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Drug Action I > Block 2 - Dyslipidemia Med Chem > Flashcards

Block 2 - Dyslipidemia Med Chem Flashcards

1
Q

Know how cholesterol is degraded?

A
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2
Q

Know the biosynthesis of TG?

A
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3
Q

What are the drugs within the bile acid sequestant class?

A
  1. Cholestyramine (Qestran, Prevalite)
  2. Colestipol (Colestid)
  3. Colesevelem (Welchol)
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4
Q

Describe the MOA of bile acid sequestants?

A

“Selectively” bind the negatively charged bile acids over other anions

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5
Q

What was Cholestyramine initially developed for?

A

Pruritus from increased bile acids

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6
Q

Describe the structure of Questran?

A

Polymer of styrene and cross linked with divinylbenzene

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7
Q

Describe the mechanism and treatment target of bile acid sequestrants?

A
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8
Q

Why is Questran poorly absorbed and not metabolized very well?

A
  1. Cholestryamine has decreased bioavailability in plasma
  2. Permanent charged amino decreases absorption
  3. Polymeric and very lipophilic structure
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9
Q

How does Colestipol different from Cholestryamine?

A

Colestid posses a more ionizable nitrogen → more bile acid binding per unit

Secondary/Tertiary amines ionized at intestinal pH

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10
Q

___ of tertiary amine leads to better binding of Colestid?

A

Methy iodide quaternization

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11
Q

Describe how Colesevelam fits the SAR of bile acid sequestrates?

A
  1. Polymeric
  2. 0% F
  3. Act in gut (localized)
  4. Changed amine
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12
Q

What are the ADRs of BA sequestants? How can it be avoided?

A
  1. Constipation: co-admin with dietary fibers or psyllium laxatives
  2. Worsen hypertriglyceridemia
  3. Should not be coadministered with other drugs (1 hr before or 4 hr after)
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13
Q

How does BAS induces TG synthesis?

A

Decreased BA → increased TG for decreased cholesterol → VLDL levels rise → Increase LDL receptors and return VLDL levels to pre-drug levels

A patient with pre-existing hypertriglyceridemia, leads to an increase in triglycerides

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14
Q

What is the MOA of HMGRI?

A

Inhibition of HMG-CoA reductase → Reducing biosynthesis of cholesterol → Compensatory increase of HMGCoA reductase and LDL receptors → Increased uptake of LDL → Cholesterol lowering

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15
Q

Treatment targets of HLD

A
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16
Q

How was Mevastatin discovered?

A

Consisted of Compactin that was a metabolite of Penicillium

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17
Q

Lovastatin (_____) is ___ more potent than Mevastatin

A

Mevacor; 2x

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18
Q

Describe the transition state of HMGCOa Reductase drugs

A
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19
Q

Describe HMGRI SAR?

A
  1. lactone ring was substituted to bicyclic ring other rings as long as it was lipophilic and contained ethylene bridges
  2. 7-substituted-3,5-dihydroxyheptanoic acids
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20
Q

Lovastatin Brand

A

Mevacor

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21
Q

Describe the metabolism of Mevacor?

A

Lovastatin undergoes lactone hydrolysis → Active from → Metabolized to more hydrophilic metabolites 6-OH or 3-OH

Increasing hydrophilicity doesn’t necessarily mean decreased activity

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22
Q

What HMGRI are prodrugs? Are they activated by esterase?

A

Lovastatin, Simvastatin

Lactone hydrolysis

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23
Q

How does Simvastatin differ from Lovastatin?

A

Additional methyl group

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24
Q

How does Pravastatin differ from Zocor and Metacor?

A

Pravachol has No lactone → Not a prodrug

17% F

Lovastatin/simvastatin = 5%

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25
Q

Pravastatin Brand

A

Pravachol

Natural

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26
Q

Simvastatin Brand

A

Zocor

Natural

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27
Q

Fluvastatin Brand

A

Lescol

Synthetic

28
Q

Why does Atorvastatin have such long half-life

A

T1/2: 14-19 hr
Non-naphthalene bicyclic HMGRI

Synthetic

Very bulky and lipophilic

29
Q

Atorvastatin Brand

A

Lipitor

30
Q

How is Lipitor metabolized?

A

Addition of OH on para or ortho positions

Both equiactive (equal activity)

31
Q

Why does Rosuvastatin have such a long half life?

