Pharmacology I: 4.3 Anti-Dyslipidemia

Niacin MOA?

- Decreases TG breakdown (adipocytes)

- Decreases Apo A1 degradation (liver)

NPC1L1 inhibitor

ezetimibe

NPC1L1 inhibitor MOA

Inhibits the intestinal cholesterol transporter

- Decreases LDL-C

- Increases number of LDL R

PCSK9 inhibitor

Evolocumab

Inclisiran

PCSK9 inhibitor MOA

Bind to and inhibit the protein that leads to LDL receptor degradation

- Decreases LDL-C

- Increased LDL-R

What does niacin bind to?

Binds to the niacin receptor on adipocytes which decreases hormone sensitive lipase--> decreases triglyceride breakdown--> decreases plasma free fatty acids

What does niacin lead to fewer levels of?

Fewer plasma free fatty acids which decreases DGAT2 activity which decreases TAG synthesis

What does decrease in App-A1 degradation by niacin lead to?

Ultimately increases HDL-C levels and binding to LDL receptor and uptake by the liver

Niacin

Vitamin B3

-- Nicotinic acid

-- Nicotinamide (metabolite)

- Adipocytes

- OTC and prescription reparations

What are uses for niacin?

• Isolated low HDL

• Low HDL with mildly elevated LDL or TAG

• Familial combined hyperlipidemia

What are very serious adverse effects with niacin?

- Hepatotoxicity

- Rhabdomyolysis

Hepatoxicity

Nicotinamide-mediated liver inflammation

Rhabdomyolysis

Damage to muscle fibers releases myoglobin into blood stream (serious and life threatening)

What can rnhabdomylosis lead to?

- Brown discoloration of urine

- Renal tubular damage--> acute renal failure

What are some other adverse effects of niacin?

• Insulin resistance (hyperglycemia)

• Increases plasma uric acid levels

• Flushing and itching (common 20%)

• Abdominal discomfort

• Dry skin- use moisturizers

Flushing and itching

• Affects compliance

• Can pretreat with low-dose aspirin -inhibit COX-1 or

• Apple sauce - slows niacin absorption in gut

• Extended release formulas

What is the mechanism with niacin-induced flushing?

Activation of GPR109A in dermal Langerhans cells

What does flushing increase the production of?

Prostaglandin D2/E2 which leads to inflammation and vasodilation

How was ezetimibe developed?

Was developed before its molecular target was identified

What did 2004 SW Altmann and HR David identify?

A cholesterol transporter from cDNA sequence data: NPC1L1

What is activity of ezetimibe like?

Active as is but also active glucuronide metabolite

What is done to the metabolite for ezetimibe?

It is recirculated via liver (extends action)

What does both forms of ezetimibe do?

Binds to NPC1L1 from transporting cholesterol and prevent NPC1L1 internalization

What does ezetimibe lower?

Lowers dietary contribution of cholesterol but mildly effective

What is ezetimibe metabolized by?

Liver and intestine UGT1A1, 1A3, and 2B15

Whaere is ezetimibe mainly excreted by?

Feces with some urine

Where can ezetimibe be added to?

Other antidyslipidemics in patients who need greater cholesterol lowering such as statins

PCSK9 MOA

Binds to LDL receptor and targets LDLR's for degradation in liver cells

What are PCSK9 inhibitor MOA?

mAb against PCSK9

Inclisiran

small interfering RNA-based therapy against PCSK9

What do they both reduce the activity of?

PCSK9 and increase LDLR on cell surface

What are clinical applications for evolocumab and inclisiran?

• Heterozygous familial hypercholesterolemia (HeFH)

• Clinical ASCVD requiring additional lowering of LDL-C

What is the clinical application for evolocumab only?

Homozygous FH

What do mAb's do?

Bind and neutralize the activity of PCSK9

What are they?

fully humanized antibodies

What are they produced by?

Recombinant DNA technology in Chinese hamster ovary cell suspension culture

How can it be given subcutaneously?

Subcutaneous (SC) dose of alirocumab (75 mg or 150 mg) 85% bioavailable

How's administration for injectables done?

Once every 2 weeks

What does it have nooo affect on?

No affect on CYP enzymes or transporter proteins, such as permeability glycoprotein (P-gp) or organic anion-transporting polypeptide (OATP)

What are adverse effects in evolocumab, alirocumab, and inclisiran?

• Injection site reaction- both are injectables

• Hypersensitivity reaction (mild or severe)

• Nasopharyngitis, upper respiratory tract infection, influenza, back pain, myalgia, arthralgia, diarrhea

What are adverse effects with evolocumab only?

Dizziness, hypertension

What are adverse effects with alirocumab only?

elevated liver enzymes