Contraindications • Severe aortic regurgitation • Severe calcifc aorto-iliac disease and/or peripheral vascular disease • Disease of the descending aorta (aortic coarctation or aneurysm) • Sheathless insertion in severe obesity effective etodolac 400mg arthritis medication that starts with a c. Despite this anticoagulation with unfractionated heparin is required which must be carefully monitored by frequent activated partial thromboplastin times (aPtts) cheap etodolac online mastercard equate arthritis pain gluten free. Treatment strategy • Bridge to decision • Bridge to recovery • Bridge to bridge (long-term device) • Bridge to transplantation order etodolac american express rheumatoid arthritis in the knee treatment. Indications • Dilated cardiomyopathy: • Ischaemic • Myocarditis • Peripartum • Post cardiotomy • Congenital heart disease • Primary graft failure post cardiac transplantation. Worldwide as the survival on VaDs has improved, the use of long-term VaDs for destination therapy has i. Complications were common and tended to be infection, bleeding or thromboembolic related. Risks and complications • air embolism • Bleeding • thrombotic risk • Stroke • Ischaemic limbs • haemolysis • Infection • Immobility. Cannulation is by percutaneous cannulation of a major vein (internal jugu- lar and/or femoral) with fuoroscopic (or tOe) guidance. Indications are ventilator refractory respiratory failure with predominant hypercapnia and respiratory acidosis. Some patients need it for longer and there may be an eventual need for a permanent pacemaker due to com- plications of surgery. The majority of patients never require pacing and it is difcult to predict which patients may need pacing. So, most surgeons implant ventricular wires (at least one) in all patients while some do so only when patients required pacing immediately prior to chest closure. Should a patient with a single ventricular wire require pacing a wire is placed under the skin and the pacing circuit completed by attaching the ventricular wire to the negative terminal of the pacing box. Also, when atrial wires are avoided to decrease possible complications when need for pacing is predicted to be of short duration or to suppress ectopic beats with overdrive pacing. There is a risk of ventricular tracking of atrial tachyarrhythmias which is of-set by setting a ‘maximum tracking rate’. The cardiac rate is captured by pac- ing at 20% of the intrinsic rate and then gradually reduced, establishing stable sinus rhythm. Manoeuvres which may be helpful: • Increasing pacemaker output • Correction of exacerbating factors listed earlier • reversing polarity of bipolar pacing wires • Changing to unipolar pacing with subcutaneous return pacing wire • Temporary transvenous or oesophageal pacing if threshold progressively increasing • Transcutaneous pacing in an emergency. Failure to sense This must be distinguished from normal pacemaker function with inappro- priate settings. Cross-talk This occurs in dual-chamber pacing modes when the atrial pacing spike is sensed by the ventricular wire and inhibits ventricular output. Stimulation threshold checked in all patients and sensing threshold once an intrinsic rhythm has been established. The underlying rhythm should be checked regularly by turning down the pacing rate and letting the endog- enous rhythm to emerge, thereby assessing ongoing need for pacing. Stimulation threshold This is the minimum output (mA) needed to consistently capture the heart. Sensing threshold This is the least sensitive setting (biggest mV value) at which the pacemaker can detect a heartbeat. Temporary epicardial pacing after cardiac surgery: a practical review: Part : General considerations in the management of epicardial pacing. Temporary epicardial pacing after cardiac surgery: a practical review: Part 2: Selection of epicardial pacing modes and troubleshooting. Chapter 29 313 Sedation and pain relief Introduction 34 Patient assessment 35 Pharmacology 37 Clinical protocols 39 314 ChaPter 29 Sedation and pain relief Introduction after cardiac surgery, patients require a short period of sedation or symp- tom control to minimize oxygen consumption while they re-establish their normal physiology. Patients after minimally invasive and of-pump procedures can be consid- ered for early extubation but still have to be supported with a satisfactory analgesic protocol. Principles of sedation We must diferentiate short-term sedation in the uncomplicated patient from long-term sedation in unstable patients who develop critical illness. Principles of pain relief experience of postoperative pain is often complex and multifactorial. Modern con- cepts of postoperative analgesia are based on • Multimodal approaches including local anaesthetics • Favourable pharmacokinetics and pharmacodynamics • Good