Hypolipidemic Drugs Flashcards
What are 5 major categories of hypolipidemic drugs?
HMG-CoA reductase inhibitors (statins) Bile-acid-binding resins Cholesterol absorption inhibitor (Ezetimibe) Nicotinic acid Fibrates
Give a brief description/overview of lipid transport and metabolism of cholesterol
- Cholesterol from liver excreted as VLDL
- TGs removed from VLDL by LPL
- Leaves remnants taken up by liver or processed to LDL
- LDL taken back up into liver or into peripheral tissues by binding to LDL-R
- Reverse cholesterol transport: take cholesterol out of tissue via ABCA1 to HDL
- HDL can then deliver cholesterol to liver or to steroidogenic tissues using scavenger receptor (SR-B1)
- Liver uses cholesterol to form bile acids and also secretes unchanged cholesterol into bile
What are the features of familial hypertriglyceridemia?
Decreased LPL
Increased VLDL secretion
What are the features of familial combined hyperlipidemia?
Increased VLDL secretion
Increased VLDL and LDL levels
What are the features of remnant removal disease?
Increased VLDL secretion
Decreased remnant lipoprotein removal (mutant ApoE2)
What are the features of familial or polygenic hypercholesterolemia?
Decreased LDL-receptor activity
Due to mutated/dysfunctional LDL-R, ApoB, etc
What are the features of familial hypoalphalipoprioteinemia?
Decreased ApoA-1
Decreased HDL
What is the primary lipoprotein effect of HMG Co-A reductase inhibitors (statins)?
Decrease LDL
What is the primary lipoprotein effect of Bile acid binding resins?
Decrease LDL (but less than statins)
What is the primary lipoprotein effect of Ezetimibe?
Decrease LDL
What is the primary lipoprotein effect of nicotinic acid (niacin)?
Increase HDL
What is the primary lipoprotein effect of fibrates?
Decrease triglycerides
What is the mechanism of action of statins?
Inhibit HMG-CoA reductase, preventing the rate limiting step in the formation of cholesterol
Fall in the level of cholesterol causes an upregulation of LDL receptors in the membrane, which will lower plasma levels of LDL
In addition to inhibiting HMG-CoA reductase, what are other effects that statins have?
Decreases isoprenylation of proteins - can prevent membrane trafficking of proteins
Decreases ubiquinone - can effect mitochondrial respiratory enzymes, need to supplement with CoQ10
What drugs are in the category of statins?
Lovastatin (prototype) Simvastatin Pravastatin Atovastatin Rosuvastatin
How are statins metabolized and why is it important?
Metabolized by CYP450 enzymes in liver
Can cause interactions with other drugs that inhibit or induce CYP450 enzymes
What are adverse effects of statins?
Hepatitis Muscle pain, myositis, rhabdomyolysis Increased risk of new onset diabetes Contraindicated in pregnancy Increased risk of peripheral neuropathy
What happens when statins and bile-acid-binding resins are used together?
Statin upregulates LDL-R expression, will lower LDL in plasma
A resin will absorb bile acids in gut, preventing recycling of bile acids, causing further upregulation of LDL receptor expression and further lowering of LDL in plasma
What is the mechanism of action of bile-acid-reducing resins?
FXR (receptor that is sensor for bile acids) regulates expression of FGF
FGF is inhibitor of enzyme (Cyp7a1) that makes bile acid from cholesterol
When you consume bile acid binding resins, have less bile acids going into cell
FXR detects lower levels of bile acids, causing reduced transcription of FGF
Reduced FGF causes reduced inhibition of Cyp7a1 enzyme
More cholesterol used to make bile acids and excreted (since cannot be taken back up)
What are adverse effects of resins?
GI distress
Adsorb anionic vitamins & drugs
Can increase plasma TGs in hypertriglyceridemia
What is the mechanism of action of Ezeimibe?
Blocks intestinal uptake of cholesterol and plant sterols by the NPC1L1 receptor
In what genetic condition is Ezetimibe very useful?
Sitosterolemia (plant sterol hyperabsorption)
Sitosterolemia is caused by mutations in the ATP-binding cassette transporters (ABCG5, ABCG8) that normally release plant sterols back into lumen. Elevated plant sterols causes similar detrimental effects as high LDL.
Ezetimibe blocks uptake of plant sterols and will lower levels
What is the mechanism of action of niacin?
Binds niacin receptor on fat cells that inhibits lipolysis –> decreased FFA –> decreased TG synthesis –> decreased VLDL
Also decreases breakdown of ApoA1 –> increased HDL
What is a major adverse effect of niacin?
Prostaglandin flush response - cutaneous vasodilation and burning sensation on face and upper body
What is the mechanism by which niacin causes prostaglandin flush?
Beta arrestin signaling pathway causes production of prostaglandins (vasodilation)
What two drugs are in the category of fibrates?
Gemfibrozil
Fenofibrate
What is the mechanism of action of Fibrates?
Acts on PPAR-alpha - nuclear transcription factor that is a sensor for fatty acids
PPAR increases lipoprotein lipase (LPL) expression and downregulates expression of ApoCIII –> increased lipolysis
PPAR also decreases triglyceride synthesis and increases HDL
What is the mechanism of action of PCSK9-targeted monoclonal antibodies?
Block interaction between PCSK9 and LDL-R
LDL-R is then recycled and able to decrease plasma LDL
