Atherosclerosis and Lipoprotein Metabolism Flashcards
what is atherosclerosis
the build up of a waxy plaque on the inside of blood vessels
in greek, athere means:
gruel
in greek skleros means:
hard
what is atherogenesis
formation of abnormal fatty or lipid masses in arterial walls
main risk factor for atherosclerosis and atherogenesis is:
high blood cholesterol
what is the primary treatment to reduce cholesterol
statins
very high risk patients may need _____ to reach LDL less than 70mg/dL
combination therapy
what are the lipoproteins
- chylomicrons
- VLDL
- LDL
- HDL
which lipoprotein has the highest proportion of triglycerides
chylomicrons
what is the optimal total cholesterol level
less than 200 mg/dL
what is the optimal level for HDL
greater than 60 mg/dL
what is the optimal level for LDL
less than 100mg/dL
what is the optimal triglyceride level
less than 150 mg/dL
what is the Friedewald Formula
total cholesterol = LDL + HDL + TG/5
what are the risk factors for ASCVD
- smoking
- hypertension
- hyperlipidemia (high LDL and TC, low HDL)
- DM
- Age (men greater than 45 yo, women greater than 55yo)
- obesity
- physical inactivity
what are the clinical manifestations of ASCVD
- established coronary artery disease (CAD)
- history of stroke or TIA
- peripheral artery disease (PAD)
when do you need to calculate ASCVD
if the patient has clinical ASCVD
what are the steps of atherogenesis
- 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
what removes cholesterol from vessel walls
HDL
what is reverse cholesterol transport
the process of HDL mobilizing cholesterol and transporting back to the liver
what are the patient symptoms for atherosclerosis
angina -> acute coronary syndrome -> unstable angina, NSTEMI, STEMI
what is the exogenous pathway of lipoprotein metabolism
- 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 cholesterol esters) return to the liver
- cholesterol in liver may be stored, turned into bile, enter endogenous pathway
what is the endogenous pathway in lipoprotein metabolism
- 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
what are the lipid lowering medications
HMG-CoA reductase inhibitors (statins)
what is the mechanism of action of 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 statins of lipid parameters
- total cholesterol: decrease of 13-40%
- LDL: decrease of 17-55%
- triglycerides: decrease 2-28%
- HDL: increase 2-10%
what is the definition of high and moderate intensity statin therapy
- high: daily dose lowers LDL by greater than 50%
- moderate: daily dose lowers LDL by 30-50%
what are the high intensity statins
atorvastatin and rosuvastatin
what is the primary prevention with statins
- target age 40-75 YO with LDL 70-189 mg/dL
- use ASCVD risk score to guide therapy
- coronary calcium score helpful
- diabetes- all patients get at least moderate intensity statin
what is the secondary prevention for statins
- all patients under 75 YO with established ASCVD
- high intensity statin
- very high risk consider combo therapy if LDL greater than 70 mg/dL
what are the positive pleiotropic effects of statins
- plaque stabilization
- reduced inflammation
- improved endothelial function
- reduced platelet aggregability
- increased neovascularization of ischemic tissue
what are the negative/neutral pleiotropic effects of statins
- inhibition of germ cell migration during dvelopment - pregnancy contraindication
- immune suppression
what are the adverse drug reactions for statins
- H- hepatotoxicity
- M- myopathy - ranging from myositis to rhabdomyloysis
- Girls and growing children
what are the drug-drug interactions for statins
- many DDI due to hepatic metabolism
- impaired statin metabolism -> increased risk of hepatotoxicity or myopathy
- impaired clearance of competing drug -> increased drug of competing drug ADRs
- pravastatin and rosuvastatin are not cleared via CYP450
- impaired stain absorption -> decreased statin efficacy
- increased risk of myopathy
what are the other lipid lowering medications
- fibrates
- ACL- I
- ezemtimibe
- PCSK-9
- BABA
- niacin
what is the mechanism of PCSK-9 inhibitors
- block the action of proprotein subtilisin kexin type 9
- PCSK-9 promotes the degradation of LDL receptors
- inhiibition of PCSK-9 results in more active LDL receptors and lower serum LDL
what are the names of PCSK-9 inhibitors
- alirocumab
- avolocumab
what are PCSK-9 inhibitors effects on lipid parameters and how are they given
- decrease LDL by 60%
- most potent medication for LDL lowering
- given by SQ injection
- cost is $5,800/year
what is the use, ADRs, drug interactions and dental implications for alirocumab
- use: familial hyperlipidemia and high risk CV patients
- ADRs: injection site reactions, diarrhea, decreasing LDL too low
- drug-drug interactions: none to dentistry
- dental implications: none
what is the drug name of ATP- citrate lyase inhibtor and what does it do
- bempedoic acid