ability to titrate to patient’s requirements • No or minimal adjustments in patients with organ dysfunction • Pharmaco-economics. It is based on a com- bined assessment of the mental status beyond the infuence of pharmaco- logical sedation. Normally used as an -point scale with 0=no pain and 0 (00) represent- ing the worst imaginable pain. Optimizing patient recovery this includes faster achievement of recovery goals such as extubation and mobilization, but also allows more efective physiological and functional recovery, e. Further reading haenggi M, Ypparila-Wolters h, hauser K, Caviezel C, takala J, Korhonen I, et al. Most drugs work synergistically when used together, so lower doses/concentrations of each component is advisable. Opioids Morphine Popular and efective opioid that also has sedative characteristics. Mainly used intravenously by nurse-controlled boluses or patient-controlled anal- gesia. Unsuitable for long-term exposure due to high variability in pharmaco- dynamics and metabolism. Shallow dose–response curve allows it to be used in spontaneously breathing patients. Remifentanil Ultra-short-acting fentanyl congener with context-sensitive half-time of only 3–4 minutes. Increasingly used for short-term postoperative sedation until and after extubation. Pethidine (meperidine) a relatively old phenylpiperidine with characteristics similar to morphine. Sedatives/hypnotics Propofol Popular hypnotic that is easy to titrate and rapid to recover from. When used for long-term sedation, triglyceride levels should be checked regularly. Midazolam Widely used short-acting benzodiazepine that acts as sedative, anxiolytic, amnesic, and anticonvulsant. Sedative and respiratory depressant charac- teristics are potentiated with concomitant use of opioids. Similar to droperidol, it can alter the Qt interval and trigger torsade de pointes arrhythmia in vulnerable patients. In many cardiac critical care units the default strategy is executed and managed by nurses and nurse practitioners. Pain management there are two major stages that characterize the analgesic requirements of a postoperative cardiac patient.
Symptoms decline 13 to 4 weeks after starting the drug and resume 1 week after stopping the drug etodolac 400 mg fast delivery lower back arthritis relief. Pharmacokinetics Administration is oral purchase etodolac with paypal arthritis northwest, and absorption is rapid but incomplete (50%–60%) buy generic etodolac 300 mg on line arthritis statistics. Alosetron undergoes extensive metabolism by hepatic cytochrome P450 enzymes, followed by excretion primarily in the urine. Drug Interactions Alosetron does not interact with theophylline, oral contraceptives, cisapride, ibuprofen, alprazolam, amitriptyline, fluoxetine, or hydrocodone combined with acetaminophen. Because alosetron is metabolized by cytochrome P450 enzymes, drugs that interfere with these enzymes (e. Adverse Effects and Contraindications Although alosetron is generally well tolerated, it can cause severe adverse effects. The most common problem is constipation (29%), which can be complicated by impaction, bowel obstruction, and perforation. B l a c k B o x Wa r n i n g : A l o s e t ro n Alosetron can cause ischemic colitis (intestinal damage secondary to reduced blood flow). Ischemic colitis and complications of constipation have led to hospitalization, blood transfusion, surgery, and death. If, after 4 weeks, the dosage is well tolerated but inadequate, it can be increased to 1 mg twice a day. If, after 4 weeks at the higher dosage, treatment is still inadequate, the drug is not likely to help and should be stopped. Patients who develop constipation or signs of ischemic colitis (rectal bleeding, bloody diarrhea, new or worsening abdominal pain) should immediately inform the prescriber and discontinue the drug. Those with constipation may resume treatment, but only after constipation has resolved and only on the advice of the prescriber. A decreased dose of 75 mg twice daily is recommended for patients without a gallbladder, those who are unable to tolerate the higher dose, and those who have mild or moderate hepatic impairment. The most common adverse reactions include constipation, nausea, and abdominal pain. Unfortunately, benefits are modest: the drug can reduce abdominal pain and discomfort, but only in a small percentage of patients. As discussed in Chapter 63, lubiprostone causes selective activation of chloride channels in epithelial cells of the intestine and thereby (1) promotes secretion of chloride- rich fluid into the intestinal lumen and (2) enhances motility of the small intestine and colon. Ulcerative colitis is characterized by inflammation of the mucosa and submucosa of the colon and rectum. Four aminosalicylates are available: sulfasalazine, mesalamine, olsalazine, and