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Cardio Lecture 6
Therapeutics of Dyslipidemia and Pharmacology of Lipid Modifying Agents 1/22/13
87
Pharmacology
Graduate
01/22/2013

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Term
Define primary prevention
Definition
Prevention of 1st cardiovascular event in high risk patients
Term
Define secondary prevention
Definition
Prevention of subsequent cardiovascular events after an initial event. Pt has CHD (MI, angina, CABG, PCI, CVA).
Term
What are the suggested LDL cholesterol ranges?
Definition
<100 optimal
100-129 Near optimal
130-159 Borderline high
160-189 High
>190 Very high
Term
What are the suggested total cholesterol ranges?
Definition
<200 Desirable
200-239 Borderline high
>240 High
Term
What are the suggested LDL cholesterol ranges?
Definition
<40 Low
>60 High
Term
List the 5 major risk factors that modify LDL goals
Definition
1. Smoking
2. HTN >140/90
3. Family history of premature CHD
4. Age (men>45, women>55)
5. Low HDL

*HDL>60 subtract risk factor
Term
List Risk Equivalents (risk of having a coronary event is equal to that of established CHD)
Definition
1. Peripheral arterial disease
2. Abdominal aortic aneurism
3. Symptomatic carotid artery disease
4. Diabetes
5. Multiple risk factors that confer a 10-year risk for CHD >20%
Term
Define Framingham Risk Assessment
Definition
A table that allows assessment of 10-year CHD risk in patients with 2+ risk factors present without CHD or CHD risk equivalent

If >20% this equals a risk equivalent
Term
What is the primary target of cardiovascular event prevention?
Definition
LDL unless TG>500
Term
What is the LDL goal for a person with CHD and CHD risk equivalents?
Definition
LDL <100
Term
What is the LDL goal for a person with 2+ risk factors?
Definition
LDL <130
Term
What is the LDL goal for a person with 0-1 risk factor?
Definition
LDL <160
Term
What is "very high risk"?
Definition
Presence of established CVD plus multiple risk factors (especially poorly controlled, smoking, or metabolic syndromes) or acute coronary syndromes
Term
What are the three levels of 10 year risk on the Framingham Risk Assessment?
Definition
>20% is a CHD risk equivalent
10-20%
<10% is low risk
Term
When do you initiate drug therapy in a person with risk?
Definition
When their LDL is 30mg/dL higher than their individual goal

(With the exception of 10-20% risk, which should start at 130mg/dL)
Term
What is the LDL goal of a patient with "very high risk"?
Definition
<70mg/dL
Term
List major components of Therapeutic Lifestyle Changes
Definition
Diet therapy
Weight Control
Increased physical activity
Alcohol/smoking cessation
Term
What is the first line therapy for LDL reduction?
Definition
Statins
Term
What is the MOA of statins?
Definition
Inhibits cholesterol synthesis through inhibition of HMG CoA reductase, the rate limiting step in cholesterol biosynthesis; this results in decreased cholesterol content in the liver, increased LDL receptor activity which removes VLDL, IDL and LDL from the blood
Term
How much will statins typically lower LDL?
Definition
18-62%

For every doubling of the dose of a statin, the LDL will lower 6-7% on average
Term
How much will statins typically raise HDL?
Definition
5-15% increase

This may actually decrease in patients receiving more potent LDL lowering statins (eg Lipitor or Crestor)
Term
How much will statins typically lower TG?
Definition
7-30% reduction

Dose-related effect, greatest with Lipitor. Statins should not be used as monotherapy to lower TG.
Term
List pleiotropic effects of statins
Definition
Endothelial cell function (enhanced vasodilation)
Plaque stability ?
Decreased inflammation
Decreased lipoprotein oxidation
Decreased coagulation
Term
List side effects of statins
Definition
Myopathy, rhabdomyolysis, GI upset, LFT elevations, HA
Term
List some warnings of statins
Definition
history of myopathy with statin use, Renal insufficiency, LFT’s 3x ULN prior to initiation (need to identify reason for elevation)
Term
List contraindications of statins
Definition
Active or chronic liver disease, pregnancy, CrCl< 30 ml/min for lovastatin, pravastatin & simvastatin;
Term
Which statins have shorter half lives?

Does this affect dosing instructions?
Definition
Lovastatin, simvastatin, pravastatin, fluvastatin

Dose in PM
Term
Which statins have longer half lives?
Definition
Atorvastatin, rosuvastatin, pitavastatin

