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SWG Cardio Exam 1: Lipid Pharmacology (P900/SL)
Terms in this set (68)
Statins are another name for what?
HMG CoA Reductase Inhibitors
RECALL: HMG CoA Reductase catalyzes the conversion of HMG CoA to what?
Mevalonic acid (and ultimately to cholesterol)
TEST: Statins (increase/decrease) free hepatic cholesterol which will (increase/decrease) hepatic LDL receptors. What is the clinincal signficance of this?
Statins DECREASE free HEPATIC cholesterol which will INCREASE LDL receptors (compensatory mechanism)
- By increasing LDL receptors, it removes even more CIRCULATING LDL/cholesterol as a way to replenish the hepatic cholesterol!! So statins are not only inhibiting cholesterol synthesis, but also removing more free cholesterol from the blood!
What is the mechanism of low free cholesterol levels in the hepatocyte leading to an increase in LDL-C receptors?
Activation of SREBP (sterol regulatory element binding protein), which translocates to nucleus to bind to SRE of LDL receptor gene --> increasing txn of LDL receptor
TEST: Statins (increase/decrease) IDL levels. Explain the MOA.
MOA: Since statins increase hepatic LDL receptors, it will also recognize the apoB-100 on IDL and uptake them as well! This decreases circulating IDL levels!
TRUE or FALSE: A decrease in IDL levels contributes to an increase in LDL levels
FALSE! IDL is the precursor to LDL, so if you decrease IDL then you decrease LDL!
TEST: Statins (increase/decrease) VLDL levels. Explain the MOA. VLDLs are rich in what two major lipids?
MOA: The increase in LDL-C receptors caused by statins binds and uptakes more VLDL due to apo E and apoB-100
Also, VLDLs contains a high % of cholesterol, so if you inhibit cholesterol synthesis you also inhibit VLDLs
VLDLs are rich in Cholesterol and TAGs
TEST: Statins (increase/decrease) triacylglycerol (TAG) levels. Explain the MOA.
MOA: Statins decrease secretion of VLDL from the liver (as well as increase their clearance via LDL-C receptors). Since VLDLs are rich in TAGs, their levels go down!
TEST: Statins (increase/decrease) HDL levels. Explain the MOA.
MOA: The function of HDL is to donate Apo (C-II and E) as well as cholesterol esters (CE) to VLDL and LDL. As LDL and VLDL levels decrease, it causes an increase in HDL because it isn't used as much (decreased catabolism)
RECALL: Most of the cholesterol from our diet is (esterified/unesterified), which is (well/poorly) absorbed. On the flip side, the cholesterol made in our liver is (esterified/unesterified) which is (well/poorly) absorbed.
DIET: Mostly ESTERIFIED, POORLY absorbed (so we just excrete it out)
LIVER: Mostly UNESTERIFIED, WELL absorbed (so it can get recycled into the bloodstream or get absorbed by intestine or by peripheral tissues)
TEST/RECAP: List whether statins increase or decrease the circulating levels of:
1) Cholesterol DECREASES
2) LDL DECREASES
3) VLDL DECREASES
4) IDL DECREASES
6) TAGs DECREASES
TEST: When is the recommended time to take statins? Why?
A single dose AT BEDTIME, because cholesterol synthesis is at MAXIMAL RATE between midnight to 2 AM!!
TEST: The main use of statins is for ____________, but it can also act as an anti-_________ by what mechanism?
Main use: For Hypercholesterolemias
Can also act as an ANTI-INFLAMMATORY by inhibiting OXIDATION pathways that contribute to inflammation
TRUE or FALSE: Statins are safe for use during pregnancy. Why or why not?
FALSE! Statins are in the PREGNANCY CATEGORY X, because HMG Coa reductase is involved in guiding migration of primordial germ cells!!
(Not discussed in PPT or Lecture but still salient)
TEST: Most statins are administered as _________ acid form, EXCEPT which two statins? What is the reason for these exceptions?
Most statins are administered as BETA-HYDROXY acid form, except:
Reasoning: These two are actually PRODRUGS that have LACTONE RINGS that will only break once metabolized, which then forms active OH residues.
What mediates the first-pass hepatic uptake of statins?
