Antihyperlipidemics Flashcards
- 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
- 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)
- 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.
- What are the common secondary causes of hypertriglyceridemia?
- diabetes mellitus
- chronic renal failure
- hypothyroidism
- alcohol excess
- contraceptives
- B-blockers
- Glucocorticoids
- What are the common secondary causes of hypercholesterolemia?
- hypothyroidism
- nephrotic syndrome
- obstructive liver disease
- glucocorticoids
- 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]
LDL=TC-[HDL+(TAG/5)]
- What is the first line drug to lower lipids?
Statins
- What are the 5 main classes of drugs used to treat hyperlipidemias?
- HMG-CoA reductase inhibitor [**most important]
- Niacin
- Bile acid-binding resins
- Fibric acid derivatives
- Cholesterol absorption inhibitors
- What are examples of HMG-CoA reductase inhibitors (Statins)?
- Atorvastatin – second most potent behind Rosuvastatin (2) [also lowers TAGs]
- Fluvastatin – least potent (5)
- Lovastatin – (4), prodrug
- Pravastatin – (4)
- Rosuvastatin – most potent in lowering LDL (1) [also lowers TAGs]
- Simvastatin – 3rd most potent (3), prodrug?
* *potency depends on ability to lower LDL
- 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.
- Who should NOT receive statins?
Women who are pregnant, lactating or likely to become pregnant
- What are the 4 categories of people who SHOULD be treated with statins?
- pts with clinical atherosclerotic CV disease
- pts with LDL greater than 190 mg/dL
- pts b/t age 40-75 with diabetes and LDL 70-189 mg/dL
- 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
- Other than lowering LDL, what are the other beneficial effects of statins?
- improve endothelial function
- decrease platelet aggregation
- stabilize atherosclerotic plaque
- reduce inflammation
- What are the adverse effects of statins?
- Elevated aminotransferase – usually not associated with other liver toxicity
- Myopathy and rhabdomyolysis – rhabdomyolysis may cause myoglobinuria leading to renal injury
- 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].
- Other than lowering LDL, what are the other beneficial effects of Niacin?
- decrease in fibrinogen levels and increase in tissue plasminogen activator leading to decreased endothelial cell dysfunction
- effective in combination with statins
- What are the adverse effects of Niacin tx of hyperlipidemia?
- intense cutaneous flush after each dose that can be decreased by aspirin administration 30 minutes prior to niacin ingestion
- pruritis, rashes, dry skin, acanthosis nigricans
- nausea, abdominal discomfort
- HEPATOTOXICITY AND HYPERGLYCEMIA
- Use cautiously in pts with diabetes mellitus due to induced insulin resistance leading to severe hyperglycemia
- Niacin elevates uric acid levels precipitating gout
- May cause atrial arrhythmias
- Toxic amblyopia and toxic maculopathy
- What are examples of fibrate drugs that control hyperlipidemia?
- Gemfibrozil
2. Fenofibrate
- 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 (???).
- What drugs cause the most TAG reduction?
Fibrates are the most effective, followed by niacin, w-fatty acids, statins and ezetimibe.
- What are the adverse effects of fibrate tx?
- mild GI disturbance
- myositis in pts with renal insufficiency
- avoid fibrates in pts with hepatic or renal dysfunction
- lithiasis due to fibrates increasing biliary cholesterol excretion leading to gallstone production
- 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
- What are examples of bile acid binding resin drugs that control hyperlipidemia?
- Cholestyramine – impair liposoluble vitamin absorption (DAKE)
- Colestipol – impair liposoluble vitamin absorption (DAKE)
- Colesevelam
- 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.
