionine synthesis pathway as the cause of neurologic problems Whatever the biochemical explanation for neurologic damage, the important point is that administration of folic acid in the setting of vitamin B12 deficiency will not prevent neurologic manifestations even though it will largely correct the anemia caused by the vitamin B12 deficiency Clinical Pharmacology Vitamin B12 is used to treat or prevent deficiency The most characteristic clinical manifestation of vitamin B12 deficiency is megaloblastic, macrocytic anemia (Table 33–2), often with associated mild or moderate leukopenia or thrombocytopenia (or both), and a characteristic hypercellular bone marrow with an accumulation of megaloblastic erythroid and other precursor cells The neurologic syndrome associated with vitamin B12 deficiency usually begins with paresthesias in peripheral nerves and weakness and progresses to spasticity, ataxia, and other central nervous system dysfunctions Correction of vitamin B12 deficiency arrests the progression of neurologic disease, but it may not fully reverse neurologic symptoms that have been present for several months Although most patients with neurologic abnormalities caused by vitamin B12 deficiency have megaloblastic anemia when first seen, occasional patients have few if any hematologic abnormalities Once a diagnosis of megaloblastic anemia is made, it must be determined whether vitamin B12 or folic acid deficiency is the cause (Other causes of megaloblastic anemia are very rare.) This can usually be accomplished by measuring serum levels of the vitamins The Schilling test, which measures absorption and urinary excretion of radioactively labeled vitamin B12, can be used to further define the mechanism of vitamin B12 malabsorption when this is found to be the cause of the megaloblastic anemia The most common causes of vitamin B12 deficiency are pernicious anemia, partial or total gastrectomy, and conditions that affect the distal ileum, such as malabsorption syndromes, inflammatory bowel disease, or small bowel resection Strict vegans eating a diet free of meat and dairy products may become B12 deficient Pernicious anemia results from defective secretion of intrinsic factor by the gastric mucosal cells Patients with pernicious anemia have gastric atrophy and fail to secrete intrinsic factor (as well as hydrochloric acid) These patients frequently have autoantibodies to intrinsic factor Historically, the Schilling test demonstrated diminished absorption of radioactively labeled vitamin B12, which is corrected when intrinsic factor is administered with radioactive B12, since the vitamin can then be normally absorbed This test is now rarely performed due to use of radioactivity in the assay Vitamin B12 deficiency also occurs when the region of the distal ileum that absorbs the vitamin B12–intrinsic factor complex is damaged, as when the ileum is involved with inflammatory bowel disease or when the ileum is surgically resected In these situations, radioactively labeled vitamin B12 is not absorbed in the Schilling test, even when intrinsic factor is added Rare cases of vitamin B12 deficiency in children have been found to be secondary to congenital deficiency of intrinsic factor or to defects of the receptor sites for vitamin B12–intrinsic factor complex located in the distal ileum Alternatives to the Schilling test include testing for intrinsic factor antibodies and testing for elevated homocysteine and methylmalonic acid levels (Figure 33–2) to make a diagnosis of pernicious anemia with high sensitivity and specificity Almost all cases of vitamin B12 deficiency are caused by malabsorption of the vitamin; therefore, parenteral injections of vitamin B12 are required for therapy For patients with potentially reversible diseases, the underlying disease should be treated after initial treatment with parenteral vitamin B12 Most patients, however, not have curable deficiency syndromes and require lifelong treatment with vitamin B12 Vitamin B12 for parenteral injection is available as cyanocobalamin or hydroxocobalamin Hydroxocobalamin is preferred because it is more highly protein-bound and therefore remains longer in the circulation Initial therapy should consist of 100–1000 mcg of vitamin B12 intramuscularly daily or every other day for 1–2 weeks to replenish body stores Maintenance therapy consists of 100–1000 mcg intramuscularly once a month for life If neurologic abnormalities are present, maintenance therapy injections should be given every 1–2 weeks for months before switching to monthly injections Oral vitamin B12–intrinsic factor mixtures and liver extracts should not be used to treat vitamin B12 deficiency; however, oral doses of 1000 mcg of vitamin B12 daily are usually sufficient to treat patients with pernicious anemia who refuse or cannot tolerate the injections After pernicious anemia is in remission following parenteral vitamin B12 therapy, the vitamin can be administered intranasally as a spray or gel FOLIC ACID Reduced forms of folic acid are required for essential biochemical reactions that provide precursors for the synthesis of amino acids, purines, and DNA Folate deficiency is relatively common, even CHAPTER 33 Agents Used in Cytopenias; Hematopoietic Growth Factors 599 Folic Acid Supplementation: A Public Health Dilemma Starting in January 1998, all products made from enriched grains in the United States and Canada were required to be supplemented with folic acid These rulings were issued to reduce the incidence of congenital neural tube defects (NTDs) Epidemiologic studies show a strong correlation between maternal folic acid deficiency and the incidence of NTDs such as spina bifida and anencephaly The requirement for folic acid supplementation is a public health measure aimed at the significant number of women who not receive prenatal care and are not aware of the importance of adequate folic acid ingestion for preventing birth defects in their infants Observational studies from countries that supplement grains with folic acid have found that supplementation is associated with a significant (20–25%) reduction in NTD rates Observational studies also suggest that rates of other types of congenital anomalies (heart and orofacial) have fallen since supplementation began There may be an added benefit for adults N5-Methyltetrahydrofolate is required for the conversion of homocysteine to methionine (Figure 33–2; Figure 33–3, reaction 1) Impaired synthesis of N5-methyltetrahydrofolate results in elevated serum concentrations of homocysteine Data from several sources suggest a positive correlation between elevated serum homocysteine and occlusive vascular diseases such as ischemic heart disease and stroke Clinical data suggest that the folate supplementation program has improved the folate status and reduced the prevalence of hyperhomocysteinemia in a population of middle-aged and older adults who did not use vitamin supplements There is also evidence that adequate folic acid protects against several cancers, including colorectal, breast, and cervical cancer though the deficiency is easily corrected by administration of folic acid The consequences of folate deficiency go beyond the problem of anemia because folate deficiency is implicated as a cause of congenital malformations in newborns and may play a role in vascular disease (see Box: Folic Acid Supplementation: A Public Health Dilemma) Chemistry Folic acid (pteroylglutamic acid) is composed of a heterocycle (pteridine), p-aminobenzoic acid, and glutamic acid (Figure 33–4) Various numbers of glutamic acid moieties are attached to the pteroyl portion of the molecule, resulting in monoglutamates, triglutamates, or polyglutamates Folic acid undergoes reduction, catalyzed by the enzyme dihydrofolate reductase (“folate reductase”), to give dihydrofolic acid (Figure 33–3, section 3) Tetrahydrofolate is subsequently transformed to folate cofactors possessing one-carbon units attached to the 5-nitrogen, to the 10-nitrogen, or to both positions (Figure 33–3) Folate cofactors are interconvertible by various enzymatic reactions and serve the important biochemical function of donating one-carbon units at various levels of oxidation In most of these, tetrahydrofolate is regenerated and becomes available for reutilization Although the potential benefits of supplemental folic acid during pregnancy are compelling, the decision to require folic acid in grains was controversial As described in the text, ingestion of folic acid can partially or totally correct the anemia caused by vitamin B12 deficiency However, folic acid supplementation does not prevent the potentially irreversible neurologic damage caused by vitamin B12 deficiency People with pernicious anemia and other forms of vitamin B12 deficiency are usually identified because of signs and symptoms of anemia, which typically occur before neurologic symptoms Some opponents of folic acid supplementation were concerned that increased folic acid intake in the general population would mask vitamin B12 deficiency and increase the prevalence of neurologic disease in the elderly population To put this in perspective, approximately 4000 pregnancies, including 2500 live births, in the United States each year are affected by NTDs In contrast, it is estimated that more than 10% of the elderly population in the United States, or several million people, are at risk for the neuropsychiatric complications of vitamin B12 deficiency In acknowledgment of this controversy, the FDA kept its requirements for folic acid supplementation at a somewhat low level There is also concern based on observational and prospective clinical trials that high folic acid levels can increase the risk of some diseases, such as colorectal cancer, for which folic acid may exhibit a bell-shaped curve Further research is needed to more accurately define the optimal level of folic acid fortification in food and recommendations for folic acid supplementation