Flashcards in Antihyperlipidemics Deck (37):
1. What is the increased risk of cardiovascular mortality most closely linked to?
Elevated levels of LDL cholesterol and decreased levels of HDL cholesterol
**note that hyper-TAGs represents an INDEPENDENT risk factor
2. What are the 6 categories of Fredrickson Classifications of Lipid disorders?
Type I → familial hyperchylomicroenmia [elevated chylomicrons due to LPL or apoCII def]
Type IIA → familial hypercholesterolemia [elevated LDL due to decreased LDL function] – DO NOT BENEFIT FROM STATIN TX due to defective LDL receptors
Type IIB → familial combined hyperlipidemia [elevated LDL and VLDL due to overproduction of VLDL by liver]
Type III → familial dysbetalipoproteinemia [elevated IDL due to abnormal apoE]
Type IV → familial hypertriglyceridemia [elevated VLDL due to impaired catabolism of VLDL]
Type V → familial mixed hypertriglyceridemia [elevated chylomicrons and VLDL due to increased production/decreased clearance of VLDL and chylomicrons]
**These are all primary hyperlipidemias most commonly seen in children, not adults (secondary hyperlipidemias are associated with adults)
3. What is the most important secondary cause of hyperlipidemia in the developed world?
Sedentary lifestyle with excessive dietary intake of saturated fat, cholesterol and trans fatty acid.
4. What are the common secondary causes of hypertriglyceridemia?
1. diabetes mellitus
2. chronic renal failure
4. alcohol excess
5. What are the common secondary causes of hypercholesterolemia?
2. nephrotic syndrome
3. obstructive liver disease
6. How are lipoprotein disorders measured?
Lipoprotein disorders are usually detected by measuring serum lipids after a 10 hr fast [TAGs are less than 400 mg/dL]
7. What is the first line drug to lower lipids?
8. What are the 5 main classes of drugs used to treat hyperlipidemias?
1. HMG-CoA reductase inhibitor [**most important]
3. Bile acid-binding resins
4. Fibric acid derivatives
5. Cholesterol absorption inhibitors
9. What are examples of HMG-CoA reductase inhibitors (Statins)?
1. Atorvastatin – second most potent behind Rosuvastatin (2) [also lowers TAGs]
2. Fluvastatin – least potent (5)
3. Lovastatin – (4), prodrug
4. Pravastatin – (4)
5. Rosuvastatin – most potent in lowering LDL (1) [also lowers TAGs]
6. Simvastatin – 3rd most potent (3), prodrug?
**potency depends on ability to lower LDL
10. What is the MOA of statins?
Statins are analogs of HMG that act as competitive inhibitors of HMG-CoA reductase – the 1st committed step of cholesterol biosynthesis. By inhibiting de novo cholesterol synthesis they decrease intracellular supply of cholesterol leading to an upregulation of HMG-CoA reductase and LDL receptors thereby clearing LDL from the blood.
11. Who should NOT receive statins?
Women who are pregnant, lactating or likely to become pregnant
12. What are the 4 categories of people who SHOULD be treated with statins?
1. pts with clinical atherosclerotic CV disease
2. pts with LDL greater than 190 mg/dL
3. pts b/t age 40-75 with diabetes and LDL 70-189 mg/dL
4. pts without atherosclerotic CV disease (ASCVD) or diabetes with LDL 70-189 mg/dL with estimated10 yr risk of ASCVD of 7.5% or greater
13. Other than lowering LDL, what are the other beneficial effects of statins?
1. improve endothelial function
2. decrease platelet aggregation
3. stabilize atherosclerotic plaque
4. reduce inflammation
14. What are the adverse effects of statins?
1. Elevated aminotransferase – usually not associated with other liver toxicity
2. Myopathy and rhabdomyolysis – rhabdomyolysis may cause myoglobinuria leading to renal injury
15. What is the role of Niacin (nicotinic acid) in tx of hyperlipidemias?
Niacin inhibits adenylyl cyclase in adipocytes through Gi activation leading to inhibition of adipocyte hormone-sensitive lipase. By inhibiting this enzyme there is a reduced transport of fatty acids to the liver and decreases hepatic TG synthesis (inhibited synthesis and esterification of FAs). Therefore, Niacin leads to a decreased hepatic VLDL production and release, reduction of LDL, reduction of Lp(a), increase of HDL [decreased HDL catabolism].
16. Other than lowering LDL, what are the other beneficial effects of Niacin?
1. decrease in fibrinogen levels and increase in tissue plasminogen activator leading to decreased endothelial cell dysfunction
2. effective in combination with statins
17. What are the adverse effects of Niacin tx of hyperlipidemia?
1. intense cutaneous flush after each dose that can be decreased by aspirin administration 30 minutes prior to niacin ingestion
2. pruritis, rashes, dry skin, acanthosis nigricans
3. nausea, abdominal discomfort
4. HEPATOTOXICITY AND HYPERGLYCEMIA
5. Use cautiously in pts with diabetes mellitus due to induced insulin resistance leading to severe hyperglycemia
6. Niacin elevates uric acid levels precipitating gout
7. May cause atrial arrhythmias
8. Toxic amblyopia and toxic maculopathy
18. What are examples of fibrate drugs that control hyperlipidemia?
19. What is the MOA of Fibrates in tx hyperlipidemia?
Fibrates are the drug of choice for severe hypertriglyceridemia as they lower serum TGs and increase HDL levels by activating nuclear receptors (peroxisome proliferator-activated receptor-a – PPAR-a). This receptor is expressed in the liver and brown adipose tissue (and to less of an extent in the kidney, heart and skeletal muscle). By activating the receptor there is an increase in LPL expression, decreased hepatic apoC-III expression and increased hepatic oxidation of fatty acids → decreasing plasma TG levels. Fibrates can increase LDLs, esp if TAGs are greater than 400 mg/dL (???).
