Lipid Lowering drugs Flashcards
What is the normal physiologic role of lipoproteins?
- triglycerides are an essential energy source
- cholesterol is necessary to produce:
- cell membranes
- bile acids
- steroid hormones
What are lipoproteins?
- a carrier required to transport lipids to and from cells in the periphery
- produced via an exogenous pathway
- dietary fat
- cholesterol
- fat soluble vitamins
- Or produced endogenously
- synthesized in liver
Order the density of lipoproteins from lowest to highest
- chylomicrons
- very low density lipoproteins
- intermediate density lipoproteins
- low density lipoproteins
- bad b/c they carry cholesterol out to periphery
- high density lipoproteins
- good b/c they carry cholesterol back to liver
Why is hyperlipidemia a problem?
- High cholesterol is associated with increased CAD
- High triglycerides are associated with pancreatitis
How is atherosclerosis formed?
- When there is excess LDL, the LDL molecules will deposit into the tunica intima
- the LDL is then oxidized, which attracts macrophages
- The macrophages will take up the LDLs and will become foam cells
- foam cells promote migration of smooth muscle cells from the tunica media to the tunica intima and smooth muscle cell proliferation
- Smooth cell proliferation causes increased formation of collagen, which causes hardening
- during this process, foam cells will die, releasing lipid content and driving the growth of the plaque
- the plaque can rupture, leading to thrombosis
What is primary hyperlipidemia?
- genetic heterozygous condition resulting in elevated total cholesterol level or triglyceride level
- often called Familial hypercholetolemia or familial hypertriglyceridemia
- total cholesterol usually >200, triglycerides often >500
What is secondary hyperlipidemia?
- Usually associated with another disease
- DM
- hypothyroidism
- obstructive liver disease
- chronic renal failure
What drugs can increase LDL and decrease HDL?
- progestins
- corticosteroids
- anabolic steroids
- protease inhibitors
What are desireable levels for
total cholesterol?
HDL?
LDL?
- Total cholesterol:
- desireable: <200
- high: >240
- HDL:
- low <40
- high >60
- LDL
- optimal <100
- high 160-189
What are the newest ACC/AHA guidelines?
What were the previous guidelines?
- the newest guidelines focus on the relative reduction of ASCVD (atherosclerotic cardiovascular disease) using statins
- Previous guidelines focused on screening pts for hyperlipidemia and treating it to try to bring it down to a goal LDL level
How is ASCVD assessed?
- History of choronary heart disease
- angina
- MI (anybody who has had an MI should go on statins)
- coronary interventions (PTCA, stents, CABG)
- Peripheral arterial disease
- peripheral areterial disease
- symptomatic carotid artery disease
- abdominal aortic aneurysm
- Risk factors (separate card)
What are the risk factors for ASCVD?
- Gender
- age- older
- race
- total cholesterol
- HDL cholesterol- less concern if HDL is robust
- BP- CV risk doubles with every 20 pt increase in BP
- treatment for high blood pressure
- DM
- smoking
What are the four groups that warrant statin therapy?
- Clinical ASCVD
- LDL > 189
- Ppl 40-75 with D< and LDL 70-189 without ASCVD
- ppl 40-75 with DM and LDL 70-189 and a 10 year ASCVD risk of 7.5% or higher
What is the intensity of statin therapy based on?
- Presence of clinical ASCVD
- risk of developing ASCVD
- presence of DM with/without hyperlipidemia
- presence of isolated hyperlipidemia (genetic)
How much does High intensity statin therapy lower LDL?
moderate insensity?
low intensity?
(chart)
In what situations would the addition of a non-statin be considered?
- High risk patients who have a less than anticipated response to statins
- patients that are unable to tolerate the recommended intensity of a statin or are completely intolerant
What are secondary treatment goals?
- Treat elevated triglycerides
- if triglycerides are > 200 and LDL goal has been achieved, add additional treatment for TGs
- Treat low HDLs (<40)
- If HDLs are <40 and LDL and TG goals have been achieved, add another treatment for HDLs
What are statins?
