Twenty Five Flashcards
What are LDL and HDL and how do they relate to heart disease?
LDL
• Most of the cholesterol in plasma is carried in low-density
lipoproteins (LDL or LDL-C)
• high plasma concentrations of LDL-cholesterol are associated
with an increased risk of coronary heart disease.
• Oxidized LDL is atherogenic. • Therefore, LDL is often referred to as “bad cholesterol”
HDL
- High-density lipoprotein cholesterol (HDL or HDL-C)
- associated with a reduced risk of coronary heart disease.
Therefore, HDL is often referred to as “good cholesterol”. • The relationships between coronary heart disease and HDL
& LDL are true: – in men and women, – in different racial and ethnic groups, – and at all adult ages.
Describe the two sources of lipids
- Cholesterol is synthesized by the liver – Endogenous
- Cholesterol absorbed from the diet – Exogenous
- Cholesterol absorbed from animal products – meat, fish, egg yolks, cheese
- Plants are not a significant source of dietary cholesterol
• The mechanisms by which cholesterol is transported in the blood differ depending on the cholesterol source
(exogenous/dietary or endogenous)
Describe the control of de novo lipid production in the liver.
The“Sterol regulatory element binding proteins” (SREBPs) – discovery in 1993 was a key event leading to our current understanding of the molecular mechanisms
involved in regulating intracellular levels of lipids
In the presence of sterols, SREBP binds to SCAP (Srebp cleavage activating protein) and INSIG (insulin-induced gene 1) proteins in the ER. INSIG remains in the ER,
serving to prevent activation.
In the absence of sterols, SREBP and SCAP are lysed from INSIG and end up on the golgi apparatus. There, SREBP is cleaved and enters into the nucleus to regulate genes.
Srebp1a/c
Responsible for regulating genes required to make fatty acids
Srebp2
Regulates cholesterol metabolism
sterol-regulatory element binding protein-1a/c (SREBP-1a/c)
- Transcription factor stimulated by insulin, nutrients and sterol depletion.
- “Drives” the expression of the complete lipogenic program in liver.
Describe the concept of Selective Insulin resistance
Concept of “selective insulin resistance” in the liver as a contributor to dyslipidemia in obesity
Normally, insulin, through SREBP1a/c will lead to increased lipid production in the liver. It will also lead to increase glucose absorption and decreased glucose production.
When cells become resistant to glucose, only the glucose pathway is affected. Therefore, there will be more glucose in the bloodstream while b/c of the resistance, and there will still be dyslipidemia due to the lack of resistance in that pathway.
Describe 4 hyperlipoproteinemias.
- Primary familial hypercholesterolemia (heterozygous or homozygous) results from a deficiency in functional LDL receptors that leads to impaired clearance of LDL from plasma and incr. LDL and incr. plasma cholesterol.
- Familial defective apolipoprotein B, results in poor binding of LDL to the LDL receptors also resulting in reduced cholesterol clearance and incr. LDL and incr. plasma cholesterol.
- Polygenic hypercholesterolemia - unknown etiology. Most common – Most likely caused by a combination of genetic defects and environmental influences resulting in an incr. LDL and incr. plasma cholesterol.
• Primary hypertriglyceridemia
– a deficiency of lipoprotein lipase or ↓apo-CII, ↑apo-CIII
• increased chylomicrons in the blood and increased
VLDL secretion by the liver. – This is almost always associated with ↓ HDL.
• also develop early coronary artery disease.
• Nearly 150 LDL mutations have been identified with lipid transport and uptake.
What are some other etiologies of hyperlipidemia?
• Forms of secondary hyperlipidemia result from some
illnesses, drugs or a metabolic disturbance. These hyperlipidemias are associated mainly with:
– diabetes mellitus
– renal and liver disease
• Drugs/substances known to increase endogenous
triglyceride concentration are: – Alcohol, oral estrogens, diuretics, isotretinoin (Accutane®), sertraline (Zoloft®), and beta-adrenergic blocking agents
What are 5 classes of lipid lowering drugs?
- HMG-CoA reductase inhibitors (statins)
- Bile acid-binding resins
- Fibric acid derivatives
- Niacin (nicotinic acid)
- Intestinal cholesterol uptake blockers
What is the mechanism of action of statins? In what patients do they not work as well? Why? What can help?
• Most cholesterol synthesis occurs at night, therefore statins with short half lives (e.g., simvastatin) are given at night time.
• Most cholesterol in the body is endogenous, therefore inhibition of cholesterol synthesis results in reduced levels.
• Reduced cholesterol levels activates SREBP2, which increases expression of the LDL Receptor. LDL and VLDL are then drawn out of the circulation into the liver where cholesterol is reprocessed into bile salts and excreted.
