Atherosclerosis and Lipoprotein Metabolism Flashcards
What are the different types of lipoproteins?
IMPORTANT
- Chylomicrons
— Highest proportion of triglycerides - VLDL
— Very Low-Density Lipoprotein - LDL
— Low Density Lipoprotein
— “Bad Cholesterol” - HDL
— High Density Lipoprotein
— “Good Cholesterol”
What are the optimal cholesterol/lipoprotein levels?
- Total Cholesterol
— ≤ 200mg/dL - HDL
— ≥ 60mg/dL - LDL
— ≤ 100mg/dL - Triglycerides
— ≤ 150mg/dL
What are the levels of lipoproteins in atherosclerotic disease (ASCVD)?
Hyperlipidemia
* ↑ LDL and TC
* ↓ HDL
What are the risk factors for atherosclerotic disease?
IMPORTANT
- Smoking
- Hypertension
-
Hyperlipidemia
— ↑ LDL and TC
— ↓ HDL - Diabetes mellitus
- Age (men ≥45 yo, women ≥55yo)
- Obesity
- Physical Inactivity
- Race
- Family history of premature CVD
What is the process of formation of an atherosclerotic plaque?
IMPORTANT
- Endothelial dysfunction
- Endothelial injury
- LDL deposits into vessel wall
- Formation of foam cells (Macrophages filled with LDL)
- Fatty Streak
- Inflammation (Smooth muscle growth)
- Fibrous cap over lipid core
HDL removes cholesterol from vessel walls at steps 3, 4, and 5
Atherosclerotic plaque formation in picture form
What is the process of lipoprotein metabolism exogenous?
- Cholesterol and TG absorbed from diet transported as chylomicrons to muscle and adipose tissue
- Chylomicrons metabolized by lipoprotein lipase to release TG
- Chylomicron remnants (mostly cholesteryl esters) return to the liver
- Cholesterol in liver may be
— 1) stored
— 2) turned into bile
— 3) enter endogenous pathway
What is the process of lipoprotein metabolism endogenous?
- Cholesterol and TG made in liver leave as VLDL
- VLDL metabolized by lipoprotein lipase
to release TG- VLDL becomes LDL - LDL provides cholesterol source for cells to make cell membranes- also atherogenesis
- Cell use an LDL-receptor to take up LDL
- Liver releases HDL to collect cholesterol and return to liver (reverse cholesterol transport)
- Cholesteryl ester transfer protein (CETP) facilitates the transfer of cholesterol to HDL
Lipoprotein metabolism process in a chart…
What is the mechanism of action of HMG-CoA reductase inhibitors (Statins)?
- Inhibit HMG-CoA reductase
- Rate-limiting step in endogenous cholesterol production
- Also induce an increase in hepatic LDL receptors
What are the effects of HMG-CoA reductase inhibitors (Statins) on lipid parameters?
- they do everything we want them to do… lower the bad stuff and raise the good stuff
What are the relative potencies for HMG-CoA reductase inhibitors (Statins)?
High
- Daily dose lowers LDL by ≥ 50%
Moderate
- Daily dose lowers LDL by 30% -<50%
What are the high intensity statins?
- Atorvastatin
- Rosuvastatin
What are the clinical benefits of HMG-CoA reductase inhibitors (Statins)?
Primary Prevention
* Target age 40-75 YO with LDL 70-189mg/dL
* Use ASCVD risk score to guide therapy
— >7.5% to ≤ 20% risk ≈ moderate intensity statin
— > 20%- high intensity statin
* Coronary Calcium Score helpful
* Diabetes
— All patients get at least moderate intensity statin
Secondary Prevention
* All patients under 75 YO with established ASCVD
* High intensity statin
* Very-high risk consider combo therapy if LDL > 70mg/dL
What are the pleiotropic effects of HMG-CoA reductase inhibitors (Statins)?
Positive:
* Plaque stabilization
* Reduced inflammation
* Improved endothelial function
* Reduced platelet aggregability
* Increased neovascularization of ischemic tissue
Negative/Neutral:
* Inhibition of germ cell migration during development (Pregnancy contraindication)
* Immune suppression
Whta are the common adverse drug reactions for HMG-CoA reductase inhibitors (Statins)?
IMPORTANT
Adverse Drug Reaction
H - Hepatotoxicity
M - Myopathy ranging from mild soreness to Myositis to rhabdoMyolysis
Contraindications
G - Girls (during pregnancy) & Growing children
- and memory loss apparently
What are the drug-drug interactions for HMG-CoA reductase inhibitors (Statins)?
- Many DDI due to hepatic metabolism (via CYP450 3A4 or PgP)
— Impaired statin metabolism→ increased risk of hepatotoxicity or myopathy
— Impaired clearance of competing drug → increased risk of competing drug ADRs
— Pravastatin and Rosuvastatin are not significantly cleared via CYP450 and have the least amount of DDI of this type - Impaired statin absorption → decreased statin efficacy
— Example: Bile acid binding agents - Increased risk of myopathy (pharmacodynamics interaction)
— Other drugs that also have a risk of myopathy (ex. Fibrates)
Determine dental implications of lipid-lowering medications
- Myopathy may present as weakness with chewing or brushing teeth
What are examples of other lipid-lowering medication agents?
- PCSK-9 inhibitors
- ATP-citrate lyase (ACL) inhibitor
- Inhibitors of cholesterol absorption (ezetimibe and bile acid binding agents)
- Fibrates
- Nicotinic acid or its derivatives
- Other miscellaneous agents (evinacumab, inclisiran, and lomitapide)
What is the mechanism of action for PCSK-9 inhibitors?
- Block the action of proprotein subtilisin kexin type 9 (PCSK9)
- PCSK-9 promotes the degradation of LDL receptors
- Inhibition of PCSK-9 results in more active LDL receptors and lower serum LDL
What are the effects on lipid parameters for PCSK-9 inhibitors?
Most potent medication for LDL lowering
What are the common adverse drug reactions for PCSK-9 inhibitors?
IMPORTANT
Injection site reactions, diarrhea, decreasing LDL too low
Alirocumab, Evolocumab, Inclisiran
What are the common drug-drug interactions of PCSK-9 inhibitors?
None of significance to dentistry
What is the mechanism of action for ATP-citrate lyase (ACL) inhibitor?
Inhibit cholesterol synthesis two steps ahead of statins (HMG-CoA reductase inhibitors)
