13/14 - Chemistry of Lipid Drugs Flashcards

1
Q
A

5-a-steroid

Plate / FLAT

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2
Q
A

5-B-steroid
Cholic Acid

has a KINK

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3
Q

Prenyl Pyrophosphates

A

SUPPLY SIDE
of the
Cholesterol Biosynthesis

Include:
HMG-SCoA Reductase –> Melavonate

PHOSPHATES + ATP

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4
Q

Steroid Formation
Ianosterol

A

Intermediate Steps
of
Cholesterol Biosynthesis

SQUALENE

IANOSTEROL

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5
Q

Cholesterol as a SUBSTRATE

ACAT & LCAT

A

Cholesterol Fatty Esters

  • *HDL Cholesterol –> ACAT**
  • *(Acyl-Coa Acyl Transferase)**
  • *EXCESS Cholesterol <–> LCAT**
  • *(Lecithin Cholesterol Acyl Transferase)**
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6
Q

Formation of Bile Acids
from Cholesterol

A

DEMAND side of the equation

Catabolism of Cholesterol

BILE ACID** = **SURFACTANT / EMULSIFIER

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7
Q

Lipoproteins

A

LIPID CARRIERS** for **Cholesterol** & **TGs
Transport lipophilic compounds

Lipophilic CORE
Cholesterol Esters + TGs

Surrounded by more Hydrophilic Lipids
Phospholipids + non-esterfied cholesterol
&
Proteins
apolipoproteins

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8
Q

Types of Lipoproteins

A

5 Main Lipoproteins classified based on their DENSITY

HDL
MOST DENSE = protein rich

LDL

IDL

VLDL

  • *CHYLOMICRONS**
  • least dense* = lipid rich
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9
Q

Apoprotein

A

Recognition sites for Receptors
for
lipoproteins = carriers for TG / Cholesterol

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10
Q

LDL Consistancy

A

40nm = 1000x smaller than eukaryotic cell

SINGLE APO-B100 PROTEIN
wrapped around

1500 Cholesterol Ester molecules

500 unesterfied Cholesterol

800 Phospho lipids

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11
Q

Methods to CONTROL Cholesterol

A

Catabolism of cholesterol

GI uptake of Cholesterol

Fat uptake from GI

Diet with choleseterol

INHIBIT
major steps of biosynthesisb

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12
Q

Switches and Feedbacks in Cholesterol Uptake and Metabolism

4 of them

A

Free Cholesterol in cells –> Inhibits de novo synthesis

Cholesterol –> ↓uptake by
inhibiting expression of LDL receptor

Efficient bile acid RECYCLING:
_inhibits cholesterol synthesis & uptake_

Synthesis of cholesterol ESTERS
cholesterol synthesis

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13
Q

Which Early Cholesterol Drugs were

DISCONTINUED & WHY?

A

Triparanol** & **Diazacholesterol
inhbited LATE stage reductaces

Accumulation of:
Desmosterol in Serum & Liver
Severe ADR’s

Choleseterol synthesis

  • should NOT be stopped at LATE STAGES*
  • rather earlier stages*
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14
Q

Biochemical Mechanism of HMG-CoAR

Major Requirement

A

2 Steps:
reduction of HMG with NADPH occurs via a:
CHIRAL TETRAHEDRAL INTERMEDIATE
VVV
1st = ALDEHYDE –> 2nd = ALCOHOL

Reduction is stereoselective

OH group –> LYS side chain
interacts with

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15
Q

Statins vs HMG-CoA

A

Statins are:
Competitive with HMG
HMG-like Pharmacophore
but
NON-competitive with NADPH

TRANSITION STATE ANALOGUE

Pharmacore = most important, but acccesory affects are for:
affinity / rates of entry / availability / clearance & metabolism

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16
Q

Which Statins are PRODRUGS?

A

Lovastatin
&
Simvastatin

Both are:
“Natural Products”
from fungal metabolites

17
Q

Lovastatin + Simvastatin + Pravastatin

A

Pravastatin = Active drug, not prodrug

Applicable to:

  • *HETEROZYGOUS pts w/ FC**
  • not with HOMOzygous FC*

LDL & ↑VLDL receptor’s mRNA
Serum Cholesterol & ↓LDL

no buildup of sterol intermediates

18
Q

Fluvastatin / Atorvastatin / Rosuvastatin

A

SYNTHETIC STATINS

Good water solubility & Bioavailability
similar efficacy

↓LDL 20-25% after 9 weeks
TGs
HDL (little)

no other effects on LIPOPROTEIN levels

19
Q

Baycol = Cerivastatin

A

RECALLED due to:
SEVERE RHABDOMYOLYSIS
thought to be caused by drug’s hydrophobicity

incidence was 18-80x greater than other statins

COMBINED WITH FIBRATES = Bigger issue

20
Q

Prodrugs due to the

CLOSED RING @ top

A

Pravastatin = OPEN RING = Active rug

21
Q

Which Statin?

A

LIPITOR

22
Q

Which Statin?

A

Rosuvastatin

23
Q

Which Statin

A

Vytorin
Zocor + Zetia

24
Q

MoA
Bile Acid Resins

A
  • *ANION BINDING RESINS**
  • NEG- Charge binds to **Bile Acids @ Intestine
  • -> bile acid EXCRETION**

enterohepatic recirculation of bile:
Cholesterol 7-a Hydroxylase / ↑Cholesterol -> BA / ↑BA SECRETION
VVV
LDL & ↑VLDL REMOVAL + ↑LDL Receptors

↓LDL-C NET EFFECT

25
Q

Bile Acid Sequestrants

MoA & Effects

A

Cholestyramine > Colestipol

MoA:

  • *Bind -NEG- charged carboxylate group of BILE SALTS**
  • *SEQUESTERING** them from intestinal lumen –> excreted
  • stopping BILE SALT RECYCLING*

↑Cholesterol conversion into Bile Salts

LDL Cholesterol
good with statins, not with fibrates

26
Q

PCSK9 Inhibitors

MoA / Uses

A

Alirocumab** + **Evolocumab
Praluent / Repatha

Effective in FAMILIAL HYPERCHOLESTEROLEMIA

  • *Recombinant MABs** –> bind PCSK9
  • PCSK9 normally PREVENTS LDLR recycling –> LDLR recycling*

Inhibition of PCSK9 –> ↑LDLR –> ↑Uptake of LDL
lowers choleseterol

27
Q

Zetia** = **Ezetimibe

Function / MoA

A

Inhibit cholesterol UPTAKE
absorption of biliary & dietary cholesterol from the small intestine
without affecting vitamins / TG’s / Bile acids

Monotherapy + STATIN combination (VYTORIN)

HDL 2.5-5%

LDL 15-20%

28
Q

Stanols

A

Benecol
margarine containing stanol esters

Inhibit Cholesterol UPTAKE

LDL 15%
good when used with statins

29
Q

Fibrates

MoA / Function

A

Fenofibrate / Gemfibrozil / Clofibrate
a-Substituted Carboxylic Acids

MoA:
PPAR-a + Fibrate binds RXR
ternary complex = active transcription factor

Activation of PPAR-a = nuclear transcription factor
induces expression of a number of genes involved in
LIPID METABOLISM
↓Lipoxygenases
&↓Cyclooxygenases

Good at ↑HDL&TGs

30
Q

New Treatments for HyperCholesteremia

LOMITAPIDE

A

Inhibits MTP

MTP = Microsomal Triglyceride Transfer Protein
that:
LIPIDATES apoB** –> **VLDL

inhibits the TRANSFER of lipids

VLDL assembly