Atherosclerosis and lipoprotein metabolism Flashcards
Atherosclerosis=
Atherosclerosis= the build up of a
waxy plaque on the inside of
blood vessels
Atherogensis=
Atherogensis= formation of
abnormal fatty or lipid masses in
arterial walls
main risk factor of atherosclerosis and atherogenesis
high blood cholesterol
High Blood Cholesterol
* Estimated _____ million adults ≥ 20YO have TC ≥ _____
* New Cholesterol guidelines in 2018:
* Focused on?
* primary treatment to reduce cholesterol?
* Very high risk patients may need?
High Blood Cholesterol
* Estimated 28.5 million adults ≥ 20YO have TC ≥ 240mg/dL (High)
* New Cholesterol guidelines in 2018
* Focused on identifying high risk and very high risk patients
* Statins are the primary treatment to reduce cholesterol
* Very high risk patients may need combination therapy to reach LDL ≤ 70mg/dL
lipoproteins of interest
chylomicrons, LDL, HDL, VLDL
- Chylomicrons
% TG % pro
- Highest proportion of triglycerides
- VLDL
%TG %chol %pro
- Very Low Density Lipoprotein
- LDL
%TG %chol %pro
- Low Density Lipoprotein
- “Bad Cholesterol”
- HDL
%TG %chol %pro
- High Density Lipoprotein
- “Good Cholesterol”
lipoprotein density scale
Optimal Cholesterol Levels:
* Total Cholesterol
* HDL
* LDL
* Triglycerides
- Total Cholesterol: ≤ 200mg/dL
- HDL: ≥ 60mg/dL
- LDL: ≤ 100mg/dL
- Triglycerides: ≤ 150mg/dL
Friedewald Formula
less predictive with TG>400
Risk Factors for ASCVD
- Smoking
- Hypertension
- Hyperlipidemia: increased LDL and TC/ decreased HDL
- Diabetes mellitus
- Age (men ≥45 yo, women ≥55yo)
- Obesity
- Physical Inactivity
multiple risk factor effects
additive
ASCVD Risk Assessment
risk factors included? estimates? used to guide?
ASCVD Risk Score can be calculated with online tool
* Risk Factors used include: age, gender, total and HDL cholesterol, smoking status, blood pressure, diabetes,
and race
* Estimates 10-year risk of MI or stroke
* Used to guide lipid therapy
No need to calculate ASCVD score if patient has?
No need to calculate ASCVD score if patient has Clinical ASCVD
Clinical ASCVD:
* Established Coronary Artery Disease (CAD)
* History of stroke or TIA
* Peripheral Artery Disease (P
atherogenesis steps
HDL involvment?
- 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
at steps 3-5 HDL may remove cholesterol from vessel walls (The process of HDL mobilizing cholesterol and transporting back to the liver is called ‘reverse cholesterol transport)
normal Aa with athersclerosis
status of plaque and pt symptoms
Lipoprotein metabolism
* Exogenous pathway
- 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, or
3) enter endogenous pathway
Lipoprotein metabolism
* Endogenous pathway
- 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
HMG-CoA reductase inhibitors (Statins)
Mechanism of Action
- Inhibit HMG-CoA reductase
- Rate-limiting step in endogenous cholesterol production
- Also induce an increase in hepatic LDL receptors
HMG CoA inhibitor names
all end in -statin
HMG-CoA reductase inhibitors (Statins)
Effects on Lipid parameters
HMG-CoA reductase inhibitors (Statins)
Relative potency
high intensity statins
Atorvastatin 40-80mg
Rosuvastatin 20-40mg
HMG-CoA reductase inhibitors (Statins) Clinical benefits for primary prevention
* Target age? LDL?
* Use what to guide therapy?
* >7.5% to ≤ 20% risk?
* > 20% risk?
* helpful test?
* Diabetes?
- 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
HMG-CoA reductase inhibitors (Statins) Clinical benefits secondary prevention
* All patients that are?
