Dyslipidemia Flashcards
1
Q
Lipoproteins
A
- Lipids (ex. cholesterol and triglycerides) are insoluble in plasma
- Lipoproteins are responsible for carrying lipids to various tissues:
Energy utilization
Lipid deposition
Steroid hormone production
Bile acid formation
2
Q
Hyperlipidemia
A
elevations in any lipoprotein species
a.k.a Hyperlipoproteinemia
3
Q
Hyperlipemia
A
increased levels of triglycerides
4
Q
Lipoprotein Structure
A
- Lipophilic core:
Esterified cholesterol and Triglycerides - Outer layer: Phospholipids and unesterfied cholesterol (hydrophilic)
- Apolipoproteins (apoproteins)
Determines lipoprotein function
–> Classification of lipoproteins
5
Q
5 Classifications of Lipoproteins
A
- Chylomicrons
- Very low density lipoprotein (VLDL):
- Intermediate density lipoprotein (IDL)
- Low density lipoprotein (LDL)
- High density lipoprotein (HDL)
6
Q
Chylomicrons
A
very large particles that carry dietary lipids
7
Q
Very low density lipoprotein (VLDL):
A
carries triglycerides and to a lesser degree cholesterol
8
Q
Intermediate density lipoprotein (IDL)
A
carries cholesterol esters and triglycerides
9
Q
Low density lipoprotein (LDL)
A
carries cholesterol esters (Bad)
10
Q
High density lipoprotein (HDL):
A
carries cholesterol esters
good
11
Q
Apoprotein Function
A
Apoproteins B-100 and B48 convey lipids into the tissue and artery walls
- VLDL, IDL, LDL, chylomicrons
Plaque formation
–> Atherosclerosis
12
Q
HDL Function:
A
- Scavengers”
- Acquire and transport cholesterol from atherosclerotic plaques and peripheral tissues to the liver
- -> Reverse cholesterol transport
- Elevated HDL reduces the risk of coronary heart disease (CHD)
13
Q
Atherosclerosis
A
- Leading cause of death in the US
- Approximately 16.3% of U.S. adults have high cholesterol ≥ 240 mg/dL
> 50% have a TC > 200 mg/dL - Estimated that < 50% of patients with elevated cholesterol are receiving pharmacotherapy
14
Q
Who should receive a lipid panel?
A
- Healthy adults over the age of 20 should receive a lipid panel every 5 years
- Lipid panel should be obtained after a 9 to 12 hour fast
15
Q
What is in a lipid panel?
A
Total cholesterol (TC)
Triglycerides
HDL
LDL and VLDL are calculated
16
Q
How calculate VLDL?
A
VLDL = Triglycerides/5
17
Q
How calculate LDL?
A
LDL=TC-(HDL+VLDL)
18
Q
Primary hyperlipidemia
A
a.k.a. “familial” hyperlipidemia
Lipid metabolism defect Fredrickson Classification (Type I-V)
19
Q
Secondary hyperlipidemia
A
a.k.a. “acquired” hyperlipidemia
Diabetes Hypothyroidism Renal failure Obstructive liver disease Drugs induced (anabolic steroids, corticoid steroids, HIV protease inhibitors)
20
Q
Step 1 for ATP III Cholesterol Guidelines
A
Determine lipoprotein levels:
LDL < 100 Optimal 100-129: Near optimal/above optimal 130-159: Borderline High 160-189: high >190: very high
HDL
< 40 Low
> 60 High
Total cholesterol: < 200 Desirable
200-239 Borderline high
> 240 High
21
Q
Step 2 for ATP III Cholesterol Guidelines
A
Identify coronary heart disease (CHD) risk
Does the patient have any of the following?
