Antilipemics Flashcards
What are Lipids?
Fat soluble substance present throughout the body, many of which are necessary for normal function Cholesterol Fatty Acids/Triglycerides Glycerophospholipids Eicosanoids Bile salts Steroid hormones Fat-soluble vitamins
What is cholesterol?
The primary structural compound of cell membranes,
Precursor to bile salts and steroid hormones
What are fatty acids/triglycerides?
lipid fuel source
What are glycerophospholipids/sphingolipids?
They create the hydrophobic barrier between water and cholesterol, found at the edges of cell membranes
What are eicosanoids?
prostaglandin precursors that regulate numerous body processes
What is the action of bile salts?
to emulsify dietary fat
What are the steroid hormones?
glucocorticoids
mineralocorticoids
sex hormones
What are the fat soluble vitamins?
ADEK- important for vision, growth, clotting, prevention of oxidative damage
What is the process of triglyceride (triacylglycerol) ingestion?
Fats are ingested => emulsified by bile salts in sm intestine and broken down by lipase => 2 monoacylglycerols and FFA => packaged into micelles and absorbed by intestinal epithelial cells => recombined as TGs =>packaged with proteins and phospholipids into chylomicrons (now water soluble) => chylomicrons ejected into lymphatic system => thoracic duct leads to bloodstream => HDL transfers proteins to chylomicrons (gives purpose and destination) => reaches target tissue and digested in BM by lipoprotein lipase (LPL) => FFAs released to be stored (adipose) or oxidized as energy (muscle) => chylomicron remnants travel back to bind to hepatocyte receptors => degraded and recycled
What is the process of cholesterol ingestion?
Similar to TGs: Dietary cholesterol => combines with bile salts in the gut =>bile salt micelles =>micelles absorbed into intestinal epithelial cells =>packaged into chylomicron to travel through plasma =>cholesterol portion of chylomicron travel back to bind to hepatocyte receptors => enter free cholesterol pool =>increase in pool inhibits cholesterol synthesis by liver
What is the process of fatty acid synthesis?
Synthesized in liver with dietary glucose as main precursor: Dietary sucrose broken down in gut by alpha glucosidase => glucose and fructose => glycolysis produces pyruvate => converted to TGs => TGs packaged with apoproteins, phospholipids, and cholesterol => VLDL (water soluble) => VLDL secreted into blood stream => proteins transferred from HDL to VLDL => LPL in basement membrane of capillaries digest TGs/FFAs in VLDL => FFAs stored or oxidized
What is the process of cholesterol synthesis?
synthesized in most body cells, esp. liver and intestine, Acetyl CoA as precursor: 2 Acetyl CoAs combine with third to form HMG-CoA using HMG-CoA Syntase => HMG-CoA reductase pathway creates cholesterol => cholesterol packaged with TGs and proteins to form VLDL => LPL digests TGs, making VLDL more dense (IDL) => IDLs are unstable and become LDL => LDL returns to liver and take up by hepatocyte LDL receptors => cholesterol is recycled into free cholesterol pool
How is the hepatic cholesterol pool maintained?
- Ingested cholesterol => chylomicron remnant
- Synthesized cholesterol => LDL- regulated by LDL receptors
- Intracellular synthesis => HMG-CoA reductase pathway (most important)
Large cholesterol pool => decreased LDL receptors => increased LDL in circulation=> decreased synthesis of HMG-CoA reductase =>low cholesterol in pool => increased LDL receptors => increased HMG-CoA reductase
What is a chylomicron?
water soluble transport for ingested lipids
What is VLDL?
water soluble transport for synthesized lipids (esp. TGs)
What is IDL?
unstable result of VLDL breakdown
What is LDL?
IDL breakdown (fewer TGs)
What does HDL do?
From the liver and gut, it is secreted into blood where it interacts with chylomicrons and VLDL, dropping off apoE and apoCII
HDL picks up cholesterol from the cell membrane and transports it to the hepatic cholesterol pool
What are Bile Acids?
produced in liver, stored in gall bladder
synthesized from cholesterol
released into gut after a meal to digest dietary lipids (emulsification)
95% of bile acids are reabsorbed and recycled
What are lipids role in Atherosclerosis?
