Week 2 Lipid Lowering (everything) Flashcards
Lipoprotein classification is based on
relative density
Name the 5 Lipoprotein classes:
- Chylomicrons 2. Very Low-density lipoproteins (VLDL) 3. Intermediate-density Lipoproteins (IDL) 4. Low-Density lipoproteins (LDL) 5. High-Density lipoproteins (HDL)
Exogenous Lipoprotein metabolism
bile emulsifies dietary fats, cholesterol, and lipid soluble vitamins
Endogenous lipoprotein metabolism
hepatic cholesterol synthesis and its distribution to the peripheral tissues
Exogenous pathway small intestines:
bile emulsifies dietary fat and cholesterol
Exogenous Pathway: Pancreas:
lipase excreted by the pancrease Hydrolyzes triglycerides
Exogenous pathway: Intestinal Endothelium
takes up the products (from small intestine and pancreas) by endocytosis and packages lipids into large chylomicrons, which then enter the lymphatic system
Process in which the intestinal endothelium takes up byproducts of SI and pancreas
endocytosis
exogenous pathway after endocytosis, what happens?
lipids are packaged into large chylomicrons and enter the lymphatic system
Exogenous pathway in order: Chylomicrons →
Chylomicrons → travel through thoracic duct → enter blood stream → interaction with lipoprotein lipase (LPL) in vascular endothelial cells → yields glycerol and free fatty acids
these can be utilized by peripheral tissues for fuel or storage
glycerol and free fatty acids
During the Exogenous metabolism pathway, Chlomicrons shrink and become
chylomicron remnants
Chylomicron remnants →
Remnants → transport to liver → taken up by hepatocytes via endocytosis → then hydrolyzed
Endogenous Pathway: What process happens in the liver? Hepatocytes do what?
Hypatocytes synthesize: -Cholesterol -Lipids -Proteins -which are assembled into VLDL and excreted into the blood stream
Endogenous Pathway: Cholesterol, Lipids , and proteins synthesized and assembled into
VLDL (very low density lipoproteins) and excreted into the blood stream
Endogenous Pathway: Endothelial cell LPL hydrolyzes the
fats in VLDL particles -which then shrink form IDL and LDL
Endogenous Pathway: What particles contain most of the cholesterol in the plasma?
LDL particles
Endogenous Pathway: LDL particles are cleared from the blood by
binding to LDL receptors (LDL-R) on hepatocytes
Endogenous Pathway: Essential cofactors of the hydrolysis of VLDL are: (2)
Apoproteins C and E
Endogenous Pathway: Apoproteins C and E are contributed by which particles?
HDL particles
Endogenous Pathway: What also transfers ApoC-II to chylomicrons in the exogenous pathway?
HDL
HDL is also responsible for reverse
reverse cholesterol transport
Explain reverse cholesterol transport:
excess cholesterol is delivered from the peripheral tissues to the liver for excretion in the bile *HDL responsible for this
A minority of lipid disorders arise from:
-genetic defect in lipoprotein metabolism
When may genetic lipoprotein metabolism defects appear?
pediatric or young adults
Familial hypercholesterolemia arises from:
a defect in the gene for LDL-R
In Familial hypercholesterolemia HETERozyogotes for this defect experience accelerated
atherosclerosis *and represent 1 in 500 persons
in Familial hypercholesterolemia, HOMOzygotes are more rare:
- Total LDL cholesterol levels 4 x normal - extreme propensity for Atherosclerosis
- Total LDL cholesterol levels 4 x normal - extreme propensity for Atherosclerosis lipid disorder?
HOMOzyogote familial hypercholesterolemia
atherosclerosis represented in ~ 1 in 500 persons Lipid disorder?
Familial hypercholesterolemia HETERozyogotes
Secondary Causes that hyperlipidemia may arise from include:
- obesity 2. DM 3. Alcohol abuse 4. Hypothyroidism 5. Glucocoriticoid excess 6. Hepatic or Renal Dysfunction
Most cases of hyperlipidemia in adults arise from
combo of: -genetics -environment (poor diet /lack of exercise) -Secondary causes
Elevated LDL is associated with
Increase R/O CV Disease
Elevated HDL reduces:
Reduces risk of atherosclerosis and CV events
How does increased HDL help reduce risk of atherosclerosis and CV events?
