Lipid-Lowering Drugs Flashcards
1
Q
Lipoproteins –What is normal physiologic role?
A
- Triglycerides are an essential energy source
- Cholesterol is necessary for the production of
- Cell Membranes
- Bile Acids
- Steroid Hormones
2
Q
What are Lipoproteins?
A
- Required for transport of lipids to and from cells in periphery.
- Produced via exogenous pathway (dietary fat, cholesterol, fat-soluble vitamins) or endogenous pathway (synthesis by liver)
3
Q
Lipoproteins and Density
A
- Vary in density:
- Chylomicrons (least dense)
- Very low density lipoproteins
- Intermediate density lipoproteins
- Low density lipoproteins (transport cholesterol out to the body—shuttles to tissues)
- High density lipoproteins (transport cholesterol back to the liver for removal from circulation)
4
Q
Why is hyperlipidemia a
problem?
A
- Hypercholesterolemia
- Hypertriglyceridemia
- Elevated LDL
5
Q
Decreasing LDL’s by ______, can reduce risk of CV event by _____.
A
Decreasing LDL’s by 39 g/dL, can reduce risk of CV event by ~22%.
6
Q
Primary Hyperlipidemia
A
-
Genetic (or inherited) heterozygous condition resulting in elevated total cholesterol or triglyceride level.
- Homozygous = rare 4X higher cholesterol levels and much higher atherosclerosis risk
- Total cholesterol usually > 200, triglycerides often > 500
- Often referred to as
- Familial hypercholesterolemia
- Familial hypertriglyceridemia
7
Q
Secondary Hyperlipidemia
A
- Diabetes
- Hypothyroidism
- Obstructive liver disease
- Chronic renal failure
- Drugs that increase LDL and decrease HDL
- Progestins
- Corticosteroids
- Anabolic steroids
- Protease Inhibitors (HIV meds)
8
Q
Total Cholesterol Level
A
- Desirable < 200 mg/dL
- Borderline 200-239 mg/dL
- High > 240 mg/dL
9
Q
HDL Level
A
- Low < 40
- High > 60
10
Q
LDL Cholesterol
A
- Optimal < 100
- Near optimal 100-129
- Borderline High 130-159
- High 160-189
- Very High > 190
11
Q
Assessing for Atherosclerotic Cardiovascular Disease
A
- History of coronary heart disease (CHD)
- Angina
- Myocardial infarction
- Coronary interventions (PTCA, Stents, CABG)
- Peripheral Arterial Disease
- Peripheral (extremity) arterial disease
- Symptomatic carotid artery disease
- Abdominal aortic aneurysm
12
Q
Atherosclerotic Cardiovascular disease (ASCVD) Risk Factors
A
- Family history of ASCV, Gender, Age, Race
- Chronic LDL > 160 mg/dL
- HDL-Cholesterol
- SBP
- Diabetes
- Smoker
- Renal disease
- Metabolic syndrome
- History of preeclampsia
13
Q
Intensity of Statin Therapy is based on:
A
- Presence of Clinical ASCVD
- Risk of Developing ASCVD
- Presence of Diabetes +/- hyperlipidemia
- Presence of isolated hyperlipidemia (genetic component)
14
Q
High-Intensity Statin Therapy
A
- Lowers LDL by ≥ 50%
- Atorvastatin 40-80mg
- Rosuvastatin 20-40mg
15
Q
Moderate-Intensity Statin Therapy
A
- Lowers LDL by 30-49%
- Atorvastatin 10-20 mg
- Rosuvastatin 5-10 mg
- Simvastatin 20-40 mg
- Pravastatin 40 mg
- Lovastatin 40 mg
- Fluvastatin XL 80mg
- Fluvastatin 40 mg bid
- Pitavastatin 2-4 mg
16
Q
Low-Intensity Statin Therapy
A
- Lowers LDL by < 30%
- Simvastatin 10 mg
- Pravastatin 10-20 mg
- Lovastatin 20 mg
- Fluvastatin 20-40 mg
- Pitavastatin 1 mg
17
Q
High risk patients that might be started on non-statin cholesterol-lowering therapy.