Organic anion transporter OATP1B1
TEST: All statins have drug-drug interactions with drugs that alter either _________ or ________ activities, EXCEPT which statin and why?
Alter either CYP3A4 or OATP1B1 activities, EXCEPT PRAVASTATIN because it interacts with other drugs with lower magnitude (and subsequently isn't affected by them as much)
TEST: List the 7 statins presented in class
AGAIN: Which two are prodrugs? Which one has less drug-drug interactions?
3) Lovastatin - PRODRUG
5) Simvastatin - PRODRUG
6) Pravastatin - LESS Rx INTERACTIONS
TEST: Which 3 statins are NOT extensively metabolized by CYP3A4?
(Not in Lecture)
The two prodrug statins (are/are not) extensively metabolized by CYP3A4
ARE extensively metabolized by CYP3A4
RECALL: What are some things that alter CYP3A4 activities? Do these things stimulate or inhibit CYP3A4?
GRAPEFRUIT & Pomelos
Itraconazole (conazoles in general)
Ca channel blockers
Nicotinic acid (Niacin)
All of these INHIBITS CYP3A4, thus increasing the amount of statins (which is why you need to decrease the dosage)
TEST: High doses of Simvastatin has been associated with an increased risk of what?
When is it safe to give high doses of Simvastatin then?
Increased risk of MUSCLE INJURY or MYOPATHY (Rhabdomyolysis)
Safe to give for patients that have been taking simvastatin for over 12 months and have never experienced myopathy
TEST: List 5 of the MOST common side effects of statins
1) GI upset
2) Increase in plasma transaminases
3) MYOPATHY (worst case = rhabdo leading to acute renal failure)
4) Tendon rupture (from inhib of MMPs)
Which four statins increase prothrombin time, and by what mechanism?
(Not important for exam)
These all inhibit metabolism of COUMADIN!!
TEST: What is the MOA of bile acid sequestrants?
They are anion exchange resins which bind NEGATIVELY charged bile acids in exchange for CHLORIDE ions, facilitating the EXCRETION of bile acids! (Inhibits reuptake by liver)
TEST: Bile acid sequestrants (increase/decrease) the excretion of bile acids in the gut, which are made of ________. This (increases/decreases) the amount of bile acids being returned to the liver, which will drive (more/less) hepatic cholesterol synthesis. Why?
Bile acid sequestrants INCREASE excretion of bile acids in the gut, which are made of CHOLESTEROL. This DECREASES the amount of bile acids being returned to the liver, which will drive MORE hepatic cholesterol synthesis because cholesterol is a precursor to bile acids!
The liver senses it has low bile acids, so it needs to increase hepatic cholesterol synthesis in order to make MORE BILE!
TEST: Bile acid sequestrants will cause an (increase/decrease) in hepatic LDL receptors, which will in turn (increase/decrease) plasma LDL and cholesterol. How is this important as part of the therapeutic properties of this class of drugs?
Bile acid sequestrants will cause an INCREASE in hepatic LDL receptors, which will in turn DECREASE plasma LDL and cholesterol.
This is important because the hepatic cells replenish their own cholesterol stores by removing cholesterol/LDL from the blood! This decreases the amount of circulating cholesterol/LDL and lowers overall cholesterol levels!
TEST: The therapeutic effect of bile acid sequestrants is counteracted by what? What class of drugs would you give to address this problem and enhance the effectiveness of the bile acid resins?
Counteracted by an upregulation of HMG CoA reductase! This causes increased hepatic cholesterol synthesis, which negates some of the therapeutic effects of bile acid sequestrants!
Therefore, you should add STATINS to it!!!!!
TEST: What are the 3 bile acid sequestrants?
Bile acids (do/do not) have significant systemic side effects. Why or why not?
They DO NOT have significant SYSTEMIC side effects! This is because the bile binding resins are NOT absorbed, but just excreted!!!
However, pts may experience some bloating/abdominal discomfort/constipation
Bile acid sequestrants can often enhance ________, which is why you would want to include ______ when giving these drugs.
Enhance IMPACTION (causing constipation), which is why you would want to include FIBER (or fluids/stool softener) when giving them.
