Restless leg, Cardiology

1. Restless leg, Cardiology

2. Which of the following agents is associated with exacerbations of restless legs syndrome (RLS)? A) Diphenhydramine B) Iron C) Zolpidem D) Gabapentin

3. Answer • A) Diphenhydramine

4. Diagnostic criteria for RLS include: A) Urge to move legs during periods of inactivity B) Symptoms that may be relieved by movement C) Symptoms that occur or worsen exclusively during evening or night D) All the above

5. Answer • D) All the above

6. Pathophysiology • dopaminergic dysfunction • related to decreased iron concentrations in substantia nigra • Common descriptions of RLS: “creepy crawly” sensation (eg, sensation of worms crawling out of feet or ankles) • sensation of running water • often difficult for patients to describe sensations • Diagnostic criteria: urge to move limbs, accompanied by uncomfortable or unpleasant sensations • urge to move begins during periods of inactivity • symptoms may be relieved by movement • symptoms occur exclusively or worsen during evening or nigh • Symptoms described as most troublesome by patients: • disruption of sleep • uncomfortable feeling • inability to stay still • Pain • Jerking • daytime fatigue

7. Differential diagnosis • attention-deficit/hyperactivity disorder • agitated depression • essential tremor • Nocturnal leg cramps • Radiculopathy • peripheral neuropathy (starts at toes, with sensation often described as burning) • arthritic disease (occurs more often with weight bearing) • vascular disease • Exacerbations: can involve other parts of body (eg, arms) • always occurs in legs first • often exacerbated by levodopa and carbidopa (eg, Parcopa, Sinemet-10/100, Sinemet-25/100) • Laboratory tests: check serum ferritin level • iron saturation <20% considered abnormal • check metabolic panel and creatinine • Common clinical features: positive family history • response to dopaminergic therapy • periodic leg movements in sleep (PLMS) often noticed by bed partner in 50% of RLS patients • movements occur frequently (eg, every 40 sec) • patients often prefer sleeping with feet uncovered • symptoms generally do not respond to typical sleep hygiene (eg, refraining from watching television before bedtime)

8. Nonpharmacologic strategies • physical activity • Avoid caffeine and alcohol • stimulate legs • traveling on long flights —select aisle seat • occupy mind with, eg, food, computer games, or movie

9. Choose the correct statement about levodopa. A) Onset slow B) Best choice for intermittent usage when RLS symptoms occur occasionally C) No risk for augmentation D) Long duration of action

10. Answer • B) Best choice for intermittent usage when RLS symptoms occur occasionally

11. Pharmacotherapy • dopaminergic agents (eg, levodopa, dopamine agonists) • anticonvulsants (eg, gabapentin, carbamazepine) • Opioids • sedative-hypnotic agents (eg, clonazepam [Klonopin]) • supplement iron to bring saturation to >20% (vitamin C may improve absorption; consider side effects of iron) • Ropinirole (Requip); pramipexole (Mirapex; use lower doses than those used for Parkinson disease) • levodopa —fast onset; best choice for intermittent usage when symptoms occur occasionally • dopamine agonist recommended for daily symptoms • Other drawbacks of dopaminergic agents: augmentation— exacerbation and increased intensity of symptoms • spread of symptoms to arms • associated with levodopa (>200 mg/day) and carbidopa • effects less dramatic when medication stopped • rebound —symptoms occur early in morning • occurs with use of levodopa and carbidopa due to short action • side effects—include increased gambling or sexual urges • Gabapentin: start with 100 mg/day (recommended maximum dose 300 mg/day) • side effects include dizziness • Carbamazepine: monitoring levels not required • secondor third-line therapy for patients with neuropathy • Sedative-hypnotic agents: clonazepam may be less addictive than other agents • Zolpidem • use for RLS off Pharmacotherapy: label (more data needed) • no evidence of augmentation • patients may require higher doses • Opioids: third-line agents • tramadol recommended over hydrocodone for long-term us

12. RLS is a: A) Neurodegenerative disorder B) Physical condition C) Mental condition D) Vascular disease

13. Answer •  B) Physical condition

14. Children and RLS • “growing pains” may be manifestation of RLS • trials evaluating potential pharmacologic treatments under way • check family history • benzodiazepines, anticonvulsants, and opioids prescribed for children with other conditions, but levodopa should be used with caution • Summary of RLS: not neurodegenerative disorder; physical rather than mental condition