A
- ASCVD
- LDL > 190 mg/dL
- Diabetes
- Age 40-75
18
Q
Secondary Treatment Goals
A
- Treat elevated triglycerides
- If triglycerides > 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 additional treatment for HDLs
19
Q
HMG-CoA Reductase Inhibitors
Agents
(3-hydroxyl-3 -Methylglutaryl Coenzyme A Reductase inhibitors)
A
- Fluvastatin (Lescol)
- Lovastatin (Mevacor)
- Atorvastatin (Lipitor)
- Pravastatin (Pravachol)
- Simvastatin (Zocor)
- Rosuvastatin (Crestor)
20
Q
HMG-CoA Reductase Inhibitors
Mechanism
(3-hydroxyl-3 -Methylglutaryl Coenzyme A Reductase inhibitors)
A
- “Statins” - Inhibit enzyme (HMG- CoA reductase) that catalyzes rate-limiting step in formation of cholesterol by liver.
- Specifically, inhibits conversion of HMG-CoA to mevalonate
- Effect is to:
- 1) decrease cholesterol synthesis in liver
- 2) enhance LDL receptor expression which increases LDL uptake by liver
- Decreases LDLs, decrease TGs, and increase HDLs
21
Q
HMG-CoA Reductase Inhibitors
Beneficial Effects
(3-hydroxyl-3 -Methylglutaryl Coenzyme A Reductase inhibitors)
A
- Beneficial for primary & secondary prevention beyond normalization of lipids:
- Promote plaque stability
- ↓ cardiac M&M w/periop admin in high risk pt.
- Antioxidant, anti-inflammatory, vasodilatory
- RCT show ↓ risk for CV events even w/ normal LDL level
- ↓heart failure, stroke, MI, hospitalization, PVD, death
- Helpful in diabetics
- Increased bone formation
- May reduce osteoporosis – studies underway
- Promote plaque stability
22
Q
HMG-CoA Reductase Inhibitors
PHARMACOKINETICS
A
- Lovastatin and simvastatin are prodrugs
- Highly protein bound (except pravastatin)
- Extensive CYP450 metabolism (except pravastatin)
- E½t (1-4 hrs) (except atorvastatin – 14 hrs)
- Clinical effects last for 24 hrs though
23
Q
Adverse Effects of Statins
Common
A
- Headache
- Rash
- GI disturbances
- Myalgias (up to 1/3 of patients)
24
Q
Adverse Effects of Statins
Rare
A
- Hepatotoxicity (0.5-2%)
- Peripheral neuropathy
- Myopathy/rhabdomyolysis (0.1-0.5%)
- Fatal rhabdomyolysis < 1 in 1 million
25
Q
Individuals at risk for myopathy
A
- Pre-existing muscle disease
- Age > 80,Smallbody frame and frailty,Female, Asian,
- Hypothyroid
- Alcohol abuse
- Impaired renal or hepatic system
- High statin levels (see drug interactions)
26
Q
Statin Pregnancy Category
A
X
27
Q
Statins: Significant Drug Interactions
A
- Other Drugs known to induce myopathies: Niacin, Gemfibrozil
- Cyclosporine increases [] of all statins & r/f myopathy
-
Dabigatran + simvastatin or lovastatin = increase r/f MAJOR hemorrhage
- (mechanism unclear)
- The following drugs are CYP3A4 inhibitors, which decrease metabolism of Lovastatin and Simvastatin, increasing their []:
- Grapefruit juice
- Itraconazole (Sporanox)
- Verapamil
- Amiodarone
- Cyclosporin
- HIV protease inhibitors
- Erythromycin
- Clarithromycin (Biaxin)
- Ketoconazole (Nizoral)
28
Q
Drugs to Avoid for Pregnant & Nursing Women
A
- Statins
- Ezetimibe
- Niacin
- Fibric acid derivatives
Bile acid-binding resins are currently the only lipid-lowering meds safe to use during pregnancy
29
Q
Bile acid sequestrants/resins
Action
A
- Non-absorbable resin that binds bile acids and other substances in the GI tract preventing absorption and promoting GI excretion.
- Results in liver using hepatic cholesterol to produce more bile acids and increased LDL receptor expression on hepatocytes.