How do they work?
effects?
- HMG-COA reductase inhibitors
- inhibit the enzyme that catalyzes the rate-limiting step in the formation of cholesterol by the liver
- specifically inhibits the conversion of HMG-COA to mevalonate
- Effect is to:
- decrease cholesterol synthesis in liver
- enhance LDL receptor expression which increases LDL uptake in liver
How much do statins decrease LDLs?
TGs?
increase HDLs?
- decrease LDLs 20-60%
- decrease TGs 10-20%
- increase HDLs about 10%
What are the statin agents?
- Lovastatin (Mevacor)
- Simvistatin (zocor)
- Atorvastaton
- Rosuvastatin (Crestor)
- Pravastatin (Pravachol)
- Fluvastatin (Lescol)
What are some other beneficial effects of statins besides normalization of lipids?
- promote plaque stability
- decreases M&M when administered perioperatively to a high risk patient
- Antioxidant, anti-inflammatory, vasodilatory
- Reduction in CV events even in pts with normal LDL levels
- also helpful in diabetics
- increased bone formation
What are the pharmacokinetics of statins?
- Lovastatin and simvastatin are prodrugs
- Highly PB (except pravastatin)
- extensive CYP450 metabolisme (except pravastatin)
- E1/2t: 1-4 hours (clinical effects last for 24 hours)
- atorvastatin 14 hours
What is the incidence of side effects of statins?
What are the common side effects of statins?
The rare ones?
- 5%- similar to placebo
- common
- HA
- rash
- GI disturbances
- myalgias
- Rare
- hepatotoxicity
- peripheral neuropathy
- myopathy/rhabdomyalysis- can be fatal
Who is at higher risk of myopathies with statins?
- pts with pre-existing muscle disease
- >80 yrs
- female
- asians
- small body frame and frailty
- impaired renal or hepatic system
- alcohol abuse
- hypothyroid
- high statin levels
What pregnancy category are statins?
Category X- the fetus NEEDS cholesterol/triglycerides to grow
What are the drugs we care about regarding statin interactions?
- Ketoconazole
- erythromycin
- clarithromycin
- amiodarone
- protease inhibitors
How do bile acid sequestrants/resins work?
What is the effect?
- It is a non-absorbable resin that binds bile acids and other substances in the GI tract, preventing absorption and promoting GI excretion
- results in the liver using hepatic cholesterol to produce more bile acids and increased LDL receptor expression on hepatocytes
- effect is to decrease LDLs, increase HDLs, no change to TGs
What are some of the bile acid sequestrant drugs?
cholestyramine (Questran)
Colestipol
colesevelam
How are bile sequestrants dosed?
- It is a powder that gets mixed with liquid
- take 30 min. before, during, or after a meal
- increase dose gradually
What are some bile acid sequestrant drug interactions?
- Can interfere with absorption and/or form complexes with many PO meds
- synthroid
- oral contraception
- sulfonylurea antibiotics
- phenytoin
- thiazide diuretics
- fat soluble vitamins
What are some advers effects of bile acid sequestrants?
- GI- severe constipation, flatulence, N/V
- high fiber diet
- stool softener
- reduced folate levels with long term use
- cholestyramine (chloride) hyperchoremic acidosis
- seen in young or small pts
How does Nicotinic acid (Niacin) work to improve cholesterol?
What is the effect?
- MOA unclear: reduces the production of VLDLs
- works on liver and adipose tissue to inhibit TG production
- increases HDLs more effectively than any other drug, how it does this is unknown
- Effect:
- reduces LDLs and TGs
- increases HDLs
What are some nicotinic acid agents?
- Nicotinic acid in immediate release, extended release, sustained release
- Niaspan
How much does niacin improve long term outcomes?
It does little to improve long term outcomes. “Reduction in risk factors does not translate to reduction in actual risk”
What are the adverse effects of Niacin?