15. Patients with _______ have muscle aches or weakness without elevations in creatinine kinase (CK). A) Myalgia B) Myositis C) Rhabdomyolysis D) All the above

16. Answer • A) Myalgia

17. Definitions • myalgia—ache or weakness without elevation of creatine kinase (CK) • myositis —ache or weakness with elevation of CK • rhabdomyolysis —muscle symptoms with marked elevation of CK (>10 times normal) and elevated serum creatinine • Incidence of myalgias: higher in clinics than in trials, possibly due to increased direct-to-consumer advertising of medications, voluntary nature of Food and Drug Administration (FDA) Adverse Event Reporting System, and exclusion from clinical trials of patients with myalgias, extremes of age or lifestyle, or use of drugs that could cause myalgias • study —looked at 7900 patients on high-dose statin for 3 mo, or with decreased dose or discontinuation of statin in last 3 mo • medications included atorvastatin (Lipitor; 40-80 mg/day), fluvastatin (extended-release; 80 mg/day), pravastatin (40 mg/day), or simvastatin (Zocor; 40-80 mg/day) • 10% had muscle symptoms • incidence highest (20%) with simvastatin and lowest with fluvastatin • 60% had widespread pain • most patients had pain in thighs and calves • 25% had tendonitis • 27% regarded pain as minor distraction • 26% reported that pain interfered with major exertion, and 20% with minor exertion • 20% of patients discontinued therapy • 17% wanted reduced dose • myalgia generally occurred within first or second month (time of onset may be affected by other medications that increase plasma levels

18. Which of the following statins appears least associated with high plasma levels due to high first-pass metabolism? A) Simvastatin B) Atorvastatin C) Fluvastatin D) Pravastatin

19. Answer •  C) Fluvastatin

20. Risk factors for myalgias • alcohol use • heavy exercise • primary muscle disease • increased statin levels— use of high doses • low body mass index • drug interactions (eg, cytochrome P450 • 3A4 inhibitors) • verapamil, diltiazem, SSRIs, amiodarone, and colchicine tend to increase plasma levels (especially in older patients, who may have altered kidney or liver function) • Pharmacogenomics: SLCO1B1 gene —encodes for organic transporter that brings statin to liver and enhances uptake • deficiency in transporter results in higher plasma levels of statin and higher risk for complications • Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) —12,000 patients in United Kingdom randomized to 20 mg or 80 mg of simvastatin after myocardial infarction (MI) • isolated 120 patients who had myalgic complaints and elevations of CK • genome-wide scanning found C allele defect associated with 5- to 6-fold higher risk • patients with more complaints of myalgia had less reduction in cholesterol due to low uptake of drug • Management: no recommendation for routine monitoring of CK before therapy (consider in higher-risk patients [eg, patients who exercise heavily]) • change statin or statin dose • fluvastatin associated with high first-pass metabolism (ie, less likely to result in high plasma levels) • ezetimibe (Zetia) and colesevelam expensive, with modest benefits • niacin may be beneficial

21. Alternative statin dosing • based on small studies • Rosuvastatin (Crestor) —tolerability of 80% and lipid reduction of 29% seen with 5 to 20 mg/wk • similar results seen in other studies with 2.5 to 20.0 mg/wk, or dosing every other day (average dose 5 mg) • studies—1) looked at patients on ezetimibe (10 mg/day) for few months, followed by addition of atorvastatin (10 mg twice weekly) for 3 mo • saw good tolerability and reduction in low-density lipoprotein (LDL) • 2) looked at rosuvastatin (5 or 10 mg twice weekly) and saw reasonable LDL • Reduction • atorvastatin and rosuvastatin (drugs with long half-lives) could potentially be used every other day, or 1 to 2 times/wk with reasonable reductions in LDL • 3) looked at patients with previous coronary disease and myalgia on different statins • average LDL 175 mg/dL; after 3 mo, 16% LDL reduction seen with ezetimibe (10 mg/day), 33% with fluvastatin (extended release; 80 mg/day), and greater reduction seen with combination of both agents • myalgia complaints highest with ezetimibe, and lower with combination therapy • small number of patients discontinued therapy • 4) small studies of ezetimibe and colesevelam saw 42% reduction in LDL • 5) niacin (homeopathic dose, 500 mg; therapeutic dose, 2-3 g) shown to reduce LDL by 5% to 25%; plant • stanols can be used