in different populations and age groups Pharmacokinetics The average American diet contains 500–700 mcg of folates daily, 50–200 mcg of which is usually absorbed, depending on metabolic requirements Pregnant women may absorb as much as 300–400 mcg of folic acid daily Various forms of folic acid are N H 2N N – COO N N OH Pteridine derivative CH2 CH2 HN H N C PABA Pteroyl (pteroic acid) Polyglutamation site CH2 CH COO– O Glutamic acid Folic acid FIGURE 33–4 The structure of folic acid (Reproduced, with permission, from Murray RK et al: Harper’s Biochemistry, 24th ed McGraw-Hill, 1996 Copyright © The McGraw-Hill Companies, Inc.) 600 SECTION VI Drugs Used to Treat Diseases of the Blood, Inflammation, & Gout present in a wide variety of plant and animal tissues; the richest sources are yeast, liver, kidney, and green vegetables Normally, 5–20 mg of folates is stored in the liver and other tissues Folates are excreted in the urine and stool and are also destroyed by catabolism, so serum levels fall within a few days when intake is diminished Because body stores of folates are relatively low and daily requirements high, folic acid deficiency and megaloblastic anemia can develop within 1–6 months after the intake of folic acid stops, depending on the patient’s nutritional status and the rate of folate utilization Unaltered folic acid is readily and completely absorbed in the proximal jejunum Dietary folates, however, consist primarily of polyglutamate forms of N 5-methyltetrahydrofolate Before absorption, all but one of the glutamyl residues of the polyglutamates must be hydrolyzed by the enzyme α-1-glutamyl transferase (“conjugase”) within the brush border of the intestinal mucosa The monoglutamate N 5-methyltetrahydrofolate is subsequently transported into the bloodstream by both active and passive transport and is then widely distributed throughout the body Inside cells, N 5-methyltetrahydro-folate is converted to tetrahydrofolate by the demethylation reaction that requires vitamin B12 (Figure 33–3, section 1) Pharmacodynamics Tetrahydrofolate cofactors participate in one-carbon transfer reactions As described earlier in the discussion of vitamin B12, one of these essential reactions produces the dTMP needed for DNA synthesis In this reaction, the enzyme thymidylate synthase catalyzes the transfer of the one-carbon unit of N 5, N10-methylenetetrahydrofolate to deoxyuridine monophosphate (dUMP) to form dTMP (Figure 33–3, section 2) Unlike all the other enzymatic reactions that use folate cofactors, in this reaction the cofactor is oxidized to dihydrofolate, and for each mole of dTMP produced, mole of tetrahydrofolate is consumed In rapidly proliferating tissues, considerable amounts of tetrahydrofolate are consumed in this reaction, and continued DNA synthesis requires continued regeneration of tetrahydrofolate by reduction of dihydrofolate, catalyzed by the enzyme dihydrofolate reductase The tetrahydrofolate thus produced can then reform the cofactor N 5, N10-methylenetetrahydrofolate by the action of serine transhydroxymethylase and thus allow for the continued synthesis of dTMP The combined catalytic activities of dTMP synthase, dihydrofolate reductase, and serine transhydroxymethylase are referred to as the dTMP synthesis cycle Enzymes in the dTMP cycle are the targets of two anti-cancer drugs: methotrexate inhibits dihydrofolate reductase, and a metabolite of 5-fluorouracil inhibits thymidylate synthase (see Chapter 54) Cofactors of tetrahydrofolate participate in several other essential reactions N 5-Methylenetetrahydrofolate is required for the vitamin B12-dependent reaction that generates methionine from homocysteine (Figure 33–2A; Figure 33–3, section 1) In addition, tetrahydrofolate cofactors donate one-carbon units during the de novo synthesis of essential purines In these reactions, tetrahydrofolate is regenerated and can reenter the tetrahydrofolate cofactor pool Clinical Pharmacology Folate deficiency results in a megaloblastic anemia that is microscopically indistinguishable from the anemia caused by vitamin B12 deficiency (see above) However, folate deficiency does not cause the characteristic neurologic syndrome seen in vitamin B12 deficiency In patients with megaloblastic anemia, folate status is assessed with assays for serum folate or for red blood cell folate Red blood cell folate levels are often of greater diagnostic value than serum levels, because serum folate levels tend to be labile and not necessarily reflect tissue levels Folic acid deficiency is often caused by inadequate dietary intake of folates Patients with alcohol dependence and patients with liver disease can develop folic acid deficiency because of poor diet and diminished hepatic storage of folates Pregnant women and patients with hemolytic anemia have increased folate requirements and may become folic acid-deficient, especially if their diets are marginal Evidence implicates maternal folic acid deficiency in the occurrence of fetal neural tube defects (See Box: Folic Acid Supplementation: A Public Health Dilemma.) Patients with malabsorption syndromes also frequently develop folic acid deficiency Patients who require renal dialysis are at risk of folic acid deficiency because folates are removed from the plasma during the dialysis procedure Folic acid deficiency can be caused by drugs Methotrexate and, to a lesser extent, trimethoprim and pyrimethamine, inhibit dihydrofolate reductase and may result in a deficiency of folate cofactors and ultimately in megaloblastic anemia Long-term therapy with phenytoin also can cause folate deficiency, but it only rarely causes megaloblastic anemia Parenteral administration of folic acid is rarely necessary, since oral folic acid is well absorbed even in patients with malabsorption syndromes A dose of mg folic acid orally daily is sufficient to reverse megaloblastic anemia, restore normal serum folate levels, and replenish body stores of folates in almost all patients Therapy should be continued until the underlying cause of the deficiency is removed or corrected Therapy may be required indefinitely for patients with malabsorption or dietary inadequacy Folic acid supplementation to prevent folic acid deficiency should be considered in high-risk patients, including pregnant women, patients with alcohol dependence, hemolytic anemia, liver disease, or certain skin diseases, and patients on renal dialysis ■■ HEMATOPOIETIC GROWTH FACTORS The hematopoietic growth factors are glycoprotein hormones that regulate the proliferation and differentiation of hematopoietic progenitor cells in the bone marrow The first growth factors to be identified were called colony-stimulating factors because they could stimulate the growth of colonies of various bone marrow progenitor cells in vitro Many of these growth factors have been purified and cloned, and their effects on hematopoiesis have been extensively studied Quantities of these growth factors sufficient for clinical use are produced by recombinant DNA technology 1236 Index Preload, 215f, 216 Premature depolarizations, 218 Premenstrual dysphoric disorder, 533 Prescribing, rational, 1148–1149 Prescribing authority, 1152t Prescriptions, 1147f, 1148–1155 abbreviations in, 1149t compliance in, 1150–1151 conversions for, 1148 elements of, 1147f, 1147–1148 e-prescribing in, 1150, 1151 errors in, 1148–1149 errors of omission in, 1149–1150 inappropriate drug prescriptions in, 1150 legal factors in, 1151–1154 controlled substances, 1153, 1153t drug safety surveillance, 1153–1154 FDA, 1151 labeled and off-labeled uses, 1153 right to prescribe, 1151, 1152b poor writing of, 1150 rational prescribing in, 1148–1149 security of, 1151 socioeconomic factors in generic prescribing, 1154–1155 other cost factors, 1155 Preservatives, 901 Presynaptic regulation, autonomic, 100, 102t, 103 Prevertebral ganglia, 91 Prilocaine, 462, 471, 472t See also Anesthetics, local Primaquine, 919f, 920t, 925–926 Primary amine, 9, 60t Primary chemotherapy, 949 Primary generalized glucocorticoid resistance, 710 Primidone seizures treated with, 424–425, 425f, 433t, 436t tremor treated with, 503 Principal cells, 258, 258f Principles, pharmacology, 3–10 drug–body interactions in, 5–10 drug groups in, 10 nature of drugs in, 3–5 Prinzmetal angina, 194 Private pharmacy benefits manager, 1154 Probenecid, 660f, 661, 1171t Procainamide, 237–239, 239t, 240t, 250t Procaine, 460f, 461b, 472t Procaine penicillin G, 799 See also Penicillin(s) Procarbazine, 955t, 956 Prochlorperazine, 1105–1106 Procyclidine, 501t, 508t Prodrug, Profile, pharmacologic, 12 Progabide, 487 Progesterone, 721f, 727–731 adverse effects of, 731 clinical uses of, 731 contraindications and cautions with, 731 diagnostic uses of, 731 pharmacokinetics of, 728 physiologic effects of, 729–731 Progesterone receptor synthesis, estrogens in, 725 Progestin-only contraception, 736 Progestins, 727–731 adverse effects of, 731 clinical uses of, 731 contraindications and cautions with, 731 diagnostic uses of, 731 natural (progesterone), 721f, 727–728 pharmacokinetics of, 728 physiologic effects of, 729–731 synthetic, 728, 728t, 729, 729f, 730t–731t Proguanil, 919f, 926 Proinsulin, 747 Proinsulin C, 748f Projection neurons, 373, 373f Prokinetic agents, 1096–1098, 1115t cholinomimetic agents, 1097 macrolides, 1098 mechanism of action of, 1096–1097, 1097f metoclopramide and domperidone, 1097–1098 preparations available, 1117t Prolactin antagonist, 679 See Dopamine agonists Prolactin (PRL), 668, 668f, 669t, 679 Proliferation signal inhibitors, 986–987 Promethazine, 283t, 383, 1105–1106 Pro-opiomelanocortin, 703 Propafenone, 239t, 240t, 242–243, 251t Propantheline, 126f Prophylaxis, antimicrobial nonsurgical, 914, 915t, 916 NRC wound classification criteria and, 914b surgical, 913–914, 914t Propiverine, 131 See also Muscarinic receptor blockers Propofol, for anesthesia, 450f, 450t, 450–452 Propoxyphene, 568 See also Opioid agonists Propranolol, 24, 