Dose any time of day
Term
List drugs metabolized by CYP3A4 that should not be taken with statins
Definition
Macrolides, azole antifungals, cyclosporine, protease inhibitors, nefazodone,
Term
List drugs that should not be taken with statins (but for a different reason than CYP3A4)
Definition
Coumadin, Bile Acid Sequesterants, Fibrates and Niacin
Term
Which statin has the least drug interactions?
Definition
Pravachol
Term
Which statin has the most drug interactions?
Definition
Lovastatin and simvastatin
Term
When can you dose simvastatin 80mg/day?
Definition
Only if the patient has been taking it over a year already without any symptoms
Term
What new contraindications were published in 2011 for simvastatin?
Definition
CYP3A4 inhibitors (itraconazole, ketoconazole, posaconazole, HIV protease inhibitors, erythromycin, clarithromycin, telithromycin, and nefazodone)

gemfibrozil, cyclosporine, or danazol
Term
What dosing limitations were published for simvastatin in 2011?
Definition
Do not exceed simvastatin 10mg daily if taking verapamil or diltiazem

Do not exceed simvastatin 20mg daily if taking amiodarone, amlodipine, or ranolazine

In Chinese patients, do not use simvastatin >20mg if they are also taking >1g niacin
Term
Did the FDA find that statins change glucose and A1c?
Definition
They found small evidence of incidence diabetes, but usually small changes in blood sugar with statins (except pravastatin)

Risks very small, don't stop taking statins
Term
Did the FDA find that statins lead to memory loss and other cognitive adverse effects?
Definition
They found symptoms are not serious and are reversible
Term
Does the FDA suggest LFT with statins?
Definition
Not anymore, just check at baseline and as clinically indicated
Term
What monitoring should be done with statins?
Definition
FLP- baseline, 6-12 weeks
LFT- baseline, then if clinically indicated
CPK- baseline, then if symptomatic
Term
List the statins from most potent to least potent
Definition
Rosuvastatin
Atorvastatin
Simvastatin (/pitavastatin)
Pravastatin/Lovastatin
Fluvastatin
Term
What should a patient be dosed with if they need LDL lowered by 27% ?
Definition
10mg Simvastatin
20mg Pravastatin/Lovastatin
40mg Fluvastatin
Term
What should a patient be dosed with if they need LDL lowered by 34% ?
Definition
10mg Atorvastatin
20mg Simvastatin
40mg Pravastatin/Lovastatin
Term
What should a patient be dosed with if they need LDL lowered by 41% ?
Definition
20mg Atorvastatin
40mg Simvastatin
80mg Pravastatin/Lovastatin
Term
What should a patient be dosed with if they need LDL lowered by 48% ?
Definition
10mg Rosuvastatin
40mg Atorvastatin
80mg Simvastatin
Term
What should a patient be dosed with if they need LDL lowered by 55% ?
Definition
20mg Rosuvastatin
80mg Atorvastatin
Term
What should a patient be dosed with if they need LDL lowered by 62% ?
Definition
40mg Rosuvastatin
Term
What is the MOA of bile acid sequesterants?
Definition
Binds bile acid in the GI tract

The positive charge on the BAS binds to the negative charge on the bile acids in the gastrointestinal tract; this reduces enterohepatic recirculation of bile acids which increases hepatic bile acid synthesis
Term
How do bile acid sequesterants influence lipoproteins?
Definition
They could raise TG
Lower LDL
Term
How much do bile acid sequesterants change lipoproteins?
Definition
LDL 15-30% reduction (dose dependent)
HDL 3-5% increase
TG no effect or increase
Term
List side effects of bile acid seuqesterants
Definition
GI upset, fecal impaction, TG elevations, transient LFT elevations (occurs ~4-6 weeks)
Term
List warnings of bile acid sequesterants
Definition
TG > 200 mg/dL, constipation

Always take with a full glass of water
Term
List contraindications of bile acid sequesterants
Definition
familial dysbetalipoproteinemia, TG > 400 mg/dL, chronic constipation, preexisting biliary obstruction
Term
What monitoring needs to be done with bile acid sequesterants?
Definition
FLP- baseline and after 6 weeks at target dose
Term
Describe drug interactions of bile acid sequesterants
Definition
Numerous because of binding; separate administration of other medications by 1 hour before or 4-6 hours after

E.g.: HCTZ, loop diuretics, warfarin, propranolol (other beta blockers), digoxin, fat soluble vitamins
Term
List the available forms of niacin
Definition
Crystalline nicotinic acid (Niacin)- available OTC
Extended release nicotinic acid (Niaspan)- requires Rx
Sustained Release nicotinic acid- OTC (not recommended)
Term
What pathways have they proposed to explain the MOA of niacin?
Definition
Adipose tissue- inhibits lipolysis
Liver- inhibits fatty acid synthesis
LPL- enhances activity
Altered composition of LDL
Term
List side effects of niacin
Definition
LFT elevations, hyperuricemia, hyperglycemia, GI upset/dyspepsia, flushing (occurs b/c of prostaglandin release therefore causing vasodilation), myopathy, HA (occurs b/c of prostaglandin (PG) release therefore causing vasodilation)

