Peter J. Cawley, MD

• Acting Assistant Professor of Medicine
• Division of Cardiology, University
• of Washington School of Medicine
• Seattle, Washington

In addition acne 5 months postpartum generic 5gm bactroban visa, the drug is approved for severe refractory rheumatoid arthritis in nonpregnant adults (see Chapter 73) skin care quotes order 5 gm bactroban visa. Although uncommon at usual therapeutic doses acne zits cysts and boils popped buy generic bactroban on line, neutropenia and thrombocytopenia from bone marrow suppression can be serious concerns acne ziana trusted bactroban 5 gm. Accordingly tretinoin 005 acne buy generic bactroban canada, complete blood counts should be performed at baseline and periodically thereafter skin care bandung buy discount bactroban 5 gm online. More than 10% of patients experience nausea or vomiting, pancreatitis, and blood dyscrasias. Azathioprine is mutagenic and teratogenic in animals, and hence should be avoided during pregnancy. Allopurinol delays conversion of mercaptopurine to inactive products, and thereby increases the risk of toxicity. If allopurinol and azathioprine are used concurrently, the dose of azathioprine must be reduced by about 70%. Imuran is available in 50-mg tablets for oral dosing, and as a powder to be reconstituted with sterile Mitoxantrone Like methotrexate, mitoxantrone was developed to treat cancer (see Chapter 102), and then used later for immunosuppression, owing to its toxic effects on macrophages and B and T lymphocytes. As an immunosuppressant, mitoxantrone has only one indication: reduction of neurologic disability and clinical relapse in patients with multiple sclerosis. Mitoxantrone is a potentially hazardous drug reserved for patients unresponsive to safer agents. The basic pharmacology of the drug and its use in multiple sclerosis are discussed in Chapter 23. Mycophenolate mofetil is approved for prophylaxis of organ rejection in patients receiving allogenic heart, liver, or kidney transplants. Major adverse effects include diarrhea, vomiting, severe neutropenia, sepsis (primarily cytomegalovirus viremia), and pure red-cell aplasia (a form of anemia characterized by selective reductions in red blood cell precursors in bone marrow). Very rarely, patients have developed progressive multifocal leukoencephalopathy, a severe infection of the brain. Absorption of mycophenolate can be decreased by antacids that contain magnesium and aluminum hydroxides and by cholestyramine, a drug that lowers blood cholesterol. When given to pregnant rats in doses at or below those used clinically, mycophenolate causes fetal malformations and fetal resorption. Because of the serious risk of fetal toxicity, the drug should be avoided during pregnancy. During therapy, women of child-bearing age should use two reliable forms of contraception. Mycophenolate mofetil is available in 250-mg capsules, 250- and 500-mg immediate-release tablets, and a 200-mg/mL suspension. If a severe hypersensitivity reaction occurs, the drug should be permanently discontinued. Lymphocyte immune globulin [Atgam] is prepared by extraction from the serum of horses that have been inoculated with human T lymphocytes. Therapeutic effects result from a decrease in the number and activity of thymus-derived lymphocytes. Lymphocyte immune globulin has two approved uses: (1) preventing rejection of renal transplants and (2) treating aplastic anemia. Investigational uses include treatment of multiple sclerosis and myasthenia gravis, and suppressing rejection of liver, bone marrow, and heart transplants. Lymphocyte immune globulin is usually employed in combination with glucocorticoids and azathioprine. Because these other immunosuppressants are present, immune reactions to this horsederived drug are generally mild (chills, fever, leukopenia, skin reactions). Accordingly, epinephrine and facilities for respiratory support should be immediately available. The first dose should be administered within 24 hours before or after transplantation. Treatment of aplastic anemia-10 to 20 mg/kg/day for 8 to 14 days, followed, if needed, by alternate-day dosing for up to a total of 21 doses. The preparations discussed below are used to suppress allograft rejection in transplant recipients. Basiliximab has only one indication: prophylaxis of acute organ rejection following renal transplantation. In clinical trials, basiliximab helped reduce the incidence of acute organ rejection during the first 6 months after transplant surgery, but had little or no impact on graft survival after 1 year. In contrast to other immunosuppressants, basiliximab does not increase the risk of opportunistic infections. Rarely, basiliximab causes severe, acute hypersensitivity reactions, including anaphylaxis. Grapefruit juice inhibits cyclosporine metabolism, and can thereby greatly increase cyclosporine levels. Like cyclosporine, tacrolimus causes renal damage, and hence should not be combined with other nephrotoxic drugs. Immunosuppressant applications of glucocorticoids include suppression of transplant rejection and treatment of rheumatoid arthritis and other autoimmune disorders. Prolonged use of glucocorticoids can cause osteoporosis, thinning of the skin, increased risk of infection, impaired growth in children, and adrenal insufficiency (secondary to suppression of the hypothalamic-pituitary-adrenal axis). Cytotoxic immunosuppressants (eg, azathioprine) decrease immune responses by killing B and T lymphocytes. Cytotoxic immunosuppressants (except mycophenolate mofetil) injure all proliferating cells. Immune responses can be suppressed with basiliximab, and other antibodies directed against components of the immune system. Identifying High-Risk Patients Cyclosporine has the following contraindications: hypersensitivity to cyclosporine or its intravenous vehicle (polyoxyethylated castor oil), pregnancy, recent inoculation with a live virus vaccine, and chickenpox or herpes zoster (or recent contact with a person with either infection). Use with caution in patients taking potassium-sparing diuretics and in those with intestinal malabsorption, hypertension, hyperkalemia, active infection, and renal or hepatic dysfunction. Preparations Cyclosporine is available under three trade names: Sandimmune, Neoral, and Gengraf. Sandimmune