164t, 165, 170t See also b-receptor antagonist drugs angina pectoris treated with, 210t arrhythmia treated with, 239t–240t, 243, 251t case study on, 20, 40 hypertension treated with, 179t, 182–183, 191t hyperthyroidism treated with, 696, 699, 700, 701t migraine headache prophylaxis uses of, 168, 291 physiologic effects of, 38 structure of, 163f tremor treated with, 503 Propylene glycol as dermatologic vehicle, 1082 keratolytic actions of, 1082 Propylthiouracil (PTU) description of, 693–695, 694f, 701t thyrotoxicosis in pregnancy treated with, 700 Prorenin, 301 Prorenin receptors, 305 Prostacyclin (PGI2), 323 Prostaglandin(s) effects of, 327–331 on kidney, 259 structures of, 333f Prostaglandin analogs gastric mucosa protection using, 1096 structures of, 333f Prostaglandin endoperoxide synthase products, 323, 324f Prostaglandin F2α (PGF2α), 333f Prostanoid biosynthesis, 323, 324f Prostanoid mediators, from arachidonic acid, 646f Prostanoid receptors, 326–327, 327f, 328t Prostate cancer androgen suppression for, 743, 745t chemotherapy for, 972 degarelix and abarelix for, 679 gonadotropin-releasing hormone agonists for, 677–678 Prostatectomy, 124, 136 Protamine sulfate, 614 Protease inhibitors (PIs) atazanavir, 871t, 879–880 darunavir, 871t, 880 fosamprenavir, 872t, 880 fundamentals of, 879 hepatitis C treated with, 889–891, 890f human immunodeficiency virus treated with, 879–882 indinavir, 872t, 880–881 lopinavir, 872t, 881 nelfinavir, 872t, 881 in pregnancy, 879t ritonavir, 872t, 881 saquinavir, 872t, 881–882 simeprevir, 890–891 sofosbuvir, 889 tipranavir, 873t, 882 Index 1237 Protein binding albumin concentration in, 53 capacity-limited, 53 factors in, 53 plasma, 53, 53b Protein C, 611 Protein S, 611 Protein tyrosine kinase, 27 Prothrombin complex concentrates, 616 Prothrombin deficiency, 622t Prothrombin time (PT), 615 Proton-pump inhibitors (PPIs), 1091–1095 adverse effects of, 1094–1095 chemistry and pharmacokinetics of, 1091–1093, 1092f, 1092t clinical uses of, 1093–1094 drug interactions of, 1095 OTC, 1122t pharmacodynamics of, 1093 preparations available, 1117t Prototype drugs, 10 Protriptyline, 546t Proximal convoluted tubule (PCT), 254–256, 255f Prucalopride, 1100 Prussian blue, 1033 Pseudocholinesterase, 69, 132 See Butyrylcholinesterase (BCHE) Pseudoephedrine, 150 Pseudovitamin D deficiency rickets, 788 Psilocybin description of, 577t Gio protein-coupled receptor activation by, 577t, 582–583 Psoralens, 1076 Psoriasis acitretin for, 1078 alefacept for, 1079 calcipotriene and calcitriol for, 1078–1079 fumaric acid esters for, 1079 tazarotene for, 1078 TNF inhibitors for, 1079 ustekinumab for, 1079 Psychosis drugs for, 511–524, 528t–529t nature of, 512 Psyllium, 1098 Pteroylglutamic acid, 606t See also Folic acid p-Tertiary amylphenol, 899 PTSD, Posttraumatic stress disorder, 544 PU-14, 269 Pulmonary disease, 72 See also specific disease Pulmonary edema, acute, 563 Pulmonary embolism heparin for, 608, 625 thrombolytics for, 619 Pulmonary hypertension case study of, 321, 338 eicosanoids for, 335 nitric oxide for, 344 preparations available, 318t treatment of, 313b Purine analogs, 1109–1110, 1116t Purine antagonists cladribine, 958t, 961 fludarabine, 958t, 961 6-thiopurines, 958t, 960–961, 961f Purines, in CNS, 380 “Purple glove syndrome,” 418 Pyrantel pamoate, 939t, 945–946 Pyrazinamide, 842, 843t, 846, 851t Pyrethrum, 1012, 1013f Pyridostigmine, 122t myasthenia gravis treated with, 119 neuromuscular blockade reversal using, 484 Pyrimethamine, 919f, 926 Pyrimidine analog, 855f, 856, 861t Pyrimidine synthesis inhibitors, 988–989 Pyronaridine, 928 Q Qinghaosu, 922–923 Quantal dose–effect curves, 37, 37f Quantity, of exposure, 1005 Quaternary amine, Quaternary ammonium compounds, 899–900 Quazepam, 393t See also Benzodiazepines Quetiapine, 514f, 515, 520t, 529t “Quicksilver,” 1027 Quinagolide, 679 Quinapril, 187 Quinestrol, 723f See also Estrogen(s) Quinidine arrhythmia treated with, 239t, 240, 240t, 250t drug interactions of, 1171t malaria treated with, 923–924 Quinine, 919f, 920t, 923–924 Quinolone antibiotics, 1171t–1172t Quinupristin-dalfopristin, 822, 824t, 825t R Rabbit syndrome, 506 Rabeprazole, 1091–1095 See also Protonpump inhibitors (PPIs) Rabies immune globulin intravenous for, 1180t vaccine for, 1177t Radiation, nausea and vomiting after, 1104–1105, 1116t, 1117t Radical cure, 917 131 Radioactive iodine ( I, RAI), 695–696, 701t Radiofrequency catheter ablation, 246b Raloxifene description of, 737f, 738 osteoporosis treated with, 780b, 787, 790t Raltegravir, 872t, 884 Ramelteon, 287b, 382, 384b, 394t See also Melatonin receptor, agonists of Ramipril, hypertension treated with, 187 Ramucirumab, 968, 993 Randomization, 15b Randomized controlled trails (RCTs), 15b Ranibizumab, 995 Ranitidine, 1089–1091 See also H2-receptor antagonists RANK ligand (RANKL) description of, 775 inhibitors of, for hyperparathyroidism, 790t Ranolazine angina pectoris treated with, 207, 210t, 211t arrhythmia treated with, 247 Rapamycin, 1058 Rare disease treatment, 18 Rasagiline, 500, 508t Rasburicase, 80t, 82 Rate of administration, 51 Rate of elimination, 45 Rational drug design, Rational prescribing, 1148–1149 Rattlesnake envenomation management, 1045 Rattlesnake hyperimmune globulin, 991 Raxibacumab, 995 Reactive oxygen species (ROS), 63, 65 Reactivity, drug, 3–4 See also specific drugs “Rebound rhinitis,” 1128 Reboxetine, 151 Receptor, 20–36 See also specific drugs and receptors in addiction, 576 as agonist and antagonist mediators, 20–21 alterations in number or function of, 38 autonomic, 98–99, 99t definition of, 3, 20 drug concentration and response, 20, 21–26 drug concentration reaching, 38 drug development and, 35–36 on drug dose and clinical response, 36–40 See also Dose, clinical response and in drug selectivity, 20 “gene-active,” 27 1238 Index Receptor (Cont.): history of, inert binding sites in, intracellular, for lipid-soluble agents, 27, 27f macromolecular nature of, 21 nomenclature for, 4–5 orphan, 21 response distal to, changes in components of, 38–39 signaling mechanisms and drug action in, 26–35 spare, and receptor-effector coupling, 22f, 22–23 types of, 21 Receptor–drug interactions, Receptor-effector coupling, spare receptors and, 22f, 22–23 Receptor ligand, endogenous, 38 Receptor recycling, opioid, 559 Receptor regulation, 32, 33f Receptor reserve, 22, 22f Receptor tyrosine kinases description of, 27–28, 28f signaling function of, 27 Receptor uncoupling, opioid, 559 Recombinant factor VIIa (rFVIIa), 616, 622t, 623, 624t Recombinant human insulin-like growth factor-binding protein-3 (rhIGFBP-3), 672 Red blood cells, 53 Red thrombi, 609 Reductase inhibitors, 632 See HMG-CoA reductase inhibitors Reductions, 61t Red yeast rice, 634 Reentry, 234 Refractory period, 232–233, 233f Regadenoson, 206b Regulation, drug, 10–18 See also Development and regulation, drug Regulation, flexible, 35 Regulatory proteins, as drug receptors, 21 Relaxin, ovarian, 732 Relay neurons, 373, 373f Relcovaptan, 308, 317t See also Vasopressin receptor antagonists Release inhibitors, histamine in, 281 Remifentanil, 555t, 567, 572t See also Opioid agonists Remodeling, cardiac, 216 “REM rebound,” 388 Renal baroreceptor, on renin release, 301 Renal failure from ADH antagonists, 269 diuretics for, 270–271 loop diuretics for, 263 from potassium-sparing diuretics, 267 Renal potassium wasting, from carbonic anhydrase inhibitors, 261 Renal tubule transport mechanisms, 254–259 in collecting tubule system, 255f, 257–259, 258f in distal convoluted tubule, 255f, 257, 257f in loop of Henle, 255f, 256–257, 257f nephron segments and functions in, 256t in proximal tubule, 254–256, 255f renal autacoids in, 259 Renin control of release of, 301–302, 302f description of, 300–301 Renin-angiotensin-aldosterone system in blood pressure regulation, 174 sites of action of drugs interfering with, 187, 188f Renin-angiotensin system inhibitors of, 304–305 angiotensin-converting enzyme inhibitors, 304–305 angiotensin receptor blockers, 304–305 prorenin receptors, 305 renin inhibitors, 302f, 305 suppression of, hypertension treated with, 300, 320 Renin inhibitors heart failure treated with, 220 hypertension treated with, 192t preparations available, 318t on renin-angiotensin system, 302f, 305 on vasoactive peptides, 316t Renshaw cells, 378 Repaglinide, 759, 768t Repinotan, 286 Research See also specific topics basic, 14b translational, 12 Reserpine, 285 Huntington’s disease treated with, 508t hypertension treated with, 179t, 182, 191t Resistance, antibiotic, 793 Reslizumab, 357, 363t, 994 Respiratory depressants, sedative-hypnotics, 389 Respiratory depression, opioid-induced, 561 Respiratory syncytial virus (RSV), 1181t Response axis, 36, 36f Response elements, 27 Response fluctuations, from levodopa, 497 Responsiveness, drug idiosyncratic, 38 quantitative variations in, 38 variation in, 37–39 Responsive neurostimulator, 411 Resting potential on action potentials, 232–233, 233f of sodium channels, 233f Restless legs syndrome, 506–507 Rest tremor, 504 Resynchronization, cardiac, 223 Retapamulin, 1070 Reteplase, 619 Retigabine, 411, 421, 433t, 437t Retinoic acid derivatives, 1077 Retrograde signaling, 372 Retrograde transmission, 90 Retroviral agents, 870–884 drug-drug interactions of two-drug combinations of, 877t entry inhibitors, 882–883 fundamentals of, 870 integrase strand transfer inhibitors, 883–884 nonnucleoside reverse transcriptase inhibitors, 876–879 nucleoside and nucleotide reverse transcriptase inhibitors, 870–876, 871t–872t in pregnancy, 879t protease inhibitors, 879–882 Reye’s syndrome, 1128 Rh0(D) immune globulin, 991 Rheumatoid arthritis description of, 649 treatment of, 642–659 See also Analgesics; specific drugs case study, 642, 666 disease-modifying antirheumatic drugs, 649–659, 664t nonsteroidal anti-inflammatory drugs, 643–649, 645t Rhinitis medicamentosa, 1128 Rho kinases (ROCK), 207 rhPTH 1–84, 775, 790t Rhythm, normal cardiac, 228–233 Ribavirin