The general rule for taking other drugs with bile acid sequestrants is to take them either ___ hr before or ___ hrs after taking a resin. List some drugs that these bile acid resins interact with (what do they all have in common)?
Take them either ONE hour before or FOUR hours after taking a resin.
Bile acid resins will interact with any CHARGED compounds:
- Thyroxine, digoxin, anticoagulants, thiazides, furosemide, propranolol, tetracyclines, ASA, PRAVA/FLUVA-statin, vitamin C, folic acid
Bile acid resins should be cautioned in patients with ________, why?
In patients with DIABETES, because these resins can INCREASE TRIGLYCERIDES if taken with sulfonylurea or insulin (which diabetics could be taking).
TEST: What are the 3 major MOAs of Nicotinic acid (Niacin)?
1) Upon binding to GPCR (HM74A receptors) on adipocytes, it INHIBITS hormone sensitive lipase (HSL). This DECREASES peripheral TAG catabolism, which leads to DECREASED flux of free fatty acids to the liver --> DECREASED triglycerides and LDL
2) Increases half life of Apo A1, which increases HDL levels
3) Increases the activity of lipoprotein lipase (LPL), which also DECREASES TAGs
RECAP: Niacin decreases the levels of ____ and _______ while increasing the levels of _____.
Niacin decreases the levels of TRIGLYCERIDES and LDL while increasing the levels of HDL.
What are two classes of drugs you can give in combination with Niacin to really increase its LDL lowering effects?
Statins and bile acid resins!!
- Statins decrease hepatic cholesterol synthesis, which increases LDL-C receptors that draw more LDL out of the blood.
- Resins excrete more bile acids, which also triggers an increase in LDL-C receptors in the liver
Niacin is also known as vitamin ___, which is (safe/unsafe) for use in pregnancy if taken as a vitamin.
If taken for hyperlipidemia, it is (safe/unsafe) for pregnancy.
Niacin = Vitamin B3 = SAFE for pregnancy (Category A)
If taken for hyperlipidemia, it is UNSAFE for pregnancy (Category C)
Niacin can either be given as a ______, which the dosage is around 13-20 (mg/grams), or for ___________, which the dosage is around 1-2 (g/grams).
Given either as a VITAMIN, which the dosage is around 13-20 mg
for HYPERLIPIDEMIA, which the dosage is around 1-2 GRAMS two to three times per day
What are two main formulations of niacin? Which one has higher incidences of side effects? How many times a day would you give each formulation?
1) Immediate release - HIGH incidence of flushing, GI issues, and a rise in blood sugar
- Given 3x/day
2) Extended release - LESS side effects
- Given 1x/day
TEST: List at least 4 major side effects of Niacin
1) Vasodilation, leading to headaches/flushing/burning/pruritus, + PALPITATIONS (from REFLEX tachycardia)
2) Hepatotoxicity with high doses (increases AST/ALT levels)
3) Increase in plasma glucose
4) Increase uric acid levels and gout attack
What is the mechanism behind flushing seen in patients on Niacin?
Niacin stimulates HM74A receptors on epidermal Langerhans cells --> increased intracellular Ca --> activation of Ca sensitive PLA2
PLA2 FREES arachnidonic acid, which forms PGs through COX --> increased synthesis of PGD2/E2 --> Acts through Gi coupled receptors --> VASODILATION
What is this, MCBM?
TEST: What drug can you give to help alleviate the flushing caused by Niacin? Why?
Remember, aspirin inhibits COX which will inhibit the rest of the pathway that causes vasodilation!
Niacin Side Effects
- Hepatic Abnormalities (Inc risk of rhabdomyolysis with statins) $$$
- Increase plasma glucose
- Increase uric acid levels
TEST: What is the MOA of fibric acid derivatives, and list the 4 main effects on lipids.
MOA: Binds and activates PPARα
1) Increase LPL transcription (degrades TAGs)
2) Decrease transcription of apo C-III, which is an inhibitor of LPL
3) Increase transcription of VLDL receptor mediated clearance
4) Increase HDL by txn of genes coding for apo A-I and A-II
#1 and 2 leads to decreased TAGs!!
TEST: Stimulation of PPARalpha (increases/decreases) fatty acid oxidation, which reduces the synthesis of _____ in the liver.