22. Xuezhikang • study in China in 4800 patients with previous MI saw significant reduction in event rates • supplement combines other substances (eg, plant stanols) with red yeast rice (fermented form of mold) • active ingredient (monacolin K) same as that of lovastatin • 4800 mg equal to 10 mg of lovastatin; concerns raised by questionable manufacturing standards and lack of approval by FDA • available in China, but not in United States • tolerability appears similar to that of statins; some cases of renal failure reported

23. Statins with long half-lives (eg, atorvastatin, rosuvastatin) could potentially be used every other day or 1 to 2 times weekly, with reasonable reductions in low-density lipoprotein. A) True B) False

24. Answer •  A) True

25. Red yeast rice A) Active ingredient (monacolin K) same as that of lovastatin B) Absorption increased by vitamin C; associated with marked CK elevations C) Blood levels shown to be reduced by pravastatin; data inconclusive D) Immediate-release form generally associated with more side effects and hepatotoxicity than extended-release form

26. Answer •  A) Active ingredient (monacolin K) same as that of lovastatin

27. Coenzyme Q10 A) Active ingredient (monacolin K) same as that of lovastatin B) Absorption increased by vitamin C; associated with marked CK elevations C) Blood levels shown to be reduced by pravastatin; data inconclusive D) Immediate-release form generally associated with more side effects and hepatotoxicity than extended-release form

28. Answer • C) Blood levels shown to be reduced by pravastatin; data inconclusive

29. Niacin A) Active ingredient (monacolin K) same as that of lovastatin B) Absorption increased by vitamin C; associated with marked CK elevations C) Blood levels shown to be reduced by pravastatin; data inconclusive D) Immediate-release form generally associated with more side effects and hepatotoxicity than extended-release form

30. Answer • D) Immediate-release form generally associated with more side effects and hepatotoxicity than extended-release form

31. Vitamin D and coenxyme Q10 • epidemiologic markers suggest hypovitaminosis D associated with myalgia • nuclear receptors for vitamin D present in myocytes • study —looked at >600 patients in lipid clinic • 120 had statin myalgia, and 82 had vitamin D levels <32 ng/mL (mean level, 28 ng/mL) • significant number of patients improved with statin plus vitamin D (50,000 IU for 3 mo • 92% myalgia-free); problems with study include subject reporting and lack of placebo arm • Coenzyme Q10 (coQ10): blood levels shown to be reduced by pravastatin • studies —1) study saw 40% reduction in pain with coQ10 (100 mg/day), compared to vitamin E and statin therapy • 2) Japanese study compared coQ10 to placebo in patients on atorvastatin (10 mg/day) • no difference in CK levels • no reports on symptoms • 3) study compared coQ10 (200 mg/day) to placebo in 44 patients on simvastatin (40 mg/day) • No difference in pain scores • summary —data about coQ10 inconclusive

32. Conclusion • muscle complaints with statin use common • mechanisms unclear • treat patients symptomatically • No outcome data suggest any other strategy reduces events • Questions and answers: ezetimibe —not likely harmful • renal disease —ezetimibe plus simvastatin (Vytorin) beneficial • no studies comparing combination drug to ezetimibe or simvastatin alone • Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial —ezetimibe plus simvastatin reduced risk for MI, compared to placebo • no good outcome data for ezetimibe alone • niacin —outcome data modest (mostly surrogate data) • Small amount of mortality data available • mortality data about ezetimibe limited • over-the-counter or flush-free niacin (inositol) —not beneficial in reducing cholesterol • Slow niacin may be effective • “if it doesn’t flush, it’s not niacin” • speaker prefers extended-release formulation (Niaspan; expensive) • immediate-release niacin formulations generally associated with greater flushing and more side effects and hepatotoxicity, compared to extended-release niacin

33. Which of the following should be used initially to identify gastroesophageal reflux disease (GERD) in a patient who presents with heartburn and no alarm symptoms? A) Empiric trial of acid suppression for 4 to 8 wk B) Esophagogastroduodenoscopy C) Barium radiography D) pH probing