Warning: mild to moderate gout
Term
How can one avoid flushing with niacin?
Definition
Take aspirin 30min prior
Be compliant
Titrate up
Avoid hot beverages, hot temperatures, and alcohol
Term
List contraindications of niacin
Definition
chronic and active liver disease, severe gout, active PUD
Term
List warnings of niacin
Definition
moderate to mild gout/hyperuricemia, DM, hx PUD, diabetes
Term
How should niacin be monitored
Definition
FLP- baseline and 6 weeks
LFTs- baseline and 6-12 weeks
CPK- baseline and if symptomatic
BG- only if have diabetes
Uric acid- if hx of gout
Term
What is the mechanism of action of fibrates?
Definition
Unclear:

Binds to peroxisome proliferation-activated receptor-alpha (PPARα) in the liver and brown adipose tissue, this stimulates increased fatty acid oxidation and increased LPL synthesis

Stimulates ApoA1 and AII

Antithrombic effect
Term
How do fibrates affect lipoproteins?
Definition
LDL 5-20% reduction (nonhypertriglyeridemic pts;if hypertriglyeridemic may increase)

HDL 10-20% increase (greater in severe hypertriglyceridemia)

TG 20-50% reduction
Term
List contraindications of fibrates
Definition
Severe renal or hepatic impairment, preexisting gall bladder disease
Term
List warnings of fibrates
Definition
Use caution in combination with other drugs that may cause myopathy or LFT elevations (statins or niacin)
Term
List adverse effects of fibrates
Definition
Its typically well tolerated

LFT elevations, myopathy, GI upset, increased gallstone
Term
List drug interactions with fibrates
Definition
Niacin, statins, Coumadin, BAS
Term
List monitoring to be done with fibrates
Definition
FLP- baseline and 6-12weeks
LFTs- baseline and 6-12 weeks, then 3-6mo after
CPK- baseline and if symptomatic
Renal function- baseline and as needed
Term
What is the MOA of Zetia?
Definition
Acts on the brush border of the small intestine and inhibits the absorption of cholesterol, therefore decreasing the delivery of dietary cholesterol to the liver which will decrease cholesterol stores and increase clearance of cholesterol from the blood
Term
How does Zetia affect lipoproteins?
Definition
Lowers LDL 18%, 25% if with statin

HDL and TG not clinically significant
Term
List adverse effects, warnings, and contraindications of Zetia
Definition
Adverse effects: fatigue, arthralgias, GI upset

Warnings: moderate to severe hepatic insufficiency

Contraindications: hypersensitivity
Term
How is Zetia dosed?
Definition
10 mg QD (most beneficial when utilized with statins, minimal clinical benefit when used with other lipid lowering agents)
Term
List monitoring to be done with Zetia
Definition
FLP- baseline and 6-12 weeks
LFT- baseline and as directed for statin
CPK- baseline and as directed for statin
Term
What Omega-3 Fatty Acid medications are on the market?
Definition
Fish Oil capsules- available OTC

Lovaza- requires Rx (indicated for TG >500mg/dL)
Term
Describe the MOA of Omega-3 Fatty Acid
Definition
Omega-3 fatty acids are poor substrates for the enzymes responsible for TG synthesis and they inhibit esterification of other fatty acids; also increase hepatic beta-oxidation

May lower thromboxane-A2
Term
What effects do Omega-3 Fatty Acids have on lipoproteins?
Definition
LDL- may increase
HDL- only small increases (less than fibrates); inconsistent
TG- primary effect to lower TG, but likely modest result
Term
List adverse effects of Omega-3 Fatty Acids
Definition
dyspepsia, possible diarrhea with higher doses, possible prolonged bleeding time
Term
List warnings and cautions of Omega-3 Fatty Acids
Definition
Warnings:
Use caution in patients with known fish allergy
Due to possible prolongation of bleeding time, use caution in those using anticoagulants
Safety and efficacy not established in children or pregnancy

Contraindicated: hypersensitivity
Term
List drug interactions of Omega-3 Fatty Acids
Definition
Anti-coagulants, drugs that may increase TG
Term
How is fish oi OTC dosed?
Definition
Typical daily dose- 1g BID or TID
Potentially effective dose is 10-18g/day
Term
How is Lovaza dosed?
Definition
1g QD or BID

Typical daily dose 4g (??)
Term
Describe monitoring to be done with Omega-3 Fatty Acids
Definition
FLP- baseline and 6-12 weeks
LFT- baseline and 6-12 weeks
Term
List the clinical identification of metabolic symdrome in men
Definition
Waist >40in
TG >150
HDL <40
BP >130/85
Fasting glucose >100
Term
List the clinical identification of metabolic symdrome in women
Definition
Waist >35in
TG >150
HDL <50
BP >130/85
Fasting glucose >100
Term
How many clinical IDs must someone have to have metabolic syndrome?
Definition
3 or more
Term
List the ranges of TG level classification
Definition
Normal triglycerides: <150 mg/dL
Borderline-high triglycerides:150-199 mg/dL
High triglycerides:200-499 mg/dL
Very high triglycerides:>500 mg/dL
Term
If TG are > 200mg/dL after LDL is reached, what is the new goal?
Definition
Treat Non-HDL cholesterol (total cholesterol – HDL)
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