HDL is critical in role in reverse cholesterol transport
Decreased plasma concentrations of TOTAL and LDL with medication reduces
the risk of CV events in pts WITH and WITHOUT CAD
Hypertriglyceridemia is known to cause:
pancreatitis
Hypertriglyceridemia has a casual relationship with
atherosclerosis *need to clarify this point in the ppt
Flood, pg 542- the casual relationship of Hypertriglyceridemia to atherosclerosis is less well established
Safety and efficacy of statins
are well established
3-hydroxyl-3-methlyglutaryl coenzyme A reductase [HMG-CoA reductase] inhibitors
AKA Statins
Statin use guidelines are set by:
-American College of Cardiology (ACC) -American Heart Association (AHA)
Statin guidelines no longer recommend:
- target reductions of TOTAL or LDL cholesterol 2. the use of other drugs other than statins
the mainstay of tx for hyperlipidemia
Statins
Table 23-2 Statin Benefit Groups
[add image]
Table 23-3 Drugs for Tx of Hyperlipidemia
[add image]
treatment with statins results in:
↓ LDL by 20% - 60%
↑HDL by 10%
↓ Triglycerides 10% - 20% in statin treated pts
Down and dirty MOA of statins
combined effect of ↓ cholesterol synthesis and ↑ LDL uptake by liver
Statin drugs: examples (6)
- Atorvastatin
- Fluvastatin
- Lovastatin
- Pravastatin
- Simvastatin
- Rosuvastatin
how do statin drugs reduce cardiac events?
- Lowering LDL
- Stabilize existing atherosclerotic plaques
- statis may be pleiotropic (producing more than one effect) including anti-inflammatory, antioxidant and vasodilatory properties
CV uses/considerations for statin drugs
- lowers cardiac events (mortality from MI-CVA-PVD) in pts with or without atherosclerosis
- benefits coronary stenosis (native vessel or graft)
- Acute coronary syndrome
- early initiation follow acute MI is recommended
Atorvastatin, Fluvastatin & Rosuvastatin
•Completely synthetic compounds.
Lovastatin, Simvastatin & Pravastatin either naturally or synthetically originate from what?
- Aspergillus terreus
- lovastatin naturally ocurring
- simvastatin & pravastatin synthetically derived
which statins are pro drugs
Lovastatin, Simvastatin
require metabolism to the open β-hydroxyl acid form to be pharmacologically active
which statins are administerd as active β-hydroxyl acid form
atorvastatin, fluvastatin & pravastatin
what can decrease the absorption of statins
bile acid-binding resins
which statin is efffected by food intake
lovastatin: food intake increases plasma concentrations (has minimal effect on other statins)
which statin is not highly protein bound?
pravastatin
what is unique regarding pravastatins metabolims
•only statin that does not undergo extensive metabolism by Hepatic P450 enzymes
elimination time of statins
except atorvastatin
1 - 4 hours
elimination time of atorvastatin is 14 hours
which statin has the longest elimination time
atorvastatin: 14 hours
what is uniqe about excretion of atorvastatin and fluvastatin
•minimal renal excretion and may not require renal dose adjustments
which 3 statins may need dose adjustments for renal patients
Pravastatin and to a lesser extent Lovastatin and Simvastatin
how long do the pharmacokinetic effects of statins last
•24 hours despite short elimination half-times
what patients would you not expect to be on statins due to a negative characteristic?
Pregnant patients: statins are teratogenic
what is the most common intense side effect of Niacin
intense prostagladin induced cutaneous flushing in 10% of patients
what can be administered 30 minutes before ingestion of niacin to decrease flushing
ASA
larges doses of Niacin produce
Hepatic dysfunction, jaundice
name 3 other seemingly general side effects of niacin
ABD pain, N/V/D, Malaise
in non dibetic patients on niacin what may occur
hyperlycemia and abnormal glucose tolerance
what disease process can be reactivated by niacin
PUD
This patient is complaining of orthrostatic hypotension associated with his antihypertensive drugs and myopathy associated statins.- what drug is he taking
Niacin
how does niacin worsen gout
increased concentrations of uric acid in plasma and increased incidence of gouty arthritis
Lomitapide - experimental and emerging agents- trials in patients with genetic lipid disorders has shown what favorable reductions
LDL and Triglycerides
does omega 3 fatty acids fish oil prevent heart disease
•No evidence prevents heart disease.