A

T1/2: 19-20
Non-naphthalene bicyclic HMGRI
Synthetic
Bulky, lipophilic, contains a F

32
Q

Rosuvastatin BRand

A

Crestor

33
Q

What is PCSK9?

A

Protein convertase subtilizing/kexin type 9 that is activated by by proprotein converses to an activated PCSK9

Important for the degradation of LDL-R (normal process for regulation)

34
Q

What is an examples of PSCK9 Inhibitors?

A

Alirocumab (Praluent)
Evolocumab (Repatha)

35
Q

What are some of the characteristics of PSCK9 inhibitors?

A
  1. Monoclonal human antibodies
  2. Longer half-life (14-18 days)
  3. Dosing Q2W
36
Q

Alirocumab Brand

A

Praluent

37
Q

Evolocumab Brand

A

Repatha

38
Q

What is ACL?

A

ATP-citrate lyase that converts citrate to acetyl-coA

39
Q

Exampels of ACL inhibitors?

A

BEmpedoic acid (Nexletol)

40
Q

What are similarities of citrate and NExletol?

A

Bempedoic acid is a longer chain → prodrug → binds to CoA (Bempedoyl CoA)

41
Q

What is the MOA of ACAT inhibitors?

A

Acyl CoA-cholesterol acyltransferase (ACAT) inhibitors
1. inhibits the synthesis of cholesterol esters
2. Inhibits the esterification of cholesterol in intestinal mucosa
3. Less absorption of cholesterol

42
Q

Example of ACAT inhibitors?

A

Ezetimibe (Zetia)

43
Q

Describe the SAR of ACAT inhibitors?

A

Pharmacophore for cholesterol absorption inhibitors

44
Q

How does Zetia undergo metabolism?

A
45
Q

Looking at Ezetimibe structure describe its PK properties?

A
  1. Crystalline powder
  2. Long half-life due to out compete cholesterol
46
Q

Why is ezetimiebe a last-resort drug?

A

Thicken arterial walls, unknown mechanisms

47
Q

What are vibrates?

A

Compounds that lower plasma cholesterol and total lipid levels

48
Q

Describe fibrate SAR?

A
  1. Aromatic ring-O-spacer group-isobutyric acid
  2. Isobutyric acid (or ester) head group is essential

Class: Phenoxyisobutyric acid

49
Q

What are fibrite examples?`

A
  1. Gemfibrozil (Lopid)
  2. Fenofibrate (Tricor, Trilipix)
50
Q

What are some counseling points when using vibrates?

A
  1. Indicated for hypertriglyceridemia and familial combined HLD
  2. Co-administered with other classes
  3. Should be take with food to increase absorption
51
Q

What are example of lipolysis inhibitors?

A

Nicotinic Acid (Niacin)

52
Q

What is nicotinic acid?

A

Derivative of nicotine that reduces cholesterol levels in humans and lowers serum triglycerides

53
Q

Describe the Niacin MOA?

A
54
Q

How does Niacin have such a short half-life and fast onset?

A

Very small and easily identified by metabolic enzymes

55
Q

ADRs of Niacin?

A
  1. Cutaneous VD → flushing/pruritus (Niacin flush)
  2. Requires titration to prevent ADRs
56
Q

Is niacin ER good?

A
  1. Concurent use with statins → less carotid thickening
  2. Increased risk for stroke
  3. Still an ongoing debate
57
Q

What is ANGPTL3?

A
  1. Enzyme that blocks lipoprotein lipase (LPL) and endothelial lipase (EL) → LPL/EL converts VLDL to VLDL remnants (IDL) and IDL to LDL
58
Q

What happens if you inhibit ANGPTL3?

A

Production of more VLDL remnants (IDL) which is cleared by HoFH

Shifts the concentration of IDL to lower causing circulating LDL to re-equalibrate to IDL thus less LDL

59
Q

What are examples of ANGPTL3 inhibitors?

A

Evinacumab (Evkeeza)

60
Q

Describe the overall effect of HMG-CoA reductase inhibitor?

A

Best for LDL control

61
Q

Describe the overall effect of Fibrates?

A
62
Q

Describe the overall effect of Niacin?

A
63
Q

Describe the overall effect of Bile acid sequestrants?

A
64
Q

Describe the overall effect of cholesterol absorption inhibitors?

A
65
Q

Describe the overall effect of PCSK9?

A

Strong decrease in LDL
Increase in HDL

66
Q

Describe the overall effect of ANGPRL?

A

Decrease in TG

Drug Action I (32 decks)

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