• Competitive inhibitors of HMG-CoA reductase (first committed enzyme of the HMG-CoA reductase pathway)
• Structurally similar to HMG-CoA - take the place of HMG-CoA in the enzyme
• A variety of statins are produced by Penecillium and Aspergillus fungi as secondary metabolites - may function as naturally occurring inhibitors HMG-CoA reductase enzymes in these organisms.
• Statins do not lower LDL levels in LDL receptor-negative,
homozygous familial, hypercholesterolemic subjects.
• Transplantation of a normal liver into these subjects lowers LDL-C levels and statins lead to further reductions in LDL-C.
What is the Pharmacology (Absorption, Fate, Interactions, half-life) of statins?
- High first-pass metabolism by liver (5-20% reach circulation).
- > 95% protein bound.
- Some statins are metabolized mainly by cyp 3A4 in liver – Cyp 3A4 is inhibited by grapefruit juice ↑statin in patient. – Competition by other drugs for cyp 3A4 metabolism ↑statin.
- T1/2 1-4 hours [except atorvastatin with T1/2 of 14 hours and pitavastatin with a T1/2 of 11 hours].
What are the lipid effects of statins?
- Statins decr. LDL (18-55%), incr. HDL (5-15%) and decr. TG (7-30%)
- The improvement in cardiovascular endpoints derived from statin therapy is incompletely explained by changes in LDL-cholesterol (42-47%)*
What are the non-lipid effects of statins?
– Statins stabilize endothelial cell nitric oxide synthase mRNA, reversing atherosclerosis-mediated endothelial cell dysfunction.
– Statins inhibit monocyte infiltration into arterial wall and reduce matrix metalloproteinase secretion.
– They prevent smooth muscle cell proliferation by enhancing apoptotic cell death.
– Statins reduce lipoprotein oxidation by (1) reducing the time LDL stays in the circulation (due to enhanced uptake by LDL receptors) and by (2) increasing the plasma level of an antioxidant enzyme, paraoxonase, associated with HDL.
What are the adverse effects of statins?
• Statins are generally well tolerated.
• Mild GI disturbances, minor muscle pain (myopathy) • 2% of patients develop increased serum transaminase levels indicatingsome liver dysfunction.
• Serious muscle pain with weakness and extensive muscle wasting have been reported in ~0.01-1% of patients with statin drugs (rhabdomyolysis). Most significant, potentially fatal adverse effect.
– Identified by ↑ plasma creatine kinase (CK) levels and lactate dehydrogenase levels.
• Acute pancreatitis*, rare, reversible when statins are stopped.
• Increased risk for type 2 diabetes
What are the drug drug interactions for statins? Which statins are at highest risk? Less risk? Lowest risk? Why?
• In a 2005 study, 7% of patients had a potentially harmful interaction
between a statin and other agents – 70% of the interactions were with inhibitors of CYP 3A4
• Highest Risk – lovastatin and simvastatin – metabolized by gut wall
CYP 3A4
• Relatively low risk – atorvastatin (metabolized by CYP 3A4, but
mostly in the liver – not in gut wall) • Lowest Risk – fluvastatin (metabolized by CYP 2C9) and rosuvastatin,
pravastatin and pitavastatin (mostly conjugated to glucuronide in liver.
Name some bile-acid resins. What are their effects? What is the their mechanism of action?
- The bile acid-binding resins
- cholestyramine (Questran)
- colestipol (Colestid) and
- colesevelam (Welchol)
• All can decr. LDL cholesterol (15-30 %), incr. HDL (3-5 %)
without lowering TG.
- Anion exchange resins that are not absorbed, but stay within the GI tract.
- They exchange a chloride anion for negatively charged bile acids and prevent cholesterol reabsorption by enterohepatic recirculation.
- 97% of bile acids are normally reabsorbed
- Increased hepatic LDL receptor expression and increased HMG-CoA reductase expression due to loss of sterol repression (like statins).
- LDL decreases, but VLDL may increase.
What are some adverse effects of bile-acid resins?
• Cholestyramine and colestipol must be taken orally as a mixture
of the resin in liquid before each meal. The texture is sandy or
gritty in quality.
- Colesevelam is a tablet taken with water.
- Constipation occurs frequently and may be accompanied by
heartburn, nausea, and other GI disturbances.
• Bile acid-binding resins also interfere with absorption of fat-soluble vitamins and fat-soluble drugs – this interference can be minimized by giving other drugs
either 2 hours before or 4 to 6 hours after the bile acid-
binding resin.
• Plasma concentrations of triglycerides may rise.
