Antihyperlipidemic drugs Flashcards
Core of lipoprotein
TG, cholesterol esters
_____ releases FFA’s from lipoproteins
Lipoprotein Lipase system
Transports dietary lipids to liver and adipose
Chylomicrons
Secreted by liver into blood as a source of TG’s
VLDL
VLDL–> IDL –> LDL
ApoA1
Structural in HDL
Ligand of ABCA1 receptor
**Mediates reverse cholesterol transport (produced in liver and intestine
ApoB-100
Structural in VLDL, IDL, LDL
Ligand for LDLR
Produced in liver
ApoB-48
Structural in Chylomicrons
Produced in intestine
ApoE
Ligand for LDL receptor (remnant receptor)
**Reverse cholesterol transport with HDL
Produced in liver and other tissues
ApoCII
Chylomicrons, VLDL, HDL
Lipoprotein Lipase cofactor
ApoCIII
Chylomicrons, VLDL, HDL>LDL
Inhibits LpL and interferes with ApoB and ApoE
What happens with loss of function in ApoC3
People who have this mutation have better cholesterol profiles
LPL location
Capillaries of fat, cardiac, sk. muscle
LCAT
CETP
Lethicin-Cholesterol Acyltransferase
Cholesterol Ester Transfer Protein
Major source of cholesterol
De novo synthesis
Liver synthesis is the most critical to total body burden
Steps of Cholesterol Synthesis
- Acetoacetyl CoA
- ACoA + HMGCoA Synthase
- HMGCOA
- 2 NADPH + HMGCOA Reductase
- Mevalonate
- IPP + DMAP
- GPP + IPP
- FPP
- Squalene
- Lanosterol
- Cholesterol
Ratio of Total Cholesterol to HDL important for _______
assessing risk of CVD
>4.5 is at increased risk
less than 3 is optimal
____ may be a better indicator of cardiovascular health (than ratio)
ApoA1
Hyperliproteinemia predisposes to…
Atherosclerosis
Premature CAD
CVA
Hypertriglyceridemia predisposes to
Pancreatitis
Xanthomas
Increased risk of CHD
Effect of Oxidized LDL on T cell
Cytokine production
(results in the proliferation of SMC’s)
Modified LDL taken up by what receptor?
CD36
ABCA1
transporter mediates freeing of ApoA1
(Lipid-free ApoA1 –> ApoA1 + FC)
Three transporters in HDL handling
ABCA1
SRBI
ABCG1
____ cause cholesterol to be esterified
ACAT1, CEH
ACoA:Cholesterol acetyltransferase
Cholesterol ester hydrolase
Association of cholesterol reduction and CHD incidence
10% Cholesterol = 10-30% CHD
Drugs mainly for high cholesterol
HMG-CoA reductase inhibitors
Bile Acid Binding Resins
Inhibitors of choesterol absorption
Drugs mainy for high triglycerides
Fibrates
Niacin
Omega 3 Fatty Acids
Bile Acid-Binding Resin MOA
Examples?
Inhibit reabsorption of bile acids from intestine by forming insoluble complex (exchange chloride ion for bile acids)
*Also upregulate LDL receptors in the liver
Cholestyramine, Colestipol
Cholesterol is converted to _____ by _____
Cholic acid, CYP450’s
Bile acid binding resins - Use
AE’s
1’ Hypercholesterolemia (↑LDL) - drops by 20%
(May cause 5% increase in HDL)
AE’s = Constipation, bloating
DDI’s for BABR’s
Acetaminophen
Thiazides
Warfarin, Digoxin
Fibrates, Ezetimibe
Oral Contraceptives
Corticosteroids
Thiazolidinediones
Ezetimibe MOA
Cholesterol Absorption Inhibitor
**Inhibits NPC1L1 (Neimann-Pick C1-like 1)
Inhibits intestinal absorption of cholesterol from dietary sources and reabsorption of cholesterol excreted in bile
NPC1L1 expressed where?
On the apical surface of enterocytes and sm. intestine
Mediate clathrin-dependent internalization
Ezetimibe indication and AE
Indication = mostly reduce LDL (17%), used in combination with statins (enhance statins by 20%)
AE = Low incidence of skeletal muscle/liver damage
HMGCoA reductase inhibitors (statins)
Examples
Contain what group?
