Week 5: Lipid Pharmacology

Question 1

Statin Drugs MOA

Answer 1

Competitively Inhibits HMG CoA Reductase

So inhibits the conversion of HMG-CoA to Mevalonate

Question 2

What is statin intolerance?

Answer 2

The characteristic feature is muscle pain

Think it has something to do with the by-products of cholesterol synthesis (specifically geranyl pyrophosphate and farnesyl pyrophosphate)

As with most drugs, there are other consequences besides the intended therapy

Question 3

How does a competitive inhibitor work

Answer 3

resembles the substrate of the target molecule but contains a chemical group is added that alters the enzyme’s structure enough to inhibit their activity

Question 4

How do competitive inhibitors affect the kinetics

Answer 4

Question 5

Does the Km ever change

Answer 5

The Km is inherent to the enzyme, however, if for example a competitive inhibitor were added the Km does change but it called the apparent Km

Question 6

What is Km?

Answer 6

Concentration of drug @ 50% maximum velocity

Question 7

Describe how a Lineweaver-Burke

Answer 7

Question 8

Statin effects on HMG CoA levels

Answer 8

↓cholesterol

with decreased INSIG dissociated from SCAT and translocates to the Golgi and get cleavage of SREBP and get transcription factor and activates SREBP transcription factor activity

which increases LDL receptor and HMG CoA reductase expression

Question 9

What effect does statin effects on increased LDL receptors have?

Answer 9

We are taking it out of the blood which is good for the liver because it can synthesize bile which can dispose of cholesterol

However, Statins it also increases LDL receptor levels in all cell and other cells don’t have a way to get rid of cholesterol so it can exacerbate cholesterolemia problems

Question 10

When is cholesterol synthesis maximized?

Answer 10

12 AM - 2 AM

Question 11

ADME AKA

Answer 11

Absorption

Distribution

Metabolism

Excretion

Question 12

Statins metaboolized by

Answer 12

CYP3A4

Question 13

Describe ADME of statins

Answer 13

?

Question 14

Overview of HMG CoA reductase inhibitors

Answer 14

Question 15

Key adverse effects of HMG CoA reductase inhibitors

Answer 15

• Rhabdomyolysis
• Myoglobinemia

Question 16

Describe the typical dose timing of Statins

Answer 16

Question 17

Describe Liver detoxification systems

Answer 17

Question 18

Contraindicated with statin therapy

Answer 18

Drugs that use CYP3A4

Also Grapefruit

Question 19

Ezetimibe MOA

Answer 19

(dietary cholesterol uptake inhibitor)

NPC1L1 receptor

Question 20

NPC1L1 receptor AKA

Answer 20

• Nieman-Pick C1-Like 1 receptor
• dietary cholesterol receptor

Question 21

Nieman Picks disease

Answer 21

Mutation of NPC1 which is a sphingolipid transporter which is a key component of myelin so usually die young…. learn more about this

Question 22

What is the most common detoxifying enzyme?

Answer 22

CYP3A4 detoxifies 90% of drugs

Question 23

Ways to make drugs more hydrophilic to excrete them (Phase 2)

Answer 23

• Bile salt synthesis
• bilirubin conjugation (glucuronic acid) di-glucuronide bilirubin conjugate
  *

Question 24

Issue with drinking grapefruit juice and many drugs including?

Answer 24

Statins

other drugs that use CYP3A4

Question 25

Cholestyramine MOA

Answer 25

• Is a bile acid resin and binds bile acids and inhibits the reabsorption of bile acids in the terminal ileum
• This causes bile to be synthesized using up cholesterol
• Net effect is ↓ LDL Cholesterol

Question 26

Where are bile acids typically absorbed?

Answer 26

In the terminal ileum

Question 27

Niacin MOA

Answer 27

Question 28

Rate limiting step of bile acid synthesis enzyme

Answer 28

7α hydroxylase

Question 29

Bile synthesis regulation

Answer 29

if there is a lot of bile then it will inhibit 7α hydroxylase

If bile is being excreted 7α hydroxylase will be activated to synthesize more

Question 30

Niacin AKA

Answer 30

• Nicotinic acid
• Vitamin B3

Question 31

Niacin MOA

Answer 31

binds to heterotrimeric G protein Gαi on adipocytes

Gαi inhibits FA release from adipocytes by inhibiting adenylate cyclase

Also inhibits triglyceride synthesis from free FAs in the liver

net effect is preventing efflux of FAs by adipocytes leading to reduced VLDL formation

keeps lipids in fat cells

Question 32

What stimulates FA release from adipocytes

Answer 32

heterotrimeric G protein Gαs

Question 33

Niacin ideal for

Answer 33

Hypertriglyceridemia

Question 34

Problems with niacin treatment

Answer 34

weight loss is difficult because blocking FA efflux from adipocytes

Causes flushing by increasing prostaglandin synthesis in endothelial cells which can have an effect on vasal tone and decrease it and increase flow to the periphery causing flushing

Question 35

List of fibrates

Answer 35

Fenofibrate

gemfibrozil

clofibrate

benzafibrate

Question 36

Fibrates MOA

Answer 36

• Binds PPAR-α which is a transcription factor for metabolism which translocates to the nucleus and binds with RXR (retinoic Acid X Receptor)
• RXR is a cotranscription factor that help with gene expression
• PPAR-α increases oxidative reactions (primarily in the liver but also in skeletal muscle) Really increases β-oxidation to help reduce hyperlipidemia
• Net effect is increase β-oxidation to reduce hypertriglyceridemia

Question 37

PPAR-γ target of

Answer 37

antidiabetic drugs, more in endocrine

Question 38

PPAR AKA

Answer 38

Peroxisome Proliferator Activated Receptor

Question 39

What is PPAR?

Answer 39

referred to as master transcription factors of metabolism

Question 40

PCSK9 Inhibitor MOA

Answer 40

• Normally PCSK9 binds to LDL receptor causing the degradation of LDL receptor after it binds to LDL
• Monoclonal Antibody inhibition of PCSK9 removes it from the LDL receptor and increases LDL receptor expression to clear more LDL from the blood, so now the LDL receptors aren’t degraded and they can take up LDL-C and then return to the surface

Question 41

List of PCSK9 Inhibitors

Answer 41

Alirocumab

Question 42

What usually happens when LDL receptor is down-regulated?

Answer 42

LDL levels go up

Question 43

What are some ways to downregulate the LDL receptor

Answer 43

PCSK9 inhibitors

more

Question 44

How do monoclonal antibodies not cause a severe immune response

Answer 44

Monoclonal antibodies are humanized by taking the FC region and replacing it with human sequences reducing the immunoreactivity