- Effect is to decrease LDLs and increase HDLs (little effect on TGs- may actually increase is susceptible patients)
30
Q
Bile acid sequestrants/resins
Agents
A
- Cholestyramine (Questran)
- Colestipol
- Colesevelam
31
Q
Bile Acid Sequestrants
Dosing
A
- Formulated as a powder mixed with liquid
- 30 min before, during, or 30 min after meal
32
Q
Bile Acid Sequestrants
Drug Interactions
A
- Can interfere w/ absorption and/or form complexes w/ many PO meds:
- Fat soluble vitamins
- Synthroid
- Thiazides
- Oral contraception
- Phenytoin
- Sulfonylureas
33
Q
Bile Acid Sequestrants
Adverse Drug Reactions
A
- Minimal:
- GI – severe constipation (encourage high fiber diet and adequate hydration), flatulence, N/V
- Use stool softener
- Reduced folate levels w/ long-term use
- GI – severe constipation (encourage high fiber diet and adequate hydration), flatulence, N/V
- Cholestyramine (chloride) can cause hyperchloremic acidosis (young/small pts)
34
Q
Nicotinic Acid (Niacin)
MOA/Effects
A
- MOA unclear
- Niacin acts on liver and adipose tissue to inhibit TG production but HDL change remains a mystery
- Drug of choice in pts at r/f pancreatitis (TG levels)
- ↓Hepatic synthesis of VLDL by several potential mechanisms (↓ release of FAs), and this leads to a ↓ in LDL and ↓TGs.
-
↑ HDL levels more effectively than any other drug
- ↓ HDL breakdown = levels ↑by 20-30mg/L
- Works by ↓ production of VLDLs. Effect is to ↓ LDLs , ↓ TGs, and ↑ HDLs.
- *Niacin does little to improve long term outcomes “reduction in risk factors does not translate to reduction in actual risk.”!!
35
Q
Nicotinic Acid (Niacin)
Agents
A
- Nicotinic acid (Immediate-release, extended-release, and sustained-release or Niaspan)
36
Q
Statin + Niacin =
A
Increased r/f hepatic dysfunction
37
Q
Nicotinic Acid (Niacin)
Adverse Effects
A
- Skin: intense flushing, itching
- Can pretreat w/ aspirin 30 min before dose
- Decreased w/ sustained release version of niacin
- Vision changes
- GI: peptic ulcer exacerbation
- Hyperglycemia
- Gouty arthritis
- Can raise blood levels of uric acid (check kidney function, encourage 2-3 L/d water intake)
- Hepatotoxicity (assess liver function)
38
Q
Nicotinic Acid (Niacin)
Dosing
A
-
Gradually increase dose, extended-release formulations help
- ASA 30 min prior to admin
- Cautions: contains yellow dye #5
39
Q
PCSK9 Inhibitors:
Mechanism and Efficacy
A
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme that binds to LDL receptors and promotes lysosomal degradation of the receptors.
- Alirocumab (Praluent) and evolucumab (Repatha) are monoclonal antibodies that bind PCSK9, preventing subsequent binding of PCSK9 to LDL receptors.
