antihyperlipidemic agents
Terms
undefined, object
copy deck
- LDL contains high levels of ___ which readily deposits in the subendothelial space of arteries. Chylomicrons & VLDL cannot, although VLDL gives rise to ILD which can.
- Cholesterol
- high LDL increases the incidence of adverse events associated with coronary artery disease whereas ___ is antiatherogenic by removing free cholesterol generated from the metabolism of chylomicrons & VLDL.
- HDL
- “STATINS†are __________
- HMG CoA REDUCTASE INHIBITORS (HMG = 3-hydroxy-3-methylglutarate) –
- Statins inhibit the conversion of HMG CoA to _________, the rate-limiting step in the synthesis of cholesterol. Cholesterol synthesis is, therefore, decreased.
- mevalonic acid
- Statins are heavily extracted by the _____.
- liver
- Peripheral levels are very low. Therefore, their effect is predominantly on __________.
- hepatocytes
- As hepatocyte cholesterol synthesis decreases, the number of LDL receptors __________.
- decreases
- WHAT IS THE CLINICAL SIGNIFICANCE OF THIS?
- -
- Macrophages can also take up LDL that contains acetylated or oxidized ____.
- apoB-100
- Excessive uptake by macrophages of modified (acetylated or oxidized) LDL transforms macrophages into ______.
- FOAM CELLS
- STATINS also decrease ___ b/c they also contain apoB-100 which is recognized by LDL receptors and is internalized by hepatocytes.
- IDL
- The decrease in IDLs CONTRIBUTE TO THE decrease IN PLASMA LDL? WHY?
- --
- Hepatic synthesis of _____ is also decreased.
- apoB-100
- WHY IS decrease of Hepatic synthesis of apoB-100 THIS IMPORTANT?
- -
- Cholesterol contains high levels of ___ which readily deposits in the subendothelial space of arteries. Chylomicrons & VLDL cannot, although VLDL gives rise to ILD which can.
- LDL
- VLDL is composed mainly of _________.
- triacylglycerol
- With statins, triglyceride levels decrease _____ .
- 10-30%
- With statins, HDL levels increase _____.
- 5-10%
- WHY do HDL levels rise.
- HDL donates cholesterol exters to other lipoP (i.e. LDL & IDL) ; in the process of doing that it gets modified so that it is no longer a HDL. when we decrease the LDLs to donate to, less HDL is modified.
- The increase in HDL removes more free unesterified _______ from extrahepatic tissues which contributes to the decrease in plasma cholesterol.
- cholesterol
- All STATINS are therapeutically ____.
- equal
- Significant effects occur in ___ wks with maximal effects in ___ wks.
-
1-2
4-6 - Recommend giving statins as a single daily dose at _____ .
- bedtime
- WHY?
- Has to do with when most cholesterol synthesis takes place – in the evening
- Statins are used for a wide variety of __________
- hypercholesterolemia
- STATINS have anti-inflammatory activity as assessed by ____________ levels which are ↑ during systemic inflammation, a part of the atherosclerotic process.
- C REACTIVE PROTEIN
- High levels of C REACTIVE PROTEIN are associated with _____ survival rates
- lower
- MECHANISM
- Statins inhibit various oxidation pathways (anti-oxidant). CRP is an end product of oxidation & inflammation. Statins have an anti-inflamatory effect reduces risk of CV dz.
- STATINS are in PREGNANCY CATEGORY X: which means:
- Documented fetal abnormalities in animals or humans or evidence of fetal risk in humans. Risk outweighs benefits.
-
-ProRx
-Metabolized by cyp 3A4. avoid grapefruit juice. Macrolides ( erythromycin, clorithromicin, azythromicin, derithromycin), itroconasole( conazoles are anti fungals) increase risk of rabdomyolisis. - LOVASTATIN (Mevacor)
- SIMVASTATIN (Zocor)
- proRx
- low protein binding results in short half life (2hrs)
- PRAVASTATIN (Pravachol)
- FLUVASTATIN (Lescol)
- -
- longest acting.
- ATORVASTATIN (Lipitor)
- atorvastatin + amlodipine =
- CADUET
- WHAT IS AMLODIPINE?