34. Answer •  A) Empiric trial of acid suppression for 4 to 8 wk

35. Dyspepsia and peptic ulcer disease (PUD) • differentiated from gastroesophageal reflux disease (GERD) • intermittent epigastric pain (gnawing or aching) may improve with meals • absence of heartburn and regurgitation • reflux should not be bloody • Infantile GERD: concerns—increased or persistent forceful vomiting (rule out pyloric stenosis) • green, yellow, or bloody vomit • difficulty breathing after vomiting • food refusal that causes weight loss or poor weight gain • pain related to eating or swallowing • “test and treat”—start with H2–receptor antagonist or proton pump inhibitor (PPI) • if ineffective, can try erythromycin, antacids, or cytoprotective agents (and consult pediatric gastroenterologist) • diagnostic studies—barium swallow or upper gastrointestinal (GI) series to rule out congential abnormalities • pH probe • upper endoscop (esophagogastroduodenoscopy [EGD]) • gastric emptying study • parental education—smaller or more frequent feedings • Elevate head of infant’s crib or bassinet • hold infant upright • burp child appropriately • use bottles that minimize swallowing of air • thickening formulas with cereal and introduction of solid food should be discussed with physician • involve pediatric gastroenterologist if conventional measures fail • need for surgery rare

36. Categorization of GERD • nonerosive reflux disease (NERD)— 90% of cases • erosive esophagitis—Los Angeles classification system based on size and extent of erosions across esophagus • other—Barrett esophagus • esophageal adenocarcinoma (EAC) • GERD algorithm: initiate treatment for heartburn with PPI or H2- receptor antagonist • if initial response good and patient symptom- free, maintain with lowest effective dose • screen high-risk patients (eg, white men >50 yr of age with long-term symptoms who smoke) for Barrett esophagus • if no initial response, use step-up therapy (ie, start with lowest effective dose, then increase to twice-daily dosing • if patient on H2-receptor antagonist, switch to PPI if patient on PPI, increase to maximum dose or twice-daily dosing) • if still no response, confirm diagnosis with pH probing or endoscopy • if alarm symptoms present, or 8-wk trial of PPI fails, refer for endoscopy

37. In patients with atypical GERD and moderate to severe persistent asthma, twice-daily proton pump inhibitor (PPI) therapy for 24 wk is most likely to: A) Reduce asthma exacerbations B) Reduce albuterol use C) Cause chest pain D) Improve pulmonary function

38. Answer •  A) Reduce asthma exacerbations

39. Diagnosis • no gold standard • 50% of patients who undergo EGD have normal findings • sensitivity and specificity of pH probing high, but false-positive and false-negative results occur • sensitivity of EGD for pathologic reflux low • Usefulness of barium radiography limited • empiric trial of acid suppression for 4 to 8 wk can identify GERD in patients without alarm symptoms • recommend lifestyle modifications (eg, avoid eating 3-4 hr before recumbency) • Alarm symptoms: black or bloody stools • Choking • Chronic cough • Dysphagia • early satiety • Hematemesis • Hoarseness • Iron deficiency anemia • Odynophagia • unexplained weight loss

40. Pharmacologic treatment for atypical GERD • H2-receptor antagonists, PPIs, and prokinetic agents • PPIs should be taken 30 to 60 min before meals • NERD—step-up therapy (H2-receptor antagonist followed by PPI if no improvement) and step-down therapy (PPI followed by lowest dose of acid suppression) equally effective • step-down therapy does not necessarily change natural history of disease, but can decrease pharmacy costs • erosive esophagitis—PPI treatment of choice for acute and maintenance therapy • on-demand therapy—patients take medications as needed • minimizes pharmacy costs • efficacious • Newer pharmacologic agents: baclofen—gama-aminobutyric acid agonist • works on smooth muscle • frequent dosing often required (may be sedating or cause central nervous system side effects) • arbaclofen—R-isomer of baclofen • small trials showed efficacy in reducing number of heartburn events at all dose levels studied • cisapride (Propulsid)—effective in minimizing GERD symptoms, but associated with cardiac effects • mosapride—small study saw decrease in GERD symptoms and improved gastric emptying when given with omeprazole to patients resistant to omeprazole alone • Laryngeal symptom and asthma exacerbations: no significant long-term benefits shown with twice-daily PPI for laryngealinduced cough or chronic hoarseness • twice-daily PPI therapy for 24 wk shown to reduce asthma exacerbations in patients with moderate to severe persistent asthma • treatment may improve quality of life, but may not reduce symptoms or albuterol use • no improvement in pulmonary function • Patients with chronic cough should be prescribed antisecretory therapy, even with no reportable GI symptoms • PPI therapy reduces symptoms of noncardiac chest pain, and can be used as diagnostic test for abnormal reflux

