Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Drug design wikipedia , lookup
Pharmaceutical industry wikipedia , lookup
Neuropharmacology wikipedia , lookup
Pharmacokinetics wikipedia , lookup
Drug discovery wikipedia , lookup
Drug interaction wikipedia , lookup
Patent medicine wikipedia , lookup
Prescription costs wikipedia , lookup
Terms of Use The In the Clinic® slide sets are owned and copyrighted by the American College of Physicians (ACP). All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of ACP. The slide sets may be used only by the person who downloads or purchases them and only for the purpose of presenting them during not-forprofit educational activities. Users may incorporate the entire slide set or selected individual slides into their own teaching presentations but may not alter the content of the slides in any way or remove the ACP copyright notice. Users may make print copies for use as hand-outs for the audience the user is personally addressing but may not otherwise reproduce or distribute the slides by any means or media, including but not limited to sending them as e-mail attachments, posting them on Internet or Intranet sites, publishing them in meeting proceedings, or making them available for sale or distribution in any unauthorized form, without the express written permission of the ACP. Unauthorized use of the In the Clinic slide sets constitutes copyright infringement. © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. * For Best Viewing: Open in Slide Show mode (Click on in bottom right) or From the View menu, select the Slide Show option © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. in the clinic Dyslipidemia © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. What preventive lifestyle measures should clinicians recommend to reduce risk for dyslipidemia? Healthy diet Regular exercise Tobacco avoidance Improved lipid profiles Reduced CAD risk for all Unlikely to achieve marked change Many require drugs © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. What preventive lifestyle measures should clinicians recommend to reduce risk for dyslipidemia? Greatest risk reduction if: • CAD • CAD equivalents CAD equivalents: •Diabetes •Aortic aneurysm •Periph vasc disease •Carotid disease w/sxs •Framingham risk > 20% © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. Who should be screened for dyslipidemia? No direct evidence: Screening & treatment reduced CVD or stroke Indirect evidence to screen: Men > 35 years Women > 45 years © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. Who should be screened for dyslipidemia? USPSTF: Men > 20 years & women > 35 if: •Risks for CAD •FH premature CAD, or lipid d/o •PE suggests hyperlipidemia NCEP- ATP III: All adults > 20 years •Promote healthy behavior •Public awareness •Identify those at risk •Benefit unclear © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. Who should be screened for dyslipidemia? Children/Adolescents American Association of Pediatrics: > 2 years: Screen if FH or other CVD risks Untreated hyperlipidemia increases adult risk Lifestyle counseling if: CVD risk factor High LDL cholesterol Overweight/obese with low HDL or high triglycerides Consider meds if high LDL after counseling © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. Who should be screened for dyslipidemia? Adults > 65 years Moderate evidence for screening Higher baseline risk of CHD Total cholesterol predicts CHD As in younger pts, screen all with CHD, or CAD risk equivalents CAD Equivalents: •Diabetes •Aortic aneurysm •Periph vasc disease •Carotid disease w/sxs •Framingham risk > 20% © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. How and how often should clinicians screen for dyslipidemia? AHA & NCEP: Fasting lipid profile Every 5 years for adults >20 years Initial to include triglycerides & indirect LDL calculation USPSTF: Fasting or nonfasting profile Men >35 years, women >45 years with CHD risk Total cholesterol and HDL only LDL and triglycerides only to guide Rx © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. How and how often should clinicians screen for dyslipidemia? LDL is primary treatment target Triglycerides are secondary target LDL = Total cholesterol – Triglycerides - HDL 5 Best after > 8 hours fasting Measure LDL directly if TG > 4.52 mmol/L (400 mg/dL) © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. Screening © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. How should clinicians interpret lipid screening results in relation to overall cardiovascular risk? Use equations to estimate CV risk More accurate than lipid levels alone or counting risk factors NHLBI (Framingham risk