- Fluvastatin
- Rosuvastatin
- Atorvastatin
- *Lovastatin and Simvastatin are prodrugs
Contain Mevalonic acid group (or analog)
Statins MOA
Competitively inhibit HMG CoA Reductase
Structurally similar to HMG-CoA
(Enzyme requires 2NADPH + 2H+)
Explain SREBP/SCAP
- SCAP and SREBP are bound in presence of high sterol
- When sterols drop, COP2 vesicle brings SREBP to Golgi where it is cleaved by S1P and S2P
- Basic helix-loop-helix (bHLH/BZip) domain released (imported to nucleus via importin)
- Binds to sterol response element (SRE) for LDL receptor transcription
- –> Increase LDLR on surface of cell
Statin indications
Hypercholesterolemia (↑LDL w/wo slightly ↑TG’s)
Post-MI (irrespective of lipid levels!)
Expected results of statins
20-60% reduction in LDL
10-33% reduction in TG
5-10% increase in HDL
Dosing statins w/ short T1/2
Taken in evening to inhibit nocturnal cholesterol synth
(Lovastatin in evening)
(Rosuv, Ator, Pravachol are one dose per day)
Statin Metabolism
3A4 = Lovastatin, Simvastatin, and Atorvastatin
(DDI Macrolide, Cylosporine, Ketoconazole, grapefruit)
2C9 = Fluvastatin and Rosuvastatin
Inhibited by Cimetidine, metronidazole, amiodarone
Sulfation = Pravastatin (No CYP, most is excreted unchanged)
Statin AE
(also include what you monitor and other factors involved)
-
Rhabdo (with renal dysfxn secondary to myoglobinuria)
- Dose related
- Monitor CPK
- Increased with CYP inhibitors
- Can occur with Gemfibrozil
-
Hepatotoxicity
- Monitor Serum Transaminase activity
- 2% incidence
Inhibits ApoB synthesis
Juxtapid (Lomitapide)
Juxtapid MOA
Inhibitor of microsomal TG transfer protein –> Inhibits assembly of ApoB-containing lipoproteins in liver and intestine
Also interferes with chylomicron production = ↓Lipid absorption
Juxtapid Indications
AE?
Homozygous Familial Hypercholesterolemia (LDLR Mutation)
High risk of liver damage! (restricted Rx program)
Mipomersen MOA
Phosphorothioate antisense oligonucleotide inhibitor of ApoB100 (Hybridizes B100 in the liver and promotes degradation)
Indicated as adjunct treatment for HFH
High risk of liver damage (Restricted Rx)
Fibrates MOA
Peroxisome Proliferator Activated Receptor-alpha Activators (PPAR-a)
Clofibrate, Ciprofibrate, Fenofibrate, Gemfibrozil, Bezafibrate
____ is a fibrate that must undergo bioactivation
Fenofibrate
(to fenofibric acid)
Fibrates bind to ____, and regulate…
PPARa, and reguate gene transcription along with the retinoic acid recepto (RXR)
Effects of Fibrates
Indications
AE’s and DDI’s
- ↓LDL 6-20%
- ↓TG’s 35–53%
- Elevate HDL 15-30%
Hypertriglyceridemia (with high VLDL)
Second line for mixed hyperlipidemia
AE’s = gallstones, rhabdo (caution using with statins)
DDI’s = Potentiate the effects of warfarin
Lovaza MOA
It’s an ethyl ester of omega 3 FA
Reduces synth of TG in the liver because O3FA’s are bad substrates for TG synth enzymes
(inhibits esterification of other fatty acids)
Metabolites of Eicosapentaenoic Acid (EPA)
TXA3 (Less potent than TXA2)
PGI3 (As potent as PGI2)
Niacin MOA
Reduces serum TG (and LDL)
↑ Lipase activity (↑clearance of VLDL)
Lowers VLDL production in liver
Usually increases HDL levels
____ is inhibited by Nicotinic Acid
DGAT2
Diacylglycerol acetyltransferase 2
Niacin Targets in Adipose, Liver, and MQ
Adipose = ↓ TG lipolysis by HSL (Decreases FA transport to liver) by activating GPR109A (Gai coupled GPCR)
Liver = ↓FA synthesis and esterification (reduces TG export by VLDL)
MQ = ↑ CD36 and ABCA1 expression (decreases CE content via HDL-mediated reverse transport)
Niacin indications
Expected effects
AE’s
Mixed hyperlipidemia (also hyperTG with risk of pancreatitis)
Decreases TG by 25%, Increases HDL 15-35%
- Vasodilation, itch/tingling, headache with initial dosing (PG’s mediate!! Treat with ASA or NSAID)
- Hepatotoxicity sustained-release preps
