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92 Cards in this Set
- Front
- Back
How many classes of Antihyperlipidemic drugs are there? What are the classes?
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FOUR:
1. Hmg-CoA Reductase inhibitors 2. PPAR activators/fibric acid 3. Bile acid resins 4. Others |
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What are the HMG-CoA Reductase inhibitors called?
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Statins
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What are the 2 statins to know?
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Lovastatin
Atorvastatin |
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What is the PPAR activator to know?
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Gemfibrozil
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What is the bile acid resin?
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Cholestyramine
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What are the 2 others?
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Niacin
Ezetimibe |
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Acronym for all the antihyperlipidemics?
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GLANCE
-Gemfibrozil -Lovastatin -Atorvastatin -Niacin -Cholestyramine -Ezetimibe |
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How do the HMG-CoA reductase inhibitors work?
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By acting as reversible competitive antagonists of HMG-CoA Reductase for its active site
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What does inhibiting the active site of HMG-CoA Reductase do?
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Prevents HMG-CoA from being converted to mevalonate which is the RLS in cholesterol biosynthesis particularly in liver hepatocytes.
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How does the affinity of the statins compare to the natural substrate for HMGCoAR?
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Statins have higher affinity!
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How does inhibiting liver cholesterol biosynthesis de novo reduce plasma cholesterol levels?
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The liver has an increased need for exogenous cholesterol so it upregulates LDL receptors and catabolizes more LDL from peripheral tissues.
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In what patients are the statins not very useful?
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Patients with familial hypercholesterolemia - their ldl receptors are defective so upregulating them won't have any effect.
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What are the 2 statins to know?
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-Lovastatin
-Atorvastatin |
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Where do all statins seem to preferentially upregulate LDL receptors by inhibiting HMG-CoA reductase?
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In the liver
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Why do the statins have a preferential effect on the liver?
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Because there is significant first pass uptake which limits systemic exposure to the active drug.
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Which statin is a prodrug and which is given in an active form?
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Lovastatin - prodrug
Atorvastatin - active |
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Which statin has the longest half life and what is it?
What is the half life of the other statins? |
Atorvastatin - 20 hrs
All others - 1-4 hrs |
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What are the statins metabolized by?
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Liver Cyp3A4
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What is the major adverse effect of the statins?
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Myopathy and rhabdomyolysis
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What can be detected in the blood as a result of the rhabdomyolysis?
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CK
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When is the risk of rhabdomyolysis even greater?
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When statins are given in combo with naicin or fibrates
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What may the increased risk of rhabdomyolysis in combo therapy be due to?
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Inhibition of cyp3A4, thus higher levels of active drug
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What inhibits Cyp3A4?
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Drugs and grapefruit juice
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What is a major contraindication for giving Statins?
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Pregnancy or breastfeeding
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How do the statins affect lipoprotein profiles?
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-Reduce TG
-Increase HDL -Significantly reduce LDL |
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So what is the major clinical use of the statins?
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First Line Therapy for patients at high risk of MI dt hyper cholesterolemia
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What is the bile-acid binding resin to know?
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Cholestyramine
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What is the mechanism by which Cholestyramine works?
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-Binds bile acids in intestines
-Inhibits reabsorption of BA's via enterohepatic recycling |
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Why does blocking bile acid reabsorption from the intestines reduce blood cholesterol levels?
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-Bile acids are the only way to excrete cholesterol
-By making more bile acids get excreted, more cholesterol gets converted to bile salts and thus excreted |
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What is the major way that the bile acid resins reduce plasma cholesterol?
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The liver senses decreased plasma cholesterol so upregulates LDL receptor and thus more is cleared.
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How exactly do the BA binding resins bind to them in the intestine?
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By exchanging chloride for the bile acids
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How exactly does the decreased enterohepatic recycling of BA's increase their synthesis in the liver?
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By not giving feedback inhibition to 7a-hydroxylase, the RLS in BA synthesis.
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What minor effect does increased cholesterol catabolism by 7a-hydroxylase have on liver HMG-CoA Reductase?
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Its synthetic activity increases but only a little bit - not enough to compensate for lower plasma LDL levels
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Why is it good that the compensation by HMG-CoA Reductase doesn't increase plasma cholesterol levels much?
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Because then the liver still wants to upregulate LDL receptors which is the whole goal to lower plasma LDL anyway.
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How is Cholestyramine administered?
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Orally as a Chloride salt and insoluble in water
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Is Cholestyramine absorbed into circulation?
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No but it may interfere with the absorption of other agents.
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How long will Cholestyramine take for its effects and lower serum LDL to be seen?
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~ 1 month
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What is the main problem with giving Cholestyramine?
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Patient compliance due to gas, bloating, cramps, and nausea.
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How will Cholestyramine affect the lipoprotein profile?
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-TG will be increased!
-HDL will be increased -LDL will be reduced |
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What is the major clinical use of Cholestyramine?
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Treatment of hypercholesterolemia caused by dietary sources - NOT LDL receptor defects
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How will cholestyramine affect patients with familial hypercholesterolemia?
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-Homozygotes - no effect
-Heterozygotes - some effect |
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When is Cholestyramine NOT recommended?
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For patients with hypercholesterolemia and increased TG - it may increase the TG even more.
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What is Niacin?
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Water soluble Vit B
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What does Niacin do?
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Activates a GPCR coupled to Gi in adipocytes
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What is the effect of activating the Gi coupled receptor on adipocytes?
