13/14 - Chemistry of Lipid Drugs

Question 1

Answer 1

5-a-steroid

Plate / FLAT

Question 2

Answer 2

5-B-steroid
Cholic Acid

has a KINK

Question 3

Prenyl Pyrophosphates

Answer 3

SUPPLY SIDE
of the
Cholesterol Biosynthesis

Include:
HMG-SCoA Reductase –> Melavonate

PHOSPHATES + ATP

Question 4

Steroid Formation
Ianosterol

Answer 4

Intermediate Steps
of
Cholesterol Biosynthesis

SQUALENE

IANOSTEROL

Question 5

Cholesterol as a SUBSTRATE

ACAT & LCAT

Answer 5

Cholesterol Fatty Esters

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

Question 6

Formation of Bile Acids
from Cholesterol

Answer 6

DEMAND side of the equation

Catabolism of Cholesterol

BILE ACID** = **SURFACTANT / EMULSIFIER

Question 7

Lipoproteins

Answer 7

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

Lipophilic CORE
Cholesterol Esters + TGs

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

Question 8

Types of Lipoproteins

Answer 8

5 Main Lipoproteins classified based on their DENSITY

HDL
MOST DENSE = protein rich

LDL

IDL

VLDL

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

Question 9

Apoprotein

Answer 9

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

Question 10

LDL Consistancy

Answer 10

40nm = 1000x smaller than eukaryotic cell

SINGLE APO-B100 PROTEIN
wrapped around

1500 Cholesterol Ester molecules

500 unesterfied Cholesterol

800 Phospho lipids

Question 11

Methods to CONTROL Cholesterol

Answer 11

↑Catabolism of cholesterol

↓GI uptake of Cholesterol

↓Fat uptake from GI

↓Diet with choleseterol

INHIBIT
major steps of biosynthesisb

Question 12

Switches and Feedbacks in Cholesterol Uptake and Metabolism

4 of them

Answer 12

↑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

Question 13

Which Early Cholesterol Drugs were

DISCONTINUED & WHY?

Answer 13

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*

Question 14

Biochemical Mechanism of HMG-CoAR

Major Requirement

Answer 14

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

Question 15

Statins vs HMG-CoA

Answer 15

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

Question 16

Which Statins are PRODRUGS?

Answer 16

Lovastatin
&
Simvastatin

Both are:
“Natural Products”
from fungal metabolites

Question 17

Lovastatin + Simvastatin + Pravastatin

Answer 17

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

Question 18

Fluvastatin / Atorvastatin / Rosuvastatin

Answer 18

SYNTHETIC STATINS

Good water solubility & Bioavailability
similar efficacy

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

no other effects on LIPOPROTEIN levels

Question 19

Baycol = Cerivastatin

Answer 19

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

Question 20

Prodrugs due to the

CLOSED RING @ top

Answer 20

Pravastatin = OPEN RING = Active rug

Question 21

Which Statin?

Answer 21

LIPITOR

Question 22

Which Statin?

Answer 22

Rosuvastatin

Question 23

Which Statin

Answer 23

Vytorin
Zocor + Zetia

Question 24

MoA
Bile Acid Resins

Answer 24

• *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

Question 25

**Bile Acid Sequestrants** **MoA & Effects**

Answer 25

**_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_***

Question 26

**_PCSK9 Inhibitors_** **MoA / Uses**

Answer 26

**_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

Question 27

**_Zetia**_ = _**Ezetimibe_** **Function / MoA**

Answer 27

**_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%

Question 28

**_Stanols_**

Answer 28

**_Benecol_** margarine containing **stanol esters** **_Inhibit Cholesterol UPTAKE_** ↓**LDL** 15% good when used with statins

Question 29

**Fibrates** **MoA / Function**

Answer 29

**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**

Question 30

**New Treatments for HyperCholesteremia** ## Footnote **_LOMITAPIDE_**

Answer 30

**_Inhibits MTP_** **MTP = Microsomal Triglyceride Transfer Protein** that: **LIPIDATES _apoB**_ --\> _**VLDL_** ***_inhibits the TRANSFER of lipids_*** ↓**VLDL** **assembly**