Lecture 4: Antihyperlipidemics Flashcards
1
Q
What does the drug classes of Antihyperlipidemics treat?
A
Dyslipidemia or Increases HCl
2
Q
Which drug(s) are HMG-CoA reductase inhibitors (5)?
Drug class
All end in -statin
A
- Atorvastatin
- Rosuvastatin
- Simvastatin
- Pravastatin
- Lovastatin
3
Q
Which drug(s) are Lipolysis inhibitors?
Drug class
A
- Niacin
- Nicotinic acid
- Vitamin B3
4
Q
Which drug(s) are Fibrates?
Drug class
A
- Gemfibrozil
- Fenofibrate
5
Q
Which drug(s) are Bile acid sequestrants?
Drug class
A
- Cholestyramine
- Colestipol
- Colesevelam
6
Q
Which drug(s) are Cholesterol absorption inhibitors?
Drug class
A
Ezetimibe
7
Q
Which drug(s) are Triglyceride transfer protein inhibitor?
Drug class
A
Lomitapide
8
Q
Which drug(s) are PCSK9 inhibitor?
Drug class
A
Evolocumab (monoclonal antibody)
9
Q
Which drug(s) are Fish oils?
A
Omega-3-acid ethyl esters
10
Q
Which drug(s) are ATP Citrate Lyase Inhibitor?
Drug class
A
Bempedoic acid
11
Q
Which drug(s) are siRNA?
Drug class
A
Inclisiran
12
Q
What accounts for 50% of all deaths in the USA?
A
Coronary heart disease (CHD)
13
Q
What does CHD correlate with regarding cholesterol?
HIGH yield
A
- ↑ LDL (bad chol) and TAG
- ↓HDL (good chol)
- LDL&HDL=carriers of cholesterol (chol)
- TAG=triacylgcerol
14
Q
What are other risk factors of CHD?
A
- Smoking
- Hypertension
- Obesity
- Diabetes mellitus (DM)
15
Q
What causes high cholesterol?
A
- ↓ excercise
- ↑ saturated fatty acids
16
Q
What is Hyperlipidemia?
HIGH yield
A
Genetic defect in lipoprotein metabolism
17
Q
What is the treatment plan for hyperlipidmias and the proposed outcome?
A
- Lifestyle changes + drugs (↓ coronary plagues)
- ↓mortality of CHD≈35%
18
Q
True or False? Antihyperlipidemics are taken chronically
A
TRUE
(do Not cure, just manage and alleviate)
19
Q
List the lipoprotein in order of clinical importance (according to atherogenicity)
A
LDL>VLDL>chylomicrons>HDL
20
Q
What is the amount of LDL present that is associated with CHD?
A
100 (↑LDL)
High LDL and low HDL are both risk factors for CHD
21
Q
What is the amount of HDL needed to decrease heart disease risk?
A
40 (↑HDL)
Note: If HDL gets too low can cause CHD
22
Q
What is the primary goal of anthyperlipidemic therapy?
A
the lower LDL levels
More aggresive therapy for pts with ↑ risk of heart disease
23
Q
What are the components of the Total Cholesterol (Below 200) in a healthy individual?
A
HDL (>40) + LDL (<100) + VLDL
24
Q
What is the intitial treatment guidline for a patient w/ high cholesterol?
2018-19 ACC/AHA Guidelines on the Management of Blood Cholestrol
A
Healthy lifestyle (e.g. diet, exercise, emphasized over the entire course of life)
25
What is the treatment guildline for a patient w/ **Clinical Atherosclerosis Cardio Disease (ASCVD)?**
## Footnote
2018-19 ACC/AHA Guidelines on the Management of Blood Cholestrol
* ↓ LDL by ≥ 50% w/ **high-intesity statin** (Atrovastatin/Rosuvastatin)
* Add nonstatain when LDL ≥ 70 mg/dL (Ezetimibe/Cholestyramin)
26
What is the treatment guidelines for a Pt w/ **Severe hypercholesterolemia (LDL≥190 mg/dL)** ?