balsalazide. Sulfasalazine Sulfasalazine [Azulfidine] belongs to the same chemical family as the sulfonamide antibiotics. However, although similar to the sulfonamides, sulfasalazine is not employed to treat infections. Therapeutic Uses Sulfasalazine is most effective against acute episodes of mild to moderate ulcerative colitis. Preparations, Dosage, and Administration Sulfasalazine [Azulfidine] is available in 500-mg immediate- and delayed- release oral tablets. Mesalamine can be administered by retention enema, by rectal suppository, or by mouth (in tablets and capsules that dissolve when they reach the terminal ileum). The most common adverse effect is watery diarrhea, which occurs in 17% of patients. Balsalazide Balsalazide [Colazal] is an aminosalicylate indicated for mildly to moderately active ulcerative colitis. The most common adverse effects are headache, abdominal pain, diarrhea, and nausea. Prolonged use of glucocorticoids can cause severe adverse effects, including adrenal suppression, osteoporosis, increased susceptibility to infection, and a cushingoid syndrome. Glucocorticoids are indicated primarily for induction of remission—not for long-term maintenance. Systemic effects are lower than with other glucocorticoids because absorbed budesonide undergoes extensive first-pass metabolism. Immunosuppressants Immunosuppressants are used for long-term therapy of selected patients with ulcerative colitis and Crohn disease. Thiopurines: Azathioprine and Mercaptopurine These drugs are discussed together because one is the active form of the other. Because onset of effects may be delayed for up to 6 months, these agents cannot be used for acute monotherapy. Furthermore, because these drugs are potentially more toxic than aminosalicylates or glucocorticoids, they are generally reserved for patients who have not responded to traditional therapy. Major adverse effects are pancreatitis and neutropenia (secondary to bone marrow suppression). Cyclosporine Cyclosporine [Sandimmune, Neoral, Gengraf] is a stronger immunosuppressant than azathioprine or mercaptopurine—and acts faster, too. Cyclosporine is a potentially toxic compound that can cause renal impairment, neurotoxicity, and generalized suppression of the immune system. Methotrexate In patients with Crohn disease, methotrexate can promote short-term remission and thereby reduce the need for glucocorticoids. Because the doses employed are low (25 mg once a week), the toxicity associated with high-dose therapy in cancer patients is avoided. Immunomodulators The drugs discussed in this section are monoclonal antibody products that modulate immune responses. However, some authorities now recommend their use early in treatment, with the hope of inducing remission quickly and maintaining remission longer. The drug is indicated for moderate to severe Crohn disease and ulcerative colitis. In clinical trials, infliximab reduced symptoms in 65% of patients with moderate to severe Crohn disease and produced clinical remission in 33%. During clinical trials, 5% of patients dropped out because of serious adverse effects. Infusion reactions include fever, chills, pruritus, urticaria, and cardiopulmonary reactions (chest pain, hypotension, hypertension, dyspnea). Infliximab may also increase the risk for lymphoma, especially among patients with highly active disease or those on long-term immunosuppressive therapy. For patients with Crohn disease or ulcerative colitis, treatment consists of an induction regimen (5 mg/kg infused at 0, 2, and 6 weeks) followed by maintenance infusions of 5 mg/kg every 8 weeks thereafter. Antibiotics Antibiotics, such as metronidazole and ciprofloxacin, can help control symptoms in patients with mild or moderate Crohn disease. Metronidazole In patients with mild or moderate Crohn disease, metronidazole [Flagyl] is as effective as sulfasalazine. Furthermore, because relapse is likely if metronidazole is discontinued, long-term therapy is required. Unfortunately, prolonged use of high-dose metronidazole poses a risk of peripheral neuropathy.
Patients are monitored on an electrocardiogram generic etodolac 400 mg fast delivery diet untuk gout arthritis, while they perform graded exercise on a tread- mill buy cheap etodolac 300mg on line severe arthritis definition. In t he example illust rat ed by Figure I– 1 buy etodolac 200mg mastercard does arthritis in dogs go away, if a 99 95 1 90 2 80 70 50 5 60 20 50 10 10 5 40 2 % 30 20 % 1 20 30 40 10 50 60 5 70 80 2 90 1 95 99 Posttest Like lihood ra tio: Pretest probability S e ns itivity probability 1 Specificity Figure I–1. If one knows the sensitivity and specificity of the test used, one can calculate the likelihood ratio of the posit ive t est as sensitivity/ (1 – specificity). Post t est pr ob- abilit y is calculat ed by mult iplying t he