has lower bioavailability than Neoral or Gengraf, and hence is not interchangeable with them. Patient Education for Oral Administration Dispense the oral liquid into a glass container using the specially calibrated pipette. Refill the glass container with additional diluent and drink to ensure ingestion of the complete dose. To improve palatability, mix the concentrated drug solution with apple or orange juice just before dosing. Ongoing Evaluation and Interventions Evaluating Therapeutic Effects Graft tenderness or fever may indicate rejection. Therapeutic failure can be confirmed with ultrasound, a biopsy, or renal flow scan. Inform patients about early signs of infection (fever, sore throat), and instruct them to report these immediately. Advise women of child-bearing age to use a the patient that the effect is reversible. Phenytoin, phenobarbital, carbamazepine, rifampin, terbinafine, and trimethoprim-sulfamethoxazole can reduce cyclosporine levels, leading to organ rejection. Azole antifungal drugs (eg, ketoconazole), macrolide antibiotics (eg, erythromycin), and amphotericin B can elevate cyclosporine levels, thereby increasing the risk of toxicity. Grapefruit juice inhibits cyclosporine metabolism, and can thereby increase cyclosporine levels. Cyclosporine can increase levels of repaglinide, a drug for diabetes, and cause hypoglycemia. Intravenous Dosage and Administration Dilute 1 mL of concentrate in 20 to 100 mL of 0. Because of the risk of anaphylactic reactions, monitor the patient closely for 30 minutes after starting administration. Dosage Adjustment Adjust dosage on the basis of nephrotoxicity and cyclosporine trough levels. Draw blood for drug levels just before *Patient education information is highlighted as blue text. Release of histamine from mast cells and basophils is produced by allergic and nonallergic mechanisms. The initial requirement for allergic release is production of antibodies of the immunoglobulin E class. These antibodies are generated following exposure to specific allergens (eg, pollens, insect venoms, certain drugs). When the individual is reexposed to the allergen, the allergen becomes bound by the antibodies. Binding of allergen to adjacent antibodies creates a bridge between those antibodies. By a mechanism that is not fully understood, this bridging process mobilizes intracellular calcium. The calcium, in turn, causes the histamine-containing storage granules to fuse with the cell membrane and disgorge their contents into the extracellular space. Note that allergic release of histamine requires prior exposure to the allergen; an allergic reaction cannot occur during initial allergen exposure. Several agents (certain drugs, radiocontrast media, plasma expanders) can act directly on mast cells to trigger histamine release. The compound plays an important role in allergic reactions and regulation of gastric acid secretion. Accordingly, the chapter begins with a discussion of histamine, emphasizing its contribution to allergic responses. In the vascular system, histamine dilates small blood vessels and increases capillary permeability. Despite this impressive spectrum of actions, clinical use of histamine is limited to diagnostic procedures. However, although its clinical utility is minimal, histamine is still of great interest owing to its involvement in two common pathologic states: allergic disorders and peptic ulcer disease. Physiologic and Pharmacologic Effects Histamine acts primarily through two types of receptors, named H1 and H2. In the periphery, histamine is synthesized and stored in two types of cells: mast cells and basophils. Mast cells are present in the skin and other soft Effects of H1 Stimulation Vasodilation. Activation of H1 receptors causes dilation of small blood vessels (arterioles and venules). Vasodilation is prominent in the skin of the face and upper body, causing the area to become warm and flushed. If extensive vasodilation occurs, total peripheral resistance declines and blood pressure falls. Receptor activation causes capillary endothelial cells to contract, creating openings between these cells through which fluid, protein, and platelets can escape. We know this because, in the presence of H2 blockade, acetylcholine and gastrin are unable to elicit acid secretion. Role of Histamine in Allergic Responses Allergic reactions are mediated by histamine and other compounds (eg, prostaglandins, leukotrienes, tryptase). The intensity of an allergic reaction is determined by which mediator is involved. The symptoms of mild allergy (eg, rhinitis, itching, localized edema) are caused largely by histamine acting at H1 receptors. As a result, mild allergic conditions (eg, hay fever, acute urticaria, mild transfusion reactions) are generally responsive to antihistamine therapy. Severe allergic reactions manifest as anaphylactic shock, a syndrome characterized by bronchoconstriction, hypotension, and edema of the glottis. Although histamine is involved in anaphylaxis, it plays a minor role; other substances (eg, leukotrienes) are the principal mediators. Since histamine has little to do with producing anaphylaxis, it follows that antihistamines are of little help as treatment. Because H2 antagonists do not block H1 receptors, these drugs are of no use for treating allergies. If histamine is administered to an individual with asthma, severe bronchoconstriction will follow. However, although exogenous histamine can induce bronchial constriction, histamine is not the cause of bronchoconstriction that occurs during a spontaneous asthma attack. In addition, H1 receptors appear to have a role in seizure suppression, modulation of neurotransmitter release, and regulation of energy and endocrine homeostasis. In fact, before H2 blockers became available, the term H1 antagonist did not exist; the drugs that we now call H1 antagonists or H1 blockers were simply referred to as antihistamines. Because of its historic use, the term antihistamines is still employed as a synonym for the subgroup of histamine antagonists that produce selective H1 blockade. Here, we continue to use the term antihistamine interchangeably with H1 blocker and H1 antagonist. Although all H1 antagonists available have similar antihistaminic actions, these drugs differ significantly in side effects.