41. Classic GERD • consider twice-daily PPI, or confirm diagnosis with 24-hr pH monitoring • if patient improves, taper treatment • if symptoms recur, observe and use maintenance therapy • if pH test positive while patient taking PPI, increase dose • (if negative, reconsider diagnosis)

42. Surgical treatment • fundoplication; nearly 50% of patients require PPI therapy within 1 yr after surgery • Stretta procedure • endoscopic treatment destroys top layer of mucosa to decrease acid exposure • trial showed BARRX procedure may minimize dysplastic transformation to EAC • Complementary and alternative medicine: licorice, marshmallow root, and slippery elm (demulcents); ginger; apple cider vinegar • probiotics (controversial • may be better for lower GI issues) • digestive enzymes • relaxation, meditation, biofeedback, and acupuncture • Follow-up and surveillance: if symptoms remain unchanged in patient with previous normal endoscopy, repeating endoscopy not recommended for 10 yr • refer patients with warning signs and symptoms that suggest complications • further diagnostic testing should be considered in patients who do not respond to acid suppression, and in patients with history of chronic GERD at risk for complications • chronic reflux plays role in development of Barrett esophagus (unclear whether outcomes can be changed) • antisecretory therapy reduces need for recurrent dilatation due to formation of esophageal strictures

43. Which of the following are the 2 most common prognosticators for progression of Barrett esophagus to esophageal adenocarcinoma (EAC)? A) Smoking and age of patient B) Degree of disease and age of patient C) Presence of heartburn and male sex D) Age of patient and male sex

44. Answer •  B) Degree of disease and age of patient

45. Barrett esophagus • change in distal esophageal epithelium of any length that can be recognized as columnar-type mucosa on endoscopy, and intestinal metaplasia on biopsy of tubular esophagus • screening controversial • degree of Barrett esophagus and age of patient most common prognosticators for progression to EAC • can present without heartburn • any grade of dysplasia should be confirmed by expert pathologist • Pharmacologic acid suppression controversial • Esophageal adenocarcinoma: screening should not be performed in men <50 yr of age, or in women, due to low incidence of cancer (regardless of frequency of symptoms) • incidence in white men >60 yr of age with weekly GERD symptoms substantial and warrants screening • PPI issues: end points in PPI treatment unclear • many patients begin self-directed trial of over-the-counter PPIs • patients often left on PPI therapy without adequate follow-up • cost of inappropriate PPI use significant • risks—hip fractures related to osteoporosis • vitamin B12, calcium, zinc, vitamin C, and magnesium deficiencies • interactions with clopidogrel (particularly with omeprazole) • spontaneous bacterial peritonitis • contraindicated in pregnancy • Clostridium difficile diarrhea— associated with use of PPIs with antibiotics • 43-fold increase in risk with PPIs, antibiotics, and chemotherapy • Protocols suggest stopping PPI therapy on hospital admission, unless PPI specifically indicated or if symptoms extreme • 6-fold risk for community-acquired pneumonia associated with current PPI therapy started within 2 days of diagnosis • some conflicting data about risks • antiplatelet interactions

46. Regardless of the frequency of symptoms, screening for EAC in men <50 yr of age is not recommended. A) True B) False

47. Answer • A) True

48. Risks of PPI therapy include: A) Calcium deficiency B) Interactions with antiplatelet agents C) Clostridium difficile diarrhea D) All the above

49. Answer •  D) All the above

50. Most patients with peptic ulcer disease (PUD) do not complain about: A) Gnawing or burning pain B) Pain several hours after a meal C) Heartburn D) Waking between 12 am and 3 am due to pain