posit ive likelihood rat io by t he pret est prob- abilit y, or plot t ing the probabilit ies using a nomogram (see Figure I– 1). Thus, knowing something about the characteristics of the test you are employ- ing, and how to apply them to the pat ient at hand is essential in reaching a correct diagnosis and to avoid falling into the common trap of “positive test = disease” and “n e g a t i ve t e s t = n o d i s e a s e. Ap p ro a ch t o Clin ica l Pro b le m So lvin g There are typically four distinct steps to the systematic solving of clinical problems: 1. Experienced clinicians often make a diag- nosis very quickly using pattern recognition, that is, the feat u r es of the pat ient ’s illness match a scenario t he physician has seen before. If it does not fit a readily recognized pattern, then one has to undertake several steps in diagnostic reasoning: 1. T h e clin ician sh ou ld st ar t con sid er in g d iagn ost ic p ossibilit ies wit h in it ial cont act wit h t he pat ient, which are cont inually refined as informat ion is gathered. Historicalquestions and physicalexamination tests and findings arealltailored to the potential diagnoses one is considering. For example, a pat ient may come t o t he physician complaining of pedal edema, a relatively common and nonspecific finding. Laboratory testing may reveal that the patient has renal failure, a more specific cause of the many causes of edema. Examination of the urine may then reveal red blood cell casts, indicating glomer uloneph rit is, wh ich is even more specific as the cause of the renal failure. The pat ient’s problem, then, described with t he greatest degree of specificity, is glomerulonephritis. The clinician’s task at this point is to consider the differential diagnosis of glomerulonephritis rather than that of pedal edema. This means the features of the illness, which by their presence or their absence nar- row the differential diagnosis. This is often difficult for junior learners because it requires a well-developed knowledge base of the t ypical feat ures of disease, so t he diagnost ician can judge how much weight to assign to the various clini- cal clu es pr esent. For example, in the diagn osis of a pat ient wit h a fever an d productive cough, the finding by chest x-ray of bilateral apical infiltrates with cavit at ion is h igh ly d iscr im in at or y. T h er e are few illn esses besid es t uber cu losis that are likely to produce that radiographic pattern. A negatively predictive example is a pat ient wit h exudat ive pharyngit is who also has rhinorrhea and cou gh. T h e pr esen ce of t h ese feat u r es m akes the d iagn osis of st r ep t ococcal infect ion unlikely as the cause of t he pharyngit is. O nce t he different ial diag- nosis has been constructed, the clinician uses the presence of discriminating feat ures, kn owledge of pat ient risk fact ors, an d the epidemiology of diseases t o decide which potential diagnoses are most likely. Lo o k i n g f o r d i s c r i m i n a t i n g f e a t u r e s t o n a r r o w the d i f f e r e n t i a l d i a g n o s i s O nce the most specific problem has been identified, and a different ial diagnosis of that problem is considered using discriminating features to order the possibilities, the next step is to consider using diagnostic testing, such as laboratory, radiologic, or pathologic data, to confirm the diagnosis. Q uantitative reasoning in the use and interpret at ion of test s was discussed in Part 1. Clinically, the t iming and effort wit h wh ich one pursues a definit ive diagnosis using object ive dat a depend on several fact ors: the potential gravity of the diagnosis in question, the clinical state of the patient, the potential risks of diagnostic testing, and the potential benefits or harms of empiric treatment. For example, if a young man is admitted to the hospital with bilateral pulmonary nodules on chest x-ray, there are many possibilities including metastatic malignancy, and aggressive pursuit of a diagnosis is necessary, perhaps -including a thoracotomy with an open-lung biopsy. Decisions like this are difficult, require solid medical knowledge, as well as a thorough understanding of one’s patient and the patient’s background and inclinations, and constitute the art of medicine. Some diseases, such as congestive heart failure, may be designat ed as mild, moderat e, or severe based on the pat ient ’s func- tional status, that is, their ability to exercise before becoming dyspneic. With some infect ions, such as syphilis, the st aging depends on t he durat ion and ext ent of t he infection, and follows along the natural history of the infection (ie, primary syphi- lis, secondar y, lat ent period, and t ert iar y/ neurosyph ilis). If neither the prognosis nor the treatment was affected by the stage of the disease