hepatitis C treated with, 891 influenza A and B treated with, 893 Lassa fever and viral hemorrhagic fevers treated with, 893 pegylated interferon with, 80t, 85 respiratory syncytial virus treated with, 893 Rickets hereditary vitamin D–resistant, 788 nutritional, 788 pseudovitamin D deficiency, 788 Rifabutin, 843t, 849 Index 1239 Rifampin buspirone affected by, 385b drug interactions of, 1172t leprosy treated with, 851, 851t tuberculosis treated with, 842, 843t, 845, 851t Rifapentine, 843t, 849 Right to prescribe, 1151, 1152b Rilonacept, 657–658, 994 Rilpivirine, 873, 878–879 Riluzole, 487 Rimantadine, 892 Rimonabant cannabinoid dependence treated with, 588, 589t obesity treated with, 289b Riociguat, 313b Risedronate on bone homeostasis, 779–781 bone metastases treated with, 789t hypercalcemia treated with, 789t osteoporosis treated with, 780b, 786, 789t Paget’s disease of bone treated with, 789 Risk, 1005 Risk Evaluation and Mitigation Strategy (REMS), 1153 Risperidone, 514f, 515, 520t, 529t Ritanserin, 292 Ritonavir, 872t, 881 Rituximab, 993 chronic lymphocytic leukemia treated with, 970 rheumatoid arthritis treated with, 652 Rivaroxaban, 617 Rivastigmine, 1063 Rizatriptan, 291t, 296t Rocuronium See also Neuromuscular blocking drugs properties of, 478t, 479t, 489t structure of, 477f Roflumilast, 352, 361, 362t Romidepsin, 1085 Romiplostim, 602t, 604–605, 606t Romosozumab, 775, 780b Ropinirole See also Dopamine receptor agonists Parkinson’s disease treated with, 499, 508t restless legs syndrome treated with, 507, 508t Ropivacaine, 460t, 461b, 462, 471, 472t See also Anesthetics, local Rosiglitazone, 760, 768t Rosuvastatin, 83, 632–634, 639t Rotavirus vaccine, 1177t Rotenone, 1012, 1013f Rotigotine, 499 See also Dopamine receptor agonists Routes of administration, 47t, 48 Routes of exposure, 1005 Royal jelly, 1133t Rubella, immune globulin for, 1181t Rufinamide, 430, 433t, 436t Rytary, 495 S Sabal serrulata, 1141 Sacubitril, 220, 222, 225t, 310 S-adenosyl-l-methionine (SAMe), 63, 64t Safety testing, preclinical, 13, 13t Safinamide, 508t Salbutamol, 154t, 351 See Albuterol Salicylates, 645, 645t, 646f drug interactions of, 1172t in neonates, 1053t in OTC agents, 1129t poisoning management for, 1042–1043 Salicylic acid, 1082 Salicylism, 1082 Saline diuresis, 782 Salivary glands, 148 Salmeterol asthma treated with, 351, 362t structure of, 350f Salmon calcitonin, 778 Salt restriction, dietary, 221–222 Salts, nonabsorbable, 1098 Sampatrilat, 310, 317t Sanitization, 898t Saquinavir, 872t, 881–882 Saralasin, 38 Sarcomere, cardiac muscle, 213, 214f 2+ Sarcoplasmic endoplasmic reticulum Ca ATPase (SERCA) transporter, 213 Sarcoserine, 515 Sargramostim, 602, 602t, 606t Sarin, 116f, 122t See also Organophosphate cholinesterase inhibitors Sassafras, 1133t Saw palmetto (Serenoa repens, Sabal serrulata), 1141 Saxagliptin, 763, 769t Scavenger receptors, 626 Schild equation, 24 Schistosoma haematobium, 943 Schistosoma mansoni, 943–944 Schistosomiasis, 944 Schizoaffective disorders antipsychotics for, 519 lithium for, 526 Schizonticides, 917–918, 918f Schizophrenia See also Antipsychotic agents antipsychotics for, 518 case study of, 511, 531 dopamine hypothesis of, 512–513 glutamate hypothesis of, 513 lithium for, 526 nature of, 512 psychosocial and cognitive remediation for, 523 serotonin hypothesis of, 512 Sclerostin, 774f Scopolamine, 125, 130t, 135t, 284 See also Muscarinic receptor blockers action of, 127, 128f antiemetic properties of, 1106 Scorpion antivenom, 991 Screening, drug, 12–13 Sebelipase alfa, 631 Secobarbital, 383f, 393t See also Barbiturates Secondary amine, 9, 60t Second messengers, 32–34 cAMP, 32, 34, 34f cGMP, 34, 343f diffusible, in central nervous system, 369f, 370 phosphoinositides and calcium, 32–34, 34f Secukinumab, 656, 994 Sedation, 441b See also Anesthetics, general conscious, 441b deep, 441b Sedative-hypnotic drugs, 381–394, 394t actions of, 381 adverse effects of, 392 buspirone, 288–289, 383, 385b, 394t chemical classification of barbiturates, 382, 383f benzodiazepines, 381, 382f newer hypnotics, 382–383, 383f clinical pharmacology of, 390t, 390–393 anxiety states, 390–391 delirium tremens, 391 dosages, 394t other therapeutic uses, 391–392 sleep problems, 391 withdrawal from physiologic dependence, 393 dose-response curves for, 381, 382f in elderly, 1061 hypnotic actions, 381 lethal dose of, 392 overdose of, 392 pharmacodynamics of, 386–389 benzodiazepine binding site ligands in, 387–388 chloride channel GABA receptor complex versatility in, 386, 387f, 388b GABAA receptor molecular pharmacology in, 386, 387f GABA receptor heterogeneity and pharmacologic selectivity in, 387b neuropharmacology in, 386–387 organ level effects in, 388–389 1240 Index Sedative-hypnotic drugs (Cont.): pharmacokinetics of, 383–386 absorption and distribution, 383 biodisposition in, factors in, 386 biotransformation in barbiturates, 386 benzodiazepines, 384f, 384–385, 385t newer hypnotics, 385t, 386 excretion in, 386 poisoning management for, 1041t, 1045 in pregnancy, 383 preparations available, 394t ramelteon, 382, 384b, 394t sedative actions of, 381 tasimelteon, 382 tolerance and dependence on, 389–390 toxicology of direct toxic actions, 392 drug interactions in, 393 drug response alterations in, 392–393 Sedative-hypnotics, 388 Sedatives, 381 Seizures, 409 See also Epilepsy (Seizures); specific seizure antipsychotics as cause of, 522 atonic, 430 case study on, 409, 439 classification of, 409, 410t drugs for, 309–439 Selective estrogen receptor modulators (SERMs), 724, 737, 737f for bone, 790t osteoporosis treated with, 780b, 786, 790t preparations available, 790t Selective serotonin reuptake inhibitors (SSRIs), 546t, 549t See also Antidepressant agents adverse effects in, 546–547 discontinuation syndrome associated with, 547 dosing of, 546t drug interactions in, 548, 548t, 1172t pharmacodynamics of, 541–543, 542t pharmacokinetics of, 539–540, 540t preparations available, 551t teratogenicity of, 547 Selectivity, drug in beneficial vs toxic effects, 39–40 definition of, 39 in structurally identical receptors, 27f, 35 Selegiline depression treated with, 540t, 541, 546t, 550t parkinsonism treated with, 498f, 499, 508t structure of, 495f Selepressin, 308 Selexipag, 313b Self-monitoring of blood glucose, 753 Semustine, 953f Senna, 1099 Sensitivity, target organ, on target concentration, 52 Sensitization, opioid, 554 Sepsis, 343 Septic shock, 343t, 343–344 Sequential scheduling, in cancer chemotherapy, 952 Serenoa repens, 1141 Serotonin (5-HT), 285–292 chemical structure of, 1102f chemistry and pharmacokinetics of, 285f, 285–286 clinical pharmacology of, 288–289 in CNS, 374f, 376t, 379 in depression, 534, 535f discovery of, 285 functions of, 92t pharmacodynamics of, 286–288 in schizophrenia, 512 Serotonin (5-HT) receptor in CNS, 379 description of, 286, 286t Serotonin (5-HT) receptor agonists, 289–291, 296t, 394t clinical pharmacology of, 288–289 migraine headaches and, 289–291, 290f, 291t preparations available, 297t–298t Serotonin 5-HT4 receptor agonists, 1100 Serotonin (5-HT) receptor antagonists, 291–292, 297t, 298t Serotonin 5-HT3 receptor antagonists antiemetic, 1103–1105, 1116t, 1117t irritable bowel syndrome treated with, 1102, 1102f Serotonin (5-HT) receptor modulators, for depression, 550t See also Antidepressant agents chemistry of, 538 clinical pharmacology of adverse effects in, 547 drug interactions in, 548–549 pharmacodynamics of, 542t, 543 pharmacokinetics of, 540t, 541 preparations available, 551t Serotonin-norepinephrine reuptake inhibitors (SNRIs), 550t chemistry of, 536 clinical pharmacology of adverse effects in, 547 drug interactions in, 548 description of, 537 dosing of, 546t pharmacodynamics of, 542, 542t pharmacokinetics of, 540, 540t preparations available, 551t Serotonin syndrome, 288, 288b, 288t, 549, 1042 Serotonin transporter (SERT, SLC6A4) description of, 95b MDMA (ecstasy) on, 587 Sertaconazole, 1072 Sertindole, 515 Sertoli cells, 740 Sertraline, 540t, 542t, 546t, 549t See also Selective serotonin reuptake inhibitors (SSRIs) SERT transporter, 8t Serum sickness drug reactions, 999–1000 Sevelamer, for hyperphosphatemia, 784 Sevoflurane, 441–449 See also Anesthetics, inhaled properties of, 443t structure of, 443f Sex (gender), in drug metabolism, 69 Shape, drug, Shivering, opioids for, 563 Short-bowel syndrome, 1113 Sibutramine, 151, 289b Sickle cell disease, hydroxyurea and, 592b Sick sinus syndrome, 234b Side effect, 39 See also Adverse drug event (ADE) Signaling mechanisms, drug action and, 26–35 cytokine receptors in, 28–29, 29f G proteins and second messengers in, 30f, 30–32, 31f G proteins in, 31t interplay among, 34–35 intracellular receptors for lipid-soluble agents in, 27, 27f ligand- and voltage-gated channels in, 29f, 29–30 of ligand-regulated transmembrane enzymes, 27–28, 28f mechanisms of, transmembrane, 26, 26f phosphorylation in, 35 receptor regulation in, 32, 33f receptor tyrosine kinases in, 27–28, 28f second messengers in cAMP, 32, 34, 34f cGMP, 34, 343f phosphoinositides and calcium, 32–34, 34f Sildenafil, 34, 200b Silodosin, 160 Siltuximab, 994 Silver nitrate, 901 Silver sulfadiazine, 836, 901 Silybum marianum, 1138–1139 Simeprevir, 890–891 Index 1241 Simvastatin, 632–634, 639t Sinecatechins, 1083 Single nucleotide polymorphism (SNP), 69, 75t Single-twitch stimulation, 481 Sinoatrial (SA) node, 127, 228, 229f Sinus rhythm, normal, 236f Sirolimus, 986–987 Sirtuins, 1058 Sitagliptin, 762, 769t Sitaxsentan, 312, 317t See also Endothelin inhibitors Size, of drugs, Skeletal muscle calcium channel blocker effects on, 205 methylxanthines effect on, 353 Skeletal muscle relaxants, 474–491 See also specific types neuromuscular blocking drugs, 474–475 preparations available, 490t spasmolytic drugs, 485–487, 489t Skin, 1068 See Dermatologic pharmacology SLCO1B1 gene pharmacogenomics, 77t, 80t, 82–83 Sleep aids, OTC, 1127t Sleep-enabling drugs, 390b Sleeping sickness, 931 See African