Diseases

• Van Regemorter Pierquin Vamos syndrome
• Conjunctivitis
• Hearing impairment
• Fetal edema
• Triplo X Syndrome
• Cerebro facio articular syndrome
• Brachydactylous dwarfism Mseleni type
• Hypertrophic myocardiopathy

Ramelteon does not cause tolerance or dependence skin care vegetables generic 5 gm bactroban overnight delivery, and is not regulated as a controlled substance acne is a disorder associated with discount 5 gm bactroban mastercard. The drug can decrease sleep latency and prolong sleep duration skin care 2012 buy generic bactroban 5gm line, and does not cause tolerance or physical dependence skin care kit purchase bactroban 5 gm with visa. In clinical trials of adults with chronic insomnia acne 6 year old daughter order generic bactroban from india, Silenor increased total sleep time acne x out reviews purchase 5gm bactroban with visa, and maintained the effect for over 12 weeks. The initial dosage for patients age 65 and older is 3 mg, taken within 30 minutes of bedtime. Both dosages are much lower than the dosages used for depression (75 to 150 mg/day). The most common adverse effects are sedation, nausea, and upper respiratory infection. In the high doses used for depression, doxepin can cause hypotension, dysrhythmias, and anticholinergic effects (eg, dry mouth, constipation, urinary retention, blurred vision). Owing to the risk of anticholinergic effects, Silenor is contraindicated for patients with untreated narrow-angle glaucoma or severe urinary retention. In addition, Silenor is contraindicated for patients who have taken a monoamine oxidase inhibitor within the past 2 weeks. Unlike the benzodiazepines and benzodiazepine-like drugs, Silenor has little or no potential for abuse, and hence is not regulated under the Controlled Substances Act. These drugs are less effective than benzodiazepines and benzodiazepine-like drugs, and tolerance develops quickly (in 1 to 2 weeks). Daytime drowsiness and anticholinergic effects (eg, dry mouth, blurred vision, urinary hesitancy, constipation) are common. Several others- valerian root, chamomile, passionflower, lemon balm, and lavender-have very mild sedative effects, but proof of benefits in insomnia is lacking. Although benzodiazepines can cause physical dependence, the withdrawal syndrome is usually mild (except in patients who have undergone prolonged, high-dose therapy). To minimize withdrawal symptoms, benzodiazepines should be discontinued gradually, over several weeks or even months. Although benzodiazepines undergo extensive metabolism, in most cases the metabolites are pharmacologically active. As a result, responses produced by administering a particular benzodiazepine often persist long after the parent drug has disappeared from the blood. All of the benzodiazepines have essentially equivalent pharmacologic actions; hence, selection among them is based in large part on differences in time course. The principal indications for benzodiazepines are anxiety, insomnia, and seizure disorders. The principal adverse effects of benzodiazepines are daytime sedation and anterograde amnesia. Rarely, patients taking benzodiazepines to promote sleep carry out sleep driving and other complex behaviors, and then have no memory of their actions. Flumazenil, a benzodiazepine receptor antagonist, can be used to treat benzodiazepine overdose. When insomnia has a treatable cause (eg, pain, depression, schizophrenia), primary therapy should be directed at the underlying illness; hypnotics should be used only as adjuncts. Cognitive behavioral therapy is highly effective for insomnia, and hence is considered first-line treatment, even if drugs are also employed. Benzodiazepines and the benzodiazepine-like drugs (zolpidem, zaleplon, eszopiclone) are drugs of choice for insomnia. When benzodiazepines are used for transient insomnia, treatment should last only 2 to 3 weeks. Preadministration Assessment Therapeutic Goal Benzodiazepines are used to promote sleep, relieve symptoms of anxiety (see Chapter 35), suppress seizure disorders (see Chapter 24), relax muscle spasm (see Chapter 25), and ease withdrawal from alcohol (see Chapter 38). They are also used for preanesthetic medication and to induce general anesthesia (see Chapter 27). Baseline Data Determine the nature of the sleep disturbance (prolonged latency, frequent awakenings, early morning awakening) and how long it has lasted. Assess for a possible underlying cause (eg, medical illness, psychiatric illness, use of caffeine and other stimulants, poor sleep hygiene, major life stressor). Identifying High-Risk Patients Benzodiazepines are contraindicated during pregnancy and for patients who experience sleep apnea. Use with caution in patients with suicidal tendencies or a history of substance abuse. Instruct patients to swallow sustained-release formulations intact, without crushing or chewing. Warn patients not to increase the dosage or discontinue treatment without consulting the prescriber. To minimize abstinence symptoms, taper the dosage gradually (over several weeks or even months). Lifethreatening reactions (severe hypotension, respiratory arrest, cardiac arrest) have occurred, along with less serious reactions (venous thrombosis, phlebitis, vascular impairment). Reassure patients with situational insomnia that sleep patterns will normalize once the precipitating stressor has been eliminated. Ensure that correctable underlying causes of insom- nia (psychiatric or medical illness, use of stimulant drugs) are being managed. Ongoing Evaluation and Interventions Evaluating Therapeutic Effects Insomnia is usually self-limiting. Benzodiazepines should be discontinued periodically to determine if they are still required. If insomnia is long term, make a special effort to identify possible underlying causes (eg, psychiatric illness, medical illness, use of caffeine and other stimulants). Drowsiness may be present the next day when benzodiazepines are used for insomnia. Rarely, patients taking benzodiazepines to the possibility of complex sleep-related behaviors and instruct them to notify the prescriber if they occur. If the promote sleep may carry out complex behaviors (eg, sleep driving, eating, making phone calls), and