process, there would not be a reason to subcat - egorize as mild or severe. The treatment should be tailored to the extent or “s t a g e ” o f the d i s e a s e. In mak- ing decisions regarding t reat ment, it is also essent ial t hat t he clinician ident ify t he therapeutic objectives. W hen patients seek medical attention, it is generally because they are bothered by a symptom and want it to go away. When physicians institute therapy, they often have several other goals besides symptom relief, such as prevention of short- or long-term complications or a reduction in mortality. For example, patients wit h congest ive heart failure are bothered by the symptoms of edema and dyspnea. Salt restriction, loop diuretics, and bed rest are effective at reducing these symptoms. It is essential that the clinician know what the therapeutic objective is, so that one can monitor and guide therapy. Some responses are clinical, such as the patient’s abdominal pain, or temperature, or pulmonary examination. Obviously, the student must work on being more skilled in eliciting the data in an unbiased and standardized manner. The student must be prepared to know what to do if the measured marker does not respond according to what is expected. Is the next step to retreat, or to repeat the metastatic workup, or to follow up with another more specific test? Ap p ro a ch t o Re a d in g The clinical problem– oriented approach to reading is different from the classic “s y s t e m a t i c ” r e s e a r c h o f a d i s e a s e. P a t i e n t s r a r e l y p r e s e n t w i t h a c l e a r d i a g n o s i s ; hence, the student must become skilled in applying the textbook information to the clinical setting. In ot her words, t he student should read with t he goal of answering specific quest ions. One way of att acking this problem is t o develop st andard “approaches” t o common -clinical problems. With no other information to go on, the student would note that this woman has a clinical diagnosis of pancreatitis. Using the “most common cause” informa- tion, the student would make an educated guess that the patient has gallstones, because being female and pregnant are risk factors. If, instead, cholelithiasis is removed from the equation of this scenario, a phrase may be added such as: “T h e ult rasonogram of the gallbladder sh ows no st ones. Now, the student would use the phrase “patients without gallstones who have pancreatitis most likely abuse alcohol. This question is difficult because the next step may be more diagnostic informa- tion, or staging, or therapy. It may be more challenging than “the most likely diag- nosis,” because there may be insufficient information to make a diagnosis and the next step may be to pursue more diagnostic information.
Considerations This boy has a sport-related concussion buy etodolac 400mg with amex arthritis in hands crooked fingers, an injury which accounts for almost 10% of all athletic injuries during high school generic etodolac 200mg on-line arthritis effects. Concussion is a functional injury so imaging is not routinely done nor required for diagnosis cheap etodolac 300 mg visa arthritis relief foods. Instead, signs and symptoms indicating a concussion will involve one or more of the following areas: somatic, cognitive, emotional, or sleep (Table 60–1). Some of the symptoms will be immediate, such as his dizziness and the mental “fogginess,” a somatic and a cognitive symptom, respectively, which may worsen, subside, or fully resolve only to be followed by new findings. He now has symptoms from each of the categories: headache (somatic), anterograde amnesia (cognitive), fatigue (emo- tional), and increased sleep. The athlete must remain symptom free for 24 hours at each level without any medication before advancing. These inju- ries can be more significant than in professional athletes because the developing brain is more vulnerable and the cervical and shoulder musculature is less devel- oped. The immediate assessment of the child or adolescent with head injury begins at the time of the trauma. Sideline evaluation tools are available for older children, and assess for the signs and symptoms that define a concussion. The athlete should be removed from play and is not to return to any level of activity on the same day a concussion is sustained. Otherwise the child’s caregiver should be informed of the event, the definition of a concus- sion, and instructed to observe the child for 24 to 48 hours. Emergent care is to be obtained if increasing headache, vomiting, confusion, or unusual behavior develops. Cognitive exertion or physical activity can cause wors- ening of symptoms, so the best management after a concussion is physical and cog- nitive rest. A concussion is more of a functional brain injury than a structural injury so neuroimaging