1) Some LDLs are oxidized by free radicals
2) macrophages consume oxidized LDLs
3) Macrophages become engorged as ‘foam cell’
4) Foam cells accumulate in blood vessels as fatty streaks
5) Atherosclerotic plaque forms
6) Plaque calcifies, narrowing vessel lumen
What is the mechanism of action of HMG-CoA reductase inhibitors?
“Statins” suppress hepatic synthesis of cholesterol, decreasing LDL by up to 60% and modestly decreasing TGs and increasing HDL
1) Inhibit conversion of HMG-CoA to form cholesterol
2) Increases LDL receptor on hepatocytes
3) Increases LDL endocytosis
4) Decreases circulating LDLs
What are the adverse effects of statins?
myositistis, myalgia, myopathy (most common)
rhabdomyolisis
dyspepsia, diarrhea, flatulence
headache
Contraindications- Liver disease and pregnancy/lactation
What drug interactions are associated with statins?
Potentiates Coumadin
Bile Acid Binders decrease availability of Statins
Ace inhibitors with Statins => Hyperkalemia
Consider CYP450- Simvastatin, Atrovastatin, Lovastatin, Corivastatin (CYP3A4)
What Labs should be evaluated with Statins
LFTs @ start of treatment
ACC/AHA Guidelines for treatment of blood cholesterol
1) Age 21-75 with ASCVD- high intensity statin;
>75 yrs or not tolerating high intens.- mod. intensity
2) >40 yrs, with LDL >190- high intensity
3) 40-75 yrs with DM- mod. intensity; with ASCVD>7.5%- high
4) 40-75 yrs with 10 yr pooled risk >7.5- mod-high intens.
High intensity Statins
> 50% LDL reduction
Atorvastatin 40-80 mg daily
Rosuvastatin 20-40 mg daily
Moderate intensity Statins
30-49% LDL reduction Atorvastatin 10-20 mg daily Rosuvastatin 10-20 mg daily Simvastatin 20-40 mg daily Pravastatin 40-80 mg daily Lovastatin 40 mg daily
Low Intensity Statins
<30% reduction (no role in guidelines for these)
Pravastatin 10-20 mg
Lovastatin 20 mg
What benefits do Statins have beyond LDL reduction?
Pleiotropic effects: improved endothelial cell function antioxidant properties stop atheroma development, stabilize plaques inhibit inflammatory response antithrombic effects
Cholesterol Absorption Inhibitors
Ezetamibe (Zetia)- add if Statin not effective (LDL >70)
Action- Complexes with bile salts and blocks absorption of cholesterol in duodenum => decrease stores in free cholesterol pool => LDL receptors upregulated => plasma clearance of LDL up to 25%
PCSK9 Inhibitors
Alirocumab (Prament); Evolocumab (Repatha)
Action- Block PCSK9 protein (which typically interferes with function of LDL receptors to prevent overwork) from binding to LDL receptors => LDL receptors continue to remove LDL from circulation =>additional 50-60% reduction
Very expensive- often only used if on max statins and Zetia
Adverse effects- minor hypersensitivity, URI sx, back pain
Omega-3-acid ethyl esters
Icosapent ethyl (Vascepa)
Action- decreases hepatic synthesis of VLDL and enhances LPL to improve VLDL clearance, demonstrates CV risk reduction
Indicated for severe hypertriglyceridemia (>500) or <135 on statins
Fibric Acid derivitives
Gemfibrozil (Lopid), Fenofibrate (Tricor), Fenofibric Acid (Trilipix)
Trilipix only one indicated for admin with Statins
Action- Increases activity of LPL and endothelial receptor production of LPL => increased catabolism of VLDL and TGs => decreased TGs; blocks lipolysis of TGs in adipose tissue
Adverse Effects: cholelithiasis, dyspepsia/diarrhea, myositis, LFT abnormalities, HA/dizziness, impotence
Labs: Liver and renal function @ start, may decrease glucose and uric acid
Welchol
Bile Acid Sequestrant
- Action- binds bile acids in gut and interrupts reabsorption => more bile acids produced in liver => Increased LDL receptors => increase LDL absorption
- treats hyperlipidemia
- Often also used to treat diarrhea
- Adverse effects: (d/t binding) constipation, GI irritation/bleeding, LFTs abnormal, bile duct obstruction, increase TGs
- Drug interactions- decreases absorption of fat soluble vitamins, oral anticoagulants, digoxin, PCN, theyroid hormone, tetracyclines, iron salts
