Exam 2 lecture 2 Flashcards
HMG-COA reductase inhibitors also called
statins
What is mevalonic acid? used for?
The product of HMG-COA reductase. Important building block in synthesis of cholesterol in liver.
What are two prodrug statins? how are they activated
lovastatin and simvastatin.
Activated by bile acid
Which statins are not major substrates for CYP 450
Pravastatin and pitavastatin
How do statins work
bind to HMG coa reductase and inhibit it. Preventing conversion of HMG COA reductase to mevalonic acid. decreasing cholesterol in liver.
What happens when statins reduce cholesterol levels in liver
ldl receptors are increased on liver, Allowing it to take up more LDL cholesterol from Plasma.
Recognize chemical structures of statins
check brightspace
Direct vs indirect use of statin
direct- inhibit enzymatic activity of HMG-COA reductase
indirect- upregulation of LDL receptors and increased hepatic uptake of LDL
When are statins used? 2 uses
Hypercholesterolemia and immediately after MI
how do statins change LDL, HDL and TG
20-60% lowering of LDL
10-33% lowering of TG
5-10% increase in HDL
Which statins are substartes for CYP3A4
Simvastatin
Atorvastatin
Lovastatin,
Which drugs are substrates for CYP2C9
Fluvastatin
Rosuvastatin
How are pravastatin and Pitavastatin excreted
Pravastatin- excreted unchanged and undergoes sulfation
Pitavastatin- Excreted in bile unchanged, undergoes hepatic circulation
Adverse effects of HMG COA reductases
SKELETAL MUSCLE
1. Rhabdomylosis (myopathy) with renal dysfuction
- Hepatotoxicity
may increase incidence of T2 diabetes
What are two drugs that can be used in conjunction with statins
ATP citrate Lyase inhibitor (ACL)
PCSK9 inhibitors
Name a ACL drug
Bempedoic acid (nexletol)
What is ATP citrate lyase? Use of its inhibitor?
-an enzyme upstream of HMG COA in cholesterol synthesis pathway.
-used adjunct to statins to lower LDL levels
Who can use ACL
patients with HeFH and ASCVD
side effects of ACL? Route? Excretion?
May cause gout
orally taken
Excreted in kidney
PCSK9 inhibitor use
a protease that promotes LDL receptor in liver
Name PCSK9 drugs
Alirocumab(pralvent)
Evolocumab (Repatha)
dosing of alirocumab and evolocumab
Alirocumab- inject SQ every 2 weeks 75 or 150mg
Evolocuab- inj sq every 2 weeks 140 mg or once per month 420 mg
What are PCSK9 drugs used fro
Adjunct to statins in ASCVD and HeFH and ASCVD
adverse drug rxn of PCSK9 inhibitors
Arthralgia (inj site rxn)
Drugs used in homozygous familial hypercholesterolemia
Juxtapid (Lomitapide)
Mipomersen (Kynamro)
Evinakumab (evkeeza)di
difference between the drugs used to treat homozygous hypercholesterolemia
Juxtapid and mipomersen inhibit APO B
Evinakumab inhibit angiopoietin like protein 3
Juxtapid MOA
(SiRNA) inhibitor of MTTP that inhibits the assembly of APO B containing lipoproteins in liver and intestine
What does APO B do? What does its inhibition do?
APO B in liver makes VLDLs
In intestine makes chylomicrons
APO B interferes with VLDL and chylomicrons
adverse effect of juxtapid
High risk for liver damage
Mipomersen MOA. Which AOB is it more selective for?
instead of si RNA, it is an anti sense oligonucleotide inhibitor of APO B
more selective for APO B 100 (APO B made in liver). No effect in intestine
Adverse reaction of Mipomersen
Liver damage
adverse rxn of both mipomersen and juxtapid
liver damage
Evinacumab (Evkeeza) MOA
Monoclonal antibody against protein called Angiopoitein like protein 3 (ANGPTL 3)
What is ANGPL3
Plays regulatory role on activity of lipases called lipoprotein lipase (LPL) and endothelial lipase (EL)
What do ANGPTL3 inhibitors do?
By binding with ANGPTL3 with antibody, we interfere with its ability to inhibit the activity of LPL and EL, lowering LDL
Name drugs that lower triglycerides
Fibric acid derivatives
Niacin
Omega 3 fatty acids
Fibric acid derivative drugs
GEmfibrizol
Fenofibrate
Which fibric axcid drug is a prodrug
Fenofibrate
Target of fibric acid derivative drugs
bind to PPAR alpha to reduce triglyceride levels
indication of fibric acid drugs
Hypertriglyceridemia
Adverse effects of fibric acid derivatives
rhabdomylosis if used with statin
drug interactions of fibric acid derivateves
Warfarin efffects potentiated. q
Use of Niacin? what is it also known as?
Used to lower triglyceride
Vit B3
At dietary levels- no effect on lipid, 1-3 grams a day lowers lipids
MOA of niacin
Niacin blocks the mobilization of FFA from adipose tissue, Less fatty acid taken to liver leading to less triglyceride synthesis.
How does niacin affect LPL, VLDL, LDL, TG and HDL levels
increase LPL, increase VLDL clearence
reduce, VLDL
reduce LDL and TG
increase HDL
2 main tissues targeted by niacin
Hepatocytes (liver) and adipose tissue
What does Niacin do in adipose tissue
inhibits TG lipolysis by hormone sensitive lipase (HSL), decreasing FA transport to liver.
what does Niacin do in liver
Niacin inhibits fatty acid synthesis and esterification, reducing TG export via VLDL
Indication of Niacin
Pts with high levels of TG
Raise HDL levels
adverse effects of niacin
Vasodilation
leading to itching, flushing, headache, tingling
some hepatotoxicity
Name 2 omega 3 fatty acid compounds
Eicosapentanoic acid (EPA)
Docosahexaenoic acid (DHA)
difference between EPA vs DHA omega 3 fatty acids structurally
EPA- 5 double bonds
DHA- 6 double bonds
MOA of omega 3 fatty acids
reduce synthesis of TG in liver. Omega 3 fatty acids are poor substrates for enzyme responsible for TG synthesis. They also inhibit esterification of other fatty acids
indication of o-3 fatty acid
severe hypertriglyceridemia (>500)
adverse effects of omega 3 fatty acid
combo products can increase LDL, not vascepa (EPA only)
omega 3 fatty acid + ethyl ester drug name
Omtryg
Dyslipidemia sx
Mostly asymptomatic
if severe- chest pain, palpitation, sweating
what symptom do we see hen triglycerides are over 400-500
pancreatitis
Fasting lipid panel we look at
Total cholesterol
LDL
TG
HDL
Which equation estimates LDL from FLP
TC-HDL-TG/5
if asked for non-hdl, just dont include HDL in calculation
Lifestyle modification for dyslipidemia
DASH diet
lower percentage of calories from transfats and saturated fats
lower sodium intake
90-150 mins of exercise a week
smoking cessation
do omega 3 fatty acids reduce LDL?
yes