then have no memory of the event. Inform patients about patient reports driving while asleep, the benzodiazepine should be withdrawn (albeit slowly). Inform patients about possible paradoxical reactions (rage, excitement, heightened anxiety), and instruct them to notify the prescriber if these occur. To minimize physical dependence when treating insomnia, use intermittent dosing (3 or 4 nights a week) and the lowest effective dosage for the shortest duration required. With all benzodiazepines, development of dependence can be minimized by using the lowest effective dosage for the shortest time necessary and by using intermittent dosing when treating insomnia. When dependence is mild, withdrawal can elicit insomnia and other symptoms that resemble anxiety. Warn patients about possible drug-dependency When dependence is severe, withdrawal reactions may be serious (panic, paranoia, delirium, hypertension, convulsions). To minimize symptoms, withdraw benzodiazepines slowly (over several weeks or months). After drug cessation, patients should be monitored for 3 weeks for signs of withdrawal or recurrence of original symptoms. Benzodiazepines may injure the developing fetus, especially during the first trimester. Benzodiazepines readily enter breast milk and may accumulate to toxic levels in the infant. Other psychologic manifestations include vigilance, tension, apprehension, poor concentration, and difficulty falling or staying asleep. Somatic manifestations include trembling, muscle tension, restlessness, and signs of autonomic hyperactivity, such as palpitations, tachycardia, sweating, and cold clammy hands. Anxiety is an uncomfortable state that has both psychologic and physical components. The psychologic component can be characterized with terms such as fear, apprehension, dread, and uneasiness. The physical component manifests as tachycardia, palpitations, trembling, dry mouth, sweating, weakness, fatigue, and shortness of breath. When anxiety is moderate and situationally appropriate, therapy may not be needed or even desirable. In contrast, when anxiety is persistent and disabling, intervention is clearly indicated. In the United States, about 25% of people develop pathologic anxiety at some time in their lives. In this chapter, we focus on five of the more common anxiety disorders: generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, social anxiety disorder, and post-traumatic stress disorder. Although each type is distinct, they all have one element in common: an unhealthy level of anxiety. Fortunately, anxiety disorders often respond well to treatment-either psychotherapy, drug therapy, or both. For most patients, a combination of psychotherapy and drug therapy is more effective than either modality alone. These can help relieve symptoms and improve coping skills in anxiety-provoking situations. However, if symptoms are intensely uncomfortable or disabling, drugs are indicated. However, for long-term management, buspirone and the antidepressants are preferred. Unfortunately, even after extended treatment, drug withdrawal frequently results in relapse. Patients should be warned about these effects and informed that they will subside in 7 to 10 days. Because of their abuse potential, benzodiazepines should be used with caution in patients known to abuse alcohol or other psychoactive substances. Accordingly, clinicians must differentiate between a withdrawal reaction and relapse. To minimize withdrawal symptoms, benzodiazepines should be tapered gradually-over a period of several months. However, there is no proof that any one benzodiazepine is clearly superior to the others. Buspirone [BuSpar] is an anxiolytic drug that differs significantly from the benzodiazepines. Its major disadvantage is that anxiolytic effects develop slowly: Initial responses take a week to appear, and several more weeks must pass before responses peak. Since buspirone has no abuse potential, it may be especially appropriate for patients known to abuse alcohol and other drugs. Because it lacks depressant properties, buspirone is an attractive alternative to benzodiazepines in patients who require long-term therapy but cannot tolerate benzodiazepineinduced sedation and psychomotor slowing. However, the drug has been taken for as long as a year with no reduction in benefit. Hence, when patients are switched from a benzodiazepine to buspirone, the benzodiazepine must be tapered slowly. Furthermore, since the effects of buspirone are delayed, buspirone should be initiated 2 to 4 weeks before beginning benzodiazepine withdrawal. The drug binds with high affinity to receptors for serotonin and with lower affinity to receptors for dopamine. Buspirone is well absorbed following oral administration, but undergoes extensive metabolism on its first pass through the liver. Administration with food delays absorption but enhances bioavailability (by reducing first-pass metabolism). The most common reactions are dizziness, nausea, headache, nervousness, sedation, lightheadedness, and excitement. Furthermore, it poses little or no risk of suicide; huge doses (375 mg/day) have been given to healthy volunteers with only moderate adverse effects (nausea, vomiting, dizziness, drowsiness, miosis). Levels of buspirone can be greatly increased (5- to 13-fold) by erythromycin and ketoconazole. Elevated levels may cause drowsiness and subjective effects (dysphoria, feeling "spacey"). Buspirone has been used for up to a year without evidence of tolerance, physical dependence, or psychologic dependence. There is no cross-tolerance or cross-dependence between buspirone and the sedative-hypnotics (eg, benzodiazepines, barbiturates). Buspirone appears to have no potential for abuse, and hence is not regulated under the Controlled Substances Act. Other common reactions include headache, anorexia, nervousness, sweating, daytime somnolence, and insomnia. Combining venlafaxine with a monoamine oxidase inhibitor can result in serious toxicity, and hence must be avoided. For escitalopram, dosing begins at 10 mg once daily and can be increased to 20 mg once daily after a week. The basic pharmacology of venlafaxine, paroxetine, escitalopram, and duloxetine is discussed in Chapter 32.

