Cardio Exam 1 (L+S)

Increased LDL + TriG lipoproteins concentrations can lead to

Atherosclerosis / CVD

• Can be reduced w/ lipid lowering drugs

CVD

• LDL: cholesterol rich low-density lipoprotein

• MOST CHOLESTEROL IS CARRIED BY LDL

• ↑ Lipoproteins (LDL/TriG) → leads to atherosclerosis/CVD → leading cause of death

  • Western diet + sedentary lifestyle

Main contributor to lipoprotein abnormalities in western countries?

Diet + sedentary lifestyle (+ genetics)

Lipids

• Insoluble/Hydrophobic sparingly soluble molecules

• Essential for membrane biogenesis & integrity

• Energy source, hormone precursor, and signaling molecule

• Non-polars lipids are packaged inside lipoprotein via blood

What are the seven types of blood lipids?

Transported in lipoprotein complexes (hydrophobic center hides)

• Cholesterol/ Esters

• TriG

• Free fatty acids

• LDL

• HDL

• VLDL

What are plasma lipids transported in?

complexes called lipoproteins

Metabolic disorders that elevate lipoproteins are called

Hyperlipoproteinemia & hyperlipidemia → Dyslipidemia

Dyslipidemia

abnormal function and/or levels of plasma lipids

T/F: Cholesterol is essential for life

True

What is cholesterol produced by?

liver and peripheral tissues

• (ovary, skin, muscle, intestine, and adrenal cortex); can also be obtained through diet

Where is cholesterol mainly exported to?

peripheral tissues and converted to bile acids/salts in the liver

What is high cholesterol one of the major risk factors for?

Coronary artery disease, heart attacks, and strokes

As blood cholesterol ↑ then atherosclerosis will

↑ atherosclerosis risk

What is the ranking of lipoprotein classes, from lowest to highest density?

chylomicrons, VLDL, IDL, LDL, HDL

What is the ranking of lipoprotein classes, from lowest to highest diameter?

HDL, LDL, IDL, VLDL, chylomicrons

What is the relationship between density and diameter of lipoprotein classes?

They are inversely proportional; as density increases, diameter decreases, and vice versa

How is the size of a lipoprotein affected by lipid content?

As lipid content increases, so too does the size/diameter

What is the main component of chylomicrons?

triglycerides

What is the main component of VLDL?

triglycerides

What is the main component of IDL?

triglycerides and cholesterol

What is the main component of LDL?

cholesterol

What is the main component of HDL?

protein

What apoprotein is associated with chylomicrons?

B48

What apoprotein is associated with VLDL?

B100

What apoprotein is associated with IDL?

B100, E

What apoprotein is associated with LDL?

B100

What apoprotein is associated with HDL?

A-I, A-II

What is the normal level of LDL?

What is the normal level of TC?

What is the normal level for HDL?

40-60

What is the normal level for TG?

<150

***>500 → treat TriG

What are some risk factors for hyperlipidemia?

• CHD,

• smoking,

• HTN,

• DM,

• high cholesterol,

• lack of exercise,

• obesity,

• high homocysteine,

• menopause,

• infections/inflammation of artery wall

What lipoproteins are affected in isolated hypercholesterolemias?

LDL

What lipoproteins are affected in isolated hypertriglyceridemias?

VLDL and chylomicrons

What lipoproteins are affected in mixed hypertriglyceridemia and hypercholesterolemia?

VLDL and LDL; can also include IDL

Where are chylomicrons formed?

in the intestine shortly after a meal (disappear after 2 hours)

What do chylomicrons do?

transport fat from small intestine →

to adipose tissue, liver, and muscle cells

• Richest in TG

Where are VLDL produced?

liver

• composed of TG & cholesterol (w/ little proteins)

What do VLDL do?

Carry newly synthesized TG from liver to adipose and peripheral tissues

How are LDL formed?

from catabolism of VLDL

What portion of LDL receptors are located on hepatocytes (in the liver)?

2/3

• responsible for removing ~70% of LDL from plasma

LDL deposits what and where?

deposits cholesterol on artery wall → Increased can lead to atherosclerosis and CHD

Atherosclerosis is a disease of:

the arteries characterized by the deposition of plaques of fatty material on their inner walls

Macrophages can engulf what?

oxidized LDL

Scavenger receptor

a protein on the surface of macrophages that binds to oxidized LDL cholesterol and allows it to be taken up by the cell lysosome

What is the site of action of statins?

HMG-CoA reductase in the liver

• competitively inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis

What is the MOA of statins?

Inhibition of HMG-CoA reductase, which decreases cholesterol, leading to up-regulation of LDL receptors through SREBP expression

• ↓ LDL (18-60%)

  • LDL is ↓ by 6% w/ each doubling dose

• ↓ TG (7-30%)

• ↑ HDL (5-15%)

• ✓ ↓ CV events

What are some additional effects of statins?

• decreased coagulation,

• decreased inflammation, and

• decreased acute-phase reactants (C-reactive protein)

Which statins are prodrugs?

lovastatin and simvastatin

• need to be transformed in the liver to B-hydroxy acid forms

Which statins don’t have active metabolites?

pravastatin and Fluvastatin

Which statins are eliminated by CYP3A4?

• atorvastatin

• lovastatin

• simvastatin

Fluvastatin is metabolized by:

• CYP2C9

• Small amount of CYP2C8

How should statins be taken?

Due to short half-life, they should be given in the evening (besides rosuvastatin and atorvastatin)

• Peak plasma concentration 1-4hr after ingestion

When is cholesterol synthesis at maximum?