is usually normal. For optimal patient safety, graduated return-to-play protocols have been devel- oped and provide guidelines for a stepwise approach to advance activity while monitoring for symptoms. The protocol is not initiated until the athlete has been asymptomatic for 24 hours without the use of any medications, including acetamino- phen, ibuprofen, or aspirin. Within these protocols, a 24-hour symptom-free period is also required before advancing to the next level. It takes a minimum of 5 days to complete the protocol and no limit exists on how long the athlete may remain at a certain level. Signs and symptoms of concussions have been documented to worsen with activity so if recurrence is noted, the protocol is discontinued until the athlete is asymptomatic for a 24-hour period. Then the protocol can be resumed at the level the athlete was at before symptom onset. Failure to properly manage concussions can lead to serious long-term conse- quences ranging from second impact syndrome to chronic traumatic encephalopa- thy. All reported cases of second impact syndrome have been in athletes younger than 20 years. Returning to play too early and/or repeat concussions can be det- rimental; it is important to educate the child or adolescent and parent about the dangers of returning to activity before the concussion has resolved. Athletes who have symptoms lasting over 3 months or who sustain three concussions in a single season should be disqualified from return to the sport. Thus, the child with failure to thrive (Case 10) due to child abuse (Case 38) may have symptoms of head injury. Secondary head- ache (Case 48) is a common complaint among those who have sustained a concussion-producing injury. Acute onset of neurologic symptoms in the patient with sickle cell disease (Case 13) may be confused with concussion, especially if the stroke causes a fall with resultant head injury. The adolescent with substance abuse disorder (Case 49) often participates in high-risk activi- ties, thus has a higher rate of accidents and concussion. She initially had a headache when the injury occurred but it resolved and her energy level has returned to normal. She has now gone back to school but gets a headache about 20 minutes after she starts her first class of the morning. She does not get the headache if she takes acetaminophen before leaving for school. Her mother is concerned because school standardized testing is beginning in 48 hours and her daughter seems to be falling behind in her studies. Reassure the mother that her daughter will be fine and there is no reason to be concerned about the testing. Recommend continued treatment with acetaminophen or ibuprofen for symptom relief, and obtain a more thorough history regarding the head- ache to determine if she has migraines. Explain to the mother that the persistent headache is still secondary to the concussion and provide documentation to the school for the girl to have reduced assignments and defer the testing until she recovers. Ask the girl if she is in danger of failing and ask the mother if her daugh- ter might be trying to avoid taking the tests for fear of a poor performance. He has been strictly following your orders of physical and cognitive rest and has been asymptomatic for 2 days. Allow him to start the graduated return to play protocol with his athletic trainer since he has been asymptomatic. Allow him to participate in practice only if he promises not to strike the ball with his head. Second impact syndrome is a rare but potentially lethal complication of sustaining another concussion in close proximity to a prior concussion that is not fully recovered. The earliest an athlete should anticipate returning to play is within 5 days, and this timeframe would presume the symptoms of the concus- sion had already resolved for 24 hours. Even if no loss of consciousness is sustained at the initial injury, a con- cussion requires the athlete to be removed from play that day. Initial management of a concussion includes rest from physical activity, not just the competitive training, and also rest from academic work. A shorter recovery time is expected in a younger child because their concussions are milder because they cannot really hit as hard as older athletes. The patient is still exhibiting symptoms of her concussion which is not unexpected since most take 7 to 10 days to resolve. Standardized testing should be discouraged during the recovery phase because it is not cognitive rest and some studies have documented lower scores result. Nausea, fatigue, and difficulty falling asleep are symptoms of concussion that can last several months but do not require imaging. An asymptomatic period without the use of any medications for over 24 hours suggests a graduated return to play protocol may be initiated. Graduated return to play is best because symptoms of concussion often worsen or can recur with exertion. Because this injury is his first concussion, it is unlikely he would be out for the season. Younger athletes generally require longer recovery time and they are at higher risk for more severe injuries due to a developing brain and less devel- oped cervical and shoulder musculature. An 18-month-old girl is seen by the pediatric nurse practitioner for an episode of cyanosis and a concern for poor eating.
