Anti-hyperlipidemic Drugs Flashcards
Ways that statin treatment improves patient outcomes
Less mortality, CVD disease, stroke
Normal significance of cholesterol and triglycerides?
Cholesterol – Essential to cell membranes, sterol/steroid precursor
Triglyceride – Storage form of fuel to support high energy compound generation, in structural lipids
What are lipoproteins all about?
Lipoproteins transport cholesterol and triglycerides in blood. Exterior phospholipid, cholesterol, and protein. Interior triglycerides and cholesterol. Regulated by apoproteins.
Signiificance of Chylomicrons
Involved in transport of dietary lipids from gut to liver and adipose tissue
Importance of apoliprotein A-1
Structural in HDL, ligand of ABCA1 receptor
Mediates reverse cholesterol transport
Made in liver and intestine
Importance of apoliprotein B-100
Structural VLDL, IDL, LDL, LDL receptor ligand in liver
Importance of apoliprotein B-48
Structural in chylomicrons
Produced in Intestine
Importance of apoliprotein E
Ligand for LDL receptor
Reverse cholesterol transport with HDL
Produced in liver
Importance of apoliprotein CIII
Foudn in chylomicrons, VLDL, HDL>LDL
Inhibits Lipoprotein lipase and interferes with ApoB and ApoE binding to hepatic receptors
Lipoprotein Lipase is an important part of what conversion
Chylomicrons –> Chylo remnant
VLDL –> IDL
Enzyme that converts from HDL to IDL
CETP
Most important enzyme in the synthesis of cholesterol in the liver
HMG CoA Reductase
Lipoprotein disorders are detected by measuring….
serum lipid after a 10 hr fast
Key measurements in assessing risk of CVD
Ratio of Total Cholesterol to HDL-Cholesterol
Ratio over 4.5 is associated with risk, under 3.5 desired
Important details on hyperlipoproteinemia
Elevated Cholesterol/LDL Levels
Atherosclerosis – Excess accumulation of cholesterol in vascular smooth muscle
Prematures CAD
Stroke Risk
Hypertriglyceridemia is associated with…
Pancreatitis
Xanthomas
CHD risk
Subendothelial uptake of cholesterol by mps is largely facilitated by…
Scavenger Receptos
LDLR
mLDL – SR-A, CD36
Mp recetors that allow mature HDL to withdrawl cholesterol
SR-B1
ABCG1
Mp receptor associated with giving cholesterol to an immature HDL
ABCA1
Three types of drugs used primarily for high cholesterol
HMG CoA Reductase Inhibitors
Bile Acid Binding Resins
Inhibitors of Cholesterol Absorption
Drugs used mainl for high triglycerides
Fibrates
Niacin
Omega 3 FAs
Mechanism of Bile Acid Binding Resins
- Inhibit the reabsorption of bile acids from intestine by binding bile acids to form insoluble complex that is excreted in feces
- Loss upregulates LDL receptors in the Liver
Examples of Bile Acid Binding Resins
Cholestyramine (Queastran)
Colestipol (Colestid)
Important therapeutic data abotu Bile Acid Binding Resins
Treatment of hypercholesterolemia, 20% drop in 2-4 weeks
Taken before meals
Can increase HDL
Side effects of Bile Acid Binding Resins
Constipation and Bloating aided by high fiber diet and water
Major drug groups that interfere with Bile Acid Binding Resins absorption
Acetaminophen Thiazides Warfarin, Digoxin Fibrates Oral Contraceptives
Mechanism of Action of Ezetimbe (Zetia)
Inhibits intestinal absorption of cholesterol from dietary sources and reabsorption of cholesterol excreted in bile by inhibiting NPC1L1
What is NPC1L1’s function?
Expressed on the apical surface of enterocytes of the SI.
It senses levels of sterol in the lumen. When there is plenty, triggers a large internal absorption via clathrin)
Adverse effects of Ezetimibe
Low incidence of liver/skeletal muscle damage
Usually pretty well tolerated tho
How to distinguish between a stain and a statin prodrug
All the statins have a mevalonic acid ring, which is open. If the ring is closed, it is a prodrug and metabolism will open it.
Name three non-prodrug statins
Fluvastatin
Rosuvastain (Crestor)
Atorvastatin (Lipitor)
Name two statin prodrugs
Lovastatin and Simvastatin
How do HMG-CoA Reductase inhibitors work
Competitively inhibit HMG CoA Reductase, the rate-limiting enzyme in cholesterol biosynthesis
- Also upregulates LD receptors in the liber, reducing plasma cholesterol
Explain the mechanism of hepatic LDL receptor upregulation
Statins help bind sterols and SCAP in the ER. The lower levels of free statins allow SREBP to be moved to the golgi, where it is cleaved by SCAP to send bHLH to the nucleus. This will upregulate LDL expression in the liver
Why give an HMG-CoA Reductase Inhibitor
Hypercholesterolemia
Standard practive to initiate after MI
Details on Dosing Statins..