* intensity statin?
* Very-high risk consider?
- All patients under 75 YO with established ASCVD
- High intensity statin
- Very-high risk consider combo therapy if LDL > 70mg/dL
HMG-CoA reductase inhibitors (Statins) Pleiotropic effects Positive:
* Plaque?
* inflamm?
* endothelial function?
* platelets?
* neovascularization?
- Plaque stabilization
- Reduced inflammation
- Improved endothelial function
- Reduced platelet aggregability
- Increased neovascularization of ischemic tissue
HMG-CoA reductase inhibitors (Statins)
Pleiotropic effects* Negative/Neutral:
pregnancy?
immune?
- Inhibition of germ cell migration during development (Pregnancy contraindication)
- Immune suppression
HMG-CoA reductase inhibitors (Statins)
Adverse Drug Reactions & Contraindications
HMG-CoA reductase inhibitors (Statins) Drug-Drug Interactions
* Many DDI due to?
* Impaired statin metabolism→?
* Impaired clearance of competing drug →?
* Pravastatin and Rosuvastatin?
- 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 → ?
what can cause this?
Impaired statin absorption → decreased statin efficacy
* Example: Bile acid binding agents
statin Increased risk of myopathy from interaction?
Increased risk of myopathy (pharmacodynamics interaction)
* Other drugs that also have a risk of myopathy (ex. Fibrates)
atorvastatin ADRs
- ADRs: Elevated liver enzymes(hepatotoxicity), myopathy, rhabdomyolysis
- Pregnancy category: X (contraindicated)
atorvastatin drug interactions
* Increased risk of myopathy with?
* Increased effects of?
- Increased risk of myopathy with erythromycin, ketoconazole, itraconazole
- Increased effects of midazolam when used in combination
atorvastatin dental
Dental implications: Myopathy may present as weakness with chewing or brushing teeth
Atorvastatin
* MOA:
- MOA: HMG-CoA reductase inhibitor
PCSK-9 Inhibitors Mechanism of Action
- 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
PCSK-9 Inhibitors names
Alirocumab
Evolocumab
PCSK-9 Inhibitors
Effects on Lipid parameters (TC, LDL, TG, HDL)
PCSK-9 not common why?
PCSK-9 inhibitors are given by SQ injection
Cash price was $14,500/year in 2018 price was 60% to ~$5,800/year
Alirocumab
* MOA
* Dental implications
- MOA: Binds to proprotein subtilisin kexin type 9 (PCSK9).
Preventing PCSK9 from binding LDL receptors, thereby
promoting LDL degretation within the liver - Dental implications: none
alirocumab ADRs
Injection site reactions, diarrhea, decreasing LDL too low
alirocumab interactions
none of dental significance
ATP-citrate lyase (ACL) inhibitor
Bempedoic acid (Nexletol®) only drug in class
* Inhibit cholesterol synthesis two -steps ahead of statins (HMG- CoA reductase inhibitors)
* Approved by the FDA in February 2020
* Not addressed in clinical guidelines
Bempedoic acid
Effects on Lipid parameters (TC, TG, LDL, HDL)
Bempedoic acid and ezetimibe
Synergistic LDL lowering when combined with ezetimibe therapy
Bempedoic acid
* MOA
* Drug-Drug interactions:
* Dental implications:
- MOA: Inhibit cholesterol synthesis two-steps ahead of statins
- Drug-Drug interactions: None of significance to dentistry
- Dental implications: none
bempedoic acid ADR
Elevated uric acid, back pain, elevated liver enzymes
Inhibitors of cholesterol absorption names
(Ezetimibe and Bile acid binding agents )
Absorption inhibitors:
* Ezetimibe
* Ezetimibe/Simvastatin
Bile acid binding agents:
* Cholestyramine
* Colesevelam
* Colestipol
Ezetimibe
Mechanism of Action
- Blocks cholesterol absorption in the intestine
(duodenum) - Blocking transport protein NPC1L1 in the brush border of the enterocyte
- Does not affect absorption of fat-soluble vitamins, triglycerides, or bile acid
Ezetimibe
Effects on Lipid parameters
Ezetimibe synergestic with?