equation) http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=prof 10-yr risk of CV event: Low <10% Moderate 10%–20% High >20% © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. What tests should clinicians obtain before starting therapy for dyslipidemia? Prospective studies: Elevated LDL w/>2 CAD risk factors 10-yr risk >20% for MI or CAD death Rx to reduce LDL decreases risk for CHD death Focus on identifying & treating elevated LDL cholesterol levels Identify causes of elevated LDL Set targets of diet & drug therapy © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. How should clinicians measure and interpret triglyceride levels? Elevated TGs: Increased CAD risk: Women > Men Normal: <1.70 mmol/L (<150 mg/dL); Borderline: 1.70–2.25 mmol/L (150–199 mg/dL) High: 2.26–5.64 mmol/L (200–499 mg/dL) Very high: >5.65 mmol/L (>500 mg/dL) ATP III: TGs secondary Rx goal Borderline familial abnormalities High ? Other issues (DM, EtOH, renal failure, nephrosis) Very high pancreatitis risk; warrants Rx © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. How should clinicians measure and interpret HDL levels? HDL: inverse association with coronary events 2% decrease coronary events/1% increase in HDL HDL >1.6 mmol/L (>60 mg/dL) decreased risk HDL <1.0 mmol/L (<40 mg/dL) increased risk © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. How should clinicians measure and interpret HDL levels? HDL <1.0 mmol/L (<40 mg/dL) ? Acquired: Tobacco Obesity Inactivity Hypertriglyceridemia Type 2 diabetes mellitus Carbohydrates Genetic mutations β-blockers, androgenic steroids © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. What should clinicians look for in the history and physical examination of a patient with dyslipidemia? Coronary risks Secondary causes: drugs BP BMI Peripheral, carotid pulses/bruits Drugs & Dyslipidemia • Corticosteroids • Androgenic steroids • Progestogens • Thiazides • β-blockers • Retinoic acid derivatives • Oral estrogens Secondary causes: liver, thyroid © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. What are the causes of secondary dyslipidemia, and how should clinicians diagnose them? Drugs & Dyslipidemia • Corticosteroids • Androgenic steroids • Progestogens • Thiazides • β-blockers • Retinoic acid derivatives • Oral estrogens Hypothyroidism Obstructive liver disease Nephrotic syndrome Renal failure Uncontrolled diabetes Tobacco or alcohol use Medications consider stopping Address secondary causes before drug therapy Dyslipidemia may resolve Rx may be ineffective © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. When should clinicians consider specialized lipid tests or referral to a specialist? Suspicion of familial hypercholesterolemia Apolipoprotein measurements (e.g., apo A and B) More accurate than lipids when values very high May suggest cause Guide choice of therapy Assess risk of atherothrombosis Strongly consider screening first-degree relatives © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. Diagnosis © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. What should clinicians advise patients about lifestyle changes? Normal-weight pts w/dyslipidemia (BMI 18.5-24.9 kg/m2): • Focus on healthy eating • Regular exercise Overweight and obese pts (BMI ≥25 kg/m2): • Reduce caloric intake from fats, simple carbohydrates • ≥30 mins physical activity most days Diet (rich fruits, veg, nuts, whole grains, monounsaturated oils; low red meat, animal fat) Reduces LDL 5–15% (ATP III TLC diet) Aerobic exercise: Running, walking, cycling, swimming enhance weight reduction Facilitates achieving optimum lipid levels Adopt lifestyle changes regardless drug Tx Set goals, select strategies, risk factor ctrl Schedule periodic weight checks, counseling © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. When should drug therapy be recommended? Implementation of Interventions Based on NCEP-ATP III Goals Patients ≤1 cardiac risk factor • LDL-C ≥4.14 mmol/L (≥160 mg/dL lifestyle changes • LDL-C ≥4.9 mmol/L (≥190 mg/dL), add drug Tx • LDL-C 4.14–4.89 mmol/L (160–189 mg/dL), consider drug Tx/pt preference Patients w/ ≥2 risk factors and 10-y risk <10% • LDL-C ≥3.35 mmol/L (≥130 mg/dL lifestyle changes • LDL-C ≥4.14 mmol/L (≥160 mg/dL), consider drug Tx © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. When should drug therapy be recommended? Implementation of Interventions Based on NCEP-ATP III Goals Patients w/ 10-y risk 10% to 20% • LDL-C ≥3.35 mmol/L (≥130 mg/dL), strongly consider drug Tx w/lifestyle changes • LDL-C 2.59-3.34 mmol/L (100-129 mg/dL), consider drug Tx w/ lifestyle changes based on pt pref Patients w/ 10-y risk >20%, CAD, or CAD risk equivalents • LDL-C ≥2.59 mmol/L (≥100 mg/dL), drug Tx & lifestyle changes • LDL-C 