- Result: high [] of LDL receptors = enhanced clearance of LDL-C
- FOURIER trial: Evolucumab reduced LDL-C
- Lower risk of MI, CV death, stroke, unstable angina, PCI
- ODYSSEY trial = when added to statin, reduces death from CV causes
40
Q
↑ HDL levels more effectively than any other drug
A
Nicotinic Acid (Niacin)
41
Q
PCSK9 Inhibitors:
Adverse Effects and Interactions
A
- Appear well tolerated with no significant interactions
- Muscle aches, rash, uticaria, mild injection site reactions
- Abnormally low LDL-C < 25 mg/dL– does not appear to be problematic based on current info
- May cause neural tube defects – unclear at this time
42
Q
Fibric Acid Derivatives
MOA/Effects
A
- Interacts w/ a receptor (PPAR alpha), increases synthesis of lipoprotein lipase (LPL), and decreases an apolipoprotein that inhibits LPL = more LPL
-
Increase lipolysis of TG’s (↓ VLDL levels)
- Most effective drugs available for ↓TG levels (40-50%)
- Can ↑HDL cholesterol by about 15-25%
- Very little decrease in LDLs
43
Q
Fibric Acid Derivatives
Agents
A
- Three drugs in the United States
- Gemfibrozil (Lopid) – only fibrate associated w/ beneficial CV outcomes
44
Q
Drug of choice in pts at r/f pancreatitis
A
Nicotinic Acid (Niacin)
(TG levels)
45
Q
Fibric Acid Derivatives
Adverse Drug Reactions/Interactions
A
- Rashes (common)
- GI disturbances (common)
- Headache
- Myopathy & rhabdo –avoid use w/ statins
- Can increase [] of statins
- Gallstones (D/C if this occurs and avoid use w/ ezetimibe)
- Liver injury (hepatotoxic- LTFs)
- Can potentiate oral anti-hyperglyemic drugs
-
Displaces warfarin from plasma albumin = ↑ r/f bleeding if on warfarin
- Measure INR frequently
46
Q
Most effective drugs available for decreasing triglyceride levels
A
Fibric Acid Derivatives
47
Q
Combination Therapy:
Statin and Fibric Acid Derivatives
A
- Primarily assist in decreasing triglycerides
- Increased risk of myopathies
- Contraindicated w/ severe hepatic disease
48
Q
Ezetimibe (Zetia) Action
A
- Works by inhibiting cholesterol and phytosterol absorption from brush border of intestines (disrupts complex between annexin-2 and cavolin-1 proteins). Increases expression of LDL receptors.
- No effect on absorption of fat soluble vitamins: (A, D, E, K)
- No apparent effect on CYP450 enzymes
- Intended for use in combo w/ a statin
49
Q
Ezetimibe (Zetia): Drug interactions
A
- Ezetimibe…
- …may increase bleeding risk w/ Warfarin
- …is increased by and will increase [] of cyclosprorin
- …when used w/ Gemfibrozil = increased r/f gallstones (combo contraindicated)
- …absorption inhibited by bile acid sequestrants
50
Q
Ezetimibe (Zetia): Drug interactions
Simvastatin and Ezetimibe (Vytorin)
A
- More effective than simvastatin alone.
- IMPROVE-IT trial:
- Simvastatin + ezetimibe = ↓ LDL.
- Also ↓ in end point of CV death, major coronary events, or nonfatal CVA
- Unclear if this is based on overall ↓ of LDL or +ezetimibe but undercuts idea that only statins provide a mortality benefit
51
Q
What’s Next? Apolipoproteins
A
- The atherogenic lipoprotein particle (LDL, IDL, VLDL, chylomicrons, lipoprotein A) is composed of a core of cholesterol and triglycerides surrounded by the phospholipid membrane with apolipoproteins imbedded within
- Apolipoproteins necessary for assembly of lipoproteins, provide structural integrity, act as co-activators of enzyme activity, and as receptor ligands for cellular uptake
- These apolipoprotein particles bind w/ arterial wall and begin oxidative and inflammatory process that encourages atherogenesis
- Evidence suggests atherogenesis tracks more closely w/ apolipoprotein B (located on VLDL, IDL, and LDL) numbers than w/ LDL or non-HDL numbers
- Evidence shows that, just as w/↓ in LDLs, ↓ in apolipoprotein B = ↓ CV dz risk
- Monitoring apolipoprotein B can be useful as additional means of monitoring efficacy of treatment regimen
52
Q
What’s New?
A
-
Mipomersen- Antisense oligonucleotide targeted to human mRNA for apolipoprotein B-100. Hybridization of mipomersen to the apoB mRNA results in degradation and loss of translation of the apoB protein
- FDA-approved for Hx familial hyperlipidemia
- Adverse effects include hepatic dysfunction and steatosis/hepatotoxicity, flu-like symptoms, nausea, and HA
-
Lopitamide - Microsomal triglyceride transfer protein inhibitor, resides in ER, prevents assembly of apoB-containing lipoproteins in enterocytes and hepatocytes
- Inhibits synthesis of chylomicrons and VLDL in liver
- Up to 50% reduction in plasma LDL levels
- Major adverse effect is hepatic steatosis