- Short half-life ones are takin in evenings, because nighttime is the biggest cholesterol synthesis time.
- Take lovastatin w/ food
- Otherwise, a single dose whenever
Lovastatin, Simvastatin, and Atorvastatin are broken down by _________. This makes them tend to accumulate in patients taking…
CYP3A4
Macrolides, Cyclosporine, Ketoconazole, Grapefruit Juice
Fluvastatin and Rosuvastatin are broken down by _____. They tend to accumulate with ……
CYP2C9
Cimetidine, Metronidazole, Amiodarone
Adverse effects of Statins….
Rhabdomyolysis (which will cause renal dysfxn)
Hepatotoxicity
statin rhabdomyolysis is especially associated with coadministration wtih…
Gemfibrozil
Drugs that work by inhibiting ApoB Lipoprotein synthesis?
Juxtapid
Mipomersen
How does Juxtapid work?
Small molecule inhibitor of microsomal TG transfer protein, which stopds assembly of ApoB lipoproteins in the liver and intestine (decreasing absorption).
Who should you prescribe Juxtapid or Mipomersen for?
Homozygous Familial Hypercholesterolemia
High risk of liver damage, only use if desperate
How are Juxtapid and Mipomerson dosed?
Jux – Oral
Mipo – SubQ Injection
How does Mipomersen work?
Hybridized ApoB100 mRNA in the liver to promote its degredation
Name same important Fibric Acid Derivatives
Gemfibrozil, Fenofibrate
Clofibrate, Ciprofibrate, Benzafibrate
Fibric Acid Derivative mechanism of action
bind to PPAR-alpha and regulate gene transcription w/ retinoic acid receptor. Cause a complex set of effects, but include reduced LDL, serum TGs, and elevated HDL.
What are some important mecahnisms by which PPARs have their effect on blood lipids
Increased in Lipoprotein Lipase
Decreased ApoCIII synth –> lower VLDL
Increased ApoA1, AIII synthesis –> higher HDL
Therapeutic indications fo Fibric Acid Derivatives
Hypertriglyceridemia in which VLDL predominate
Second line for mixed hyperlipidemia
Side effects of Fibric Acid Derivatives
Gall Stones
Skeletal Muscle Effects (Rhabdo) – ESPECIALYL W/ Statins
Importna tdrug interaction of Fibric Acid Derivatives
Potentiates the effects of Warfarin
What is Lovaza? Mechanism of Action?
Combo of Ethyl Esters from Omega 3 Fatty Acids
Reduced TG synthesis in liver, inhibit esterification of other FAs
Therapeutic indications for Lovaza
Following a Lipid Lowering Diet Severe hypertriglyceridemia (over 500)
Adverse effects of Lovaza
Can increase LDL (usually OK if you combine with a statin)
Potential way that Omega 3 FAs may promote CV health
Very similar structure to PGI3, which is a potent inhibitor of platelet aggregation
In order for Niacin to influence lipids, doses must be…
1-3 g/day
Typically a supplement beyond any dietary level
How does Nicain decrease TG levels? (conceptually)
It reduces them, increasing lipase activity and thus increasing their clearance. It also drops levels of liver VLDL production while typically increasing HDL levels.
How does Niacin decrease TG levels (molecularly)?
Hits GPR 109A of adipocytes, which drops cAMP and inhibits the conversion of TGs to FFAs. Fewer FFAs will cause lower production of TGs/VLDL In the liver, and thus systemically lower LDL.
What is niacin doing specifically in the adipocyte (I know these questions fuckin suck)
Acts on GPR109A to inhibit TG lipolysis by hormone sensitive lipase, decreasing FA transport to the liver.
What is niacin doing in the liver
Inhibits FA synthesis and Esterification
Reduced clearance of apoA-1, but not CEs (inc. HDL)
What does niacin do to macrophages?
Increased CD36 and ABCA1 expression
Decreases CE content via HDL mediated reverse transport
Indications for Niacin
Effective for mixed hyperlipidemia
HyperTG w/ risk f pancreatitis
Low HDL
Usually combined with resins
Adverse effects of Niacin
- Marked vasodilation (flushing), itching, tingling of Upper body, Headache (too much PG, treat w/ ASA or ibu)
- Hepatotoxicity