- Ca++ channel blocker (CCB), treat arrhytmia’s and HTN
- decreases LDLc 46-55%
- ROSUVASTATIN (Crestor) -
- All STATINS decrease LDL decrease 25% (rosuvastatin more). For a greater effect, higher doses of _____ or _____ are recommended.
-
LOVASTATIN
SIMVASTATIN - WHY NOT USE HIGHER DOSES OF THE OTHER RXS?
- prodrug activated in the liver where it is used
- One of the SIDE EFFECTS of Statins is an ______ in plasma transaminases > 3 times the upper limit of normal. Incidence: 1-2%.
- increase
- Significance of increase in plasma transaminases is ______ damage?
- liver
- Another SIDE EFFECTS of Statins is _________– transient increase in CK-MM. Muscle tenderness, pain, weakness.
- MYOPATHY
- _______ dysfunction increases risk of rhabdomyolysis.
- Renal
- Also with Statins there have been reports of a _____ like syndrome
- lupus
- OTHER POTENTIAL USES of these two statins is to decrease the Risk of Alzheimer’s & dementias & depression.
- (pravastatin & lovastatin but not simvastatin)
- statins can also ↓ ____ in patients w/ or w/o decreasing cholesterol.
- BP
- statins may also ↓ the risk of ____.
- glaucoma
- Risk of myopathy increases in patients on ______,______ , _______, ________, & _______. Can take together if you decrease the dose of the statin.
-
cyclosporine
erythromycin
itraconazole
gemfibrozil
nicotinic acid - lovastatin & simvastatin potentiate _______ actions through an unknown mechanism, resulting in increased prothrombin time (PT).
- coumarin's
- BILE ACID SEQUESTRANTS are used Mostly for Types ___ & ____ hyperlipidemias.
-
IIa
IIb - BILE ACID SEQUESTRANTS, have Little effect on patients ________ for type IIa. These patients do not have ___ receptors.
-
homozygous
LDL - BILE ACID SEQUESTRANTS MECHANISM:
- Not absorbed systemically, action is totally in the gut—Anion exhange resin- exchange Cl- for bile acids, not absorbed so is excreted-> increased excretion of bile acids.
- WHY IS THIS IMPORTANT?
- Bile acids contain large amount of cholesterol
- WHAT DOES THIS DO TO THE LEVELS OF HEPATOCYTE CHOLESTEROL?
- Goes down—set in motion all the events previously discussed—sucks up LDL from plasma , LDL receptors go up in liver- so liver grabs the LDL when it sees apo B100
- HOW WILL HEPATOCYTES REPLACE THE BILE ACIDS?
- Make more; needs more cholesterol from plasma, LDL receptors increase on hepatocytes-
- FROM WHERE WILL HEPATOCYTES GET CHOLESTEROL?
- -plasma
- WHAT HAPPENS TO THE # OF LDL RECEPTORS? WHY?
-
-
Increase, low chol levels in hepatocytes, genes transcribe LDL receptors, so grabs apo 100 on LDL, to break down and make more bile acids. - BILE ACID SEQUESTRANTS result in a ____ drop in LDL in 1st wk with maximal effects in ~ 2 wks. HDL rises only _____.
-
10-35%
~5% - powder to mix in H20 or juice
- CHOLESTYRAMINE (Questran)
- granules & tablets
- CHOLESTIPOL (Colestid)
- tablets
- COLESEVELAM (Welchol
- SIDE EFFECTS of BILE ACID SEQUESTRANTS
- Not absorbed. No significant systemic effects
- WHAT KIND OF SIDE EFFECTS WOULD YOU EXPECT?
- -GI ( remains in gut)—bloating, cramps, constipation
- Constipation can persist resulting in _______
- impaction
- BILE ACID SEQUESTRANTS, can bind _______ charged compounds e.g. thyroxine, digoxin, anticoagulants, thiazides, furosemide, propranolol, tetracyclines, gemfibrozil, pravastatin, fluvastatin, ASA, phenobarbital
- negatively
- BILE ACID SEQUESTRANTS can decrease Absorption of ___ soluble vitamins (A,D,E,K)
- fat
- _______ and ______ absorption are also decreased.