1.81-2.59 mmol/L (70-100 mg/dL), lifestyle changes and consider drug Tx © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. What options are available for drug therapy? Statins Atorvastatin (10–80 mg/d) Fluvastatin (20–40 mg nightly or 80 mg XL nightly) Lovastatin (10–40 mg evening meal or 10–60 XL nightly) Pravastatin (10–80 mg at bedtime) Rosuvastatin (5–40 mg/d) Simvastatin (5–80 mg at evening meal) LDL-C lowering 22-63%, varies with drug; differing metabolism allows substitution if AEs Adverse effects: Abnormal LFTs (relatively uncommon) Myositis/myalgias (increased w/ fibrates): don’t give rosuvastatin w/warfarin or gemfibrozil Don’t use in pregnant /nursing women Avoid: active liver disease © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. What options are available for drug therapy? Bile acid sequestrants Colestipol (2 scoops BID or TID) Colsevelam hydrochloride (three 625-mg tabs BID) Nonabsorbed; long-term safety established; lowers LDL-C 10-15% 1st-line: children and women w/child-bearing potential 2nd-line: w/ statins for synergy by inducing LDL-C receptors Adverse effects: Unpleasant taste/texture, bloating, heartburn, constipation Drug interactions (avoid by administering 1 h before or 4 h after meals) Increased triglycerides Don’t use: triglyceride >3.39 mmol/L (>300 mg/dL) or GI dysmotility © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. What options are available for drug therapy? Fibrates (reduce VLDL synthesis and lipoprotein lipase) Gemfibrozil (600 mg 2x/day) Fenofibrate (45–145 mg/day depending on brand) Best triglyceride level-reducing drugs, lowers ≥50% in many patients; increases HDL-C level by 15% Adverse effects: Nausea, skin rash Unreliable reduction (and can increase) LDL-C Caution: W/statins myositis/myalgia W/repaglinide severe hypoglycemia Renal insufficiency or gallbladder disease © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. What options are available for drug therapy? Niacin (mechanism largely unknown) Niacin (500–750mg to 1–2g nightly XR niacin) Lowers LDL-C and triglycerides 10-30%; most effective drug to raise HDL-C level (25-35%) Drug of choice for combined hyperlipidemia and w/ low HDL-C level Adverse effects: Flushing, nausea, gout; may increase glucose, LFTs uric acid, homocysteine XR preparations limit flushing & LFT abnormal Do not use in pregnancy or nursing Long-acting OTC niacin prep not recommended: increased hepatotoxicity © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. What options are available for drug therapy? Omega-3 (polyunsaturated fatty acids inhibit hepatic triglyceride synthesis, augment chylomicron triglyceride clearance secondary to increased lipoprotein lipase activity) 4-6 g/day (higher dosing for OTC formulations) Controls triglycerides up to 45%; raises HDL-C 13% Adverse effects: Dyspepsia, nausea; may increase bleeding time; use cautiously with anticoagulants Can increase LDL-C in some w/increased triglycerides © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. What options are available for drug therapy? Ezetimibe (selectively inhibits intestinal absorption of cholesterol & related phytosterols) 10 mg 1x/day Well-tolerated; reduces LDL-C 18%, triglycerides 8%, and apolipoprotein B 16% Can use w/statins for further LDL-C and triglyceride level reduction and to increase HDL-C level Adverse effects: Contraindicated w/liver disease or elevated LFTs Don’t combine w/resins, fibrates, or cyclosporine © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. What options are available for drug therapy? Ezetimibe and simvastatin (combo drug; selectively inhibit intestinal absorption cholesterol & partially inhibit HMGCoA reductase) Ezetimibe, 10 mg nightly Simvastatin, 10–80 mg nightly Combination therapy may improve patient adherence; synergistic benefits Adverse effects: Abnormal LFTs; myositis, myalgia Avoid with fibrates, >1g; niacin; amiodarone; or verapamil due to increased risk for myopathy Contraindicated: liver disease & pregnant/nursing women © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. What options are available for drug therapy? Selection of the agent depends on type of dyslipidemia •For high LDL-C level only: Consider statins first, resins or intestinal absorption blocker second, niacin third • For high LDL-C and low HDL-C levels: Consider statins first, niacin second • For high LDL-C, low HDL-C, and high triglyceride levels: Consider niacin and statins first, fibrates second • For high triglyceride levels, w/ or w/o low HDL-C levels: Consider fibrates first, niacin second • For low HDL-C levels only: Consider niacin first, fibrates second © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. When is combination drug therapy