## Footnote
2018-19 ACC/AHA Guidelines on the Management of Blood Cholestrol
* **High intensity statin** at highest tolerated dose (Atrovastatin/Rousvastatin)
* Add a nonstatin, If LDL ≥ 100 mg/dL in high-risk Pt
27
What is treatment guideline for a Pt w/ **DM + LDL>70 mg/dL)**, 40-50 y/o?
| DM-Diabetes mellitus
## Footnote
2018-19 ACC/AHA Guidelines on the Management of Blood Cholestrol
* Moderate-intensity statin
* Considered to ↓ LDL by ≥ 50% in Pt at high risk
28
What is the treatment guildline for a Pt w/ **10 year ASCVD risk**≥7.5%, 40-75 y/o?
## Footnote
2018-19 ACC/AHA Guidelines on the Management of Blood Cholestrol
* **Consider moderate-intensity statin**
* Discussion of risk enhacing factors and coronary artery Ca
* **Can ↓LDL by ≥ 30% to 50% if 10 year risk ≥20%**
29
Which statins are High-Intensity (daily dose ↓ LDL by ≥ 50%)?
## Footnote
HIGH yield
* **Atorvastatin**: 40-80 mg
* Rosuvastatin: 20 mg
30
Which statins are Moderate-intensity (daily dose ↓ LDL by 30-50%)?
* Atrovastin: 10 mg
* Rousuvastatin: 10 mg
* Simvastatin: 20-40 mg
* Pravastatin: 40 mg
* Lovastatin: 40 mg
* Fluvastatin: 40 mg (BID)
31
Which statins are Low-intensity (daily dose ↓ LCL by < 30%)?
## Footnote
HIGH yield
* **Pravastatin**: 10-20 mg
* **Lovastatin**: 20 mg
32
Explain the mechanism of action of Statins
| ALL of the statins do this
* **Analogs of HMG** (3-OH-3-CH3-glutaryl), a cholesterol precursor
* **Inhibit HMG CoA reductase, rate-limiting step in cholesterol synthesis**
* Inhibit de nevo cholesterol synthesis→deplete intracellular supply of cholesterol
33
Rank the statin order potency of LDL lowering power
Pitavastatin, Rosuvastatin, **Atorvastatin** > Simvastatin, Pravastatin > Lovastatin, Fluvastatin
34
Explain the mechanism of statins step by step
| Review Slide 13
1. Statins inhibit HMG-CoA reductase, leading to a decreased concentration of cholesterol within the cell
2. Low intracellular cholesterol stimulates the synthesis of LDL receptors
3. Increased number of LDL receptors on the cell promotes the uptake of LDL from the blood
4. Low intracellular cholesterol decreases the secretion of VLDL
35
Explain the mechanism of action for **Atrovastatin**
* Depletion of **intracellular cholesterol→ ↑ LDL receptors** →bind & internalize circulating LDL
* **↓ LDL (24-50%)** by decreasing synthesis & increasing catabolism
* **↑ HDL (6-12%)**
* **↑ TAG (10-29%)**
36
What are the therapeutic uses of **Atrovastain**?
* Treatment of **hyperlipidemia**
* **Substantial ↓ coronary events & death from CHD**
* Plaque stabilization
* Improve coronary endothelial function
* ↓ Clot formation, anti-inflammatory effect
37
List specific conditions that Atrovastain therapy is benefical
* CHD w/ or w/out hyperlipidema
* Males with hyperlipidema w/ out CHD
* Male and female with average cholesterol w/ out CHD
38
What disease is Atrovastatin treatment NOT effective and why?
**Homozygous familial hypercholesterolemia** d/t lack of functional LDL receptors
39
List the different side effects that can be caused by Atorvastatin
| HIGH yield
* **Constipation** (10%)
* **Muscle aches** (1%)
* **Hepatotoxicity** (0.001%)
* **Myositis or Rhabdomyolysis** (<0.1%)
* **DM** (0.2% risk/yr)
* **Confusion/Memory impairment**
* **Contraindicated in pregnancy**
40
What drugs do you NOT take w/ Atrovastatin and why?
| HIGH yield
* **Gemfibrozil and Niacin**
* Overlapping side effects can lead to liver and kidney failure
41
List other drug interactions w/ Atrovastin
* Cylosporine
* Itraconazole
* Erythromycin
42
A 43-year-old obese man with type 2 diabetes mellitus is prescribed atorvastatin for the treatment of hyperlipidemia. Which of the following is the mechanism of action of atorvastatin?
A. Triacylglycerol secretion inhibitor
B. HMG-CoA reductase inhibitor
C. Cholesterol absorption inhibitor
D. Cholesterol secretion inhibitor
B. HMG-CoA reductase inhibitor
43
What type of drug is **Niacin**?