-
Vitamin C
folic acid - TAKE ALL OTHER RXS ___ HR BEFORE OR ___ HRS AFTER TAKING A RESIN
-
ONE
4 - NICOTINIC ACID = ____
- NIACIN
- NIACIN USES are TYPES __,__,__,__ hyperlipidemias
- II, III, IV, V
- NICOTINIC ACID MECHANISM
- inhibits hormone sensitive lipase (HSL) that normally mobilizes the stored fats. Decrease mobilization of peripheral fat stores
- Inhibition of hormone sensitive lipase (HSL) decreases the delivery of FFAs to the liver which decreases the synthesis of ____ & ____. Lower levels of VLDL -> lower levels of LDL. HDL is increased (mechanism unclear).
-
VLDL
TGs - ** NIACIN is the only Rx that will decrease ______
- Lp(a)
- 50% of patients on niacin experience vasodilation -> intense ______ & ______ involving face & upper body.
-
flushing
pruritus - vasodialation might be accompanied by _______, due to baroreptor response to decrease in BP
- palpitations
- Taking _____ 30 minutes before or _______ 1 x/day has prevented these symptoms in some patients.
-
ASA
IBUPROFEN - Niacin can also cause _____ abnormalities --chronic high doses or sustained release preps can increase serum transaminases (AST/ALT).
- Hepatic
- Niacin can also cause an increase in plasma glucose – caution if patient is ______
- diabetic
- Niacin can also cause an increase in uric acid levels -> can increase risk of _____ attack
- gout
- Niacin is also ssociated with abdominal ________
- malignancy
- Niacin is contraindicated if pt has a Hx of ________ - can precipitate an attack.
- peptic ulcers
- When used with a STATIN, niacin can increase the risk of _______
- rhabdomyolysis
- FORMULATIONS of niacin are available ____. Higher doses of some may a require prescription.
- OTC
- This formulation is absorbed over 1-2 hrs. Given t.i.d.. High incidence of flushing, GI side effects and increase blood sugar.
- Immediate release
- This formulation is absorbed over 12+ hrs. Given 1x/day. Less flushing but increase risk of hepatotoxicity
- Sustained release
- This formulation is absorbed over 8-12 hrs. Given 1x/day. Less flushing and GI side effects w/o increase risk of hepatotoxicity.
- Extended release
- when giving niacin always get BASELINE ______, _____ , _______& ______
-
LIVER FUNCTION TESTS
GLUCOSE
URIC ACID
LIPID LEVELS - NIACIN + LOVASTATIN=
- ADVICOR
- In FIBRIC ACID DERIVATIVES the MECHANISM is to activate _________ that increases transcription of ___ & decreases transcription of apoC-III, an inhibitor of LPL.
-
peroxisome proliferator-activated receptor α (PPARα)
LPL - FIBRIC ACID DERIVATIVES ↑ LPL activity -> increase hydrolysis of ____ -> decrease in VLDL.
- TGs
- FIBRIC ACID DERIVATIVES ↑ HDL by increasing transcription of genes coding for apo ___ & ___ which are major apoproteins in HDL.
-
AI
AII - FIBRIC ACID DERIVATIVES also decrease levels of plasma _______ causing a decrease in platelet aggregation. This "might" have beneficial effects on the CV system. The mechanism for this effect is unclear.
- fibrinogen
- This FIBRIC ACID DERIVATIVE is for Types IV & V. It decreases LDL, VLDL & TGs
- FENOFIBRATE (Tricor)
- This FIBRIC ACID DERIVATIVE is Preferred for Type III (familial dysbetalipoproteinemia) in which there is a mutant apoE causing an increase in IDL which, in turn, increases TG & cholesterol.
- GEMFIBROZIL (Lopid)
- SIDE EFFECTS of FIBRIC ACID DERIVATIVEs are that a ______-______ SYNDROME can occur
- MYOSITIS-FLULIKE
- This CHOLESTEROL ABSORPTION INHIBITOR, Inhibits absorption of LDL and some TGs. CAUTION: Possible allergic reaction in the form of a rash or angioedema.
- EZETIMIBE (Zetia)
- EZETIMIBE + SIMVASTATIN =
- VYTORIN