Cardio Exam 2: Elsaid Dyslipidemia (DRUGS + PATHWAYS)

What are the major sites of action for cholesterol-lowering drugs?

Liver

• _____

• _____

• _____

Intestine

• _____

• _____

Statins, Bempedoic Acid, PCSK9 Inhibitors, Ezetimibe, BAS

What are the major functions of cholesterol?

• Cell membrane _____

• _____ synthesis

• _____ synthesis

• _____ synthesis

structure/fluidity, steroid hormone, sex hormone, vitamin D

What enzyme do statins inhibit?

HMG-CoA Reductase

What is the MOA of statins?

• _____ → ↓ _____ → ↑ _____ expression → ↑ _____ → ↓ _____

Inhibits HMG-CoA reductase, cholesterol synthesis, LDL receptor, LDL removal from blood, LDL-C

What are the pleiotropic effects of statins?

• Improve _____ function

• Reduce _____

• Decrease _____

• Decrease _____

• Stabilize _____

endothelial, inflammation, platelet aggregation, thrombin generation, plaques

Why do statins reduce future heart attacks?

They stabilize atherosclerotic plaques

Name all statins from your notes (6)

Atorvastatin, Rosuvastatin, Simvastatin, Lovastatin, Pravastatin, and Pitavastatin

Which statins are high-intensity?

Atorvastatin and Rosuvastatin

Which statin is the most potent HMG-CoA reductase inhibitor?

Rosuvastatin

Which statins are hydrophilic?

Pravastatin and Rosuvastatin

Why do pravastatin and rosuvastatin cause less muscle pain?

Hydrophilic drugs enter muscle tissue less readily

Increased lipophilicity increases what adverse effect?

Muscle pain (SAMS)

Which statins should generally be taken at bedtime?

Statins with short half-lives

What does SAMS stand for?

Statin Associated Muscle Symptoms

What are the four major muscle toxicities of statins?

Myalgia, Myopathy, Myositis, and Rhabdomyolysis

Which statin adverse effect is life-threatening?

Rhabdomyolysis

What liver monitoring is recommended with statins?

Baseline liver enzymes only

Which metabolic disease may occur with long-term statin use?

New-onset Type 2 Diabetes

What transporter does ezetimibe inhibit?

NPC1L1 transporter

What does NPC1L1 normally do?

Cholesterol uptake from the intestine

What is the MOA of ezetimibe?

• _____ → ↓ _____ → ↓ _____ delivery to _____ → ↑ _____

Blocks NPC1L1, intestinal cholesterol absorption, cholesterol, liver, LDL clearance from blood

Main adverse effect of ezetimibe?

Minimal GI effects

What protein is targeted by PCSK9 inhibitors?

PCSK9

What type of drugs are PCSK9 inhibitors?

Fully humanized Mabs

Which drugs are PCSK9 inhibitors?

Alirocumab (Praluent) and Evolocumab (Repatha)

How are PCSK9 inhibitors administered?

SQ injection every 2-4 weeks

How are PCSK9 inhibitors eliminated?

Protein degradation into amino acids and peptides, no renal elimination

What type of drug is inclisiran?

Small interfering RNA (siRNA)

What protein does inclisiran ultimately reduce?

PCSK9

What complex is involved in inclisiran's mechanism?

RISC (RNA-induced silencing complex)

Describe inclisiran's pathway.

• _____ delivery → _____ uptake → _____ strand binds _____ → _____ destroys _____ mRNA → ↓ _____ production → ↓ _____

GalNAc, hepatocyte, guide, RISC, RISC, PCSK9, PCSK9, LDL-C

What enzyme does bempedoic acid inhibit?

ATP-citrate lyase (ACL)

Where is ACL relative to HMG-CoA reductase?

Upstream

What is the MOA of bempedoic acid?

• _____ → ↓ _____ → ↑ _____ → ↓ _____

Inhibits ACL, cholesterol synthesis, LDL receptors, LDL-C

Which enzyme activates bempedoic acid?

ACSVL1

Why does bempedoic acid cause less muscle pain than statins?

Muscle cells lack ACSVL1, so the drug is not activated there

Which patients commonly receive bempedoic acid?

HeFH and Established ASCVD

What are bile acid sequestrants also called?

Resins

What is the MOA of bile acid sequestrants?

• _____ → Prevent _____ → _____ uses cholesterol to _____ → ↓ _____

Bind bile acids in intestine, reabsorption, liver, make more bile acids, LDL-C

Common adverse effects of BAS?

Nausea, Bloating, Constipation, and Gas

Major contraindication to BAS?

Triglycerides >300 mg/dL

Which receptor is activated by fibrates?

PPAR-alpha

What enzyme is increased by fibrates?

Lipoprotein lipase (LPL)

What is the MOA of fenofibrate?

• _____ → ↑ _____ → _____ → ↓ _____

Activates PPAR-alpha, LPL, hydrolysis of TGs, TG

Which drugs are fibrates?

Fenofibrate and Gemfibrozil (Lopid)

Which fibrate is marketed as Lopid?

Gemfibrozil

Which fibrate is commonly tested with statin-associated myopathy?

Fenofibrate

What is another name for nicotinic acid?

Niacin

What is the MOA of niacin?

• ↓ _____ tissue → ↓ _____ → ↓ _____ → ↑ _____

Free FA release from adipose, hepatic VLDL production, LDL, HDL

What enzyme activity increases with niacin?

Lipoprotein lipase (LPL)

Most famous adverse effect of niacin?

Flushing

Why should niacin be avoided in many heart disease patients?

Vasodilation can cause reflex tachycardia

What enzyme do omega-3 fatty acids inhibit?

Lipoprotein lipase (LPL)

What is the MOA of omega-3 fatty acids?

• _____ → ↑ _____ → ↓ _____ → ↓ _____

Inhibits TG synthesis, LPL, VLDL, TGs

What do EPA and DHA stand for?

Eicosapentaenoic Acid and Docosahexaenoic Acid

Name all omega-3 prescription products.

Lovaza, Epanova, and Vascepa

Which drug classes primarily lower LDL?

Statins, Ezetimibe, PCSK9 inhibitors, Inclisiran, Bempedoic Acid, and BAS

Which drug classes primarily lower triglycerides?

Fibrates, Omega-3 fatty acids, and Niacin

• STATINS = Stop Synthesis

• Ezetimibe = Exit cholesterol from intestine

• PCSK9 inhibitors = Preserve LDL receptors

• Fibrates = Fire up PPAR-α

• Niacin = No VLDL

• Omega-3 = Oppose triglycerides

• Bempedoic = Before HMG-CoA (ACL is upstream)

KNOW

KNOW IMAGE

Name the three major bile acid sequestrants.

Cholestyramine (Questran), Colestipol (Colestid), and Colesevelam (Welchol)

Which PCSK9 inhibitor is marketed as Praluent?

Alirocumab

Which PCSK9 inhibitor is marketed as Repatha?

Evolocumab

Which omega-3 product contains EPA + DHA ethyl esters?

Lovaza

Which omega-3 product contains EPA + DHA fatty acids?

Epanova

Which omega-3 product contains only EPA?

Icosapent Ethyl (Vascepa)

What are the common brand names for fenofibrate?

Tricor and Trilipix

Which statin is most potent for LDL reduction?

Rosuvastatin

Which enzyme activates bempedoic acid?

ACSVL1