1) Antihyperlipidemic Agents

What are the lipoprotein levels associated with CHD?

• ↑ LDL-C

• ↑ TG

• ↓ HDL-C

What is the source of chylomicron and VLDL? What are they mainly composed of?

• Chylomicrons are secreted by the intestinal mucosa (produced primarily from dietary lipids)

• VLDL is secreted by the liver

• Both are mainly composed of TG

Name the enzyme responsible for degradation of VLDL and chylomicron. How is it activated?

Lipoprotein lipase

• activated by apo CII

How is LDL cleared?

bind to specific receptors on the liver and extrahepatic tissues, where they are endocytosed

What are the characteristics of Type 2A hyperlipidemia?

→ characterized by ↑ LDL with normal VLDL levels due to a block in LDL degradation → ↑ serum cholesterol, but normal TG levels

• caused by defects in the synthesis or processing of LDL receptors

• ischemic heart disease is greatly accelerated

• Treatment: Diet

What is the consequence of depletion of intracellular cholesterol?

→ causes ↑ LDL receptors on cell surface

• these receptors bind and internalize circulating LDL-C → ↓ plasma cholesterol levels

Name 2 potent statins based on their ability to lower LDL-C.

1. Rosuvastatin

2. Atorvastatin

What enzyme is involved in the RLS of cholesterol synthesis? What does inhibiton of this enzyme lead to?

HMG CoA reductase - where inhibition → ↓ intracellular cholesterol & ↑ LDL receptors

What are the 2 main adverse effects of statins?

1. Liver failure

2. Myopathy

By how much does Niacin ↓LDL-C by?

10-20%

What else can Niacin be used in combination with?

can be used with Statins

What are PPARs (peroxisome proliferator–activated receptors)? What is the consequence of their activation?

→ members of the nuclear receptor family that regulate lipid metabolism

• act as ligand-activated transcription factors

.

PPAR activation leads to:

• ↑ lipoprotein lipase & ↓ apo CII expression = ↓[TG]

• ↑ apo AI & ↑ apo AII = ↑ HDL-C

Give the 3 main adverse effects of fibrates.

• Predisposition to form gallstones

• Myositis

• Mild GI disturbances

What are Bile acid sequestrant used in combo with? To treat what?

→ useful in combo with diet or niacin

• Treat type 2A & 2B hyperlipidemias

By how much does Cholesterol absorption inhibitor lower LDL-C by?

18% to 23%

What is the role of PSKC9 enzyme?

binds to the LDL receptor on hepatocyte surface → LDL receptor degradation

How does Alirocumab work?

PCSK9 inhibitor that prevents LDL receptor degradation → makes more receptors available to clear LDL-C from the serum

When combined with statin therapy, by how much can PCSK9 inhibitors provide potent LDL-C lowering?

50% to 70%

What are Omega-3 fatty acids (PUFAs)?

→ essential fatty acids that ↓ TG

• inhibit VLDL and TG synthesis in the liver

Name the 2 PUFAs and their source.

1. Eicosapentaenoic acid (EPA)

2. Docosahexaenoic acid (DHA)

.

Source: marine-derived (fish oil)

What is the risk of taking PUFAs with antiplatelet or anticoagulant drugs?

↑ bleeding risk

What is combination therapy for hyperlipidemia?

uses 2 antihyperlipidemic drugs to achieve treatment goals

What category of patients are considered for combination therapy?

Patients with

• ASCVD

• ↑ 10-year risk of ASCVD

• those who didn’t achieve intended ↓LDL-C on maximally tolerated statin therapy

Give examples of drugs in any 2 combination tablet formulations for hyperlipidemia.

1. Ezetimibe + simvastatin

2. Niacin + lovastatin extended-release

3. Niacin + simvastatin extended-release