- skin flushing and itching
- can pretreat with aspirin 30 min before dose
- GI discomfort
- hepatotoxicity- assess liver function regularly
- hyperglycemia
- gouty arthritis
- can raise blood levels of uric acid
- check kidney function, encourage 2-3 L/day water intake
How is Niacin dosed?
- gradually increase dose
- titrate: 1.5-2 g/day
- divided doses with meals
- ASA prior to dosing
- avoid hot fluids prior to use
- contains yellow dye #5
How do Fibric acid derivatives work?
How do they affect the levels of TGs, HDLs, and LDLs?
- MOA: Interacts with a receptor (PPAR alpha) that increases synthesis of lipoprotein lipase (LPL)
- and decreases an apolipoprotein that inhibits LPL
- Increases lopolysis of triglycerides
- **most effective drugs available to decrease TGs (40-50%)
- Can increase HDLs 15-25%
- Very little decrease in LDLs
What are the three Fibric acid derivative drugs?
- Gemfibrozil (Lipod)
- Fenofibrate (Tricor)
- Fenofibric acid (TriLipix)
What are the adverse drug reactions with Fibric acid derivatives?
-
displaces warfarin from albumin- can increase risk of bleeding
- measure INR
- rashes
- GI disturbances
- HA
- rhabdo & myopathy- do not give with statins
- Gallstones
- hepatotoxic- check LFTs
How does Exetimibe (Zetia) work?
- By inhibiting cholesterol and phytosterol absorption from the brush border of the intestines
- disrupts complex btw annexin-2 and cavolin-1 proteins
- increases the expression of LDL receptors
- No affect on absorption of fat soluble vitamins (A,D,E,K)
- No affect on CYP450 enzymes
- intended for use in conjunction with a statin
What did the IMPROVE-IT trial find?
- IMPROVE-IT added Exetimibe to simvistatin and reduced LDL by 24%
- also demonstrated a 2% reduction in the primary composite end point of CV death, major coronary events, or nonfatal CVA
- *unclear if this is b/c of overall lowering of LDL or the addition of exetimbe but it diminishes the idea that only statins provide a mortality benefit
- **Other studies have not shown a mortality benefit
What is the LDL deduction of a statin combined with Exetimibe?
A statin with a bile acid sequestant?
A statin with a fibric acid derivative?
A statin and Niacin?
- Extimibe = 25% reduction in LDL
- bile acid sequestant = 8-16% reduction in LDL
- Fibric acid derivative = decreases triglycerides
- increased risk of myopathies
- contraindicated with hepatic disease
- Fibric acid derivative = decreases triglycerides
- Niacin = increased risk of hepatic dysfunction
What is the only lipid lowering medication class that is safe during pregnancy?
Bile acid-binding resins
Apply all your knowledge to describe what is happening in this picture.
If you dont know this from the other 40 cards you just learned, start over.
What are apolipoproteins and how might useful?
- Apolipoproteins are embedded in the outer layer of the phospholipid bilayer that surrounds the cholesterol (all types)
- they are necessary for assembly, provide sturcture, activate enzymes, and act as receptor ligands for cellular uptake
- They are also the culprit that binds to the arterial wall, beginning the oxidative and inflammatory process that really gets the atherogenesis going
-
Apolipopotein B seems to be linked with cardiovascular disease
- monitoring apolipoprotein B may be useful as an additional means of monitoring the efficacy of a given treatment
What is Mipomerson?
- An antisense oligonucleotide targeted to human mRNA for apolipoprotein B-100
- if mipomerson combines to apoB mRNA, will result in degredation and loss of translation of the apoB protein
- FDA approved for familial hyperlipidemia
- Adverse affects: hepatic dysfunction, steatosis, flu-like symptoms, Nausea, HA
- hepatotoxicity = black box warning
What is lopitamide?
- A Microsomal triglyceride transfer protein inhibitor
- presents assembly of apoB-containing lipoproteins in enterocytes and hepatocytes
- inhibits the synthesis of chylomicrons and VLDL in liver
- up to 50% decrease in plasma LDL levels
- Adverse affect: hepatic steatosis