trypanosomiasis Sleep-wake cycle, melatonin receptors in, 384b Slow acetylator, 69 SLV306, 316t Small interfering RNAs (SiRNAs), therapeutic, Smoking, 120, 583 See Nicotine Smoking cessation aids, OTC, 1127t Smooth muscle alcohol effects on, 398 calcium channel blocker effects on, 204 contraction of, calcium channel blocking drugs on, 196f, 197 methylxanthines effect on, 353 prostaglandins effect on, 327 thromboxanes effect on, 327 SN-38, 964 Snake bite treatment coral snake, 991, 1181t rattlesnake, 991, 1045, 1181t SNAP-25, 95 Sniffing, 585 Social anxiety disorder, 544 + Sodium (Na ) dietary restriction of, 189 in membrane electrical activity, 229–230, 230f in OTC agents, 1129t Sodium bicarbonate antacid actions of, 1089 aspirin overdose treated with, 1, 19 Sodium-calcium exchanger, 213, 230 Sodium channel, 230 antiarrhythmic state- and use-dependent block of, 236, 238f in cardiac action potential, 231f, 231–232 resting potential of, 233f Sodium channel blockers angina pectoris treated with, 207, 210t, 211t arrhythmia treated with, 237–243, 239t, 240t, 250t class 1A disopyramide, 239t, 240t, 240–241, 250t procainamide, 237–239, 239t, 240t, 250t quinidine, 239t, 240, 240t, 250t class 1B lidocaine, 239t, 240t, 241f, 241–242, 250t mexiletine, 239t, 240t, 242, 250t class 1C flecainide, 239t, 240t, 242, 251t moricizine, 243, 251t propafenone, 239t, 240t, 242–243, 251t preparations available, 251t Sodium etidronate, for Paget’s disease of bone, 789 Sodium ferric gluconate complex, for irondeficiency anemia, 595, 605t Sodium-glucose cotransporter (SGLT2) description of, 256, 256f inhibitors of, 261–262, 272t, 274t, 763–764, 769t Sodium hypochlorite, 899 Sodium nitroprusside, 342 Sodium phosphate, 1098 Sodium pump, 214f, 217, 230 Sodium removal, for chronic heart failure, 221–222 Sodium stibogluconate, 930f, 932t, 933 Sodium sulfacetamide, 1071–1072 Sodium thiosulfate, 199 Sodium valproate, 426f, 426–427, 436t Sofosbuvir, 889 Solanezumab, 1063 Solid organ transplantation, 996 Solifenacin, 131, 135t See also Muscarinic receptor blockers Solvents, 1009–1010 aromatic hydrocarbons, 1009–1010 halogenated aliphatic hydrocarbons, 1009 Somatic division, of autonomic nervous system, 89 Somatic motor nerves, 90f Somatomedin C, 670 Somatostatin description of, 669, 672f, 672–673, 747, 1101 variceal hemorrhage treated with, 1114 Somatostatin analogs, 672f, 672–673 Somatotropin 668f, 668–669 See Growth hormone (GH) Sonidegib, 1085 Sorafenib, 966t, 969 Sorbitol, 1098 Sotalol arrhythmia treated with, 239t, 240t, 243, 244–245, 251t properties of, 164t Sources of information, 18–19 Spareness, degree of, 22f, 23 Spare receptors, 22, 22f Spasmolytics, 485–487, 489t baclofen, 485–487, 486f, 489t botulinum toxin, 487 dantrolene, 449, 486f, 487–488, 489t diazepam, 485, 489t gabapentin, 487 glycine, 487 idrocilamide, 487 local muscle spasm treated with, 488 mechanisms of action of, 485, 486f preparations available, 490t progabide, 487 riluzole, 487 spasticity and, 485, 486f tizanidine, 486f, 487 Spasticity, 485, 486f Special carrier molecules, 8, 8f Spectazole, 1072 Spectinomycin, 832–833, 833t Spina bifida, 434 Spinosad, 1075 Spiramycin, 928 Spironolactone, 191t, 224t, 717 See also Aldosterone antagonists; Diuretics antiandrogen actions of, 745 diuresis uses of, 265f, 265–267, 273t drug interactions of, 1170t–1171t heart failure treated with, 220 SR142948A, 314 SRX251, 308, 317t See also Vasopressin receptor antagonists SSR240612, 308 St Anthony’s fire, 292 St John’s wort (Hypericum perforatum), 70, 71t, 1139–1140 Stable effort angina, 194, 211 Staccato, 435 1242 Index Stage fright, b-receptor antagonists for, 169 Stalevo, 495, 500 Staphylococcal beta lactamase-resistant penicillins, 800–801 See also Penicillin(s) Staphylococcus aureus, transpeptidation reaction in, 798, 798f State-dependent drug action, 236, 238f Statins description of, 632–634, 639t OATP1B1 on metabolism of, 83 STATs (signal transducers and activators of transcription), 29, 29f Status epilepticus, 432–433 Stavudine, 873t, 875 Steam, 901 Stem cell transplantation, autologous, 603–604 Stereoisomerism, Sterilants, 898t, 901 Sterilization, 898t Sterilox, 900 Steroids, anabolic, 740–743, 745t See also Androgens and anabolic steroids Steroid synthesis inhibitors, 743, 745t Sterol absorption inhibitors, 637, 640t Stevens-Johnson syndrome (SJS), 83, 83t Stimulant laxatives, 1099 Stimulants, 144f, 150 See Amphetamines; specific stimulant Stiripentol, 431, 433t, 435 Stones (calculi) calcium oxalate, 789 kidney from carbonic anhydrase inhibitors, 261 from potassium-sparing diuretics, 267 Stool surfactant agents (Softeners), 1098 Strabismus, 118 Stratified medicine, 74 Streptococcus pneumoniae, 592b Streptogramins, 822, 824t, 825t Streptokinase, 611, 611f, 618–619 Streptomycin description of, 827f, 829–830, 833t tuberculosis treated with, 843t, 846–847, 851t Stress-related gastritis, H2-receptor antagonists for, 1091 Stress-related mucosal bleeding, 1094 Strongyloidiasis ivermectin for, 942 thiabendazole for, 946 Strontium, for bone, 790t Strontium ranelate, 780b on bone homeostasis, 782 osteoporosis treated with, 787 Structural proteins, as drug receptors, 21 Structure-activity relationship, 35 Strychnine, 370t Stuart-Prower defect, 622t Subarachnoid hemorrhage, 205 Submucous plexus, 91f, 92 Substance P antagonists of, 317t, 318t description of, 92t, 313–314 Substituted benzamides, 1106 Substrate stabilization, 59 Succimer (dimercaptosuccinic acid, DMSA), 1030f, 1030–1031 arsenic poisoning treated with, 1027 lead poisoning treated with, 1024 mercury poisoning treated with, 1029 Succinylcholine, 488t chemistry and structure of, 476, 476f clinical pharmacology of neuromuscular transmission assessment in, 480–481 skeletal muscle paralysis in, 480 malignant hyperthermia from, 449, 483 mechanism of action of, 478f–479f, 479t, 480 pharmacokinetics of, 477–478, 478t properties of, 478t, 479t, 488t Sucralfate, 1095 Sufentanil, 555t, 567, 572t See also Opioid agonists Sugammadex, 484 Sugars, nonabsorbable, 1098 Suicide inhibitors, 61 Sulbactam, 806f, 806–807 Sulconazole, 1072 Sulfacetamide, 836 Sulfadiazine, 835 Sulfadoxine, 835, 919f, 926 Sulfadoxine-pyrimethamine, 920t Sulfamethoxazole, 835 Sulfasalazine description of, 652–653, 835 inflammatory bowel disease treated with, 1107, 1107f, 1116t Sulfate solution, 1098 Sulfinpyrazone, 660f, 661 Sulfonamides, 834–836, 840t adverse reactions of, 836 chemistry of, 835f clinical uses of, 835–836 mechanism of action and antimicrobial activity of, 835f pharmacokinetics of, 835 preparations available, 840t resistance to, 835 trimethoprim and trimethoprimsulfamethoxazole mixtures of, 836–837, 840t Sulfones, 850 Sulfonylurea receptor binding agents d-phenylalanine derivatives, 759, 768t meglitinide analogs, 759, 768t sulfonylureas, 757–759, 758t, 768t Sulfonylureas, 757–759, 768t efficacy and safety of, 758 first-generation, 758, 768t mechanism of action of, 757, 758t second-generation, 758–759, 768t Sulfotransferases (SULTs), 63, 64f, 64t Sulfur, 1075 Sulfur dioxide, 1007, 1007t Sulindac, 645t, 648–649 Sulpiride, 515 Sulthiame, 432 Sumatriptan, 289–291, 290f, 291t, 296t Sunitinib, 966t, 969 Sun protection factor (SPF), 1076 Sunscreens, 1076–1077 Superoxidized water, 900 Supplements, dietary, 3, 1141–1144 coenzyme Q10, 1141–1142 definition of, 1132 glucosamine, 1142–1143 historical and regulatory facts on, 1132 melatonin, 1143–1144 regulation of, 1132 Suramin, 934 Surface area, in dosage calculations, 1056–1057, 1057t Surgery, nausea and vomiting after, 1104–1105, 1116t, 1117t Surgical anesthesia, 446 Susceptibility, organism, 906 Susceptibility testing, 906 Suspensions, 1054 Suvorexant, 390b, 391, 394t Sweat glands, apocrine, 148 Sympathetic nervous system, 90f, 90–91 estrogens on, 725 functions of, 137 on renin release, 301 Sympathetic sacral outflow, 93 Sympathomimetics, 137–155, 154t, 191t adrenoreceptors in, 138–142 alpha, 138f, 139, 139t beta, 139t, 139–140, 140f dopamine, 139t, 140 polymorphisms of, 142 potencies of, 138 regulation of, 141 selectivity and affinities of, 141, 141t structure of, 138, 138f asthma treated with, 349–352, 350f, 362t See also specific drugs beta2-selective, 351 preparations available, 363t Index 1243 structures of, 350f toxicities of, 351–352 chemistry of, medicinal, 142–155 clinical uses of, 151–153, 154t additional, 153 anaphylaxis, 152–153 cardiovascular cardiac, 152 hypotension, acute, 151 hypotension, chronic orthostatic, 152 shock, 151 vasoconstriction, local, 152 CNS, 153 genitourinary, 153 heart failure, 226t ophthalmic, 153 pulmonary, 152 definition of, 137 direct-acting, 137–138, 141t, 144f, 146f, 149, 149f See also specific types endogenous catecholamines, 146f, 146t, 148–149 indirect-acting, 137–138, 150–151 amphetamine-like, 97f, 144f, 150 catecholamine reuptake inhibitors, 143f, 151 mixed, noradrenergic transmitter release by, 95 mixed-acting sympathomimetics, 144f, 150 noradrenergic transmitter release by, 95 mixed-acting, 144f, 150 molecular pharmacology of, 138–142 norepinephrine transporter in, 142, 143f organ system effects of cardiovascular, 101t, 102f, 144–147, 146t beta-receptor activation in, 145, 146f, 146t, 147 dopamine-receptor activation in, 147 α1-receptor activation in, 144–145, 146f, 146t, 147f α2-receptor activation in, 145 noncardiac, 145t, 147–148 in OTC agents, 1129t preparations available, 155t specific drugs in, 148–151 structure in, 142–144, 143f substitution on alpha carbon in, 143–144, 144f substitution on amino group in, 143 substitution on benzene ring in, 142–143, 144f substitution on beta carbon in, 144 types of, 154t Sympathoplegics, 176, 176f, 178–182 adrenergic neuron-blocking agents, 191t guanethidine, 181–182, 191t reserpine, 179t, 182, 191t adrenoceptor antagonist drugs, 156–172 α-adrenoceptor blockers, 184 b-adrenoceptor blockers, 179t, 182–183 See also b-receptor antagonist drugs esmolol, 183 labetalol, carvedilol, and nebivolol, 183, 192t metoprolol and atenolol, 179t, 183 