What is the effect of this on HDL particles?
INCREASES fatty acid oxidation, reducing the synthesis of TAGs in the liver.
This reduces the TAG content on HDL, which can now bring more cholesterol back from peripheral tissues!
TEST: What are the two fibric acid derivatives? Which one has been used in type III lipoproteinemia?
2) Gemfibrozil - used for type III lipoproteinemia
RECALL: What causes type III lipoproteinemia again?
Abnormal apoE, which increases CM and IDL, which increases TAGs and cholesterol!!
What are some COMMON side effects of fibric acid derivatives?
Myositis FLU-LIKE SYNDROME
Myopathy (rarely rhabdo)
TEST: Name two major drug interactions with Gemfibrozil
1) Decreases hepatic uptake of STATINS (especially simvastatin) by the OATP1B1 pathway
2) Competes with glucoronosyl transferases that also metabolize statins
Directly hinted by Dr. Silverstein during Ischemia Large Group
TEST/TRUE or FALSE: Fenofibrate is safe to use with statins. Why or why not?
TRUE! This is because statins and Fenofibrate are glucoronidated differently
TEST: What is one major cholesterol absorption inhibitor? What is its MOA?
MOA: Selective INHIBITOR of intestinal absorption of cholesterol and phytosterols by:
1) Blocking NPC1L1 receptor, a cholesterol uptake receptor on epithelial cells of duodenum
2) May also block annexin 2 and caveolin that mediates cholesterol absorption elsewhere in gut
TEST: By decreasing cholesterol absorption, there is (more/less) uptake by LDL from the plasma into hepatocytes which leads to an (increased/decreased) plasma LDL.
By decreasing cholesterol absorption, there is MORE uptake by LDL from plasma --> DECREASED plasma LDL
Ezetimibe Side Effects
Allergic rxn in the form of rash or angioedema
TEST: What class of drugs is Lovaza? What is its MOA?
What is another drug in this class?
Omega-3-acid ethyl esters (lipid regulator)
- Another drug is ICOSAPENT ETHYL
MOA: Unclear, but they REDUCE triglyceride biosynthesis and increase fatty acid oxidation in liver
Lovaza is a combination of what two omega 3 fatty acids?
DHA and EPA
What are some side effects of omega-3 acid ethyl esters?
FISHY BURPS, upset stomachs, infection, FLU-like symptoms, altered taste, back pain, skin rash
TEST: What is the only FDA approved use for omega 3 acid ethyl esters?
Lowers VERY high TG levels
TEST: What is one microsomal triglyceride transfer protein inhibitor (MTP)? What is its MOA?
MOA: Directly binds and inhibits MTP, which sits in the lumen of the ER and is responsible for adding apo B to lipoproteins --> DECREASED chylomicrons and VLDL --> DECREASED LDLs
What is the BLACK BOX WARNING for MTP inhibitors?
TEST: What is one oligonucleotide inhibitor? What is its MOA?
MOA: Antisense oligonucleotide that targets the mRNA for B-100, making it prone to DEGRADATION by RNase H. This leads to reduced translation of apoB100.
Recall: apoB100 is an apoprotein added onto LDL and VLDL (plus IDL). So less apo B 100, less of those lipids!!
TEST: What is the indication for Mipomersen?
ADJUNCT to lipid lowering meds and diet in patients with homozygous FH (familial hypercholesterolemia)
The most common side effect of Mipomersen is what? What is the BLACK BOX WARNING associated with this drug?
Most common SE = Pain at injection site
Black box warning = Hepatotoxicity and increased hepatic fat with increasing liver enzymes
What is the the function of PCSK9?
Degradation of LDL receptors
What is the mechanism of PCSK9 inhibitors?
Monoclonal antibodies that bind to PCSK9 and blocks its the degradation of LDL receptors
and when is it indicated? When should it not be prescribed?
Used only as an adjunct to diet and maximally tolerated statin therapy
- Also clinical atherosclerotic CV disease
It SHOULD NOT be prescribed in patients with statin intolerance
What are the PCSK9 Rx?
Major side effects of PCSK9 inhibitors?
Injection site reactions
Which lipid rx are only just adjunctively?
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