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Pharm Exm 4 > Antihyperlipidemic drugs > Flashcards

Antihyperlipidemic drugs Flashcards

1
Q

Core of lipoprotein

A

TG, cholesterol esters

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2
Q

_____ releases FFA’s from lipoproteins

A

Lipoprotein Lipase system

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3
Q

Transports dietary lipids to liver and adipose

A

Chylomicrons

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4
Q

Secreted by liver into blood as a source of TG’s

A

VLDL

VLDL–> IDL –> LDL

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5
Q

ApoA1

A

Structural in HDL

Ligand of ABCA1 receptor

**Mediates reverse cholesterol transport (produced in liver and intestine

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6
Q

ApoB-100

A

Structural in VLDL, IDL, LDL

Ligand for LDLR

Produced in liver

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7
Q

ApoB-48

A

Structural in Chylomicrons

Produced in intestine

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8
Q

ApoE

A

Ligand for LDL receptor (remnant receptor)

**Reverse cholesterol transport with HDL

Produced in liver and other tissues

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9
Q

ApoCII

A

Chylomicrons, VLDL, HDL

Lipoprotein Lipase cofactor

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10
Q

ApoCIII

A

Chylomicrons, VLDL, HDL>LDL

Inhibits LpL and interferes with ApoB and ApoE

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11
Q

What happens with loss of function in ApoC3

A

People who have this mutation have better cholesterol profiles

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12
Q

LPL location

A

Capillaries of fat, cardiac, sk. muscle

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13
Q

LCAT

CETP

A

Lethicin-Cholesterol Acyltransferase

Cholesterol Ester Transfer Protein

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14
Q

Major source of cholesterol

A

De novo synthesis

Liver synthesis is the most critical to total body burden

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15
Q

Steps of Cholesterol Synthesis

A
  1. Acetoacetyl CoA
    1. ACoA + HMGCoA Synthase
  2. HMGCOA
    1. 2 NADPH + HMGCOA Reductase
  3. Mevalonate
  4. IPP + DMAP
  5. GPP + IPP
  6. FPP
  7. Squalene
  8. Lanosterol
  9. Cholesterol
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16
Q

Ratio of Total Cholesterol to HDL important for _______

A

assessing risk of CVD

>4.5 is at increased risk

less than 3 is optimal

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17
Q

____ may be a better indicator of cardiovascular health (than ratio)

A

ApoA1

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18
Q

Hyperliproteinemia predisposes to…

A

Atherosclerosis

Premature CAD

CVA

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19
Q

Hypertriglyceridemia predisposes to

A

Pancreatitis

Xanthomas

Increased risk of CHD

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20
Q

Effect of Oxidized LDL on T cell

A

Cytokine production

(results in the proliferation of SMC’s)

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21
Q

Modified LDL taken up by what receptor?

A

CD36

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22
Q

ABCA1

A

transporter mediates freeing of ApoA1

(Lipid-free ApoA1 –> ApoA1 + FC)

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23
Q

Three transporters in HDL handling

A

ABCA1

SRBI

ABCG1

24
Q

____ cause cholesterol to be esterified

A

ACAT1, CEH

ACoA:Cholesterol acetyltransferase

Cholesterol ester hydrolase

25
Association of cholesterol reduction and CHD incidence
10% Cholesterol = 10-30% CHD
26
Drugs mainly for high cholesterol
HMG-CoA reductase inhibitors Bile Acid Binding Resins Inhibitors of choesterol absorption
27
Drugs mainy for high triglycerides
Fibrates Niacin Omega 3 Fatty Acids
28
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
29
Cholesterol is converted to _____ by \_\_\_\_\_
Cholic acid, CYP450's
30
Bile acid binding resins - Use AE's
1' Hypercholesterolemia (↑LDL) - drops by 20% (May cause 5% increase in HDL) AE's = Constipation, bloating
31
DDI's for BABR's
Acetaminophen Thiazides Warfarin, Digoxin Fibrates, Ezetimibe Oral Contraceptives Corticosteroids Thiazolidinediones
32
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
33
NPC1L1 expressed where?
On the apical surface of enterocytes and sm. intestine Mediate clathrin-dependent internalization
34
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
35
HMGCoA reductase inhibitors (statins) Examples Contain what group?
* Fluvastatin * Rosuvastatin * Atorvastatin * \*Lovastatin and Simvastatin are prodrugs Contain Mevalonic acid group (or analog)
36
Statins MOA
Competitively inhibit HMG CoA Reductase Structurally similar to HMG-CoA (Enzyme requires 2NADPH + 2H+)
37
Explain SREBP/SCAP
1. **SCAP** and **SREBP** are **bound** in presence of high sterol 2. When sterols drop, COP2 vesicle brings SREBP to Golgi where it is cleaved by **S1P** and **S2P** 3. Basic helix-loop-helix (**bHLH**/BZip) domain released (imported to nucleus via *importin*) 4. Binds to sterol response element (**SRE**) for LDL receptor transcription 5. --\> **Increase LDLR on surface** of cell
38
Statin indications
Hypercholesterolemia (↑LDL w/wo slightly ↑TG's) Post-MI (irrespective of lipid levels!)
39
Expected results of statins
20-60% reduction in LDL 10-33% reduction in TG _5-10% increase in HDL_
40
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)
41
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)
42
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
43
Inhibits ApoB synthesis
Juxtapid (Lomitapide)
44
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*
45
Juxtapid Indications AE?
**Homozygous Familial Hypercholesterolemia** (LDLR Mutation) High risk of liver damage! (restricted Rx program)
46
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)
47
Fibrates MOA
Peroxisome Proliferator Activated Receptor-alpha Activators (PPAR-a) Clofibrate, Ciprofibrate, Fenofibrate, Gemfibrozil, Bezafibrate
48
\_\_\_\_ is a fibrate that must undergo bioactivation
Fenofibrate (to fenofibric acid)
49
Fibrates bind to \_\_\_\_, and regulate...
PPARa, and reguate gene transcription along with the retinoic acid recepto (RXR)
50
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**
51
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)
52
Metabolites of Eicosapentaenoic Acid (EPA)
TXA3 (Less potent than TXA2) PGI3 (As potent as PGI2)
53
Niacin MOA
**Reduces serum TG** (and LDL) ↑ Lipase activity (↑clearance of VLDL) Lowers VLDL production in liver Usually increases HDL levels
54
\_\_\_\_ is inhibited by Nicotinic Acid
DGAT2 Diacylglycerol acetyltransferase 2
55
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)
56
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

Pharm Exm 4 (7 decks)

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