Week 5: Lipid Pharmacology Flashcards
Statin Drugs MOA
Competitively Inhibits HMG CoA Reductase
So inhibits the conversion of HMG-CoA to Mevalonate
What is statin intolerance?
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
How does a competitive inhibitor work
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
How do competitive inhibitors affect the kinetics
Does the Km ever change
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
What is Km?
Concentration of drug @ 50% maximum velocity
Describe how a Lineweaver-Burke
Statin effects on HMG CoA levels
↓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
What effect does statin effects on increased LDL receptors have?
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
When is cholesterol synthesis maximized?
12 AM - 2 AM
ADME AKA
Absorption
Distribution
Metabolism
Excretion
Statins metaboolized by
CYP3A4
Describe ADME of statins
?
Overview of HMG CoA reductase inhibitors
Key adverse effects of HMG CoA reductase inhibitors
- Rhabdomyolysis
- Myoglobinemia
Describe the typical dose timing of Statins
Describe Liver detoxification systems
Contraindicated with statin therapy
Drugs that use CYP3A4
Also Grapefruit
Ezetimibe MOA
(dietary cholesterol uptake inhibitor)
NPC1L1 receptor
NPC1L1 receptor AKA
- Nieman-Pick C1-Like 1 receptor
- dietary cholesterol receptor
Nieman Picks disease
Mutation of NPC1 which is a sphingolipid transporter which is a key component of myelin so usually die young…. learn more about this
What is the most common detoxifying enzyme?
CYP3A4 detoxifies 90% of drugs
Ways to make drugs more hydrophilic to excrete them (Phase 2)
- Bile salt synthesis
- bilirubin conjugation (glucuronic acid) di-glucuronide bilirubin conjugate
*
Issue with drinking grapefruit juice and many drugs including?
Statins
other drugs that use CYP3A4
Cholestyramine MOA
- 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
Where are bile acids typically absorbed?
In the terminal ileum
Niacin MOA
Rate limiting step of bile acid synthesis enzyme
7α hydroxylase
Bile synthesis regulation
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
Niacin AKA
- Nicotinic acid
- Vitamin B3
Niacin MOA
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
What stimulates FA release from adipocytes
heterotrimeric G protein Gαs
Niacin ideal for
Hypertriglyceridemia
Problems with niacin treatment
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
List of fibrates
Fenofibrate
gemfibrozil
clofibrate
benzafibrate
Fibrates MOA
- 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
PPAR-γ target of
antidiabetic drugs, more in endocrine
PPAR AKA
Peroxisome Proliferator Activated Receptor
What is PPAR?
referred to as master transcription factors of metabolism
PCSK9 Inhibitor MOA
- 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
List of PCSK9 Inhibitors
Alirocumab
What usually happens when LDL receptor is down-regulated?
LDL levels go up
What are some ways to downregulate the LDL receptor
PCSK9 inhibitors
more
How do monoclonal antibodies not cause a severe immune response
Monoclonal antibodies are humanized by taking the FC region and replacing it with human sequences reducing the immunoreactivity