Lipolysis inhibitor
44
Explain the mechanism of action of **Niacin**
* **Inhibits TAG lipolysis in adipose tissue**
* TAG is primary FA source
* Liver utilizes FA for TAG synthesis
* **↓ TAG synthesis → ↓VLDL →↓ LDL**
* **↑ HDL by↓ its catabolism**
* ↑ Tissue plasminogen activator, ↓ fibrinogen
* Reverse some endothelial cell dyfxn, contributing to clots w/ hypercholesterolemia & atherosclerosis
45
What are the therapeutic uses of **Niacin**?
* Treatment of hyperlipidemia
* **↓LDL (15-25%), ↑ HDL (25-35%) the most**
46
List the side effects that can be caused by **Niacin**
| HIGH yield
* **Flushing ( ↓w/ ASA, IBU)**
* **Pruritis**
* N/V
* **Hepatitis** (Niaspan®)
* **Hyperuricemia (gout)**
* **Hyperglycemia (DM)**
47
Explain the pharmacokinetics of Niacin
Converted into nicotinamide which has no activity
48
# Drug interactions
What drug should not be taken with **Niacin** and why?
| HIGH yield
**Statins: ↑ muscle & liver toxicity risk**
49
Explain the mechanism of action of **Gemfibrozil**
* Peroxisome proliferator-activated receptor-α **(PPAR-α) agonists**
* PPAR-α –Transcription factor that regulates lipid metabolism
* **↓ TAG (40%) → lipoprotein lipase (TAG→FA)**
* ↑HDL (15-20%) → ↑apo A-I/II
* ↓ LDL (10-15%)
50
What are the therapeutic use(s) of **Gemfibrozil**?
Treatment of hyperlipidemia
51
List the side effects that can be caused by **Gemfibrozil**
* **Hepatitis**
* **Myositis** (weakness, stiffness)
* **Gallstones** (↑ bilary cholesterol excretion)
52
What drug should not be taken with **Gemfibrozil** and why?
* ↑Warfarin INR
* Statins: ↑ muscle & liver toxicity risk
53
What is the mechanism of action of **Cholestyramine**?
| Bile acid sequestrants
* **Anion exchange resins which bind (-) charged bile acids & salts in small intestines**
* Resin/bile acid complex excreted in feces
* Inhibiting entereohepatic recycling (gets rid of bile acid)
* **↓ bile acids→liver →cholesterol→bile acids**
* ↓ Intracellular cholesterol→liver→ ↑LDL uptake via cell surface receptors
* ↓plasma LDL (10-25%) & ↑ HDL (5-10%)
54
List the therapeutic uses and side effects of **Cholestyramine**
* Therapeutic use
1. Treatment of hyperlipidemia
2. **Little effect in patients lacking functional LDL receptors**
* Side effects:
1. **Constipation**
2. **N/V**
3. **Flatulence**
## Footnote
N/V=Nausea/Vomiting
55
What are the drug interactions of Cholestyramine?
**Acidic drugs, e.g., Warfarin, Niacin, Digoxin & Vitamins A, D, E, K**
## Footnote
Interferes w/ absorption
56
What is considered the safest class of lipid-modifying drugs during pregnancy?
| HIGH yield
Cholestyramine
57
What is the mechanism of action of **Ezetimibe**?
| Cholesterol absorption inhibitors
* **Inhibits cholesterol absorption at the brush border of the intestines & liver, ↑ LDL-R expression**
* ↓ in cholesterol stores→ ↓ plasma cholesterol
* ↓ LDL (15-20%), ↓ TAG (6%), ↑ HDL (5%)
58
List the therapeutic uses and side effects of **Ezetimibe**
* Therapeutic use
1. Treatment of Hyperlipidemia
* Side effects:
1. GI upset
## Footnote
Pharmacokinetics: UGT
59
What drug class has the greatest effects on decreasing LDL?
Statins
60
What drug class has the greatest effects on decreasing TAG?
Fibrates (Gemfibrozil)
61
What drugs class has the greatest effect on increasing HDL?