- inhibit cholesterol synthesis two steps ahead of statins
what are bempedoic acid effects on lipids
- decrease in LDL by 15-20%
- synergistic LDL lowering when combined with ezetimibe therapy
what is the use, ADRs, drug interactions and dental complications of bempedoic acid
- elevated uric acid, back pain, elevated liver enzymes
- drug interactions: none to dentistry
- dental implications: nonee
what are the absorption inhibitors of inhibitors of cholesterol absorption
- ezetimibe
- ezetimibe/simvastatin
what are the bile acid binding agents in cholesterol absorption
- cholestyramine
- colesevelam
- colestipol
what is the MOA of ezemtimibe
- blocks cholesterol absorption in the intestine
- blocking transport protein NPC1L1 in the brush border of the enterocyte
- does not affect absorption of fat soluble vitamins, triglycerides or bile acid
what are ezetimibe effects on lipid parameters
decrease by LDL 18-20%
- synergistic LDL lowering when combined with statin therapy
what are the uses, ADRs, drug interactions and dental implications of ezetimibe
- use: HLD
- ADRs: rare - maybe back pain or diarrhea
- drug interactions: none to dentistry
- drug: none
what is the MOA of bile acid binding agents
- bind to bile acid in the intestine
- prevent resorption of bile acid
- result in increase uptake of LDL by liver
what are bile acid binding agents effects on lipid parameters
triglycerides increased by 2-16%
what is an example of, use, ADRs, drug interactions of bile acid binding agents
- example: colesevelam
- use: HLD
- ADRs: mainly Gi distress, constipation, abdominal pain, nausea, dyspepsia
- drug interactions: none
- dental: consider semisupine chair position for patient comfort due to GI side effects of medication
what is the MOA of fibrates
- complex mechanism of action
- agonist of PPARalpha nuclear receptor
- increase transcription of lipoprotein lipase: marked decrease in VLDL and triglycerides
- also increase LDL uptake and HDL synthesis
what are the fibrates effects on lipid parameters
decrease of 20-50% of triglycerides
what is the example, use, ADRs, drug-drug interactions for fibrates
- fenofibrate
- use: HLD- specifically hypertriglyceridemia
- ADRs: myopathy, dyspepsia, blurred vision/eye floaters, elevations in liver enzymes, GI distress
- drug interactions: none relevant to dentistryw
what are the dental implications for fibrates
- consider semisupine chair position for patient comfort due to GI side effects of medication
- avoid dental light in patients eyes, offer dark glasses for patient comfort due to vision SE
- dry mouth
what is the MOA of nicotinic acid or its derivatives
- inhibits hepatic VLDL secretion
- lowers serum triglycerides and LDL
- increases serum HDL
what are niacin effects on lipid parameters
decrease of 20-50% of triglycerides
- dose of lipid lowering effects 500-2000mg daily
what are the ADRs of niacin
- flushing: reduced by taking aspirin 30 mins before dose
- GI distress: nausea, vomiting, diarrrhea
- liver damage/dysfunction ( increase liver enzymes)
- imparied glucose tolerance
- precipitate gout flare: increased ciruclating uric acid level
what is the use, drug interactions and dental implications of niacin
- use: HLD- mainly hypertriglyceridemia
- drug interactions: none to dentistry, increased risk when combined with statin
- dental implications: minor- may cause dizziness- careful when standing up. may increase risk of bleeding
what is the MOA of evinacumab
human monoclonal antibody that binds to and inhbits angiopoietin- like ANGPTL3. promotes VLDL processing and clearance upstream of LDL formation
what is the use, ADRs, drug interactions, dental implaications and cost of evinacumab
- use: HoFH
- ADRs: nasopharyngitis (16%), influenza like illness (7%), dizziness (6%), rhinorrhea (5%), nausea (5%)
- drug interactions: none relevant to dentistry
- dental implaications: nasal adverse rxns
- cost: $15,000/month
what is the MOA of inclisiran
- small interfering RNA targeting PCSK9
- inhibits PCSK9 production in liver
- thereby prolonging activity of LDL receptors
what is the use, ADRs, drug interactions, dental implications and cost of inclisiran
- use: HeFH
- ADRs: injection site reaction (8%), arthralgia (5%), bronchitis (4%)
- drug interactions: none signficiant to dentistry
- dental implications: none
- cost: $3,500/3-6 months
what is the MOA of lomitapide
- directly binds and inhibits MTP which resides in the lumen of the endoplasmic reticulum, thereby preventing the assembly of apoB- containing lipoproteins (chylomicrons and VLDL) leading to reduction in LDL
what is the use, ADRs, drug interactions, dental implications and cost of lomitapide
-use: HoFH
- ADRs: chest pain (24%), diarrhea (79%), abdominal pain (34%), nasopharyngitis (17%), pharyngolaryngeal pain (14%)
- drug interactions: none of significance to dentistry
- dental implications: nasal/laryngeal adverse reactions/pain