20. What drugs cause the most TAG reduction?
Fibrates are the most effective, followed by niacin, w-fatty acids, statins and ezetimibe.
21. What are the adverse effects of fibrate tx?
1. mild GI disturbance
2. myositis in pts with renal insufficiency
3. avoid fibrates in pts with hepatic or renal dysfunction
4. lithiasis due to fibrates increasing biliary cholesterol excretion leading to gallstone production
22. Why should Gemfibrozil (fibrate) not be used with statins?
Gemfibrozil inhibit hepatic uptake of states by OATP1B1 thereby increase statin plasma concentration. Gemfibrozil also competes for glucoronosyl transferase which metabolizes statins. Co-administration of these drugs leads to increased risk of rhabdomyolysis.
*Fenofibrate DOES NOT inhibit statin metabolism
23. What are examples of bile acid binding resin drugs that control hyperlipidemia?
1. Cholestyramine – impair liposoluble vitamin absorption (DAKE)
2. Colestipol -- impair liposoluble vitamin absorption (DAKE)
24. What is the MOA of bile acid-binding resins in tx of hyperlipidemia?
Bile acid-binding resins are only useful in pts with ONLY elevated LDL. This drug may worsen the pts condition if other lipid profiles are elevated. Bile acid-binding resins cannot be absorbed nor metabolically altered in the intestines due to their water insolubility and large MW, therefore are completely excreted in the feces.
When ingested, these resins bind to anionic bile acids in the intestinal lumen preventing their reabsorption thereby preventing fat absorption and reabsorption of bile acids. Because there is a decrease in bile acids the lvier converts cholesterol in to bile acids therefore decreasing hepatic cholesterol. Because hepatic cholesterol is decreased there is an upregulation of LDL receptors on the liver decreasing LDL levels. There is also an upregulation of HMG-CoA reductase increasing cholesterol synthesis which partially offsets the drugs action. There is also a rise in HDL seen.
25. What are bile acid-binding resins used for?
1. used in combination with statins and niacin
2. drug of choice for children and women who are planning on becoming pregnant
3. DOES NOT WORK ON individuals who lack LDL receptors
26. What are the adverse side effects of bile acid-binding resins?
1. bloating, nausea, cramping, constipation
2. Colesevelam has the fewest GI adverse effects
3. Contraindicated in pts with TAGs as there is an elevation in TAGs with these drugs
27. What are examples of cholesterol absorption inhibitor drugs that control hyperlipidemia?
Ezetimibe – inhibits intestinal absorption of cholesterol and phytosterols to lower LDL. Do not give with bile-acid sequestrants as they inhibit absorption of ezetimibe.
28. What is the MOA of Ezetimibe?
Ezetimibe is a selective inhibitor of transport protein (NPC1L1) in jejunal enterocytes which takes up cholesterol from the lumen (from the diet OR bile acids). By inhibiting the receptor there is a decreased cholesterol absorption leading to a compensatory increase in cholesterol synthesis and upregulation of LDL receptors. When used as a monotherapy, Ezetimibe will lower LDL by 15-20%. Rather if they are used in combination with statins they prevent the enhanced cholesterol synthesis.
29. When is Ezetimibe used?
1. in combination with Statins when pts are unable to reach LDL goals on statin monotherapy
2. first non-statin med to be considered with statin
3. used as monotherapy ONLY in pts who do not tolerate statins
30. What are the adverse effects of Ezetimibe?
1. reversible impaired hepatic function (esp when given with statins)
31. What are examples of specific fish oils (w-3 fatty acids)?
1. Lovaza – contains ethyl esters EPA and DHA
2. Vascepa – contains ethyl esters of EPA only
*these are used in adjnct to the diet to reduce TAG levels in adult pts with TAG levels over 500 mg/dL
32. What is the effect of w-3 fatty acids in the tx of hyperlipidemia?
w-3 fatty acids = EPA and DHA [fish oils]
Fish oils reduce TAG biosynthesis and increase FA oxidation in the liver. Exact mechanism is unknown. Just as with nitrates, there may be an increased amt of LDL-C with this treatment if TAGs are greater than 400 mg/dL. EPA alone, may lower TG levels without increasing LDL cholesterol levels.
33. What is the initial and additional drug therapy for elevated LDL?
Initial drug → statin
Additions → Ezetimibe, niacin, resin
34. What is the initial and additional drug therapy for elevated LDL and TG?
Initial drug → statin
Additions → niacin, fibrate, w-3 fatty acids
35. What is the initial and additional drug therapy for isolated low HDL?
Initial drug → statin
Additions → niacin
36. What is the initial and additional drug therapy for isolated severe hypertriglyceridemia?
Initial drug → fibrate (or niacin or fish oil)
Additional → statin