statins, can lower LDL synergistically
Ezetimibe
* MOA:
* Drug-Drug interactions:
* Dental implications:
- MOA: Blocks absorption of cholesterol in the intestine by blocking the NPC1L1 transport protein
- Drug-Drug interactions: None of significance to dentistry
- Dental implications: none
ezetimibe ADRs
Rare- maybe back pain or diarrhea
Bile Acid Binding Agents
Mechanism of Action
- Bind to bile acid in the intestine
- Prevent resorption of bile acid
- Result in increase uptake of LDL by liver
Bile Acid Binding Agents
Effects on Lipid parameters
can actually raise Tg
Colesevelam
* MOA:
Bile acid binder
* MOA: Binds bile acid preventing resorption
colesevelam ADRs
Mainly GI distress- constipation, abdominal pain, nausea, dyspepsia
coleveselam interactions
- Drug-Drug interactions: None of significance to dentistry
- Many others due to inhibition of absorption of medications
- Take 1 hour before or 2 hours after other medication
Bile Acid Binding Agents
Example: Colesevelam-Dental Implications
- Consider semisupine chair position for patient comfort due to GI side effects of medication
Fibrates Mechanism of Action
- Complex mechanism of action
- Agonist of PPARα nuclear receptor
- Increase transcription of lipoprotein lipase= Marked decrease in VLDL and triglycerides
- Also increase LDL uptake and HDL synthesis
fibrate names
FenoFIBrate
FenoFIBric Acid
GemFIBrozil
Fibrates
Effects on Lipid parameters
mainly target Tg
Fenofibrate
* MOA:
- Drug-Drug interactions:
- MOA: PPARα nuclear receptor agonist increasing lipoprotein lipase levels
- Drug-Drug interactions: None of significance to dentistry
fenofibrate ADRs
Myopathy
dyspepsia
blurred vision/eye floaters
elevations in liver enzymes
GI distress
* Increase r/o ADRs when combined with statin
Fibrates
Example: Fenofibrate-Dental Implications
- Consider semisupine chair position for patient comfort due to GI side effects of medication
- Avoid dental light in patient’s eyes; offer dark glasses for patient comfort due to vision side effects
- May cause dry mout
Nicotinic acid or its derivatives
Mechanism of Action
- Inhibits hepatic VLDL secretion
- Lowers serum Triglycerides and LDL
- Increases serum HDL
Niacin
Effects on Lipid parameters
Dose of lipid lowering effects 500mg-2000mg daily, much higher than daily vitamins
Niacin Adverse Drug Reactions
* Flushing? counter?
* GI?
* Liver?
* glucose?
* gout?
- Flushing: Reduced by taking aspirin 30 minutes before dose
- Gastrointestinal distress: Nausea, vomiting, or diarrhea
- Liver damage/dysfunction (increased liver enzymes), Can occur at any time during therapy
- Impaired glucose tolerance: Can worsen a patient’s control of diabetes
- Precipitate gout flare: increased circulating uric acid level
Niacin
* MOA:
* Drug-Drug interactions:
- MOA: Inhibits synthesis of VLDL
- Drug-Drug interactions: None of significance to dentistry
niacin dental implications
- Dental implications: Minor- may cause dizziness so be careful when standing up, May increase risk of bleeding
niacin ADRs
flushing
GI distress
Liver dysfunction
glucose intolerance
gout flare
* Increased risk of hepatotoxicity when combined with statin
Most potent
medication for
LDL lowering?
PCSK9 inhibitors: Alirocumab, Evolocumab
what medication class could raise TG’s?
Bile Acid Binding Agents: Cholestyramine, Colesevelam, Colestipol