Tiludronate given once daily is usually Orally administrated bisphosphonates can cause esophageal effective in 3 months order etodolac toronto rheumatoid arthritis charity, whereas other bisphosphonate com- erosion generic etodolac 200 mg with amex arthritis medication that doesn't upset stomach, but this can be prevented by remaining upright pounds may require 6 months to be effective buy generic etodolac rheumatoid arthritis nutrition. If a relapse Chapter 36 y Drugs Affecting Calcium and Bone 381 occurs, another course of treatment can be given after a Indications 6-month interval. Because of its ability to inhibit osteoclast activity and de- In patients with bone cancer, bisphosphonates are useful crease bone turnover, calcitonin is used to treat osteoporosis, in the management of osteolytic bone disease and result- Paget disease of bone, and hypercalcemia. Intravenous administration of pami- In patients with osteoporosis, calcitonin treatment has dronate or zoledronic acid is the most effective treatment been shown to increase bone mass at multiple sites in the for hypercalcemia associated with cancer. Calcitonin treatment inhibits bone resorption, reduces the tumor treatment is usually reserved for women who cannot tolerate burden in bone, decreases bone pain, and reduces the risk of other treatments. Studies indicate that calcitonin increases fractures in patients whose cancer has metastasized to bone. Estrogen and Raloxifene In patients with Paget disease, calcitonin is administered Estrogen reduces bone resorption by inhibiting the pro- subcutaneously or intramuscularly every 1 to 3 days. The duction of bone cell cytokines such as interleukin-1, nasal spray is not used for this indication. Calcitonin treat- tumor necrosis factor, and granulocyte macrophage colony- ment inhibits osteoclast activity and reduces markers of stimulating factor by peripheral blood monocytes, and the abnormal bone turnover, such as serum alkaline phosphatase secretion of interleukin-6 and osteoclast-stimulating factors activity and urine hydroxyproline levels. These actions reduce the formation and acti- bone pain usually occurs 2 to 8 weeks after calcitonin therapy vation of osteoclasts and thereby slow bone loss. Estrogen is often employed to relieve menopausal symp- Hypercalcemia can be treated with subcutaneous or toms such as hot fashes, but the low doses of estrogen used intramuscular injections of calcitonin. The injections are for this purpose may not provide adequate protection against administered every 12 hours until a satisfactory response bone loss, and most authorities believe that higher doses of occurs. Denosumab offers an entirely new approach to the treat- Raloxifene is a selective estrogen receptor modulator ment of osteoporosis through the inactivation of gene tran- that mimics the effects of estrogen on bone. Although Mechanism of Action raloxifene activates estrogen receptors in bone, it has anties- Denosumab (Prolia, Xgeva) is a human immunoglobulin trogen effects in breast and uterine tissues and can cause or G2 monoclonal antibody produced in genetically engi- intensify hot fashes and other symptoms of estrogen with- neered mammalian cells that specifcally binds to and inac- drawal in menopausal women. Salmon calcitonin is 50 to 100 times more potent for osteoclast function and decreases bone resorption in both than human calcitonin. This effect was demonstrated in clinical studies by showing that denosumab reduced a Mechanisms and Effects serum bone resorption marker called type-1 telopeptide by Calcitonin binds directly to receptors on osteoclasts and about 85%. When given on a short-term basis, calcitonin inhibits osteoclast Clinical Use and Effects activity, decreases bone resorption, lowers serum calcium Denosumab (Prolia) is given by subcutaneous injection concentrations, and reduces bone pain. Cessation of teriparatide therapy may be followed by a rapid In a 3-year placebo-controlled trial of women with osteo- loss of bone. To preserve the benefts of treatment, teripara- porosis and a baseline T-score of −2. The drug also signif- rats and should not be prescribed for persons who are at cantly reduced hip and other nonvertebral fractures. Clinical trials showed that the drug Strontium ranelate is another treatment option for the pre- was equivalent