omega 3 is what type of fatty acid
unsaturated mega-3 fatty acid
what is the primary effect of omega 3 fatty acids fish oil
•Primary effect of this fatty acid is to decrease plasma concentration of triglycerides. Variable effect on plasma LDL
do we stop fish oil due to caogulation issues prior to surgery
No evidence to support stopping fish oil due to potential coagulation issues
EZETIMIBE
•Relatively new. Selective inhibitor of cholesterol absorption leading to a secondary upregulation of LDL-R
how does ezetimibe inhibit cholesterol absorption
•Cholesterol absorption is inhibited due to the disruption of a complex between annexin-2 and cavolin-1 proteins in the small intestines
LDL and HDL effects of Ezetimibe
- ↓ LDL by 8-22%; Negligible effect on HDL
- Can potentiate effects of statins by 17%
fibrates-Clofibrate: increase in noncardiovascular mortality-due to
due to low plasma cholesterol concentrations
clofibrate: Much of the increased mortality at very low plasma concentrations of cholesterol may be attributable to specific diseases, which decrease cholesterol concentrations…what does this predispose patients to?
which predispose pts to hemorrhagic stroke, particularly when systemic hypertension is present.
what are the most effective drugs for decreasing plasma concentration of triglycerides
FIBRATES
post op when are fibrates restarted
after well hydrated and able to ingest PO meds
name 3 fibrate drugs
- Gemfibrozil
- Fenofibrate
Bezafibrate:
original fibric acid drug, no longer drug of choice d/t concerns of increased noncardiovascular adverse events
Clofibrate
Fibrates provide a dose dependent
what % decrease in plasma triglycerides
what % increase in HDL
effect on LDL
- 40-50% decrease in plasma triglycerides
- 10-35% increase in HDL
- Effect on LDL is variable
gemfibrozil protein binding
elimination half time
% unchanged in the urine
99%
15 hour elimination half time
70% unchanged in urine
which fibrate is a Prodrug
Fenofibrate
fenofibrate- how do we increase absorption
Absorption increased when taken with food.
fenofibrate elimination half time
20hrs
fenofibrate what plasma concentrations increase
Increased plasma concentrations of liver transaminase enzymes are more likely to occur with fenofibrate than other fibrates.
how is fenofibrate hydrolyzed
esterases to active metobolite fenofibric acid
fenofibric acid (active metabolite) is metabolized by
conjugation with glucuronic acid that undergoes extensive renal excretion
fenofibrate most common side effect
Gi upset, abd pain, headache
this medication has increased cholesterol content of bile (lithogenicity) and may increase formation of gallstones
Gemfibrozil: ***test
Gemfibrozil administered with statins (especially lovastatin) have what increased risk
; Increase risk of myopathy and rhabdomyolysis when given with statins especially lovastatin.
gemfibrozil +warfarin=what problem?
Anticoagulant effect of warfarin is potentiated. Prudent to avoid in renal and hepatic disease.
lomitapide side effects
elevated liver enzymes
lomitapide MOA
inhibitor of microsomal triglyceride transfer protein, thought to be important for the production of chylomicrons in the intestine and VLDL by hepatocytes.
mipomersen -experimental and emerging agents- has been recently approved for the treatment of patients with..
homozygous familial hyperlipidemia.
administered via weekly sub q injection - substantial decreases in triglycerides.
Most common complaints with Statin use?
GI, Fatigue, Headache.
Most common and rare side effects with Statin use?
•Range from simple myalgias to myositis with mild creatine kinase (CK) elevation to life-threatening rhabdomyolysis (>10-fold elevation of CK)
What two side effects from Statin use is considered rare?
Myositis and rhabdomyolysis are rare.
What side effect is reported in 1/3 of Statin users?
Myalgias (muscle aches)
What drug is responsible for decreasing cholesterol synthesis and the formation of ubiquinone (coenzyme Q10) which is important for mitochondrial function and cell membrane integrity?
Statins
It is thought that Statins may possibly inhibit HMG-CoA reductase, what would this cause?
Myotoxicity
What are some examples of CYP3A4 inhibitors?
•Coumadin, Protease Inhibitors (HIV), Macrolide Abx, and Azole Antifungals.
