Flashcards in Lipid Drugs Deck (21):
Exogenous lipid transport handles ingested cholesterol and triglycerides (TGs). In this process, TGs are delivered to muscle & adipose tissues via the action of what enzyme?
Ingested cholesterol and TGs are carried in chylomicrons. TGs are off-loaded to muscle & adipose tissue via the action of lipoprotein lipase. The chylomicron then delivers the remaining cholesterol to the liver.
In endogenous lipid transport, the liver secretes VLDL particles into the circulation, which are broken down into IDL and LDL. LDL carries cholesterol to what 3 places?
LDL delivers cholesterol to peripheral tissues, atheromas, and the liver.
After internalization by the hepatocyte, LDL is hydrolyzed into amino acids and free cholesterol. What are the 3 regulatory effects of intracellular cholesterol on the liver cell?
1. decrease activity of HMG-CoA reductase
(--> decrease cholesterol synthesis)
2. activate ACAT
(--> increase cholesterol esterification for storage)
3. inhibit gene transcription for synthesis of LDL-Rs
(--> reduce cholesterol uptake)
In reverse cholesterol transport, circulating HDL acquires cholesterol from peripheral tissues and atheromas via the action of what enzyme?
What are 3 ways that HDL is anti-atherogenic?
1. HDL's role in reverse transport of cholesterol from atheroma & peripheral tissues to the liver
2. HDL protects against endothelial dysfunction
3. HDL inhibits oxidative stress
Niacin has 3 therapeutic effects on HDL/LDL/TGs.
1. It is the best agent for increasing (?) levels
2. Niacin is equal to fibrates and statins at lowering (?) levels
3. Niacin also reduces (?) levels
1. Niacin is the best agent for increasing HDL
2. Niacin is equal to fibrates and statins at lowering TGs
3. Niacin also reduces LDL levels
As a result of its effects on lipid parameters, Niacin is most useful for what type of patients?
Niacin is most useful for patients with high TGs and low HDL.
Common minor side effects of niacin include flushing and pruritis of the face and trunk, skin rashes, acanthosis nigricans, dyspepsia, and reactivation of peptic ulcer disease.What are the most serious side effects of niacin? As a result, niacin is contraindicated in what two groups of patients?
Serious side effects:
As a result of #2 and #3, niacin is contraindicated in patients with diabetes mellitus or with a history of gout.
Niacin's mechanism of action has three aspects.
1. Niacin decreases what process in adipose tissue, causing a reduction of free fatty acid transport to the liver.
2. Reduced FFA transport to the liver causes decreased (?) synthesis, resulting in reduced VLDL and LDL levels.
3. Niacin reduces hepatic clearance of (?), thus raising its levels.
1. Niacin decreases lipolysis in adipose tissue --> reduces transport of free fatty acids to the liver.
2. Reduced FFA transport to the liver --> decreased TG synthesis --> reduced VLDL and LDL levels.
3. Niacin reduces hepatic clearance of HDL --> raising HDL levels.
There are 5 fibrates. 4 of them end in -fibrate.
What is the oldest fibrate that is no longer used due to adverse side effects?
What is the only one that doesn't end in -fibrate, and what side effect does it have less of?
What are the other 3 fibrates?
The 5 fibrates are:
1. Clofibrate is the oldest and no longer used.
2. Gemfibrozil results in the least gallstone formation.
Fibrates have small effects on LDL and HDL levels.Fibrates strength is in their reduction of (?) levels, and as a result they are used in what type of patients?
Fibrates have small effects on LDL and HDL levels.
Fibrates strength is in their reduction of VLDL levels --> decreased TGs.
Thus, fibrates are used for patients with severe hypertriglyceridemia.
Fibrates actions are mediated through interaction with what receptor?
This interaction causes:
1. (stimulation/inhibition?) of (?) synthesis --> enhanced TG clearance
2. (stimulation/inhibition?) of (?) expression --> enhanced VLDL clearance
3. (stimulation/inhibition?) of (?) expression --> increased HDL levels
Fibrates interact with PPARα.
This interaction causes:
1. stimulation of LPL synthesis --> enhanced TG clearance
2. inhibition of apoC-3 expression --> enhanced VLDL clearance
3. stimulation of apoC-1 and apoC-2 expression --> increased HDL levels
What are the 4 side effects of fibrates?
1. GI side effects
2. myositis flu-like syndrome
3. potentiate actions of oral anticoagulants
4. increased lithogenicity of bile
****Gemfibrozil is best at avoiding this. Clofibrate is the worst and is no longer used.
What are the 3 bile acid sequestrants?
What is their effect (increase or decrease) on LDL, HDL, and TG levels.
Cholestyramine, Colestipol, and Colesevelam
1. lower LDL levels
2. slightly increase HDL and TG levels. (Thus, they are contraindicated in patients with severe hypertriglyceridemia.)
Bile Acid Sequestrants bind bile acids and prevent their intestinal reabsorption. The liver responds by increasing bile acid synthesis. How does this lead to lower LDL levels?
Increased bile acid synthesis in liver --> decreased hepatic cholesterol --> increased production of LDL receptors --> increased LDL clearance from circulation
Minor side effects of bile acid sequestrants (BAS) include bloating, dyspepsia, unpleasant taste, constipation, and impaired absorption of fat-soluble vitamins.What is the most important side effect of BAS?
BAS interfere with absorption of cardiac glycosides and coumarin anticoagulants.
Statins are the best agents for treating dyslipidemia. How do statins effect LDL, HDL, and TG levels?
A minor side effect is slight hepatic dysfunction.What are two serious, but very rare, side effects?
Statins are contraindicated in what patients?
Decrease LDL and TGs, and increase HDLs.
Two serious side effects are myopathy and rhabdomyolysis.
Contraindicated for pregnant or nursing women.
Statins are reversible, competitive inhibitors of (?), causing reduced hepatic cholesterol synthesis.
How does reduced hepatic cholesterol lead to increased synthesis of LDL-receptors and, ultimately, lower circulating LDL levels?
reduced hepatic cholesterol --> SREBP cleavage --> increased transcription and synthesis of LDL receptors --> reduced LDL levels
There are 7 statin drugs.
Which two have the longest names, longest half-lives, and can be taken once daily?
Which two are lactone prodrugs that must be first modified in the liver?
What are the other three statins?
Longest half-lives: Atorvastatin, Rosuvastatin
Lactone prodrugs: Lovastatin, Simvastatin
Others: Mevastatin, Pravastatin, Fluvastatin
What agent lowers LDL by inhibiting intestinal cholesterol absorption?
Ezetimibe (Use in combo with statin to maximize LDL reduction)