Fibric Acid Derivatives
• MOA
• Name them
MOA:
• Act as Ligands to for PPARa nuclear receptor
• PPARa turns on processes that help to get rid of TGs
(increased FA use in muscle, inc. apoA1/2, dec. apo CIII, inc. LDL-R)
Drugs:
• Gemfibrozil
• Fenofibrate
• Fenofibric Acid
**Statins
• MOA
• Name them
Blockage of Cholesterol Synthesis
• Competitive inhibitor of HMG-CoA Reductase
Increased LDL receptors
• causes SREBP to go from ER to Golgi and Finally to act as a transcription factor to up regulate LDLR synthesis
Drugs = Lo-SPAR:
• Lovastatin
• Simvastatin
• Pravastatin
• Atrovastatin
• Rosuvastatin
**Bile Acid Resins
• MOA
• Name them
MOA:
• Anionic ion exchange resins (they are Positively charged)
• Bind up bile acids and prevent recycling
• Cholesterol must then be pulled out of the blood to make new bile acids
Drugs:
• Colestipol
• Cholestyramine
• Coleevelam
**Ezetimibe
• MOA
• Method of administration
MOA:
• Prevents uptake of CHOLESTEROL itself in SMALL INTESTINE and leaves the bile alone
• Decreased Cholesterol uptake cause liver to UPREGULATE LDL Receptors
*Given as a pill
**Niacin
• MOA
• Name them
MOA:
• Reduces Hepatic Triglyceride Synthesis
• Reduces Hepatic ApoB synthesis
• Enhances Macrophage transfer of Cholesterol to HDL
• Promotes VLDL conversion to LDL
Name:
• Niacor - IR
•Niaspan - ER
How much can statins lower LDL compared to other drugs such as Bile acid resins, ezetimibe, or niacin?
Statins lower LDL by 25-60% while other drugs lower it by ~20%
Which statins are acted on by CYP3A4?
• Note any important differences
• Lovastatin
• Simvastatin
• Atorvastatin
**Atorvastatin is also metabolized by ß-oxidation so CYP3A4 interactions typically aren’t an issue
Which statins are the most effective at lowering cholesterol?
- How effective are they?
- What type of patients would you typically give these to?
• Atorvastatin
• Rosuvastastin
*Can give AT LEAST a 50% reduction in cholesterol **Typically given to patients who have lots of risk factors such as those with diabetes or heart disease**
What statin would you consider giving to a patient with renal dysfunction?
• if this drug were not available, what backup would you use?
• Metabolism of these drugs?
Atorvastatin (only 2% renal excretion)
• ß-oxidation and CYP3A4 metabolized
Fluvastatin (only 5% renal excretion)
• CYP2C9, hydoxylation, and ß-oxidation
What statins are acted on by CYP2C9?
Rosuvastatin
• CYP2C9, Fecal excretion
Fluvastatin
• CYP2C9, Hydroxylation, ß-oxidation
Of the statins which are most susceptible to drug-drug interactions and why?
Simvastatin and Lovastatin
• Both are metabolized primarily by CYP3A4
What are some drugs that inhibit CYP3A4?
• Macrolides
• Azole Antifungals
• Calcium Channel Blockers
• Grapefruit
• HIV protease Inhibitors
• Immunosuppressants
What is the risk of Rhabdomyolysis other than severe muscle pain?
• indicators that this is happening
Indicators:
• Very High Levels of CPK
• Tea colored Urine
Risk:
• Myoglobin released from damaged muscle is nephrotoxic and can damage Kidneys
What are some drugs that inhibit p-glycoprotein mediated intestinal reabsorption?
• Cyclosporin
• Grapefruit Juice
What drug should you not use with any of the statins and why?
Gemfibrozil - contraindicated
• Inhibits glucuronyltranserase-1 and glucuronidation used as one of the methods of elimination for almost all of the statins
How does myositis differ from Rhabdomyolysis?
Both result in high CPK and muscle pain, but Rhabdomyolysis is so severe that it can cause increased risk of Renal failure and death
Which of the statins has the lowest risk of drug-drug interactions and why?
Pravistatin
• Eliminated via Sulfation, Oxidation, and Gluroonidation
Lovastatin Simvastatin
• Metabolism
• Systemic Bioavailability
Metabolism
•CYP3A4
• Glucoronidation
Bioavailability:
• 5% (lowest)
Pravastatin
• Metabolism
• Systemic Bioavailability
Metabolism
• Sulfation
• Oxidation
• Glucoronidation
Bioavailability:
• 17%
Fluvastatin
• Metabolism
• Systemic Bioavailability
Metabolism
• CYP2C9
• Hydroxylation
• ß-oxidation
Bioavailability
• 24%
Atorvastatin
• Metabolism
• Systemic Bioavailability
Metabolism
• ß-oxidation
• CYP3A4
• Glucoronidation
Bioavailability
• 14%
Rosuvastatin
• Metabolism
• Systemic Bioavailability
Metabolism
• CYP2C9
• Fecal Excretion
Bioavailability
• 20%
Besides muscle pain what are 4 other side effects of statins?
- Pregnancy Category X
- Sleep Disturbance, Memory Loss, Reduced daytime Vigilance
- Increased Liver Enzymes (rarely Hepatitis)
- Mild GI distress
If a patient has liver disease or another disease where they can’t handle drugs in their system, what options are available to lower their cholesterol?
Bile Acid Sequesterants
• No systemic effect because they never even enter the circulation
How will your lipid profile change after taking a bile acid sequestrant?
