Lipid-Lowering Drugs Flashcards
(52 cards)
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
Individuals at risk for myopathy
* Pre-existing muscle disease
* Age **\> 80****,****Small**body frame and frailty,**Female, Asian,**
* Hypothyroid
* Alcohol abuse
* Impaired renal or hepatic system
* High statin levels (see drug interactions)
26
Statin Pregnancy Category
X
27
Statins: Significant Drug Interactions
* 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
Drugs to Avoid for Pregnant & Nursing Women
* Statins
* Ezetimibe
* Niacin
* Fibric acid derivatives
## Footnote
***_Bile acid-binding resins_ are currently the only lipid-lowering meds _safe_ to use during pregnancy***
29
Bile acid sequestrants/resins
Action
* 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
Bile acid sequestrants/resins
Agents
* **Cholestyramine** (Questran)
* Colestipol
* Colesevelam
31
Bile Acid Sequestrants
Dosing
* Formulated as a **powder mixed with liquid**
* 30 min before, during, or 30 min after **meal**
32
Bile Acid Sequestrants
Drug Interactions
* Can interfere w/ absorption and/or form complexes w/ many PO meds:
* Fat soluble vitamins
* Synthroid
* Thiazides
* Oral contraception
* Phenytoin
* Sulfonylureas
33
Bile Acid Sequestrants
Adverse Drug Reactions
* Minimal:
* GI – severe **constipation** (encourage high fiber diet and adequate hydration), flatulence, N/V
* Use stool softener
* **Reduced folate** levels w/ long-term use
* **Cholestyramine (chloride)** can cause **_hyperchloremic acidosis_** (young/small pts)
34
Nicotinic Acid (Niacin)
MOA/Effects
* 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
Nicotinic Acid (Niacin)
Agents
* Nicotinic acid (Immediate-release, extended-release, and sustained-release or Niaspan)
36
Statin + Niacin =
Increased r/f hepatic dysfunction
37
Nicotinic Acid (Niacin)
Adverse Effects
* 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)
* **Hepatotoxicit**y (assess liver function)
38
Nicotinic Acid (Niacin)
Dosing
* *Gradually* increase dose, extended-release formulations help
* **ASA 30 min prior** to admin
* _Cautions_: contains **_yellow dye #5_**
39
PCSK9 Inhibitors:
Mechanism and Efficacy
* Proprotein convertase subtilisin/kexin type 9 (**PCSK9**) is an enzyme that **binds to LDL receptors** and **promotes lysosomal degradation of** the **receptors**.
* Aliro**_cumab_** (Praluent) and evolu**_cumab_** (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
↑ HDL levels more effectively than any other drug
Nicotinic Acid (Niacin)
41
PCSK9 Inhibitors:
Adverse Effects and Interactions
* 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
Fibric Acid Derivatives
MOA/Effects
* 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
Fibric Acid Derivatives
Agents
* Three drugs in the United States
* **Gemfibrozil** (Lopid) – only fibrate associated w/ beneficial CV outcomes
44
Drug of choice in pts at r/f pancreatitis
Nicotinic Acid (Niacin)
| (TG levels)
45
Fibric Acid Derivatives
Adverse Drug Reactions/Interactions
* 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
Most effective drugs available for decreasing triglyceride levels
Fibric Acid Derivatives
47
Combination Therapy:
Statin and Fibric Acid Derivatives
* Primarily assist in **decreasing triglycerides**
* **Increased risk of myopathies**
* **Contraindicated w/ severe hepatic diseas**e
48
Ezetimibe (Zetia) Action
* 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
Ezetimibe (Zetia): Drug interactions
* 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
Ezetimibe (Zetia): Drug interactions
Simvastatin and Ezetimibe (Vytorin)
* **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
What’s Next? Apolipoproteins
* 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
What’s New?
* **_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
