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Flashcards in Lipid Lowering Drugs Deck (20)

HMG-CoA Inhibitors: Mechanism of Action

Inhibits HMG-CoA, the rate-limiting enzyme in the biosynthesis of LDL cholesterol in liver
Inhibition of LDL synthesis results in increased recycling of the LDL receptor (LDLR)
Increased LDLR enhances hepatic clearance of LDL and dramatically lowers serum LDL levels (some preparations also increase in HDL)


HMG CoA Reductase Inhibitors

Lovastatin (Mevacor®)
Pravastatin (Pravacol®)
Simvastatin (Zocor®)
Fluvastatin (Lescol®/Lescol XL®)
Atorvasatin (Lipitor®)
Rosuvastatin (Crestor®)
Pitavastatin (Livalo®, Pitava®)


Side Effects of HMG CoA Inhibitors

-Mild elevation of LFT’s occurs approximately 2 % of time
-Severe hepatoxicity is rare and usually reversible with cessation of drug

Muscle Injury :
-Myositis is most common side-effect from depletion of mitochondrial ubiquinone
-Rhabdomyolysis is rare, but most serious complication and risk is increased when combined with other medications


Drug Interactions with Statins

*Fibric Acid derivatives
Macrolide antibiotics

Increased risk with drugs metabolized via cytochrome P450 system


PKSC9 Inhibitors Available

Alirocumab (Praulent®) produce a 47-61% reduction in LDL
Evolocumab (Repatha®) produce a 61-73% reduction in LDL
No CV outcomes yet
Only approved for those with FH


Inhibitors of Cholesterol Absorption


Ezetimibe Blocks Internalization of the NPC1L1/LDL Complex to decrease LDL absorption

Inhibits LDL absorption in the intestine
Results in decreased delivery of cholesterol to the liver, reduction in hepatic cholesterol stores and promoting increased plasma clearance of LDL


Effectiveness of Ezetimide

Lowers LDL by 10-15 %
Lowers ApoB by 11-16%
Much more effective in combination with a Statin or Fibrate
**It possesses independent CV protection + additional cardioprotective effects when used in combination with statins
Are useful in avoiding higher doses of statins in patients with statin intolerance which helps achieve target LDL levels


Side Effect of Ezetimide

Requires activation by liver and infrequently associated with elevated liver functions


Mechanism of Action of Fibrates

PPAR-α Agonists

PPAR-α receptors are expressed in liver, adipose, heart and muscle which in turn inhibit lipolysis and stimulates HDL synthesis

Stimulates Lipoprotein Lipase activity
Reduces VLDL synthesis and lowers serum TG’s
Increase HDL levels by stimulating Apo A-I and Apo A-II synthesis


Fibrates Available

Gemfibrozil (Lopid® & Trilipix®)
Trilipix® is a slow-release formulation of gemfibrozil
**Finofibrate (Tricor®) - safest to use with statins
Bezafibrate (Bezalip®)
Ciprofibrate (Modalim®)


Side-Effects of the Fibrates

Myositis: rare when used as single agent
-Occurs more commonly when used in combination with high-dose “statins”
-Fenofibrate in combination with “statin” reportedly has a lower risk (Ticor)

Interferes with the clearance of warfarin & results in prolonged Pro Times/INR

GI upset (most common side-effect)


Bile Acid Sequestrants: Mechanism of Action

Bind to bile salts and sequesters them in intestine resulting in inhibition of their entero-hepatic recirculation

Bile salts are made from cholesterol, so this drug depletes liver cholesterol thus lower LDL from circulation

Most effective when combined with a Statin which enhances statin-effect by an additional 8-10 %


Bile Acid Compounds Available

Cholecystyramine (Questran®)
Cholestipol (Cholestid®)
Colesveleman (Welchol®)


Side-Effects of Bile Acid Sequestrants

Abdominal bloating, cramps, and gas
Elevated LFT’s
Impaired absorption of fat soluble vitamins and many medications (these must be taken an 1 hr before or 2 hr after the sequestrants)


Nicotinic Acid: Mechanism of Action

Receptor-mediated inhibition of lipolysis in adipocytes
Inhibition of HDL catabolism

Inhibit lipolysis
Reduction in hepatic TG’s and VLDL production, therefore lowering LDL
Increases LDL uptake by liver increasing peripheral HDL levels
Inhibits transfer of VLDL to HDL resulting in higher levels of HDL
Lowers Lp(a) and PAI-1 levels which decrease plasma fibrinogen levels & procoagulant state


Effectiveness of Nicotinic Acid

No CV protective effect when taken with statins – only time use is patient that cannot take statins with low HDL and high TG


Nicotinic Acid Preparations

Immediate Release Preparations: must be taken 3-4 times per day and most likely to cause side-effects!

Sustained Release Preparations


Cholesteryl ester transfer protein (CETP) Inhibitors

CETP is a plasma protein that facilitates the transport of cholesterol esters and TG’s from VLDL and LDL and attaches to HDL decreasing HDL concentrations
Pharmacologic inhibition of this enzyme results in much higher circulating HDL levels

Increases uptake of fat off HDL so HDL can get back into circulation


Clinical Effects of CETP Inhibitors

40% decrease in LDL from baseline with 138% increase in HDL

Compounds have not passed clinical trials
The first med caused worsening CV effects, and the other two are still in testing


Main Mechanism Targeted by Lipid Lowering Medications

In the hepatocyte, acetyl-CoA becomes HMG CoA reductase, which then binds LDL and makes cholesterol. Cholesterol can then make VLDL, bile acids, or be transferred to the intestine for elimination