• ONLY LDL decreases - there is NO EFFECT ON TRIGLYCERIDES
What are the 3 bile acid sequestering drugs?
• how are they administered?
Colestipol - Powder or Tablet
Cholestyramine - Powder
Colesvelam - Tablet
What are some common adverse effects/down sides of the Bile Acid Sequestrants?
- Gritty Texture
- Constipation, Nausea, Flatulence
• Fecal Impaction
• HYPERtriglyceridemia
What problems do the bile acid sequensterants pose when taking other drugs with them?
• how can this be avoided?
Problems:
• Prevents absorption of other drugs
*take other drugs 1 hour before or 3 to 4 hours after bile sequesterant
What conditions are bile sequestrants contrainidicated with?
• Hypertriglyceridemia
• Complex Drug Regimens
• Hx of Constipation
What is the most common use of Ezetimibe?
• Given along with Statins to achieve extremely low LDL levels required in patients with CV risk factors
What drugs can be given the BOTH LOWER LDL and RAISE HDL?
• Fibric Acid Derivatives (fibrates)
• Nicotinic Acid (niacin)
• Omega-3 (fish oil)
What is the relationship between triglycerides and HDL-C?
Inverse Relationship, if HDL falls then TGs go up and vise vesa
T or F: adding drugs besides Ezetimibe to Statins has proven to be highly effective.
False, using Niacin, Fibrates, or Fish Oil has shown little effect
What group of drugs activates PPARalpha and what is the effect?
• Name drugs
Fibrinates PPARa
• Decreased ApoCIII synthesis
• Increased Apo AI and AII synthesis
• Increased LPL synthesis
Drugs:
• Gemfibrozil
• Fenofibrate
• Fenofibric Acid
How do the Fibrates effect Lipids?
• Adverse effects?
Lipid Effects:
• Reduced TGs up to 50%
- Reduced VLDL, Increased HDL
- LDL relatively unaffected
Adverse Effects:
• GI upset
• Increased Creatinine or Liver enzyme
• Gallstones
Gemfibrozil
• Drug Class
• Metabolism
Drug Class:
• Fibrinates
Metabolism:
• LIVER - (oxidation and glucuronidation by UGTA1) - do not give other drugs that are elminated by glucoronidation (most statins) with this drug
Fenofibrate
• Drug Class
• Metabolism
Drug Class:
• Fibrinates
Metabolism:
• Hepatic to become Fenofibric acid then Renally Excreted
Between the fibrinates which do you think would be safer to give to a patient in renal failure?
• Liver disease?
Best for renal failure:
Gemfibrozil - almost entirely hepatically metabolized
Best for Liver disease:
• Fenofibric acid because it doesn’t have to undergo activation in the liver like fenofibrate
Fenofibric Acid
• Drug Class
• Metabolism
Drug Class:
• Fibrinates
Metabolism:
• Almost Exclusively Renally Excreted
Which of the Fibric Acid derivatives is contraindicated with statins? why?
Gemfibrozil - both gemfibrozil and statins are extensively metabolized in the liver and can lead to inhibition of statin effect
Do fibrinates show a benefit when added to statins?
NO, BUT due to discrepancies in studies it might be worth trying in your own patients to get them to safe cholesterol levels
What are the 2 different preparations of niacin and how should they be administered?
• Dose?
Niacor - (IR) - immediate Release
• must incrementally increase dose over time to minimize flushing
• 6 grams/day
Niaspan - (ER) - Extended Release
• Less Flushing and usually given before bed to minimize flushing
• 1-2 grams/day
What are some adverse side effects of Niacin?
• Cutaneous Flushing
• Elevated Hepatic Enzymes (also caused by statins)
• GI irritation
• Hyperuricemia/Gout
• Dry Skin
• Insulin Resistance
taking niacin with statins does not significantly reduce the risk of a CHD event
taking niacin with statins does not significantly reduce the risk of a CHD event
What are some food sources for Omega-3 and Omega-6 fatty acids?
Omega-3
• Walnuts, Flaxseed, Soybean
• Canola Oil
• Fatty fish
Omega-6
• Corn, Safflower, soybean, sunflower oils
• meat, poultry, and eggs
What is the effect of Omega-3 fatty acids on lipid profile?
- Reduced Plasma Triglycerides
- Little to NO effect on HDL or LDL cholesterol *
*May also have antiplatelet, hypotensive, and hypolidemic effects
Omega-3
• MOA
Increased Fatty acid oxidation via PPARa
PPARa
• Decreased ApoCIII synthesis
• Increased Apo AI and AII synthesis
• Increased LPL synthesis
T or F: statins have a large effect on triglycerides
False
What drugs have a significant effect on triglycerides?
- Niacin
- Fish Oils
- Fibrinates
If someone is under 75 and has known atherosclerotic CV disease what should you prescribe them?
• what is older than 75
- Under 75 - HIGH intensity statins (if no safety concerns)
- Over 75 or have safety concerns - Moderate intensity statin
What is the protocol for treatment of someone with LDL-C level is greater than 190 mg/dl?
- If over 21 = HIGH intensity statin
- Consider adding an additional drug to lower cholesterol
What treatment should you give someone with diabetes and no vascular disease age 40-75 with LDL 70-189 mg/dl?
• High intensity statin if at High (>7.5%) 10 yr risk of CV disease
• Moderate intensity statin if at Lower risk of CV disease
What treatment should you give someone without diabetes or CV disease if they are 40-75 and have LDL 70-189?
- Moderate or High Intensity statin for patients with (>7.5%) 10 yr risk of CV disease
- Moderate intensity statin for patients with (5%-7.4% risk)