- Clinical CHD
- Symptomatic carotid artery disease
- Peripheral arterial disease
- Abdominal aortic aneurysm
- Diabetes
22
Q
Step 3 for ATP III Cholesterol Guidelines
A
Determine presence of major risk factors:
- Cigarette smoking
- HTN or on antihypertensive meds
- Low HDL
- Family History of premature CHD (male < 55, femal < 65)
- Age (men > 45, women > 55)
23
Q
Step 4 for ATP III Cholesterol Guidelines
A
Assess 10-year CHD Risk –> Calculate Framingham Score if:
CHD or CHD risk equivalent
OR
2+ risk factors without CHD risk
24
Q
Step 5 for ATP III Cholesterol Guidelines
A
Determine risk category
Risk category indicates:
LDL goal of therapy
Need for therapeutic lifestyle changes (TLC)
Level for drug consideration
25
Step 6 for ATP III Cholesterol Guidelines
Initiate TLC if LDL is above goal
26
Step 7 for ATP III Cholesterol Guidelines
Consider adding drug therapy
- Consider drug simultaneously with TLC for CHD and CHD equivalents
- Consider adding drug to after 3 months of TLC for other risk factors
27
Step 8 for ATP III Cholesterol Guidelines
Identify Metabolic Syndrome and treat
28
Step 9 for ATP III Cholesterol Guidelines
Treat elevated triglycerides
29
Framingham Risk Score
```
Looks at to get 10 -year risk %:
Age
Total cholesterol
Smoking status
HDL
Systolic blood pressure
```
Low risk 20%
30
TLC Features
TLC Diet:
- Saturated fat < 7%
- Increased fiber
Weight management
Increased physical activity
31
Metabolic Syndrome
- Abdominal Obesity (men: waist circumference > 102)
- Triglycerides > 150
- HDL < 40
- BP > 130/85
- Fasting Glucose > 110
32
Treating Metabolic Syndrome
- Treat underlying causes (overweight, physical inactivity)
- Treat lipic and non-lipid risk factors
1. HTN
2. Aspirin everyday for those with risk if CHD
33
Serum Triglycerides table
< 150 Norma
150-199 Borderline high
200-499 High
> 500 Very high
34
Non-HDL Goals
Non-HDL cholesterol=TC-HDL
35
Treating Elevated Triglycerides
1. If triglycerides >500 mg/dL, first lower triglycerides to prevent pancreatitis:
- Very low-fat diet (<500 mg/dL, turn to LDL-lowering therapy
2. If triglycerides 200-499 mg/dL after LDL goal is reached, consider adding drug if needed to reach non-HDL goal
- Intensify therapy with LDL-lowering drug, or
- Add nicotinic acid or fibrate to further lower VLDL
36
Therapeutic Lifestyle Changes
Initial treatment of choice:
```
Weight management
Physical activity
TLC diet
Smoking cessation
Managing other comorbidities (hypertension, diabetes)
```
37
Pharmacologic Therapy
```
HMG-CoA reductase inhibitors
Niacin (nicotinic acid)
Fibric acid derivatives (Fibrates)
Bile acid-binding resins
Inhibitors of intestinal sterol absorption
```
38
HMG-CoA reductase inhibitors effect
↓ LDL 20-50%
↑ HDL 10%
↓ TG’s 10-20%
39
HMG-CoA reductase inhibitors MOA
Reduce hepatic cholesterol biosynthesis
Analogs of an HMG-CoA intermediate
“Statins”
40
Detailed HMG-CoA reductase inhibitors MOA
1. Increase in high-affinity LDL receptors -->
2. Increases the fractional catabolic rate of LDL
and Increases the liver's extraction of LDL precursors -->
3. Reduce LDL
41
Other beneficial effects of statins:
Decrease oxidative stress
Decrease vascular inflammation
Stabilize of atherosclerotic lesions
42
Pharmacokinetics of statins
- Bioavailability varies from 40% to 75%
Exception: fluvastatin ~100% absorbed
- High first-pass extraction by the liver
Hepatic CYP3A4
- Half-lives range from 1 to 3 hours
Exceptions: atorvastatin (14 hrs), pitavastatin (12 hrs), and rosuvastatin (19 hrs)
43
Administration of statins
- Once daily
- Most effective if taken in the evening
Endogenous cholesterol production occurs at night
- Grapefruit juice? --> inhibits enzyme that breaks down statins so statin levels rise
44
Adverse Effects of statins
- Hepatic dysfunction- elevated liver function tests (LFTs)
Aminotransferase most commonly
- Discontinue therapy if levels are elevated >3 times the upper limit or normal