Niacin
62
What is the mechanism of action of Lomitapide?
| Microsomal triglyceride transfer protein inhibitoes
* Microsomal triglyceride transfer protein inhibitor
* **Prevents assembly of apo-B containing lipoproteins** (chylomicrons & VLDL in liver & GIT)
* ↓ plasma LDL concentrations
63
List the therapeutic use and side effects of **Lomitapide**
* Therapeutic use
1. **!!Treatment of homozygous familial hypercholesterolemia!!**
2. As an adjunct to lipid-lowering medications & diet
* Side effects:
1. LFT
2. FDA Pregnancy Category X
## Footnote
Pharmacokinetics: CYP3A4 substrate: DI, Hepatic dysfunction
64
What is the mechanism of action of **Evolocumab**?
| PCSK9 inhibitor
* **Selectively binds to PCSK9** & prevents PCSK9 from degrading LDL receptors in hepatocyte lysosomes which **↑ # of recycled LDL receptors**
* **↑ # of LDL receptors → ↓ LDL plasma concentrations**
65
List the therapeutic uses and side effects of **Evolocumab**
* Therapeutic use:
1. **heterozygous or homozygous familial hypercholesterolemia**
2. Atherosclerotic cardiovascular disease
3. Adjunct to Diet + **Statin therapy**
* Side effects:
1. Nasopharyngitis
2. Upper respiratory tract infection
3. Flu
4. Back pain
5. **Allergic reactions**
6. Injection site rxns (redness, pain, or brushing)
66
List examples of Omega-3-acid ethyl esters
* EicosaPentAenoic (20:5)-**EPA**
* DocosaHexAenoic acids (22:6)-**DHA**
67
What is the mechanism of action of **Omega-3-acid ethyl esters?**
| Fish oils
* Activation of nuclear transcription factors (e.g., peroxisome proliferator-activated receptor-α (PPAR-α))
* ↑ liver fatty acid oxidation → ↓ TAG synthesis
68
List the therapeutic use(s) of **omega-3-acid ethyl esters**
* Treatment of hyperlipidemia
* ↓ TAG (14-30%), ↑ HDL (10%)
* **↑ LDL (Icosapent [Pure prescription strength] the least)**
69
What are the side effects caused by **omega-3-acid ethyl esters?**
* Thrombocytopenia
* Halitosis
* Dysgeusia
* Dyspepsia
* Infection
* Back pain
* Flu-like syndrome
70
What is the mechanism of action for **Bempedoic acid?**
* **Inhibitor of ATP citrate lyase (Enzyme in de novo cholesterol synthesis)**
* **↑ LDL-R by ↓ cholesterol synthesis**
* Prodrug
* Active metabolite produced in liver not muscle, Less muscle toxicity?
71
What are the therapeutic use(s) of **Bempedoic acid**?
Adjunct to diet & **max tolerated statin for heterozygous familial hypercholesterolemia** or atherosclerotic cardiovascular
72
List the side effects caused by **Bempedoic acid?**
* **Gout**
* **Tendon rupture**
* Anemia
* ↑ Liver enz
* Muscle spasms
73
Review Slide 40
Review Slide 40
74
What is the mechanism of action **Inclisiran?**
| siRNA
* **Small interfering RNA (siRNA) for PCSK9 mRNA**
* **Inhibits PCSK9 synthesis**
75
What are the therapeutic use(s) and side effects of **Inclisiran?**
* Therapeutic use
1. Diet, Max Statin
2. **Heterozygous familial hypercholesterolemia**
3. Secondary prevention of cardiovascular events
* Side effects:
1. Antibodies
2. Arthralgia (Joint pain)
3. Bronchitis
76
Which of the following is the most clinically important side effect of the Niacin sustained release dosage form (Niaspan®)?
A. Dermatitis
B. Meningitis
C. Nephritis
D. Hepatitis
D. Hepatitis
77
Which of the following antihyperlipidemics effect TAG the greatest?
a. Gemfibrozil
b. Ezetimibe
c. Cholestyramine
d. Atorvastatin
a. Gemfibrozil
78
Which of the following inhibits PCSK9 synthesis via siRNA
a. Inclisiran
b. Bempedoic Acid
c. Cholestyramine
d. Gemfibrozil
a. Inclisiran
79
Which of the following is safest for pregnancy?
a. Atorvastatin
b. Niacin
c. Cholestyramine
d. Lomitapide
c. Cholestyramine
80
Which of the following can treat homozygous hypercholesterolemia?
a. Lomitapide
b. Atorvastatin
c. Niacin
d. All of the above
a. Lomitapide