nadolol, carteolol, betaxolol, bisoprolol, 183 pindolol, acebutolol, and penbutolol, 183 propranolol, 179t, 182–183 centrally acting, 179t, 179–180, 191t clonidine, 179t, 179–181 guanabenz and guanfacine, 180 methyldopa, 179t, 180 preparations of, 193t ganglion-blocking agents, 181 prazosin, 179t prazosin and, 184 Synapses autonomic, 93 central nervous system, 370–371, 371f peripheral, 102t Synaptic potential, 370–371, 371f Synaptic transmitters, 29–30 See also Neurotransmitters Synaptobrevin, 94 Synaptosomal nerve-associated proteins (SNAPs), 90, 94f Synaptotagmin, 95 Syndrome of inappropriate ADH secretion (SIADH), 268 Synechia, 130 Synergism, in antimicrobial drug, 912–913 Synergistic killing, 828 Synergy studies, antimicrobial, 906 Synonymous SNPs, 75t Syntaxin, 95 Synucleinopathy, 493 Systolic heart failure See also Heart failure description of, 212 diastolic heart failure versus, 222t Systolic hypertension, 174 T T3, 687, 690–692, 701t See also Thyroid drugs biosynthesis of, 688, 688f effects of, 691, 693f in hypothalamic-pituitary-thyroid axis, 689, 691f mechanism of action of, 690–691, 693f peripheral metabolism of, 688, 689f pharmacokinetics of, 689t, 690 T4, 687, 689t, 690–692, 701t See also Thyroid drugs biosynthesis of, 688, 688f contraceptives on, female hormonal, 733 effects of, 691, 693f in hypothalamic-pituitary-thyroid axis, 689, 691f mechanism of action of, 690–691, 693f peripheral metabolism of, 688, 689f pharmacokinetics of, 689t, 690 Tachykinins, 313, 377t See also specific types Tachyphylaxis, 38 Tacrine, 120, 1063 Tacrolimus (FK 506), 986, 1074–1075 Tadalafil, 200b Taenia saginata niclosamide for, 943 praziquantel for, 945 Taenia solium niclosamide for, 943 praziquantel for, 945 Tamoxifen breast cancer treated with, 971 description of, 35, 737f, 737–738 Tamsulosin, 157f, 159t, 159–160, 170t See also Adrenoceptor antagonist drugs Tangier disease, 631 Tapentadol, 570, 572t, 573t Tapeworms niclosamide for, 943 praziquantel for, 944–945 Tar compounds, dermatologic, 1082 Tardive akathisia, 506 Tardive dyskinesia, 506, 522 Tardive dystonia, 506 Target, drug, 10–11 See also specific drugs Target concentration, 49, 51–52 drug examples of, 43t–44t pharmacodynamic variables in, 52 pharmacokinetic variables in, 51–52 rational dosage regimen based on, 49–51 loading dose in, 50–51, 51f maintenance dose in, 50, 50b, 51f strategy in, 52b TAS-102, 959–960 Tasimelteon, 287b, 382, 384b, 394t Tau protein, 1062 Tavaborole, 1072 Taxanes and other anti-microtubule drugs, 962t, 963–964 cabazitaxel, 963 docetaxel, 962t, 963 eribulin, 963–964 ixabepilone, 963 paclitaxel, 962t, 963 1244 Index Tazarotene acne treated with, 1077 psoriasis treated with, 1078 Tazobactam, 806f, 806–807 Tbo-filgrastim, 606t TCDD, 1013f, 1015 Tedizolid, 823 Teduglutide, 1113 Tegafur, 78, 79t Tegaserod, 291 chemical structure of, 1102f laxative action of, 1100 Teicoplanin, 809, 812t Telavancin, 803t, 809, 812t Telbivudine, 887 Telcagepant, 315, 318t See also Calcitonin gene-related peptide Telithromycin, 820–821, 824t Telmisartan hypertension treated with, 189 on vasoactive peptides, 316t Temazepam, 385t, 393t See also Benzodiazepines Temozolomide, 955t, 975 Tendon xanthomas, 630 Tenecteplase, 619 Tenofovir description of, 873t, 875–876 hepatitis B treated with, 887 Tenoxicam, 649 Teratogens, 1051t See also Pregnancy, pharmacology in definition of, 1050 FDA risk categories for, 1052t Terazosin, 159, 159t, 170t, 184, 191t See also Adrenoceptor antagonist drugs Terbinafine dermatologic oral, 1074 topical, 1072 description of, 861, 861t Terbutaline asthma treated with, 351, 362t structure of, 149f, 350f Terfenadine, 284 Teriflunomide, 988–989 Teriparatide, 775, 780b, 787, 790t Terlipressin, 308 See also Vasopressin receptor agonists variceal hemorrhage treated with, 1114 on vasoactive peptides, 317t Tertiary amine, 9, 60t Testicular cancer, 974 Testicular hormones, 740–745, 745t See also specific hormones androgens and anabolic steroids, 740–743, 741t, 745t androgen suppression, 743, 744f, 745t antiandrogens, 743–745, 745t contraception in men, chemical cyproterenone acetate, 745 fundamentals of, 745 gossypol, 745 preparations available, 745t Testis, 740 Testosterone, 740–743 adverse effects of, 742–743 clinical uses of, 741t, 741–742 contraindications and cautions with, 743 mechanism of action of, 741 metabolism of, 740 pharmacologic effects of, 741 physiologic effects of, 741 preparations of, 741, 741t, 745t synthesis of, 704f, 722f, 740 synthetic steroids with androgenic and anabolic action, 741, 741t in women, 732 Testosterone cypionate, 740–743, 741t Testosterone enanthate, 740–743, 741t Tetanic stimulation, 479f, 481 Tetanus immune globulin, 1181t Tetanus vaccines tetanus, diphtheria, pertussis (Tdap), 1178t tetanus-diphtheria (Td, DT), 1177t Tetrabenazine, 505, 508t Tetracaine, 460f, 461b, 472t Tetrachlorodibenzodioxin (TCDD), 1013f, 1015 Tetracyclic agents, 549t chemistry of, 538–539, 539f clinical pharmacology of adverse effects in, 547 drug interactions in, 548t, 549 pharmacodynamics of, 542t, 543 pharmacokinetics of, 540t, 541 preparations available, 551t Tetracyclines, 815–818, 824t adverse reactions to, 818 antimicrobial activity of, 816, 816f case study of, 815, 825 clinical uses of, 817–818 dosing of, 818 mechanism of action of, 816, 816f pharmacokinetics of, 817 preparations available, 825t resistance to, 816–817 structure and chemistry of, 815–816 Tetraethylammonium (TEA), 133–134, 134f See also Ganglion blockers Δ -Tetrahydrocannabinol (THC) for analgesia, on ion channels, 560b Gio protein-coupled receptor activation by, 577t, 582, 583f mechanism of action of, 380 rimonabant for dependence on, 588, 589t Tetraiodothyronine (thyroxine, T4), 687 See T4 Tetrathiomolybdate, 507 Tetrodotoxin, 370t, 464 Tezosentan, 220 Thalidomide, 15 erythema nodosum leprosum treated with, 850 immunomodulatory derivatives of, 988 immunosuppressive uses of, 987–988 multiple myeloma treated with, 971 phocomelia caused by, 1049 T helper lymphocytes (TH1, TH2), 980 Theobromine asthma treated with, 352–353 structure of, 352f Theophylline See also Methylxanthine drugs asthma treated with, 352f, 352–353, 362t drug interactions of, 1172t in neonates, 1053t poisoning with, 1041t, 1045 structure of, 352f Therapeutic index, 37 Therapeutic window, 37 Thiabendazole, 939t, 946 Thiamine acute ethanol withdrawal treated with, 406t alcohol withdrawal syndrome treated with, 403 Wernicke-Korsakoff syndrome prophylaxis using, 403 Thiazide diuretics, 177, 224t, 264f, 264–265, 273t See also Diuretics on bone homeostasis, 781 chronic heart failure treated with, 221 heart failure treated with, 221 idiopathic hypercalciuria treated with, 788 with loop diuretics, 269 with potassium-sparing diuretics, 269 preparations available, 274t Thiazolidinediones, 760–761, 768t Thick ascending limb, 257, 257f Thienopyridines, 620 Thiethylperazine, 1105–1106 Thimerosal, 901 Thioamides, 693–695, 694f, 701t Thiocyanate, 199 6-Thioguanine (6-TG), 81, 958t, 960–961 Thiols, 340–341 Thiopental, 450f, 450t Thiophosphate insecticides, 117 6-Thiopurines, 958t, 960–961, 961f Index 1245 Thiopurine S-methyltransferase (TPMT) characteristics of, 78t genetic polymorphisms in, 67t, 69 pharmacogenomics of, 77t, 79t, 81 Thioridazine See also Antipsychotic agents description of, 511–524, 513f, 528t psychosis treated with, 513f, 514–515, 520t See also Antipsychotic agents Thiotepa, 953, 953f, 955t See also Alkylating agents Thiothixene, 511–524, 513f, 515, 515t, 528t See also Antipsychotic agents Thioxanthenes, 511–524, 513f, 528t See also Antipsychotic agents derivatives of, 513f, 515, 515t structure of, 513f Thorn apple, 124 See also Atropine; Muscarinic receptor blockers Threshold limit values (TLVs), 1004 Thrombin, 609–610, 611f Thrombin inhibitors direct, 617–618 indirect, 612f, 612–614 See also Heparin Thrombocytopenia, 592 Thrombolytics, 619, 619b Thrombophlebitis, ascending, 619 Thrombopoietin (TPO), 604, 997t Thrombosis, 342, 343f Thromboxane A2 (TXA2), 259, 324, 329, 608, 619 Thromboxanes, 327–331 Thymidylate synthase (TS), 958 Thyroid drugs, 689–692, 701t See also Antithyroid drugs; specific drug basic pharmacology of, 689–692 clinical pharmacology of, 696–698 hypothyroidism, 694t, 696t, 696–698 myxedema coma, 697 preparations available, 701t Thyroid gland abnormal stimulators of, 689 autoregulation of, 688f, 689 function of on drug metabolism, 72 evaluation of, 688–689, 690t iodide metabolism in, 687 Thyroid hormones, 689–692 biosynthesis of, 687–688, 688f chemistry of, 689f, 689–690 effects of, 691, 692t mechanism of action of, 690–691, 693f metabolism of, peripheral, 688, 689f pharmacokinetics of, 689t, 690, 692t preparations of, 691–692 transport of, 688 Thyroid neoplasms, 700 Thyroid–pituitary relationships, 690, 691f Thyroid-simulating hormone (TSH, thyrotropin), 668f, 668–669, 670t Thyroid storm, 699 Thyrotoxicosis amiodarone-induced, 700 manifestations of, 691, 694t in pregnancy, 700 Thyrotropin-releasing hormone (TRH), 669, 669t Thyroxine, 687 See T4 Tiagabine, 420–421, 433t, 437t Ticagrelor, 620 Ticlopidine, 620 Tics, 493, 505–506, 508t Tigecycline, 817–818, 824t Tiludronate on bone homeostasis, 779–781 Paget’s disease of bone treated with, 789 Time course of drug accumulation, 46f, 46–47 of drug effect, 48–49 cumulative, 49 delayed, 49 immediate, 48–49, 49f of drug elimination, 46f Time-dependent killing, 910 Timing of samples, for drug concentration measurement, 53–54 Timolol, 163f, 164t, 166, 170t See also b-receptor antagonist drugs Tinidazole amebiasis treated with, 929t, 929–930, 930f description of, 896, 902t Tinzaparin, 612 See also Heparin Tiotropium, 126f, 135t See also Muscarinic receptor blockers (antagonists) chronic obstructive pulmonary disease treated with, 130, 354, 359 structure of, 126f Tipranavir, 873t, 882 Tiprolisant, 285 Tirofiban, 621 Tissue factor pathway inhibitor, 610 Tissue factor-VIIa complex, 610–611, 611f Tissue plasminogen activator (t-PA), 611, 