Lipid Pharmacology - Pfister Flashcards
What is the mechanism behind HMG CoA reductase (statins) inhibitors?
They block the formation of squalene by competitively inhibiting the active site. This is the rate limiting step in cholesterol synthesis.
Name three statins
Atorvastatin
Lovastatin
Simvastatin
What is SREBP? How is it regulated?
SREBP is a transcription factor which controls synthesis of cholesterol enzymes.
SREBP is activated by site-1 protease and site-2 protease when cholesterol levels are low.
What is SCAP?
SREBP cleavage activating protein. It senses the levels of cholesterol in the cell.
What are the pharmacokinetics of statins?
High first pass Targets liver Transported from gut by OATP1B1 High levels of plasma binding Variable Half-life
What is the active form for statins? Which statins are administered as active drugs?
Hydroxy-acids are the active statin form (compared to lactones).
Atorvastatin is administered as a hydroxy-acid.
How are statins metabolized?
CYP3A4
What are major adverse effects of statins? Minor adverse effects?
Myopathy, Rhabdomyolysis
GI side effects, Increased liver enzymes
What risk factors are there for myopathy or rhabdomyolysis?
High dose of statins
SLCO1B1 SNP
other CYP3A4 metabolized drugs
(also a bazillion other things)
these lead to higher plasma concentrations
What are contraindications for statins?
Active liver disease
Hypersensitivity
Pregnancy/Lactation
Why do statins cause myopathy?
Isoprenoids, a protective compound in muscles, are synthesized using intermediates in the cholesterol pathway
What happens to triglycerides, HDL, and LDL in a patient on statins?
Triglycerides go down (depending on [initial])
LDL goes down
HDL goes up slightly
How is cholesterol excreted?
It is used to make bile acids, which are secreted.
What is cholestyramine?
A bile-acid binding agent
How does cholestyramine work?
It is a positively charged resin that binds to the negatively charged bile acids and is too big to be reabsorbed.
How is SREBP affected by statins and cholestyramine?
SREBP upregulates LDL receptors to pull LDL out of the blood when statins and cholestyramine decrease cholesterol availability.
What are the adverse effects of cholestyramine?
Constipation/bloating
Gritty consistency
Decreased absorption of oral, negatively charged drugs
Moderate, transient increase in triglycerides
What happens to triglycerides, HDL, and LDL in a patient on cholestyramine?
Transient increase in triglycerides
Dose-dependent decrease in LDL
small increase in HDL
What is Nicotinic acid?
Vitamin B derivative
What three effects does Nicotinic acid have?
Decreases free fatty acid release
Decreases VLDL synthesis
Decreases HDL breakdown
How is Nicotinic acid administered?
Orally
Immediate release
Long acting release
Extended release
What is the most frequent adverse effect with nicotinic acid? How can it be lessened?
Flushing/pruritis
Gradually increasing dose, NSAIDs, bedtime administration
What are adverse effects associated with nicotinic acid?
GI upset, increased liver enzymes, hyperuricemia, increased resting glucose levels
What are contraindications for nicotinic acid?
peptic ulcer disease, concurrent statin use, gout, diabetes
What happens to triglycerides, HDL, and LDL in a patient on nicotinic acid?
decreased triglycerides, LDL
increased HDL
(also decreases lipoprotein A)
What is ezetimibe? How does it work?
Ezetimibe blocks cholesterol absorption from the bowel by binding to the Niemann Pick C10 like Protein.
How is ezetimibe administered?
It is given orally and glucuronidated to its active form.
What happens to triglycerides, HDL, and LDL in a patient on ezetimibe?
small decrease in triglycerides and LDL
small increase in HDL
What is PPAR-a?
A transcription factor expressed in liver and adipose tissue.
How does Retinoid X Receptor interact with PPAR-a?
It forms a heterodimer with the activated PPAR-a.
How are PPAR-a activators administered?
Fenofibrate is administered as a pro-drug
Gemfibrozil is administered as an active drug
How is fenofibrate excreted?
Fenofibrate is excreted in the urine, in glucoronidated form.
What are contraindications for PPAR-a activators?
Renal impairment
use caution with statins
What happens to triglycerides, HDL, and LDL in a patient on PPAR-a activators?
decrease in triglycerides
variable decrease in LDL
increase in HDL
What are PPAR-a activators prescribed to treat?
High triglycerides associated with metabolic disorders like diabetes
Where are omega-3 fatty acids found?
Fatty fish like tuna, salmon, mackeral
What effect do omega-3 fatty acids have on lipids?
inhibit lipogenesis
increase beta-oxidation
increase phospholipid synthesis
increase ApoB degradation
What are the pharmacokinetics of omega-3 fatty acids?
very slow acting, stop if no benefit has been seen ater two months
What are adverse effects of omega-3 fatty acids?
Fish allergy
Increased LDL
Increased liver enzymes
Prolongation of bleeding times
What is PCSK9?
A protein that targets LDLreceptors to lysosomes
What is Microsomal Triglyceride Transfer Protein?
A protein that takes cholesterol out of the membrane and assembles it into lipoproteins
How are MTP inhibitors metabolized?
CYP3A4
What are adverse effects of MTP inhibitors?
GI upset
Hepatotoxicity
What are MTP inhibitors used for?
Treatment of homozygous familial hypercholesteremia