Between midnight and 2 AM

T/F - It is standard protocol to initiate statin therapy immediately after MI

True

What groups should not take statin medications?

Pregnant women, those lactating or likely to become pregnant; those with liver disease → teratogenic

What are some adverse effects of statins?

• hepatotoxicities, myopathy/rhabdomyolysis,

• myalgias,

• myositis,

• increased risk of diabetes, and

• increased liver transaminases

What are some drug interactions with statins?

• Drugs that inhibit or compete for/induce CYP3A4 or CYP2C9;

  • grapefruit juice;

• cyclosporine,

• gemfibrozil,

  • OATP1B1 inhibited → increases concentration of statins which can increase myopathy severity

• amiodarone, and verapamil

  • Increased risk of myopathy

Counseling Pearls for Statins

• Take w/ food

• Take a night (except atorvastatin & rosuvastatin)

• Watch for muscle pains/weakness

Brand name for Lovastatin

Altoprev + Mevacor

Brand name for Pravastatin

Pravachol

• metabolized by non-P450 pathways

Brand name for atorvastatin

Lipitor

• SE allergic reaction - hives, difficulty breathing, swelling of face

• Long acting statin (14 hrs)

Brand name for simvastatin

Zocor

Brand name for Fluvastatin

Lescol

Brand name for Rosuvastatin

Crestor

Brand name for Pitavastatin

Livalo

How can you measure rhabdo s/e from statin?

measure the serum creatine kinase

What is the site of action of bile acid sequestrants?

intestinal lumen

What is the MOA of bile acid sequestrants?

Binds to bile acids in the intestinal lumen and prevents reabsorption → Upregulation of LDL receptors + decrease hepatic cholesterol content

When would you want to use a bile acid sequestrant?

If a patient has an isolated increase in LDL

Bile Acid Sequestrant Drugs

• Cholestyramine (Questran)

• Colestipol (Colestid)

• Colesevelam (WelChol)

Brand name for Cholestyramine

Questran + Prevalite

Brand name for Colestipol

Colestid

Brand name for Colesevelam

WelChol

What is a contraindication of cholestyramine?

homozygous familial hypercholesterolemia

• Lack LDL-R & PCSK9/apoB

• Worse & rare

What are some adverse effects of cholestyramine?

constipation,

bloating,

bad taste,

cholesterol gallstones

What are some drug interactions that can occur with cholestyramine?

• Delayed/reduced absorption of concomitant oral medications

  • like warfarin,

  • thiazide diuretics,

  • thyroxine,

  • beta-blockers, etc.;

• can also interfere with digestion and absorption of fat-soluble vitamins (A, D, E, and K)

Colesvelam vs cholestyramine

• Colesvelam has less GI effects

  • More specificity to bile acid

  • More hydrophobic

What is the site of action of niacin?

adipose tissue and liver

Niacin Drugs

• Niacin (Nicotinic Acid + Niaspan)

What is the MOA of niacin?

inhibits lipolysis in adipose tissue and inhibits transport of FFA to the liver

• Decreases hepatic TG synthesis

• Inhibits VLDL secretion from hepatocytes

• Decrease LCL production

What are some indications for niacin?

• Increasing HDL

• Heterozygous familiar hypercholesterolemia

• Severe mixed lipidemia

• Combined hyperlipoproteinemia

What are some contraindications for niacin?

acanthosis nigricans due to insulin resistance, liver disease, gout, and cardiac arrhythmias, diabetes

What are some adverse effects of niacin?

• flushing, tachyphylaxis, carbohydrate tolerance may be impaired, and nausea/abdominal discomfort,

• hepatotoxicity and

• increased uric acid levels

• increase glucose

What are some drug interactions with niacin?

Potentiation of antihypertensives and interference with absorption/effectiveness of tetracycline

Counseling Pearls of Niacin

• Take w/ food

• To decrease flushing take w/ ASA or ibuprofen

What is the site of action of fibrates?

Muscle and adipose tissue

What is the MOA of fibrates?

activates nuclear transcription receptor PPAR-alpha, which increases LPL, increasing removal of TBs from plasma and breakdown to fatty acids

• Decreases TG

• Increases HDL

• Decreases LDL

Fibrate Drugs

• Fenofibrate (Tricor + Trilipix)

• Gemfibrozil (Lopid)

Brand name for fenofibrate

• Prodrug

Tricor & Trilipix

Brand name for Gemfibrozil

• Active

Lopid

When would you use a fibrate?

In hypertriglyceridemia in which VLDL predominates and in dysbetalipoproteinemia, and in treatment of hypertriglyceridemia resulting from treatment with viral protease inhibitors

• TG > 500 - can lead to acute pancreatitis

What are some contraindications of fibrates?

hepatic/renal dysfunction and patients with biliary tract disease

What are some adverse effects of fibrates?

arrhythmias, hypokalemia, high aminotransferase or alkaline phosphatase levels (increased LFTs); cholesterol precipitation/gallstones

What are some drug interactions with fibrates?

increased effect of coumarin anticoagulant

• Warfarin - increased bleeding

Which fibrate has increase risk of myopathy w/ statins?

Gemfibrozil

Fibrate Structure

Isobutyrate

• Target PPARa

What is the site of action of ezetimibe?

intestinal lumen

What is the MOA of ezetimibe?

inhibits the absorption of cholesterol by enterocytes by inhibiting transport protein NPC1L1; has a synergistic effect on LDL when combined with statins

• ↓ LDL (18-20%)

• ↓ TG (5%)

• ↑ HDL (3%)

• ✓ ↓ CV events

What are some adverse effects of ezetimibe?

hepatic impairment,

increase in liver transaminases and

diarrhea