- Contraindication: active or chronic liver disease
- Myopathy- increase creatinine kinase (CK)
Dose-related
At risk: age ≥65, females, uncontrolled hypothyroidism, and renal dysfunction
- Discontinue use if symptomatic and CK activity is elevated
Rechallenge with same or alternative statin
45
Monitoring of statins
- Lipid panel 6-8 weeks after initiation of drug therapy or dosage change
Every 6 months to annually thereafter
- Obtain baseline CK and liver function test
Recheck only if patient is symptomatic or if clinically indicated
46
Drug interactions of statins
- CYP3A4 Inhibitors (statins rise):
Macrolide antibiotics, cyclosporine, ketoconazole, tacrolimus, nefazodone, fibrates, paroxetine, venlafaxine
- CYP3A4 Inducers (statins decrease):
Phenytoin, griseofulvin, barbiturates, rifampin, and thiazolidinediones
47
Atorvastatin (Lipitor®)
10, 20, 40, 80 mg tablets
48
Lovastatin* (Mevacor®)
10, 20, 40 mg tablets
49
Rosuvastatin (Crestor®)
5, 10, 20, 40 mg tablets
50
Niacin (nicotinic acid) effects
↓ LDL 10-15%
↑ HDL 10%
↓ TG’s 20-80%
51
Niacin (nicotinic acid) MOA
Reduces hepatic VLDL secretion & enhances VLDL clearance
| Therefore reducing LDL
52
Niacin (nicotinic acid) Pharmacokinetics
- Time to peak
IR formulation: 30-60 minutes
ER formulation: 4-5 hours
- Extensive first-pass effects: Converted to the amide form
Nicotinamide adenine dinucleotide (NAD), nicotinuric acid, and other metabolites
-- Excreted in the urine
53
Niacin (nicotinic acid) IR formulation Administration
Initial: 200-300mg/day in divided doses
Increase dose every 4-7 days to response
Therapeutic dose: 1.5-3 g/day in 2-3 divided doses (max dose: 4.5g/day)
54
Niacin (nicotinic acid) ER formulation Administration
Initial: 500 mg once daily at bedtime
Increase every 4 weeks until therapeutic
Maximum of 2 g/day
55
Niacin (nicotinic acid) ADR
```
Flushing, pruruitus, warmth, tingling
Hyperglycemia
Hyperuricemia (or gout)
Upper GI distress
Hepatotoxicity
```
56
Niacin (nicotinic acid) Monitoring
- Obtain liver function tests at baseline
Recheck every 6-12 weeks for first year, then periodically (approximately every 6 months)
- Uric acid if symptomatic of gout
- Blood glucose in diabetic patients
57
Niacin (nicotinic acid) Drug Interactions
- Bile acid-binding resins
May decrease the absorption of Niacin
- HMG-CoA Reductase Inhibitors
Niacin may enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors
58
Niacin (nicotinic acid) Immediate Release (OTC)
Niacin (Vitamin B3)
| 50 mg, 100 mg, 250 mg, 500 mg
59
Niacin (nicotinic acid) Extended Release
Niacor®, Niaspan® (RX)
500 mg, 750 mg, 1000 mg
Slo-Niacin (OTC)
500 mg, 750 mg
60
How to lessen ADR of Niacin (nicotinic acid)?
- Pretreat with aspirin (1 hr before)
- Try ER type
- Take before bed
- Avoid EtOH, hot showers, spicy foods
61
Fibric acid derivatives (Fibrates) Effects
↓ LDL 10%
↑ HDL 10-25%
↓ TG’s 40-50%
62
Fibric acid derivatives (Fibrates) MOA
Activate lipoprotein lipase
Promote delivery of TG’s to adipose
Interfere with VLDL formation in the liver
63
Fibric acid derivatives (Fibrates) Pharmacokinetics
- Absorption is increased with meals
- Tightly bound to plasma proteins
- Undergoes enterohepatic circulation
- Half-life is 20 hours
- Excreted in the urine (60-70%) as the glucuronide, and about 25% in feces
64
Fibric acid derivatives (Fibrates) Drugs
- Fenofibrate
- Gemfibrizol
- Lopid®
65
Fibric acid derivatives (Fibrates) Administration Fenofibrate
- Orally, once daily with food
- MANY preparations and strengths
- Adjusted for renal function:
Clcr >80 mL/minute: No dosage adjustment
Clcr 31-80 mL/minute: Adjust dose
Clcr ≤30 mL/minute: Use is contraindicated
66
Fibric acid derivatives (Fibrates) Administration Gemifibrizol
600 mg twice daily
| Administer 30 minutes before breakfast and dinner
67
Fibric acid derivatives (Fibrates) Preparations
Lopid®: 600 mg
| Available as generic
68
Fibric acid derivatives (Fibrates) ADR