611f, 619 Tissue schizonticides, 917, 918f Tizanidine See also Sympathomimetics, direct-acting description of, 149, 153, 154t spasmolytic actions of, 486f, 487, 489t T-lymphocyte-associated antigen (CTLA-4), 980 T lymphocytes, 979, 979f, 980, 981f Tobramycin, 826, 827f, 831, 833, 833t Tocilizumab, 653, 995 Tofacitinib, 656–657, 987 Tolazamide, 758, 768t See also Sulfonylureas Tolbutamide, 758, 768t See also Sulfonylureas Tolcapone, 500, 508t Tolerance, 38, 576–578 alcohol (ethanol), 400 inducer, 71 nitrates and nitrites, 200–201 opioid, 559, 561t, 564–565 sedative-hypnotic drugs, 389–390 Tolmetin, 644f, 645t, 649 See also Nonsteroidal anti-inflammatory drugs (NSAIDs) Tolnaftate, 1073 Tolterodine, 131, 135t See also Muscarinic receptor blockers Toluene, 1010 Tolvaptan, 308, 317t, 682, 684t diuresis uses of, 268–269, 273t heart failure treated with, 224 Tonic-clonic seizures, generalized, 413–421 See also Antiseizure drugs; Seizures Topiramate migraine headache prophylaxis using, 291 seizures treated with, 427–428, 433t, 436t tremor treated with, 503 Topiramate + phentermine, 289b, 290t Topotecan, 962t, 964 Torcetrapib, 638 Toremifene, 737, 737f Torsade de pointes, 233f, 234b, 237f Torsemide, 262t, 262–264, 273t Total systemic clearance, 45 Tourette’s syndrome antipsychotics for, 519 description of, 505–506, 508t Toxaphenes, 1010t, 1010–1011, 1013f Toxic dose, median (TD50), 37 Toxic effects, selectivity and, 39–40 Toxic epidermal necrosis (TEN), 83, 83t Toxicity, 3, 13, 13t See also specific drugs Toxic multinodular goiter, 699 Toxicodynamics, 1035 Toxicokinetics, 1035 Toxicology, 1003–1019 air pollutants, 1006–1009 carbon monoxide, 1006–1007, 1007t nitrogen oxides, 1007t, 1008 ozone and other oxides, 1007t, 1008–1009 permissible exposure limit values of, 1007t sources of, 1006 sulfur dioxide, 1007, 1007t 1246 Index Toxicology (Cont.): bioaccumulation and biomagnification in, 1006b definition of, ecotoxicology, 1005 environmental, 1004–1005 environmental pollutants, 1014–1017 asbestos, 1016–1017 coplanar biphenyls, 1015 endocrine disruptors, 1016 perfluorinated compounds (PFCs), 1016 polybrominated biphenyl ethers (PBDEs), 1015 polybrominated biphenyls (PBBs), 1015 polychlorinated biphenyls (PCBs), 1014–1016 polychlorinated dibenzofurans (PCDFs), 1015 polychlorinated dibenzo-p-dioxins (PCDDs, dioxins), 1015 heavy metals, 901, 1020–1029 See also Heavy metals chelators for, 1029–1033, 1033t See also Chelators herbicides, 1013–1014 bipyridyl (paraquat), 1013f, 1014 chlorophenoxy (2,4-D), 1013f, 1013–1014 glyphosate, 1013f, 1014 metals beryllium, 1017 cadmium, 1017 nanomaterials, 1017–1018 occupational, 1004 pesticides, 1010–1013 botanical, 1012–1013, 1013f carbamate, 1012, 1012t organochlorine, 1010t, 1010–1011, 1013f organophosphorus, 1011t, 1011–1012 poisoned patient management in, 1035–1046 See also Poisoned patient management solvents, 1009–1010 aromatic hydrocarbons, 1009–1010 halogenated aliphatic hydrocarbons, 1009 terminology of, 1005 Toxicology screening tests, 1039, 1039t Toxic products, drug metabolism to, 64–65, 65f Toxic syndromes, 1040–1046 acetaminophen, 65f, 1040, 1041t amphetamines and other stimulants, 1041–1042 anticholinergic agents, 1041t, 1042 antidepressants, 1041t, 1042 antipsychotics, 1042 aspirin (Salicylate), 1042–1043 beta blockers, 1041t, 1043 calcium channel blockers, 1041t, 1043 carbon monoxide and other toxic gases, 1041t, 1043, 1044t cholinesterase inhibitors, 1041t, 1043–1044 cyanide and hydrogen cyanide, 1041t, 1044, 1044t digoxin, 1041t, 1044–1045 ethanol and sedative-hypnotic drugs, 1041t, 1045 ethylene glycol, 1041t, 1045 iron and other metals, 1045 methanol, 1041t, 1045 opioids, 1041t, 1045 rattlesnake envenomation, 1045 theophylline, 1041t, 1045 Toxic uninodular goiter, 699 Toxins, Trademark, 17 Train-of-four (TOF) stimulation, 479f, 481 Tramadol, 569–570, 572t, 573t, 659 Trametinib, 975 Trandolapril, 187 Tranexamic acid, 623 Transcranial magnetic stimulation (TMS), 588 Transferases, 63, 64f, 64t See also specific types Transforming growth factor-b (TGF-b), 27–28 Transient neurologic symptoms (TNS), 469 Translational research, 12 Transmembrane enzymes, ligand-regulated, 27–28, 28f Transporter genetic variations, 82–83 Transporters MDR1, 8, 8t MRP1, 8t multidrug resistance-associated protein, 8, 8t SERT, 8t types of, 8t VMAT, 8t Transport proteins, as drug receptors, 21 Tranylcypromine, for depression, 539f, 541, 546t, 549t Trapping, drug, 9, 11f Trastuzumab, 35, 971, 993 Trauma surgery, emergency, 474, 491 Travelers immunization for, 1182 malaria prevention for, 920t Travoprost, 337 Trazodone, 160, 538, 540t, 542t, 546t, 547, 549t See also 5-HT receptor modulators Trematodes, 944–945 See also Anthelmintic drugs Tremor, 492, 503–504 beta-receptor antagonists for, 169 definition of, 492 essential, 503 intention, 504 from lithium, 527 rest, 504 Treprostinil, 324f, 335 Treprostinil sodium, 333f Triamcinolone (acetonide), 709t See also Corticosteroids, synthetic asthma treated with, 355 structure of, 706f Triamterene diuresis using, 262–267, 273t drug interactions of, 1170t–1171t Triazolam, 382f, 384, 385t, 389, 393t See also Benzodiazepines Trichlorfon, 939t, 943 2,4,5-Trichlorophenoxyacetic acid (2,4,5-T), 1013f, 1013–1014 Trichogenic and antitrichogenic agents bimatoprost, 1085 eflornithine, 1085 finasteride, 1085 minoxidil, 1084–1085 Trichomoniasis, 929 See Amebiasis drugs Trichostrongylus orientalis, 945–946 Trichuriasis See also Anthelmintic drugs albendazole for, 938–940, 939t mebendazole for, 942 Tricyclic antidepressants (TCAs), 549t See also Antidepressant agents chemistry of, 537, 538f clinical pharmacology of adverse effects in, 547 drug interactions in, 548, 1159t intoxication with, 119 pharmacodynamics of, 542t, 542–543 pharmacokinetics of, 540t, 541 poisoning with, 1041t, 1042 preparations available, 551t Trientine hydrochloride, 507 Triethylenemelamine, 953f Trifluridine, 865t, 866f, 867 Trihexyphenidyl, 501t, 508t Triiodothyronine (T3), 687, 690–692 See T3 Trilostane, 716 Trimetazidine, 207, 210t Trimethadione, 429–430 Trimethaphan, 145 Trimethobenzamide, 1106 Trimethoprim, 836–837, 840t Index 1247 Trimethoprim-sulfamethoxazole, 835–837, 840t Trimipramine maleate, 546t Triorthocresyl phosphate (TOCP), 121, 1011 Trioxsalen, 1076 Triptans, 289–291, 290f, 291t, 296t, 298t Triptorelin, 676 1,4,5-Trisphosphate-diacylglycerol cascade, 215 Troglitazone, 761 Trophotropic nervous system, 100 Tropicamide, 126f, 130t, 135t See also Muscarinic receptor blockers Tropisetron, antiemetic properties of, 1104 Trospium, 131, 135t See also Muscarinic receptor blockers TRPA1, 560b TRPV1, 560b Trypanosomiasis drugs, 931–935, 932t–933t See also Antiprotozoal drugs t-SNAREs, 95 Tuberculin hypersensitivity, 983 Tuberculosis drug-susceptible, 844t with HIV, antimycobacterial drugs for, 842, 852 Tuberculosis drugs, 842–849, 851t ethambutol, 842, 843t, 845–846, 851t isoniazid, 842–845, 843t, 851t preparations available, 852t pyrazinamide, 842, 843t, 846, 851t rifampin, 842, 843t, 845, 851t second-line, 846–849 aminosalicylic acid, 843t, 848 bedaquiline, 843t, 849 capreomycin, 843t, 847 cycloserine, 843t, 847 ethionamide, 843t, 847 fluoroquinolones, 848 kanamycin and amikacin, 843t, 848 linezolid, 848–849 rifabutin, 843t, 849 rifapentine, 843t, 849 streptomycin, 843t, 846–847, 851t types and dosing of, 843t Tuberoinfundibular system, 516 Tubocurarine, 475, 489t See also Neuromuscular blocking drugs properties of, 478t structure of, 476f Tumor necrosis factor-α (TNF-α), 997t, 998 Tumor necrosis factor-α blockers, 653–656 adalimumab, 652–654, 654f adverse effects of, 655–656 certolizumab, 654f, 654–655 etanercept, 654f, 655 golimumab, 654f, 655 infliximab, 654f, 655 for psoriasis, 1079 structures of, 654f Tumor stem cells, 948 Tumor suppressor genes, in cancer, 949 Turner syndrome, growth hormone for, 671 Type I hypersensitivity, 982, 983f, 998–1000 Type II hypersensitivity, 982–983 Type III hypersensitivity, 983, 999–1000 Type IV hypersensitivity, 983, 984f Typhoid vaccines Ty21a, oral, 1178t VI capsular polysaccharide, 1178t Tyramine, 97f, 150, 150t biosynthesis of, 97f noradrenergic transmitter release by, 95 Tyrosine, 341, 341t Tyrosine hydroxylase inhibitors, 171t Tyrosine kinase inhibitors (TKIs), 966t, 967 Tyrosine kinase receptor, 27–28, 28f U UGT1A1 pharmacogenomics, 74, 76t, 79t, 81, 87 Ularitide See also Natriuretic peptides heart failure treated with, 220 on kidney, 259 on vasoactive peptides, 317t Ultrarapid metabolism, 67 Ultrarapid metabolizer (UM), 67, 75t Umeclidinium, 130, 354 Unfractionated heparin (UFH), 612f, 612–614 See also Heparin Unicyclic agents, for depression, 549t See also Antidepressant agents chemistry of, 538–539, 539f clinical pharmacology of adverse effects in, 547 drug interactions in, 548t, 549 pharmacodynamics of, 542t, 543 pharmacokinetics of, 540t, 541 preparations available, 551t Unipolar depression, antipsychotics for, 519 See also Antipsychotic agents Unithiol, 1031–1032 for arsenic poisoning acute, 1026 chronic, 1027 for mercury poisoning acute, 1029 chronic, 1029 Unstable angina, 195, 208–209 Urantide, 316 Urapidil, 160 Urea, 1082–1083 Urea transporter UT1, 259 Ureidopenicillins, 801 See also Penicillin(s) Uric acid metabolism, 265 Uricosuric agents, 660f, 661 Uridine 5-diphosphate (UDP)-glucuronosyl transferases (UGTs), 63, 64f, 64t, 67t, 69 Uridine 5′-diphosphoglucuronosyl transferase (UGT1A1), 74, 76t, 79t, 81, 87 Urinary antiseptics, 902t methenamine hippurate, 897, 902t methenamine mandelate, 897, 902t nitrofurantoin, 895–896, 902t Urinary frequency, after prostatectomy, 124, 136 Urinary obstruction, alpha-receptor antagonists for, 161 Urinary pH manipulation, for poisoning, 1040 Urinary retention, 118 Urinary tract infection, 834, 841 Urodilatin, 309 Urofollitropin, 674, 683t Urokinase, 611, 618 Urotensin, 316 Urotensin antagonists, 318t Ursodiol, 1113, 1116t Urticaria, 278, 284 Use-dependent drug action, 236, 238f Ustekinumab, 656, 995, 1079 