04.06 - Elam Flashcards Preview

Cardio > 04.06 - Elam > Flashcards

Flashcards in 04.06 - Elam Deck (55)
Loading flashcards...

Why do lipid soluble statins have increased risk of adverse effects? Which ones?

- Because they penetrate muscle 

- Simvastatin, Lovastatin 


Why is it good that statins are metabolized in the liver?

- This is also the site of action of statins, so very little statin ever leaves the liver, making these drugs pretty safe under normal circumstances 

- Dangerous at periphery -> myositis 



Why is the OATP transporter important for statin metabolism?

Primary method of liver uptake of statins



How dose renal insufficiency affect statin tx?

- Should reduce dosage in pts with renal insufficiency

- EXCEPT Atorvastatin, which is primarily secreted by fecal mechanisms 


What are the bile acid sequestrants?

- Anionic (+ charge) ion exchange resins: interrupt enterohepatic recycling of cholesterol by binding (-) charged bile acids in the gut

- Among the oldest (and safest) hypolipidemic drugs

- Non-systemic (not absorbed from intestine), so can be safely used in children, pts with liver disease

- Available in both powder and pill formulations

- Lowers LDL-cholesterol by up to 25% at max doses

- Modest effect on HDL-C, but does NOT decrease TGs (may increase)

- GI side effects (bloating, constipation) can limit use


Which bile acid sequestrants are given only as a tablet, only as a powder, or both?

- Only tablet: Colesevelam (should be taken w/liquid)

- Only powder: Cholestyramine 

- Both: Colestipol (powder should be mixed with OJ or applesauce)


What are the common AE's of bile acid sequestrants?

- Gritty texture (slurried powder, “sand”)

- GI: bloating, nausea, flatulence, constipation (premix-refrigerate), fecal impaction (take with water!)

- Paradoxical hypertriglyceridemia 


What are the drug interactions and contraindications for the bile acid sequestrants?

- Drug interactions:

1. Prevents absorption of other drugs: digoxin, b-blockers, thyroxine, Warfarin

2. Take other meds 1 hour before or 3-4 hours after bile acid sequestrant

- Contraindications:

1. Hypertriglyceridemia

2. Complex drug regimens, critical meds

3. History of constipation (elderly patients) 


What drugs lower TG's and raise HDL?

- Fibric Acid Derivatives (Fibrates)

- Nicotinic Acid (Niacin)

- Omega-3 Polyunsaturated fatty acids (Fish Oil) 


What are the fibric acid derivatives? What is their MOA?

- Gemfibrozil, Fenofibrate

- MOA: ligand for the ligand-activated PPAR-alpha nuclear receptor (mimic fatty acids, the natural ligand)

1. INC transcription of LPL, DEC syn of ApoC-III, and ApoA-1 and -2 syn INC (increased HDL) 

2. Increased oxidation of fatty acids bc enzymes involved also regulated by PPAR -> less FA available for synthesis of TG’s

3. Whole series of metabolic genes with this binding site on them 


What are the lipoprotein effects of fibrates?

- Reduce VLDL, increase HDL 

- TG's reduced up to 50% 

- HDL-C increased up to 15% 

- LDL-C unchanged or decreased modestly (may also increase) 


What are the AE's of the fibrates?

- Gastroesophageal reflux, diarrhea, increased liver enzymes

- Fenofibrate: increased creatinine (reversible DEC in GFR; though to be related to PG syn), paradoxical HDL lowering

- Lithogenic bile: gallstones

- Teratogenic/Embryocidal in animals (no human data)

1. Pregnancy category C (use only if benefit outweighs risk) 


What are the dosage, metabolism, and excretion differences between Gemfibrozil and Fenofibrate?

- Gemfibrozil (generic): 600 mg tablet

1. Extensively metabolized by liver (oxidation, glucuronidation by UGT1A1) -- UGT1A1 also used for statins -> reduces statin metabolism, so contraindicated or dosage of statin limited

2. Can be safely given to pts w/renal disease.

- Fenofibrate (Tricor®)

1. Hepatic metabolism: active metabolite fenofibric acid dependent on renal excretion

2. Accumulates with renal insufficiency (GFR < 50 ml/min) -> dosage reduction recommended

3. NOT recommended for advanced renal disease ie GFR < 30 ml/min


What are the chemistry and preparations of nicotinic acid?

- Pyridine-3-carboxylic acid (vitamin B3, aka niacin)

- Preparations:

1. Immediate Release (IR) (Niacor®): requires slow up-titration to minimize flushing

2. Extended-Release (ER) (Niaspan®): less flushing, better tolerated


What are the adverse effects of nicotinic acid?

- Cutaneous flushing (common): give ASA; start low, INC slowly, use extended-release niacin (Niaspan)

- Elevated transaminases, hepatitis, hepatic failure (older slow release preps: SR dose limited to 2 g/d)

- GI irritation: nausea, activation of peptic ulcer disease, hyperuricemia, gout

- Conjunctivitis, cystoid macular edema, retinal detachment 

- Myositis (rare)

- Dry skin, pruritis, icthyosis, acanthosis nigricans (if you give Niacin several times, you deplete mast cells of histamine)

- Insulin resistance: glu intolerance, hyperglycemia

- Pregnancy category C: use if benefit exceeds risk 


HyperTGemia and low HDL are powerful risk predictors, but are they risk factors?

- When you do multivariate analysis, looking at risk with these, and take everything else out, very little risk remaining that can be attributed solely to these

Somehow this moderates risk, however 

- No trials showed added benefit of using these with statin therapy, which are main line of tx (exception people with high TG, low HDL, who did improve)

- Considered unproven add-on therapy


What are N-3 FA's, and how do they reduce TG's and CV risk?


What are some dietary sources of Omega-3 and -6 FA's?

- 3: walnuts, flaxseed, fatty fish, canola oil, fish oil, soybean 

- 6: corn, cottonseed, sunflower oils, black currant seed oil, 


How do N-3 FA's affect lipids?

- Reduce plasma TG's up to 35% and hepatic TG syn

- INC FA oxidation via PPAR


What are the potentially beneficial effects of N-3 FA's?

- Antiplatelet, hypotensive, hypolipidemic effects

- Dietary intake of one or more servings of fish/week reduces risk of heart attack or stroke

- Intake of fish oil capsules has not yet been shown to reduce risk 

- Studies using concentrated fish oil (EPA and/or DHA) currently underway 


How does HDL affect CHD risk?

- Epi observations: 

1. CHD risk decreases by 50% for each 0.52 mmol/L INC in HDL-C 

2. Epi association b/t low HDL-C level and CAD consistent across pops, and has been validated in all major epi studies 

3. Still just an ASSOCIATION (does NOT imply causality)


What is CETP?

- Plasma protein that catalyzes transfer of CE (chol ester) from HDL to ApoB-containing lipoproteins (VLDL and LDL) in exchange for TG's 


Will CETP inhibitors work?

- Higher HDL-C is good, but benefit of HDL-C raising has been harder to prove 

- Anacetrapib and Evacetrapib dramatically increase HDL-C (10x that seen in HPS2), AND lower LDL by 30-40% 

- Anacetrapib lowers Lp(a) by 35% 



A 55 year old male has Type II Diabetes and Coronary Heart Disease. His LDL-C is 105 mg/dl, TG is 300 mg/dl and HDLC is 32 mg/dl. What drug would be considered PRIMARY treatment to reduce his risk of recurrent coronary disease events? 



What did the PROVE-IT study show?

That while there is a benefit to using intensive statin therapy, there is still residual risk