Alendronate [Fosamax - order line bactroban, Binosto] is available alone in tablets (5 acne zip back jeans buy cheap bactroban 5 gm line, 10 skin care associates cheap generic bactroban uk, 35 acne on buttocks buy bactroban 5 gm otc, 40 skin care cheap bactroban 5 gm mastercard, and 70 mg) skin care reviews buy generic bactroban 5 gm on-line, an effervescent tablet (70 mg), and an oral solution (70 mg in 75 mL). In addition, aledronate is available in a fixed-dose combination with vitamin D (cholecalciferol) under the trade name Fosamax Plus D. Dosing for osteoporosis in women or men may be done once daily (in the morning) or once weekly (on the same morning each week). Once-weekly dosing, which is just as effective as once-daily dosing, is possible because alendronate undergoes incorporation into bone, where it remains and acts for years. Bivalent cations-including calcium, iron, magnesium, and antacids that contain calcium, aluminum, or magnesium-can decrease alendronate absorption, and hence should not be taken for at least 30 minutes after taking alendronate. As with other bisphosphonates, benefits derive from inhibiting osteoclastmediated resorption of bone. The most common adverse effects are arthralgia, diarrhea, headache, rash, nausea, and a flu-like syndrome. Like alendronate, risedronate poses a significant risk of esophagitis, and a very small risk of atypical femoral fractures. Also, the patient should be upright when swallowing, and should not lie down for at least 30 minutes. Because divalent cations-including calcium, iron, and magnesium-greatly reduce absorption, these should not be administered within 2 hours of administering either risedronate formulation. If needed, a second 2-month course can be given, provided at least 2 months have elapsed since completing the first course. Drugs Affecting Calcium Levels and Bone Mineralization of the drug is bound to serum proteins, mainly albumin. Like alendronate, tiludronate poses a risk of esophagitis, ocular problems, musculoskeletal pain, and possibly esophageal cancer. Other side effects include chest pain, edema, paresthesias, hyperparathyroidism, vomiting, and flatulence. Because aspirin and bivalent cations (eg, calcium, iron, magnesium) greatly reduce tiludronate absorption, they should not be administered within 2 hours of administering tiludronate. In addition, etidronate causes defective mineralization of newly formed bone (osteomalacia), and can thereby increase the risk of fractures. To maximize absorption, patients should wait 2 hours before ingesting food, antacids high in metals (eg, calcium, iron, magnesium, aluminum), and vitamins that contain mineral supplements. Treatment can be repeated, but not until 90 days have elapsed since completing the prior course. The dosage for preventing heterotopic ossification in patients undergoing total hip replacement is 20 mg/kg every day for 1 month before surgery and for 3 months after. For heterotopic ossification caused by spinal cord injury, the dose is 20 mg/kg/day for 2 weeks, then 10 mg/kg/day for 10 weeks for a total treatment period of 12 weeks. Although comparative studies have not been done, the drug is probably as effective as alendronate and risedronate, the only other bisphosphonates approved for oral therapy of osteoporosis. Following absorption, ibandronate undergoes rapid binding to bone or excretion in the urine. As with other bisphosphonates, bivalent cations (eg, calcium, magnesium, iron) can greatly decrease absorption. Accordingly, ibandronate should be injected slowly-over an interval of 15 to 30 seconds. Intravenous ibandronate should not be used by patients taking other nephrotoxic drugs, or by those with severe renal impairment, defined as serum creatinine above 2. The dosage for prevention and treatment of osteoporosis is 150 mg once a month, taken on the same day each month. Patients should swallow tablets whole with a full glass of water, while standing or sitting upright. For 60 minutes after dosing, patients must remain upright, and must not eat or drink anything, including medications and dietary supplements. Kidney function should be determined before each dose and, if severe renal impairment is detected, the dose should be withheld. In addition, the drug is used off-label to prevent bone loss, fractures, and other skeletal-related events in patients receiving any of a variety of therapies that create a risk of bone loss. Like other bisphosphonates, zoledronate undergoes incorporation into bone, where it remains for years. When osteoclasts ingest the drug, it inhibits their activity, preventing bone resorption. In one study, zoledronate normalized serum calcium in 88% of patients within 10 days of a single infusion. Specifically, onset is faster, duration is longer, and, perhaps most importantly, infusion time is shorter (15 minutes vs. For management of postmenopausal osteoporosis, zoledronate differs from all other bisphosphonates in that dosing is done just once a year or once every 2 years. Compared with placebo treatment, once-yearly zoledronate decreases the Tiludronate Actions and Uses. The drug decreases abnormal bone growth and, unlike etidronate, does so without interfering with bone mineralization. When osteoclasts resorb this bone, they ingest the drug, which then inhibits further osteoclast-mediated bone resorption. Postmenopausal osteoporosis, prevention-5 mg once every 2 years, infused over 15 minutes or longer. Glucocorticoid-induced osteoporosis-5 mg once a year, infused over 15 minutes or longer. The most common reaction is transient fever, followed by nausea, constipation, dyspnea, abdominal pain, and bone and joint pain. In addition, zoledronate can cause clinically significant reductions in serum levels of calcium, phosphorus, and magnesium. Accordingly, levels of these elements should be followed and corrected when indicated. Zoledronate has been associated with bone injury, most often osteonecrosis of the jaw, a condition characterized by local bone death and decreased bone strength. Other risk factors include cancer, cancer chemotherapy, use of systemic glucocorticoids, and poor