Hyperlipidemia Flashcards
Cholesterol precursor for
- steroid hormones
- bile acids
- vitamin D
(end of cholesterol pathway)
Rate limiting step in Cholesterol Synthesis
HMGCR
- target of statins
Coronary Heart Disease and Risk Factors
- high blood cholesterol/triglycerides
- high blood pressure
- high blood sugar/type II diabetes
- smoking
- gender/age/family history
Low LDL-C
time
the longer and lower the reduction in circulating LDL-C, the lower the incidence of CHD
** duration of LDL-C reduction v. important **
Familial-Hypercholesterolemia
- Lack of LDL receptors
- IDL & LDL not taken up; excess amount in system
VLDL
Very low density lipoprotein
- synthesized by liver
IDL
Intermediate density lipoprotein
VLDL remnants
LDL
Low density lipoprotein
HDL
High density lipoprotein
FFA
Free Fatty Acids
LPL
Lipoprotein lipase
SREBP
- sterol regulatory element binding protein
- transcription factor
- MASTER REGULATOR OF CHOLESTEROL LEVELS IN CELL
Low-cholesterol diet
SREBP activated
- increased cholesterol biosynthesis
- increased receptor mediated LDL endocytosis from plasma (cholesterol uptake into cell)
- decreased plasma LDL
- increased transcription of
- – LDL receptors
- – HMGCR
High-cholesterol diet
SREBP not activated - decreased cholesterol biosynthesis - decreased LDL receptors *** plasma LDL remains high *** (higher cholesterol in blood)
- fewer LDL receptors
- decreased HMGCR
Adipose Lipolysis
- inhibits adipose glycolysis
- less fat released
Statins
HMG-CoA Reductase Inhibitors
- most effective and best-tolerated
- agents for treating dyslipidemia
HMG-CoA Reductase Inhibitors
Statins
PCSK9 Inhibitors
-mab
monoclonal antibody
Cholesterol Absorption Inhibitor
Ezetimibe
Bile Acid Sequestrants
Resins
Chol-
Acid Citrate Lyase Inhibitor
Bempedoic Acid
Geranylgeranyl-PP
Farensyl-PP
Prenylated Proteins
- heme a
- dilichol
- ubiquinone
Total serum cholesterol should be lower than
200
Chylomicrons
- synthesized by the intestine
- converted to remnants by hydrolysis
- rapidly cleared from plasma by the liver
Apo B100
how lipoproteins are taken up by peripheral tissues
- cause plaque
Cholesterol delivery to cells
- ribosomes make LDL receptors
- transported golgi -> membrane
- LDL bind to LDL receptor and are taken in
- – clathrin coated pit -> vesicle -> endosome
- ** LDL -> Lysosome ***
- ** LDL receptors recycled back to membrane ***
LDL Receptors V Important
without LDL & IDL will NOT be taken up; excess amounts will be in circulation
(occurs when receptors genetically defective)
Bempedoic Acid
- inhibits Acetyl CoA synthesis
HMG-CoA reductase
rate
- rate limiting step
- inhibited by statins
Mevalonate Synthesis
- inhibited by statins
- inhibit HMG CoA reductase
PCSK9 Inhibitors
- inhibit degradation of LDL receptors
Niacin
- inhibit adipose lipolysis
- less fat released
Fibrates
- stimulate PPARa
- increase LDL (upregulate)
Gemfibrozil
fibrate
Ezetimibe
- cholesterol absorption inhibitor
- inhibits cholesterol absorption into body from gut
Cholestyramine
- bile acid resin
- inhibits bile acid resorption from gut
Effect of statins on LDL receptors and circulating LDL levels
- HMGCR inhibited -> inhibits cholesterolgenesis
- increase expression of LDL receptors
- Increase removal of LDL (VLDL, IDL) from blood
- decrease hepatic CLDL production
- SREBP is upregulated because of inhibition of HMGCoA reductase which lowers cholesterol which is made in cell, and increases cholesterol absorbed from blood
Statins
mechanism of action
Competitive inhibitors of HMG-CoA Reductase
- inhibit cholesterolgenesis
- increase expression of LDL receptors
- increase removal of LDL (VLDL, IDL) from blood
- decrease hepatic VLDL production
LDL-C levels lowered by 20-55%
Statins
(therapeutic use)
- contraindication
- alone or in combination with resins or ezetimibe
- CONTRAINIDCATED in women who are/want to be pregnant
- some indicated in children with familial hypercholesterolemia
Atorvastatin & Rosuvastatin
- longest t1/2
- most efficacious for sever hypercholesterolemia
- more TG lowering activity compared to other statins
Statins
toxic/adverse effects
- hepatotoxicity (rare and unpredictable)
- Diabetes mellitus
- – slight risk of new on-set; outweighed by statin benefits for patients with cardiovascular risk
- myopathy: reversible
Increased Simvastatin plasma levels =>
increased risk of myopathy
PCSK9 Inhibitors
- monoclonal antibodies against PCSK9 protein
- injected
- with PCSK9, LDL receptor directed to lysosome => degraded (rather than recycled back to surface)
- ** when PCSK9 INHIBITORS LDL receptors are saved and recycled back to surface, thus decreasing plasma LDL levels)
Evolocumab
STRONGEST
- PCSK9 inhibitor
- t1/2: 11-17 days
Alirocumab
- PCSK9 inhibitor
- t1/2 12 days
Ezetimibe
- cholesterol absorption inhibitor
- blocks NPC1L1 cholesterol transporter
- ** blocks uptake of cholesterol micelles from intestine ***
Ezetimibe
mechanism of action
- selectively inhibits intestinal cholesterol absorption
- targets NPCL1 transport
- – decreases intestinal delivery of cholesterol to the liver
- – increases expression of hepatic LDL receptors
- – decreases cholesterol content of atherogenic particles
- average reduction in LDL-C is ~18%
- – with statins: additional 25%
Bile Acid Sequestrants
- resins
- take up bile salts
Bile Acid Sequestrants
mechanism of action
- increase bile acid excretion; less bile acid absorbed
- – highly + charge binds - charged bile and makes too large to be absorbed
- increase hepatic bile-acid synthesis (because less amount taken up by blood)
- – hepatic cholesterol content declines
- – LDL receptors increased in hepatocytes
- – increased LDL clearance from plasma
- net effect: decrease of LDL-C
- HMG-CoA reductase upregulated
- increased cholesterol synthesis partially offsets reduction in LDL-C
- coadministered with statin
Resin induced bile production leads to increase in hepatic TG synthesis
USE EXTREME CAUTION OR AVOID in patients with sever hypertriglyceridemia
Bile Acid Sequestrants
take with
- meal or no effect (need bile present in order to be able to bind to it)
- ** take at least 4 hours before or after other medications (can interfere with absorption) ***
Bile Acid Sequestrants
adverse effects
GI Symptoms
Kepone & Brodifacoum
eliminated by bile acid sequestrants
Nexletol
Bempedoic Acid
Bempedoic Aid
ATP Citrate Lyase Inhibitor - used in combo with statins - indication: adjunct to diet and maximally tolerated statin therapy ORAL (advantage over PCSK9 Inhibitors) - 12-18% reduction in LDL-C
