Lecture 35: Drugs Affecting Lipoprotein Metabolism Flashcards
What is the paradigm for atherosclerosis generation?
Oxidized LDL is taken up by macrophage to form foamy macrophages
Who should be screened for lipids?
Everyone over 20 years old
Screened for triglycerides, total cholesterol, HDL, LDL
What is ATP when it comes to cholesterol treatment?
Adult Treatment Panel
What is the primary target of hypercholesteremia?
Reduction of LDL to appropriate level
What are the secondary goals in treating hypercholesteremia?
- Decreasing triglycerides and non-HDL cholesterol are secondary goals
- Increasing HDL cholesterol is also a secondary goal
What are LDL cholesterol goals?
Less than 100 or less than 70 if they have CHD
<160 if no risk factors
Highest risk below 70
What is a normal fasting normal TG?
<150
Elevated TG are independent risk factor for CHD
Because they are transported by the lipoproteins
What are non-HDL-C?
VLDL + IDL + LDL
Signficance is now we are trying to target other non-HDL
Aside from LDL
Also a risk factor for CHD
What is the non-HDL-C target?
30 mg/dL higher than LDL-C target
What is considered low HDL?
<40
What is the non-pharmacologic therapy for lipid disorders?
- Diet
- exercise and weight loss
- avoidance of alcohol intake
What are the purposes of the drugs for treatment of lipid disorders?
- reduce LDL-C
i. HMG-CoA Reductase Inhibitors
ii. Cholesterol Absorption Inhibitors
iii. Bile Acid Sequestrants - treat TG-HDL axis
i. Fibrates (Fibric Acid Derivatives)
ii. Omega 3 Fish Oil
iii. Niacin (Nicotinic Acid)
What are drugs that reduce LDL-C?
- HMG CoA reductase inhibitors (statins)
- cholesterol absorption inhibitors (CAI; ezetimibe)
- Bile acid sequestrants (BAS)
What are examples of different types of statins?
Always has a “statin” in the generic name
What is the MoA of statins?
Inhibits cholesterol synthesis
Targets rate limiting step of cholesterol synthesis
MoA = HMG-CoA Reductase Inhibitor
Statin mimics HMG-CoA so competitively binds
To HMG-CoA reductase
-reversible but has much greater affinity
Than normal HMG-CoA
How is the LDL receptor regulated?
Regulated by the amount of cholesterol in the liver
So if you have less cholesterol in the liver, you upregulate the production and migration of the LDL receptor to the liver surface
Thus, statins will decrease cholesterol synthesis which then upregulates LDLReceptors
Why are there very few adverse effects of statins?
Because body upregulates HMG-CoA reductase/LDL receptors to compensate for less cholesterol synthesis
Therefore, total cholesterol level remains about the same even though LDL is reduced in blood
What is the first line therapy for LDL reduction?
Statins
What are the adverse effects of statins?
- Elevated hepatic transaminases (not a big deal)
- muscle-related adverse effects
i. myalgia
ii. myopathy
iii. rhabdomyolysis
Dose-dependent
Do statins still work if you eat McDonalds every day?
Yep
What is myalgia?
Muscle ache or weakness without creatine kinase elevation
What is myopathy?
Muscle symptoms with increased CK levels
What is rhabdomyolysis?
Muscle symptoms with makred CK elevation and with creatinine elevation
Brown urine and myoglobin
What are risk factors for statin-induced myopathy?
- age, gender (female)
- frailty, low body weight
- renal insufficiency
- hypothyroidism
Why do we need drug classes aside from statins?
Because of the side effects of statin for certain populations
How is cholesterol absorbed?
NPC1L1 transporters take up cholesterol into duodenal/jejunal enterocytes
IBAT transporters also take up cholesterol into ileal enterocytes
How is cholesterol transported from enterocytes back out to lumen?
By ABC transporters
What are cholesterol Absorption Inhibitors?
Prevents absorption of cholesterol from small intestine (which is 25% diet and 75% from liver)
Increases LDL receptors ultimately!
What is the MoA of Ezetimibe?
Inhibits NPC1L1
Thus inhibits cholesterol uptake in enterocytes
What is the efficacy of Ezetimibe?
Reduces LDL by 20% as monotherapy
Minimal effects on TG
Not yet shown to reduce CV events on own
Usually added to statin therapy or used for those who cant tolerate statins
What are the adverse effects of ezetimibe?
Elevated transaminases
What are the key characteristics of bile acid sequestrants?
MoA: binds bile acids in the lumen and promotes its excretion
Prevents bile acids from being reabsorbed because the resulting complex is so big
Example:
i. cholestyramine
ii. Colestipol
iii. Colesevelam
Ultimately leads to upregulation of LDL receptors
What are the indications for bile acid sequestrants?
- statin intolerant patients or to add to statin therapy
Reduction of 15% by itself
Can raise TG levels and has minimal effects on HDL-C
What are the adverse effects of bile acid sequestrants?
- drugs are not absorbed systemically and lack systemic toxicity
- result in constipation, bloating, flatulence, heartburn and nausea
- can interfere with absorption of other drugs
- can raise TG levels
What are the similarities among statins, CAI, and bile acid sequestrants?
All 3 ultimately lead to upregulation of LDLR
What can lower LDL aside from drugs and exercise?
LDL apheresis (takes blood from patient and purges LDL cholesterol, like dialysis machine)
What is the significance of PCSK9?
PCSK9 downregulates LDL-receptors
Thus, we can target PCSK9 and inhibit the motherfucker, thereby upregulating LDLreceptors
How are triglycerides and HDL related?
Things that raise TG will lower HDL
Inversely related
What are the three drugs that target the TG-HDL axis?
- Fibric Acid Derivatives (Fibrates)
- Omega 3 Fatty acids (fish oils)
- Nicotinic Acid (niacin)
What are examples of fibrates?
Fenofibrate, Clofibrate, Gemifibrozil
What is the MOA of fibrates (fibric acid derivatives)?
Activates the nuclear PPARalpha receptor in liver and peripheral tissues
Decreases ApoC-III = less VLDL
Increases Acyl-CoA synthase = decrease FFA
Increase ApoA1, ApoA2, ABCA1 = increased HDL in blood
What is the efficacy of fibrates?
- decrease TG levels by up to 50%
- Increase HDL by 20%
But CV outcome trials have yielded mixed results
Only use with hypertriglyceridemia
What are the adverse effects of fibrates?
- typically well tolerated
- can cause myalgia/myopathy
- potentiate action of oral anticoagulants
What is the MoA of Omega 3 fatty acids?
Contains EPA and DHA
Reduces TG levels by 50%
Increases hDL by 10%
What is the MoA of niacin (nicotinic acid)?
Binds to niacin receptor on adipocyte
Decreases cAMP which downregulates
The conversion of TG to FFA
Reduces FFA release and flux to liver
What is the niacin efficacy?
Increase HDL = 20%
Decrease TG levels by 20%
Decrease LDL by 15%
Decrease Lp(a) by 15%
What is the primary adverse effect in niacin?
Flushing = 88% patients
What are cholesteryl ester transfer protein (CETP) inhibitors?
CETP converts HDL to LDL
Inhibitors therefore will increase HDL levels because there is no change of HDL to LDL
Time will tell if this works
