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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
Q

Association of cholesterol reduction and CHD incidence

A

10% Cholesterol = 10-30% CHD

26
Q

Drugs mainly for high cholesterol

A

HMG-CoA reductase inhibitors

Bile Acid Binding Resins

Inhibitors of choesterol absorption

27
Q

Drugs mainy for high triglycerides

A

Fibrates

Niacin

Omega 3 Fatty Acids

28
Q

Bile Acid-Binding Resin MOA

Examples?

A

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
Q

Cholesterol is converted to _____ by _____

A

Cholic acid, CYP450’s

30
Q

Bile acid binding resins - Use

AE’s

A

1’ Hypercholesterolemia (↑LDL) - drops by 20%

(May cause 5% increase in HDL)

AE’s = Constipation, bloating

31
Q

DDI’s for BABR’s

A

Acetaminophen

Thiazides

Warfarin, Digoxin

Fibrates, Ezetimibe

Oral Contraceptives

Corticosteroids

Thiazolidinediones

32
Q

Ezetimibe MOA

A

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
Q

NPC1L1 expressed where?

A

On the apical surface of enterocytes and sm. intestine

Mediate clathrin-dependent internalization

34
Q

Ezetimibe indication and AE

A

Indication = mostly reduce LDL (17%), used in combination with statins (enhance statins by 20%)

AE = Low incidence of skeletal muscle/liver damage

35
Q

HMGCoA reductase inhibitors (statins)

Examples

Contain what group?

A
  • Fluvastatin
  • Rosuvastatin
  • Atorvastatin
  • *Lovastatin and Simvastatin are prodrugs

Contain Mevalonic acid group (or analog)

36
Q

Statins MOA

A

Competitively inhibit HMG CoA Reductase

Structurally similar to HMG-CoA

(Enzyme requires 2NADPH + 2H+)

37
Q

Explain SREBP/SCAP

A
  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
Q

Statin indications

A

Hypercholesterolemia (↑LDL w/wo slightly ↑TG’s)

Post-MI (irrespective of lipid levels!)

39
Q

Expected results of statins

A

20-60% reduction in LDL

10-33% reduction in TG

5-10% increase in HDL

40
Q

Dosing statins w/ short T1/2

A

Taken in evening to inhibit nocturnal cholesterol synth

(Lovastatin in evening)
(Rosuv, Ator, Pravachol are one dose per day)

41
Q

Statin Metabolism

A

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
Q

Statin AE

(also include what you monitor and other factors involved)

A
  • 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
Q

Inhibits ApoB synthesis

A

Juxtapid (Lomitapide)

44
Q

Juxtapid MOA

A

Inhibitor of microsomal TG transfer protein –> Inhibits assembly of ApoB-containing lipoproteins in liver and intestine

Also interferes with chylomicron production = ↓Lipid absorption

45
Q

Juxtapid Indications

AE?

A

Homozygous Familial Hypercholesterolemia (LDLR Mutation)

High risk of liver damage! (restricted Rx program)

46
Q

Mipomersen MOA

A

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
Q

Fibrates MOA

A

Peroxisome Proliferator Activated Receptor-alpha Activators (PPAR-a)

Clofibrate, Ciprofibrate, Fenofibrate, Gemfibrozil, Bezafibrate

48
Q

____ is a fibrate that must undergo bioactivation

A

Fenofibrate

(to fenofibric acid)

49
Q

Fibrates bind to ____, and regulate…

A

PPARa, and reguate gene transcription along with the retinoic acid recepto (RXR)

50
Q

Effects of Fibrates

Indications

AE’s and DDI’s

A
  • ↓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
Q

Lovaza MOA

A

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
Q

Metabolites of Eicosapentaenoic Acid (EPA)

A

TXA3 (Less potent than TXA2)

PGI3 (As potent as PGI2)

53
Q

Niacin MOA

A

Reduces serum TG (and LDL)

↑ Lipase activity (↑clearance of VLDL)

Lowers VLDL production in liver

Usually increases HDL levels

54
Q

____ is inhibited by Nicotinic Acid

A

DGAT2

Diacylglycerol acetyltransferase 2

55
Q

Niacin Targets in Adipose, Liver, and MQ

A

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
Q

Niacin indications

Expected effects

AE’s

A

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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