oral hygiene. Zoledronate can cause dose-dependent kidney damage, which can progress to acute renal failure and, rarely, to death. Many cancer cells release factors that stimulate resorption of bone by osteoclasts. By inhibiting osteoclast activity, pamidronate can blunt cancer-mediated bone resorption, and can thereby reduce blood levels of calcium. For osteolytic bone lesions of multiple myeloma, the dosage is 90 mg infused over 4 hours once a month. For bone metastases of breast cancer, the dosage is 90 mg infused over 2 hours every 3 to 4 weeks. In contrast to etidronate, pamidronate does not interfere with bone mineralization. Owing to the risk of renal failure, zoledronate may be contraindicated in patients with significant renal impairment. When not contraindicated, dosage varies depending on the underlying condition and creatinine clearance. To minimize risk, dosage should be kept low (5 mg or less per infusion) and the infusion should be slow (15 minutes or longer). To monitor for renal damage, creatinine clearance should be determined at baseline, before each dose, and periodically after each infusion. Rarely, zoledronate has been associated with serious atrial fibrillation, resulting in disability or hospitalization. Zometa, indicated for hypercalcemia of malignancy, is supplied as a concentrated solution (4 mg/5 mL) that must be diluted in 100 mL of 0. If hypercalcemia does not resolve, or if it resolves and then returns, a second infusion can Estrogen the basic pharmacology of estrogen, as well as postmenopausal estrogen therapy, is discussed in Chapter 61. When estrogen levels decline, either because of natural menopause or surgical removal of the ovaries, osteoclasts increase in number, causing bone resorption to increase dramatically. Estrogen replacement can restore the brake on osteoclast proliferation, and can therefore suppress resorption. Because of new insight into the benefits and risks of estrogen, prolonged replacement is no longer considered appropriate for most women. That said, estrogen is still approved for preventing and treating bone loss after menopause or surgical removal of the ovaries, because treatment reduces the overall risk of fractures by 24%. Estrogen is most effective when initiated immediately after menopause; however, treatment begun later in life can still offer significant protection. Women with an intact uterus should also receive a progestin (eg, medroxyprogesterone) to minimize the risk of estrogen-induced endometrial cancer. Fortunately, for prevention and treatment of osteoporosis, we have effective alternatives: raloxifene, bisphosphonates, calcitonin, and teriparatide. However, in contrast to estrogen, which promotes cancer of the breast and endometrium, raloxifene protects against these cancers. Because of its effects on bone, raloxifene is used to prevent and treat postmenopausal osteoporosis. Because of its effects on breast tissue, the drug is used to reduce the risk of breast cancer. Raloxifene mimics the effects of estrogen on bone, lipid metabolism, and blood clotting, and blocks estrogen effects in the breast and endometrium. However, owing to extensive first-pass metabolism, absolute bioavailability is below 2%. Also, patients should minimize periods of restricted activity, as can happen when traveling or revising a pharmacology text. Raloxifene is contraindicated for patients with a history of venous thrombotic events. In animal studies, doses below those used in humans have resulted in abortion, delayed fetal development, decreased neonatal survival, and anatomic abnormalities, including hydrocephaly and uterine hypoplasia. Although use during pregnancy is obviously no concern for postmenopausal patients, it can be a concern for younger women taking the drug to prevent breast cancer. Therapeutic Uses Raloxifene offers significant benefits regarding osteoporosis and breast cancer, but also poses a risk of serious thromboembolic events. Accordingly, women must carefully weigh the risks and benefits before choosing this drug. Raloxifene reduces the risk of spinal fractures by 55%, but does not reduce the risk of fractures at other sites. Preparations, Dosage, and Administration Raloxifene [Evista] is available in 60-mg oral tablets. Women taking raloxifene to prevent or treat postmenopausal osteoporosis should ensure adequate intake of calcium and vitamin D. The drug has two actions: It (1) increases bone resorption by osteoclasts, and (2) increases bone deposition by osteoblasts. The net effect-resorption or deposition-depends on how the drug is administered. Adverse effects included nausea, headache, arthralgias, back pain, and leg cramps. Orthostatic hypotension and associated dizziness may occur within 4 hours of injection, so the patient should be in a location where it is possible to lie down, if needed. Temporary increases in serum levels of calcium, magnesium, and uric acid may occur. To date, cancer has only occurred in animal studies and has not been detected in humans. Teriparatide [Forteo] is supplied in special prefilled pen injectors that contain 600 mcg/2. For all indications, the recommended dosage is 20 mcg once daily by subQ injection into the anterior thigh or abdomen. Each pen can be used up to 28 days after the first injection, after which it should be discarded, even if some drug remains. The cost for each syringe (a 28-day supply) is over $1500, so treatment costs can be very expensive. Dosage is much higher in patients with bone metastases than in patients with osteoporosis, and hence side effects are more severe in patients with bone metastases. Prolia is used for men and women with a high risk for fractures or who have bone loss due to anticancer therapy. Denosumab was tested in a 3-year study that enrolled 7868 postmenopausal women with osteoporosis. Compared with the women who got placebo injections, those who got denosumab had 68% fewer vertebral fractures, 40% fewer hip fractures, and 20% fewer fractures at other sites (wrist, leg, or shoulder). Taken together, these data suggest that denosumab is equal to bisphosphonates for treating postmenopausal osteoporosis.