What two Statins specifically have myopathy as a frequent side effect?
Simvastatin and Lovastatin
what metabolizes Simvastatin and Lovastatin?
Metabolized by CYP3A4
If Simvastatin and Lovastatin are metabolized by CYP3A4, then if they are given with meds like coumadin, protease inhibitors, Macrolide Abx, and Azole Antifungals, what may happen?
The concentration of Simvastatin or Lovastatin will be higher for a longer amount of time bc the drugs listed to be given with the statins inhibit CYP3A4.
What two statins are Metabolized by CYP2C9 and have lowest rate of events compared to statins metabolized by CYP3A4?
Fluvastatin and rosuvastatin
Have Anesthesia drugs been shown to increase incidence of statin induced myopathy?
No
What medication would you use to treat lipid disorders that have a primarily abnormal increase in plasma LDL cholesterol concentration with a normal or near normal triglyceride level?
Bile acid resins
What drugs are included in the class of Bile acid resins?
- Colesevelam
- Cholestyramine
- Colestipol
Bile acid resins are tolerated well and have a low level of what?
low level of toxicity
What type of cholesterol issues would you have if you were to be placed on a Bile acid resin as treatment?
If you have abnormally high LDL but your triglyceride level is normal.
What form do bile acid resins come in? (liquid, inhaled, powder, shot etc?)
•Are powders and must be rehydrated before ingestion
True or false:
Bile acide resins have systemic absorption?
False, •No systemic absorption of these resins
How do Bile acid resins work?
•Bile acid resins bind bile in the intestine, interrupting enterohepatic circulation and increasing fecal excretion that increase hepatic bile acid synthesis from cholesterol stores.
Based on how Bile acid resins work, what types of cholesterol do they increase and/or decrease?
They increase the production of hepatic LDL-R and increases uptake of LDL cholesterol from the blood, lowering plasma concentrations of LDL. HMG-CoA reductase activity increases as well.
In simple terms what do Bile acid resins do to LDL?
Has the liver take out all the little LDL’s from the blood stream and get rid of em
If Bile acid resins are administerd as a solo therapy they are responsible for two main things?
- decrease plasma concentrations of LDL by 15-30%
- Plasma concentrations of triglycerides may increase 5-20% owing to increased productions of VLDLs.
With the use of Bile acid resins alone, what type of cholesterol level will rise?
•Plasma concentrations of triglycerides may increase 5-20% owing to increased productions of VLDLs.
What are two common complaints with bile acid resins?
Palatability and Constipation
What should you be making sure you have enough of if you are taking bile acid resins?
high fluid intake bc they can cause constipation.
How long before and/ or after the administration of Cholestyramine (bile acid resin) should you give other drugs?
other drugs should be give 1 hour before or 4 hours after the administration of Cholestyramine.
Which Bile acid resin has fewer GI side effects and thus is approved for adolescents with familial hypercholesterolemia?
Colesevelam
What negative ion and absorption issues are associated with the use of Cholestyramine?
a chloride form of an ion exchange resin thus hyperchloremic acidosis can occur especially in younger and smaller pts (where relative doses are larger); Impairs absorption of fat-soluble vitamins and other meds may be impaired;
What is Niacin?
Niacin: Water soluble B complex vitamin that inhibits synthesis of VLDLs in liver
How does Niacin work? (MOA)
Unknown
Even though the MOA of Niacin is unknown, we do know that it works by doing what? (think fatty stuff)
•Niacin inhibits free fatty acids from adipose tissue and increases the activity of lipoprotein lipase
What all in realation to cholesterols does Niacin actually improve?
- Decrease in plasma LDL 15-30%
- Decrease in Triglycerides 20-50%
- Increase in HDL 20-30%
- No change in synthesis of cholesterol
- Does not alter excretion of bile acids
Does Niacin undergo extensive hepatic first pass metabolism?
YES
What body system readily absorbs Niacin?
GI tract
Tell me about the metabolism of Niacin and it’s metabolites?
- Primary Route of Metabolism is Methylation to N-methyl-nicotinamide
- Also undergoes conjugation with glycine to produce nicotinuric acid
what body system is responsable for the elimination of niacin
•Metabolites undergo renal excretion and at high doses, niacin undergoes renal excretion unchanged.