Uterine leiomyomata (fibroids), 677 V Vaccines, 1175–1182, 1176t–1179t See also Immunization; specific types routine childhood, recommended schedule for, 1175, 1179t Vaccinia immune globulin, 1181t Vagus nerve on cardiovascular function, 100 on immune function, 89 Vagus nerve stimulation (VNS), for epilepsy, 411 Valacyclovir herpes simplex virus treated with, 865t, 866–867 topical dermatologic, 1074 varicella zoster virus treated with, 865t, 866–867 Valganciclovir, 868t, 868–869 Valomaciclovir, 839 Valproate, 529t See Valproic acid 1248 Index Valproic acid, 529t bipolar disorder treated with, 528, 529t migraine headache prophylaxis using, 291 myoclonic seizures treated with, 430 seizures treated with, 426f, 426–427, 430, 433t, 436t Valsartan, 310 heart failure treated with, 224t hypertension treated with, 189 on renin-angiotensin system, 305 on vasoactive peptides, 316t Vancomycin, 803t, 807–809, 812t “Vaping,” 121 Vardenafil, 200b Varenicline, 122t nicotine abuse treated with, 584, 588t smoking cessation using, 121 Variant, 75t Variant angina, 194 ergot alkaloids for diagnosis of, 295 nitrate effects in, 201 Variceal hemorrhage drugs beta-receptor blocking drugs, 1114 preparations available, 1117t somatostatin and octreotide, 1114, 1116t vasopressin and terlipressin, 1114 Varicella vaccine, 1178t Varicella-zoster immune globulin, 1181t Varicella-zoster virus (VZV) agents, 864–867 acyclovir, 865t, 866, 866f docosanol, 865t, 867 famciclovir, 865t, 867 penciclovir, 865t, 866f, 867 trifluridine, 865t, 866f, 867 valacyclovir, 865t, 866–867 valomaciclovir, 867 varicella vaccine, 1178t varicella-zoster immune globulin, 1181t Vascular endothelial growth factor (VEGF), 968 Vascular smooth muscles, 198–199 Vascular tone, 195t, 195–196, 196f, 197f Vasculitis (type III) drug reactions, 999–1000 Vasoactive intestinal peptide agonists, 317t Vasoactive intestinal peptide (VIP), 92t, 312–313 Vasoactive peptides, 300–318, 317t adrenomedullin, 315 angiotensin, 300–303 angiotensin II, 303–304 calcitonin gene-related peptide, 314–315 endothelins, 311–312 kinins, 306–307 natriuretic peptides, 308–309 neuropeptide Y, 315–316 neurotensin, 314 preparations available, 318t substance P, 313–314 urotensin, 316 vasoactive intestinal peptide, 312–313 vasopressin, 308 Vasodilators, angina pectoris treated with, 194–210, 209t–210t See also specific drug allopurinol, 207 beta blockers, 206–207, 210t calcium channel blockers, 202–206 clinical pharmacology of angina of effort, 208, 208f, 209t nitrates alone vs with beta or calcium channel blockers, 208, 209t principles of, 207 unstable angina and acute coronary syndromes, 208–209 vasospastic angina, 208 with coronary artery disease and hyperlipidemia, 194, 211 drug action in, 196–197 fasudil, 207 ivabradine, 207 newer drugs, 207t nitrates and nitrites, 197–202, 202t, 210t nitro-vasodilators, other, 202 pFOX inhibitors, 207 preparations available, 211t ranolazine, 207 special, 206b Vasodilators, nitric oxide as, 342 Vasodilators, for heart failure, 220, 225t acute, 224 chronic, 222 Vasodilators, hypertension treated with, 178f, 179t, 184–187, 191t, 192t calcium channel blockers, 179t, 186–187, 193t diazoxide, 186, 192t direct, 176 fenoldopam, 186, 192t hydralazine, 179t, 184–185 mechanisms and sites of action of, 184, 184t minoxidil, 179t, 185 preparations available, 193t sodium nitroprusside, 185–186, 192t Vasomera, 313 Vasopressin (antidiuretic hormone, ADH), 268, 308, 681–682, 684t blood pressure affected by, 175 diuresis using, 268 structures of, 681f variceal hemorrhage treated with, 1114 on vasoactive peptides, 317t Vasopressin receptor, 308 Vasopressin receptor agonists, 268, 308, 317t, 681–682, 684t preparations available, 685t on vasoactive peptides, 317t Vasopressin receptor antagonists description of, 268, 273t, 308, 682, 684t preparations available, 318t, 685t Vasospastic angina, 194, 208 Vecuronium See also Neuromuscular blocking drugs properties of, 478t, 489t structure of, 477f Vedolizumab, 995, 1112 Vehicles dermatologic, 1068–1086 drug, Velpatasvir, 889 Vemurafenib, 975 Venlafaxine, 537, 540t, 542t, 549t See also Serotonin-norepinephrine reuptake inhibitors (SNRIs) dosing of, 546t poisoning with, 1042 Venous thrombosis, 735 Ventilation, alveolar, 443–444, 444f Ventilation control, neuromuscular blockers for, 485 Ventral tegmental area (VTA), in addiction, 576, 576f, 579b Ventricular fibrillation, 236f Ventricular tachycardia ECG of, 236f polymorphic, in torsades de pointes with long QT syndrome, 233f, 234b, 237f Verapamil See also Calcium channel blockers angina pectoris treated with, 202–206, 203t, 210t See also Calcium channel blockers, angina pectoris treated with arrhythmia treated with, 239t, 240t, 245–246, 251t case study on, 20, 40 hypertension treated with, 179t, 187, 191t Index 1249 migraine headache prophylaxis using, 291 Vernakalant, 239t–240t, 247, 251t Verubecestat, 1063 Very-low-density lipoproteins (VLDLs), 165, 626, 627, 628f Vesamicol, 93 Vesicle-associated membrane proteins (VAMPs), 93, 94f Vesicle-associated transporter (VAT), 93, 94f Vesicular acetylcholine transporter (VAChT), 93 Vesicular glutamate transporter (VGLUT), 375 Vesicular monoamine transporter (VMAT), 95 Vesicular proteoglycan (VPG), 94 Vestibular disturbances, 274 Vigabatrin, 431, 433t, 437t Vilanterol asthma treated with, 351, 362t chronic obstructive pulmonary disease treated with, 152 Vilazodone, 540t, 541, 549 Vildagliptin, 763, 769t Vinblastine cancer treated with, 961–962, 962t immunosuppressive uses of, 989 Vincristine cancer treated with, 962t, 963 immunosuppressive uses of, 989 Vinorelbine, 962t, 963 Viruses, 863 cancer from, 948–949 replication of, 863, 864f Vismodegib, 1085 Visual analog scale (VAS), 562 Vitamin B1, 403 See Thiamine Vitamin B12 deficiency description of, 594t, 596, 598 megaloblastic anemia from, 591, 607 Vitamin B12 therapy, for vitamin B12 deficiency, 596–598, 597f chemistry of, 596 clinical pharmacology of, 594t, 598 cyanocobalamin, 596, 598, 606t hydroxycobalamin, 596, 598, 606t pharmacodynamics of, 596–598, 597f pharmacokinetics of, 596 preparations available, 607t Vitamin D bone homeostasis and, 773, 774f, 775–777, 776f, 777t, 789t chronic kidney disease treated with, 785–786 on gut, bone, and kidney, 778t hyperparathyroidism treated with, 784 hypocalcemia treated with, 784 hypoparathyroidism treated with, 784 intestinal osteodystrophy treated with, 785 nutritional deficiency/insufficiency of, 785 Vitamin D3 on bone homeostasis, 773, 776f vitamin D deficiency/insufficiency treated with, 785 Vitamin D2, for vitamin D deficiency/ insufficiency, 785 Vitamin D preparations, 789t chronic kidney disease treated with, 785–786 forms of, available, 790t Vitamin K bleeding disorders treated with, 614f, 621 structure of, 621 Vitamin K1 structure of, 614f warfarin reversal using, 616 Vitamin K epoxide reductase complex subunit (VKORC1) alleles of, 77t polygenic effects in, 79t, 85–86 VKORC1, 77t, 79t, 85–86 VMAT transporter, 8t Voglibose, 761, 768t Voltage-gated channels, 30, 369f, 369–370 See also specific types Volume of distribution (V), 42 initial predictions of, 54 revising individual estimates of, 54 on target concentration, 52 Vomiting, 1103, 1104f Vonicog alfa, 622 von Willebrand disease, 622t, 623 Voriconazole, 857f, 858t, 858–859, 861t Vorinostat, dermatologic, 1085 Vortioxetine, 540t, 542t, 547, 549, 549t See also 5-HT receptor modulators v-SNAREs, 94 W Warfarin, 614–616 administration and dosage of, 615–616 chemistry and pharmacokinetics of, 614, 614f CYP2C9 and VKORC1 polymorphisms on, 79t, 85–86 drug interactions of, 616, 616t mechanism of action of, 610t, 614–615, 615f reversal of action of, 616 toxicity of, 615 Water, superoxidized, 900 Weak acid examples of, 10t ionization of, 9–10 Wearing-off, 497 Wernicke-Korsakoff syndrome, 400, 403 West’s syndrome, 410, 431 White thrombi, 609 Whole bowel irrigation, for iron toxicity, 596 Wilson’s disease, 507 Withdrawal, 576–578 See also specific substances from alcohol, 403, 403f, 406t, 407t from opioids, 559 from sedative-hypnotics, 393 Withdrawal syndrome, 559, 565, 575 Wolff-Chaikoff block, 689 Wolff-Parkinson-White syndrome, 234 Wong-Baker scale, 562 Worm infections, 938–947, 939t See also Antihelminthics Wuchereria bancrofti, 941 X Xanthine oxidase inhibitors, 83 Xanthines, 352f See also Methylxanthine drugs Xeljanz, 987 Xenobiotics, 56 biotransformation of See Biotransformation, drug definition of, X-linked agammaglobulinemia, 984 X-linked hypophosphatemia, 787–788 Xylene, 1010 Y Yellow fever vaccine, 1178t Yervoy, 992 YKP3089, 435 Yohimbine, 160, 170t Z Zafirlukast, 332 See also Leukotriene receptor antagonists asthma treated with, 336, 356–357, 362t structure of, 356f Zaleplon, 382, 383f, 385t, 389, 391, 394t See also Hypnotics 1250 Index Zanamivir, 891–892 Ziconotide, 560b, 573t Zidovudine, 873t, 876 Ziegler’s enzyme, 61t, 69 Zileuton, 332 See also Leukotriene receptor antagonists asthma treated with, 336, 356–357, 362t structure of, 356f Zinc acetate, 507 Ziprasidone, 514f, 515, 520t, 529t Ziv-aflibercept, 966t, 968 Zoledronate on bone homeostasis, 779–781 bone metastases treated with, 789t hypercalcemia treated with, 782, 789t osteoporosis treated with, 786, 789t Zolmitriptan, 291t, 296t Zolpidem, 382, 383f, 385t, 391, 394t See also Hypnotics Zonisamide, 428, 428f, 433t, 436t Zoster vaccine, 1178t Zotepine, 515 ... Tablet Ferrous sulfate, hydrated 325 mg 65 mg 2 4 Ferrous sulfate, desiccated 20 0 mg 65 mg 2 4 Ferrous gluconate 325 mg 36 mg 3–4 Ferrous fumarate 325 mg 106 mg 2 3 Preparation gastrointestinal... dose-intensive chemotherapy regimens that carry a greater than 20 % risk of causing febrile 30.0 25 .0 20 .0 15.0 10.0 5.0 12 16 20 24 Study day FIGURE 33–5 Effects of granulocyte colony-stimulating... overlapping therapy is generally 5–7 days COO– – COO– OOC CH2 CH CH2 CH2 Descarboxyprothrombin OH Prothrombin CO2 Carboxylase O2 O CH3 CH3 R R O O OH KH2 KO Warfarin FIGURE 34–6 Vitamin K cycle–metabolic