Sargramostim is approved for patients in whom an autologous or allogenic bone marrow transplant has failed to take skin care greenville sc discount 5gm bactroban with mastercard. The goal is to accelerate neutrophil recovery and reduce the incidence of life-threatening infections acne 2008 discount bactroban line. In patients with aplastic anemia (a syndrome characterized by pancytopenia and high mortality from infection and bleeding) acne diet discount bactroban 5 gm line, sargramostim can increase neutrophil counts and reduce the incidence and severity of infections acne 404 nuke buy bactroban 5 gm with visa. The syndrome has a mortality rate of 66%-and those who survive often develop leukemia acne tool purchase bactroban 5gm with amex. Treatment with sargramostim can increase counts of neutrophils acne oral medication purchase discount bactroban on-line, eosinophils, and monocytes. Since the drug is a protein and thus would be degraded in the digestive tract, it cannot be administered by mouth. A variety of acute reactions have been observed, including diarrhea, weakness, rash, malaise, and bone pain that can be managed with nonopioid analgesics (eg, acetaminophen). Pleural and pericardial effusions have occurred, but only when sargramostim dosage was massive (16 times the recommended dosage). Stimulation of the bone marrow can cause excessive production of white blood cells and platelets. If the white cell count rises above 50,000/mm3, if the absolute neutrophil count rises above 20,000/mm3, or if the platelet count rises above 500,000/mm3, sargramostim should be interrupted or the dosage reduced. To prepare the final infusion solution, dilute the concentrated solution in either (1) 0. Since the solution contains no antibacterial preservatives, it should be used as soon as possible-and no later than 6 hours after preparation. In addition, the hormone acts on the mature forms of these cells to enhance their function. Also, the hormone acts on monocytes and polymorphonuclear leukocytes to enhance their actions against cancer cells. In these patients, sargramostim can (1) accelerate neutrophil engraftment, (2) reduce the duration of antibiotic use, (3) reduce the duration of infectious episodes, and (4) reduce the Adjunct to Autologous Bone Marrow Transplantation. After another 7-day hiatus, the 14-day series can be repeated once more, if needed. Continue daily infusions for 42 days, or until the absolute neutrophil count exceeds 1500 cells/mm3 on 3 consecutive days, whichever is less. Hematopoietic Agents Pharmacokinetics Oprelvekin is administered by subQ injection. Elimination is by hepatic and renal tubular metabolism, followed by excretion of the metabolites in urine. Expansion of plasma volume decreases both the hematocrit and hemoglobin concentration, causing anemia. As a result, about 48% of patients experience dyspnea (shortness of breath on exertion). The cause of cardiac effects is unclear, although expansion of plasma volume is suspected. Oprelvekin has been associated with severe allergic reactions, including anaphylaxis. Signs of oprelvekin-induced allergy include rash, urticaria, flushing, fever, hypotension, joint pain, chest pain, wheezing, shortness of breath, and edema of the face, tongue, and larynx. Patients and healthcare providers should be alert for these reactions and, if allergy is diagnosed, oprelvekin should be withdrawn and never used again. Other ophthalmic effects are transient visual blurring and papilledema (edema of the optic disk). Two drugs with similar actions-romiplostim and eltrombopag-are discussed in the section that follows. The drug is a protein nearly identical in structure and actions to human interleukin-11, a cytokine produced in bone marrow. Oprelvekin is given to stimulate platelet production in patients undergoing myelosuppressive chemotherapy for nonmyeloid cancers. Actions Oprelvekin acts on platelet progenitor cells to increase platelet production. Specifically, it stimulates proliferation of hematopoietic stem cells and megakaryocyte progenitor cells, and thereby increases synthesis of megakaryocytes, the cells that fragment into large numbers of platelets. In addition to promoting megakaryocyte synthesis, oprelvekin induces megakaryocyte maturation. In patients treated with oprelvekin daily for 14 days, platelet counts begin to increase 5 to 9 days after the first injection, peak about 7 days after the last injection, and return to baseline 14 days after that. Therapeutic Use Oprelvekin is administered to patients undergoing myelosuppressive chemotherapy to minimize thrombocytopenia (platelet deficiency) and to decrease the need for platelet transfusions. Because it stimulates the bone marrow, oprelvekin should not be given to patients with cancers of myeloid origin. In clinical trials, oprelvekin was effective for some patients but not for others. To assess its benefits, oprelvekin was given to patients who had required platelet transfusions following earlier rounds of chemotherapy. Some patients were on moderately myelosuppressive regimens and some were on highly suppressive regimens. Among those on moderately suppressive regimens, 30% were spared the need for platelet transfusions by combining oprelvekin with chemotherapy. Among those on highly suppressive regimens, only 13% were spared the need for platelet transfusions. Hence, although oprelvekin can increase platelet counts and decrease the need for platelet transfusions, not all patients benefit equally. As these data indicate, the more myelosuppressive the regimen, the less helpful oprelvekin is likely to be. Neither the powder nor the diluent contains preservatives, and so the solution must be used within 3 hours to avoid infection. Oprelvekin is administered by subQ injection into the abdomen, thigh, hip, or upper arm. Dosing should begin 4 to 6 hours after chemotherapy and should continue until the platelet count rises above 50,000/ mm3-but should not continue beyond 21 days. Nonetheless, two of these drugs-romiplostim and eltrombopag-have effects similar to those of an endogenous growth factor. And the third drug-plerixafor-is used to enhance the effects of an endogenous growth factor. In patients with hepatic impairment, drug exposure is increased by 41% (with mild impairment) and by 80% to 93% (with moderate to severe impairment). Drug exposure is also affected by race: Among patients of black ancestry, total