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Decreased cAMP, decreased PKA, decreased lipase activity and decreased FFA mobilization
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What normally stimulates this pathway for FFA mobilization from adipocytes?
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Beta receptors
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What is the main way that Niacin reduces LDL levels then?
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By reducing FFA supply to the liver, thus reducing VLDL production.
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What sort of doses of Niacin are required for it to have these effects?
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Much higher than normal vitamin levels
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What are the major side effects of Niacin?
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-Intense Flushing
-Pruritis |
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What can help reduce the flushing caused by niacin?
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Decreasing prostaglandins by giving aspirin or an NSAID
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How soon after taking Niacin does the pruritis/flushing occur?
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Within 1-2 hrs; so giving at bedtime or time release tablets may help increase compliance.
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What happens with continued use of Niacin?
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Adverse symptoms dissappear, but return if the patient misses a few doses
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How can tolerance to the flushing caused by Niacin be induced?
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By starting at low doses and gradually increasing to full doses.
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For what pre-existing condition would you want to not give Niacin?
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Peptic ulcer disease - it has adverse GI effects.
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What are 3 less common but more severe adverse effects of Niacin?
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-Abnormal liver function tests
-Hyperuricemia -Induced insulin tolerance resulting in high fasting glucose |
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So what are 3 patients for whom Niacin is contraindicated?
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-Gout patients
-Hepatic dysfunction patients -Peptic ulcer patients |
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In what patients should Niacin be used with CAUTION?
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Diabetics
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What can result from concurrent use of Niacin + Statins?
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Myopathy/Rhabdo
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How does Niacin affect the lipoprotein profile?
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-REDUCES TG
-Increases HDL - quite a bit -Reduces LDL |
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How long does it take for Niacin to reach its maximal effects in reducing LDL?
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3-6 weeks
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What else does Niacin reduce?
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Lipoprotein A - the possible risk factor associated with CHD
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What is the main clinical use of Niacin?
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Treatment of Severe hypercholesterolemia that does not respond to resin therapy
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Where does Niacin fall in the list of drugs for treating hypercholesterolemia? Why?
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2nd or 3rd - bc of its adverse side effects and poor compliance.
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What is something that Niacin is the only drug that can do?
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Reduce Lipoprotein A by 40%
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What is the PPAR activator?
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Gemfibrozil
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What is the primary thing that PPARs/Gemfibrozil do?
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Activate genes to increase clearance and reduce triglycerides
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What is PPAR?
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A nuclear receptor that is activated by Gemfibrozil
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What DOESN'T gemfibrozil do?
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Doesn't change LDL levels - only triglycerides
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What is the most important adverse effect of Gemfibrozil?
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Myopathy if used with statins
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What will the increased CK ultimately lead to?
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Renal failure
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What are the effects of Gemfibrozil like in general?
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Well tolerated
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What is the major effect that Gemfibrozil has on the lipoprotein profile?
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Decreases TG by 50%
Increases HDL May Increase LDL though |
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When should Gemfibrozil be used as therapy?
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In patients with very high serum Triglycerides that pose a risk for pancreatitis and abdominal pain
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When should Gemfibrozil NOT be used as therapy?
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In patients with elevated hypercholesterolemia but w/out hypertriglycerides
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What are 2 conditions for which Gemfibrozil has an important role?
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-Metabolic syndrome patients
-Type 2 Diabetes patients |
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Why does Gemfibrozil have an important role in treating patients with Metabolic syndrome or type II diabetes?
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Because it can reverse low HDL and high TG.
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What is the mechanism of Ezetimibe?
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Binds to a brush border protein on intestinal lumen to inhibit C transport into enterocytes.
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What effect does Ezetimibe have on serum LDL?
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-Decreases C delivery to liver
-Liver upregulates LDL receptor -Reduces plasma levels of LDL |
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How is Ezetimibe administered? Metabolized?
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Orally
By glucuronidation to an active metabolite |
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How does Ezetimibe affect the lipoprotein profile?
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Not stellar.. but it does:
-Reduce LDL -Reduce TG some -Increases HDL a little |
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What is the main clinical use of Ezetimibe?
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Treatment of primary hypercholesterolemia in patients resistant to statin therapy
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What enhances Ezetimibe's effects?
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Combination therapy with Statins
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What is the advantage of combined therapy of Ezetimibe and Statins?
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-Reduces intestinal sources of cholesterol
-Reduces de novo synthesis of cholesterol which would otherwise be increased to compensate for the reduced dietary source |
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What is the first line drug for treating hypercholesterolemia?
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Statins - HMG-CoA reductase inhibitors
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What must patients that begin Statin therapy understand?
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That they'll be on it for life
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What drug is used for patients that are 11-20 yrs old? Why?
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Cholestyramine (bile acid binding resin) - because it is safe for women of child bearing age
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What else is cholestyramine used as?
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A 2nd line for treatment of patients for whom statins don't lower their LDL
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What drug is used for treating increased TG and LDL?
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Niacin
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What added benefit does Niacin have?
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Increased HDL
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What should you always remember about niacin?
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The bad side effects of pruritis and flushing, and that combined with statins it causes myopathy.
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What is Ezetimibe approved for?
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Monotherapy or combined with statins for hypercholesterolemia resistant to statins alone.
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What are the 2 drugs of choice for hypertriglyceridemia?
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-Gemfirozil (mostly)
-Niacin |