to zoledronic acid for this indication. After oral administration, strontium is laid down on the surface of newly formed bone where it Adverse Effects decreases osteoclastic activity and reduces bone resorption. The most common adverse effects reported with deno- At the same time, strontium induces the differentiation of sumab injection are back, extremity, and musculoskeletal preosteoblasts to osteoblasts and increases markers of bone pain; hypercholesterolemia; and cystitis (bladder infamma- formation. Clinical trials found that strontium ranelate as eczema, dermatitis, and rashes was also observed in deno- reduced the risk of new vertebral fractures by about 25% and sumab subjects compared with those on placebo. Strontium may cause minor cemia may be worsened by denosumab treatments, possibly gastrointestinal problems but does not appear to have any because more serum calcium is being used for bone forma- serious adverse effects. Finally, a slight Fluoride increase in the incidence of new malignancies was observed Sodium fuoride is used to prevent tooth decay and dental in patients taking denosumab, but the relationship to drug caries, a condition in which localized destruction of calci- exposure has not been established. Teriparatide After oral administration, fuoride is stored in bone and Anabolic agents such as teriparatide are a newer type of teeth where it replaces the hydroxyl group in calcium phos- drug available to treat osteoporosis. Fluorapa- inhibit bone resorption, the anabolic agents increase bone tite deposited on the tooth surface is more resistant to formation and have the potential to reverse bone loss (see erosion than is hydroxyapatite. Several types of anabolic agents are currently the drinking water supply in many localities as a method of being developed. Liquid and chewable sodium fuo- consists of the 34 biologically active amino acids of the ride formulations are available to provide fuoride to infants hormone. Short-term sub- Fluoride also has potential application in the treatment of cutaneous administration (less than 2 years) of teriparatide osteoporosis. It increases bone crystal size and decreases its stimulates new bone formation on trabecular and cortical solubility so as to render bone more resistant to resorption. Unfortunately, the use of fuoride ratide increased markers of bone formation, skeletal mass, is limited by its tendency to cause excessive hardening and bone strength. One study found that fuoride did not reduce stimulate bone resorption more than bone formation and osteoporotic fractures. Weight- bearing exercise reduces bone loss and helps improve strength • The extracellular calcium concentration is regulated by and balance. In most postmenopausal women, osteoporosis can be • Vitamin D is converted to its most active form, cal- prevented by ensuring an adequate intake of calcium and citriol, by hydroxylation in the liver and kidneys. Dietary vitamin D is essential to prevent often used for this purpose because they can be taken orally, rickets in children. Calcitonin nasal spray is a good option for women characterized by a gradual loss of bone mass that who have taken a bisphosphonate for an extended period of leads to skeletal weakness and fractures. Teriparatide and deno- drug, calcitonin, teriparatide, estrogen, raloxifene, sumab can be effective in women with very low or rapidly denosumab, or strontium ranelate. Calcito- vents gene transcription required for osteoclast forma- nin or a bisphosphonate drug such as zoledronic acid is tion, survival, and function. Review Questions Hypercalcemia The treatment of hypercalcemia depends on the cause and 1. The major causes of hypercalcemia drug that decreases osteoclast activation but may intensify are hyperparathyroidism and cancer. Which drug was most likely given to this Saline diuresis is usually the preferred method of manag- patient? A saline infusion is used for this purpose; it serves (B) strontium ranelate to increase renal calcium excretion and to counteract the (C) calcitonin dehydration that often accompanies hypercalcemia. A woman with osteolytic bone cancer is treated with a Bisphosphonates are useful in the treatment of hypercal- drug that reduces the serum calcium level. Which drug cemia associated with cancer, sometimes in combination with is indicated for this purpose? As a last resort, intravenous phosphate infusions (A) calcitonin can be used to control hypercalcemia, but these infusions (B) ibandronate place the patient at considerable risk for acute hypocalcemia, (C) calcitriol hypotension, renal failure, and tissue calcifcation. It appears to be safe and effective for these (D) increased activation of osteoblasts conditions. A man with bone pain and deformities is placed on a drug reduces hypercalcemia in persons with malignancies.