```
Rare:
Gastrointestinal symptoms
Myopathy
Arrhythmias
Elevated aminotransferases or alkaline phosphatase
```
69
Fibric acid derivatives (Fibrates) Monitoring
Lipid panel at baseline, 3 and 6 months
LFTs periodically
Serum creatinine (SCr)
70
Fibric acid derivatives (Fibrates) Drug interactions
- Statins --> myopathies
Fibrate is preferred over gemfibrizol
- Bile acid-binding resins
Separate doses by 2 hrs
- Warfarin: ↑ warfarin effect
71
Bile acid-binding resins MOA
```
Non-absorbable anion exchange resins
Inhibits enterohepatic recycling
Bile excretion ↑ and ↓ cholesterol pool in liver
LDL receptors upregulate
LDL clearance increases
```
72
Bile acid-binding resins Effect
↓ LDL 10-20%
↑ HDL 0-2%
↑ TG’s 0-5%
73
Bile acid-binding resins Pharmacokinetics
Resin is not absorbed systemically
Remains in the gut
Eliminated in feces
74
Bile acid-binding resins Administration
- Decrease absorption of other medications
Do not take any other medication 1 hour before or 2 hours after
- Tablets: Administer with a meal
LARGE tablet --> if trouble swallowing, recommend suspension form
75
Bile acid-binding resins ADR
GI discomfort:
- Bloating
- Nausea
- -Heartburn
- Constipation
Hypertriglyceridemia
- Contraindicated in hyperlipemia (>400mg/dL)
76
Bile acid-binding resins Monitoring
- Effect on LDL in ~2 weeks
- Lipid panel at baseline
Every 6 months to 1 year after therapeutic
77
Bile acid-binding resins Drug Interactions
```
Digoxin
Thiazides
Warfarin
Thyroxine
Aspirin
Pravastatin
Fluvastatin
Ezetimibe
Iron salts
Fat soluble viatmins
```
78
Bile acid-binding resins Preparations
Cholestyramine (Questran®)
4g packet or bulk powder
Colestipol (Colestid®)
1gm tablet, 5g powder packet
Colesevelam (WelChol®)
625mg tablet, 3.75g powder packet
79
Inhibitors of intestinal sterol absorption MOA
Selective inhibition of intestinal absorption of dietary cholesterol
Effective even in the absence of dietary cholesterol inhibits reabsorption of cholesterol excreted in the bile
80
Inhibitors of intestinal sterol absorption Effects
↓ LDL 17%
↑ HDL 1.3%
↓ TG’s 6%
81
Inhibitors of intestinal sterol absorption Pharmacokinetics
- Readily absorbed
- Conjugated in the intestine to an active glucuronide
- Undergoes enterohepatic circulation
- Half-life=22 hours, peak in 4-12 hours
- Excreted in feces (78%)
82
Inhibitors of intestinal sterol absorption Administration
Single daily dose of 10 mg without regard to meals
83
Inhibitors of intestinal sterol absorption ADR
```
Diarrhea
Abdominal pain
Arthralgia
Back pain
Fatigue
```
84
Inhibitors of intestinal sterol absorption Monitoring
- Lipid panel at baseline, 6 weeks after initiation, then every 6 months to annually
When in combination with fenofibrate
- Monitor LFTs and signs and symptoms of cholelithiasis
85
Inhibitors of intestinal sterol absorption Drug interactions
```
- Fibrates
Cholelithiasis, myopathy
- Bile acid-binding resins
- Lovastatin ER, Niacin
Myopathy
```
86
Inhibitors of intestinal sterol absorption Preparations
Currently only one available
| Ezetimibe (Zetia®) 10mg tablet
87
Fish Oil (omega 3 fatty acids)
- May decrease triglycerides
- Unpleasant side effect profile:
Belching, flatulence, indigestion, altered taste
88
Fish Oil (omega 3 fatty acids) Contraindicated
Fish allergy
| Coagulopathies
89
Fish Oil (omega 3 fatty acids) Preparations
Lovaza® 4g daily (or 2g twice daily)
90
Pregnancy/lactation options
- Statins are contraindicated (category X)
Options:
- Colesevelam (category B)
- Fenofibrate, gemfibrozil, niacin, cholestyramine, ezetimibe (category C)
91
Children options
Diet and lifestyle modifications first line
| Drug of choice: cholestyramine
92
Best for LDL
Statins: largest reduction in LDL
93
Best for Triglycerides
Niacin, fibrates
| NOT bile acid-binding resins
94
What if not at goal?
Statin + bile acid-binding resin
Statin + ezetimibe
Statin + niacin
Statin + fibrate (not gemfibrizol)