for dyslipidemia warranted? When lipids severely elevated & unresponsive to monotherapy Lipid-lowering med combos: Statins, bile acid-binding resins, fibrates, nicotinic acid Specific agents more effective in combo Nicotinic acid ( HDL-C level, triglycerides) plus statin ( LDL-C level) High-dose stain monotherapy may be superior combo Tx Be vigilant for drug interxns Fibrate-statin combo meds compete for metabolism via cytochrome P450 system, may induce rhabdomyolysis Long-acting, nonflushing, OTC niacin prep can cause hepatotoxicity Ezetimibe-statin combo ezetimibe LDL-C levels (blocks absorption), but not coronary events © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. What are the therapeutic goals of treatment? Goals for Therapy Using LDL-C Levels Risk group High risk CHD/CHD risk equiv’ts, 10-y risk >20% Moderately high ≥2 risk LDL-C Goal risk factor Consider Drug Therapy mmol/L mg/dL mmol/L mg/dL mmol/L mg/dL <2.59 (optional <1.81) <100 (option’l <70) ≥2.59 ≥100 ≥2.59 ≥100 <3.35 <130 (optional <100) ≥3.35 ≥130 ≥3.35 ≥130 (consider if 100–129) <4.14 <160 ≥4.14 ≥160 ≥4.92 ≥190 (LDLC drug optional if 160-189) factors, 10-y risk <10% Lower risk ≤1 Initiate Lifestyle Changes © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. What are the goals of treatment? After LDL goals attained… Reduce triglyceride levels to <1.7 mmol/L (<150 mg/dL) Then attempt to increase HDL to >1.0 mmol/L (>40 mg/dL) By selection/combo of drugs w/ effects on multiple lipoproteins © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. How should therapy be monitored? 6 weeks after adding new lipid-lowering agent: Check fasting lipid profile, discuss adherence, side effects If LDL-C goal not achieved consider intensification of therapy (reevaluate in 6 weeks) Add new/add’l drugs 1 at a time to help assess adverse effects if they occur Routine LFTs not recommended for patients on statins Behavioral lifestyle changes may require more frequent visits to foster adherence Only 39% of patients receiving drug tx and only 34% of patients receiving dietary tx reach their NCEP goal © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. What are the side effects of drug therapy? Statins Elevated liver enzyme levels (relatively uncommon) Myositis/myalgias (use w/fibrates increases risk) Low frequency serious events; rhabdomyolysis rare Fibrates Nausea, skin rash W/statins: increased incidence myositis, myalgias Niacin Flushing, nausea, headache, glucose intolerance, gout Minimize flushing w/nonenteric-coated aspirin 1 hour before evening dose w/low-fat snack; avoid hot beverages, baths/showers around time of niacin dose © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. What are the side effects of drug therapy? W/severe side effects...discontinue may be only option W/minor side effects…weigh risks & benefits of therapy May be reasonable to substitute one statin for another when side effects occur (metabolism of various statins differ) © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. Treatment © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. What should clinicians advise patients about the use of complementaryalternative therapies for dyslipidemia? Do not substitute for drug therapy in high-risk pts Plant-based diets have shown some effectiveness Stanol ester-containing margarines or foods Oat bran Nuts in moderation Dietary changes might affect serum lipid levels by replacing fatty foods w/healthier choices © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. When should clinicians consult a lipid specialist for help in managing dyslipidemia? Management of rare or treatment-resistant lipid disorders Special monitoring or complex regimens difficult to initiate in routine practice Familial hypercholesterolemia or type III dyslipoproteinemia Very low HDL-C syndromes (HDL-C <0.5 mmol/L [<20 mg/dL]) Resistant hypertriglyceridemia (triglycerides >11.3 mmol/L [>1000 mg/dL]) Management of pts at high risk for vascular event Pts <45 years w/vascular disease Pts w/evidence disease progression despite Rx (may need multiple interventions; examine secondary causes, such as unusual lipid/lipoprotein disorders, poor med adherence) © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1. What do professional organizations recommend regarding the care of patients with dyslipidemia? Recommendations on dyslipidemia screening differ Age screening should be started Which screening tests should be used Most widely used lipid guideline: NHLBI’s NCEP-ATP III: www.nhlbi.nih.gov/guidelines/cholesterol/index.htm Comprehensive listing of guidelines at National Guideline Clearinghouse www.guidelines.gov © Copyright Annals of Internal Medicine, 2010 Ann Int Med. 153 (3): ITC2-1.