exposure is increased by 40%, and among patients of East Asian ancestry, total exposure is increased by 70%. Eltrombopag is generally well tolerated, but nonetheless can cause serious adverse effects. Like romiplostim, eltrombopag may cause bone marrow fibrosis, hematologic malignancy, and thrombotic/ thromboembolic events, and may pose a risk of bleeding from a rapid drop in platelet counts when treatment is stopped. Absorption of eltrombopag can be greatly reduced by polycations (ie, calcium, magnesium, aluminum, selenium, zinc). Accordingly, at least 4 hours should separate administration of eltrombopag and drugs (eg, antacids) or supplements that contain these elements. Do not administer within 4 hours of drugs and supplements that contain calcium, magnesium, or other polycations. The initial dosage should be reduced to 25 mg/day in patients with liver impairment, and in those of East Asian ancestry (ie, Chinese, Japanese, Korean, Taiwanese). In contrast, oprelvekin is used to increase platelet production in patients undergoing cancer chemotherapy. Symptoms include easy bruising, superficial bleeding, prolonged bleeding from cuts, spontaneous bleeding from the gums or nose, blood in the urine or stools, heavy menstrual bleeding, and profuse bleeding during surgery. Romiplostim is indicated only after one or more of these traditional measures have failed. In patients who have not already undergone splenectomy, treatment with romiplostim may render splenectomy unnecessary. In contrast to traditional treatments, which reduce platelet destruction, romiplostim increases platelet production. Romiplostim is a unique kind of molecule known as a peptibody (a combination of a peptide and an antibody). Benefits derive from mimicking the actions of thrombopoietin, an endogenous compound that stimulates the proliferation and differentiation of megakaryocytes, the cells that fragment into platelets. Romiplostim stimulates megakaryocytes by binding to the same receptor used by thrombopoietin. Platelet counts begin rising 4 to 9 days after a single subQ dose, peak between days 12 and 16, and then decline to pretreatment levels by day 28. Serum concentrations vary between patients, and do not correlate well with dosage. The most common adverse effects are arthralgia, dizziness, insomnia, pain in the extremities, abdominal pain, myalgia, shoulder pain, dyspepsia, and paresthesias. When romiplostim is discontinued, platelet counts may drop below pretreatment levels, increasing the risk of bleeding. Uncommon but serious effects are bone marrow fibrosis (replacement of blood-forming cells with fibrotic tissue), hematologic malignancy (from stimulation of bone marrow cells), and thrombotic/thromboembolic complications (from excessive production of platelets). Romiplostim [Nplate] is supplied as a powder (250 and 500 mcg in single-use vials) for reconstitution in sterile water to a final concentration of 500 mcg/mL. Plerixafor is administered by subQ injection, and plasma levels peak 30 to 60 minutes after dosing. Side effects that do occur more often with plerixafor include injection-site reactions, diarrhea, nausea, and dizziness. For patients with reduced renal function (creatinine clearance below 50 mL/min), the dosage is 0. Like romiplostim, eltrombopag increases platelet production by activating the thrombopoietin receptor on megakaryocytes, causing these cells to proliferate and differentiate. Unlike romiplostim, which is a complex peptide-antibody hybrid, eltrombopag is a relatively simple small molecule, with a molecular weight of 442. Food reduces absorption by 60%, and polycations (eg, calcium, aluminum, magnesium) reduce absorption by 70%. In some cancer patients, epoetin can accelerate tumor progression and shorten life. Filgrastim is given to elevate neutrophil counts, and thereby reduce the risk of infection. The principal adverse effects of oprelvekin are fluid retention (which causes edema and anemia), cardiac dysrhythmias (tachycardia, atrial fibrillation, and atrial flutter), and severe allergic reactions, including anaphylaxis. Since epoetin alfa, filgrastim, sargramostim, and oprelvekin stimulate proliferation of bone marrow cells, these drugs should be used with great caution, if at all, in patients with cancers of bone marrow origin. Risk is greatest when the hemoglobin level exceeds 11 gm/dL or the rate of rise in hemoglobin exceeds 1 gm/dL in 2 weeks. To minimize risk, reduce dosage when hemoglobin approaches 11 gm/dL or when the rate of rise exceeds 1 gm/dL in 2 weeks, and temporarily stop dosing if hemoglobin rises to 11 gm/dL or more. For patients taking the drug before elective surgery, anticoagulant treatment can reduce the risk of deep vein thrombosis. To reduce risk, dosage should be no higher than needed to bring hemoglobin gradually up to 12 gm/dL. Also, epoetin should be used only in cancer patients who are undergoing chemotherapy or radiation therapy. Those who are not receiving chemotherapy or radiation therapy should not get this drug. Before administration, filgrastim may be kept at room temperature for up to 24 hours. Ongoing Evaluation and Interventions Evaluating Therapeutic Effects Obtain complete blood counts twice weekly. Give all patients a Medication Guide that explains the risks and benefits of epoetin, so that they can make an informed decision on whether or not to use this drug. In addition, the drug is approved for treatment of patients for whom an autologous or allogenic bone marrow transplant has failed to take. Identifying High-Risk Patients Sargramostim is contraindicated in the presence of hypersensitivity to yeast-derived products and excessive leukemic myeloid blasts in bone marrow or peripheral blood. Exercise caution in patients with cardiac disease, hypoxia, peripheral edema, pleural or pericardial effusion, or cancers of bone marrow origin. Administer as soon as possible after diluting-and no later than 6 hours after reconstitution. Ongoing Evaluation and Interventions Minimizing Adverse Effects Leukocytosis and Thrombocytosis. If the white blood cell count rises above 50,000/ mm3, if the absolute neutrophil count rises above 20,000/ mm3, or if the platelet count rises above 500,000/mm3, temporarily interrupt sargramostim or reduce the dosage. Continue for 21 days or until platelet counts exceed 50,000/mm3-whichever comes first.

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