Hyperlipidemia/Dyslipidemia Flashcards
hypercholesterolemia
high LDL, normal TG and HDL
mixed or combined dyslipidemia
high LDL and TG and possibly low HDL
hypertriglyceridemia
high TG, normal LDL and possible low HDL
where is most cholesterol produced
75% in liver
what does cholesterol make?
hormones
Vit D
bile salts
first line conventional tx for hyperlipidemia
statins
Statins MOA
HMG-CoA reductase inhibitors (this enzyme catalyzes the rate-limiting step in cholesterol synthesis) –> liver increases cholesterol uptake from the blood stream by increasing the number of LDL receptors (PCSK9 up regulation)
Statin indications
first-line therapy for primary and secondary prevention of ASCVD; familial hypercholesterolemia
Statin C/I
active liver dz (not absolute), pregnancy (category X), or breat feeding
Statin s/e
myopathy, increase in liver enzymes, nausea, HA
if someone is predisposed to DM, these can make dz more likely
Statin pharmacokinetics
1) onset: variable, peak effect in a few weeks
2) T1/2 = 1-20 hr
3) metabolism: variable, usu. involves CYP enzyme
4) variable bioavailability
How is atorvastatin metabolized?
CYP34A
How is fluvastatin metabolized?
CYP2C9 (major)
CYP34A (20%)
How is lovastatin metabolized?
CYP3A4
How is pitavastatin metabolized?
glucoronidation (major)
CYP2C9 and CYP2C8 (minor)
How is rosuvastatin metabolized?
not extensively metabolized; the major metabolite is formed by CYP2C9 and CYP2C19
How is simvastatin metabolized?
CYP3A4
Interactions between statins and natural therapies
1) Red yeast rice - duplication of therapy, incr. risk of myopathy
2) Niacin - might interact but is also used purposefully s/t when TG are high or HDL is low
3) Alcohol - hepatotoxicity
4) Grapefruit - CYP3A4 inhibitor, OATP inhibitor
5) Hypericum - CYP3A4 inducer
6) Sweet orange - OATP inhibitor
A person on atorvastatin drinks up to 1 quart of grapefruit juice per day. (1) How might their levels of artorvastatin be effected. (2) What s/e would be of concern? (3) What alternative statins could they take?
1) Grapefruit juice inhibits CYP3A4, which metabolizes atorvastatin
2) myalgia; have pt. self monitor b/c juice doesn’t significantly affect all pt.
3) **pravastatin, pitavastatin, rosuvastatin
Ezetimibe (Zetia) MOA
prevents absorption of dietary and biliary cholesterol –> upregulates LDL receptors in the liver lowering plasma LDL-C
**inhibits cholesterol GI absorption
Ezetimibe (Zetia) indications
adjunctive therapy in homozygous familial hypercholesterolemia and primary hyperlipidemia; typically used when statin intolerant
Ezetimibe (Zetia) cautions
1) C/I in pregnancy (category C) and breast feeding
2) may incr. liver enzymes; higher likelihood of this when administered w/ statin than as a monotherapy
Ezetimibe (Zetia) efficacy
on small reduction in ASCVD when used WITH a statin
minor reduction in LDL; even smaller increase in HDL and decrease in TG
Ezetimibe (Zetia) pharmacokinetics
1) onset = 1 wk
2) T1/2 = 22 hr
3) metabolism = ~30 undergoes glucuronide conjugation in SI and liver, active metabolite; ~80% excreted in feces
Ezetimibe (Zetia) interactions with natural products
1) b/c it inhibits sterol absorption in the gut, it will lower effectiveness of green tea, omega-3 FA, sitostanol, and beta-sitosterol
2) numerous meds w/ moderate interactions that effect liver toxicity or drug absorption
**no interactions w/ niacin or red yeast rice
Fenofibrate (fibric acid) class
fibrate
Gemfibrozil class
fibrate
Fibrates MOA
lower production and increase clearance of VLDL, increase HDL production
ultimately lowers TG and increased HDL, but has variable effect on LDL
Fibrates indications
- hypercholesterolemia or mixed dyslipidemia as adjunct therapy or monotherapy in pt. who cannot tolerate statins
- hypertriglyceridemia first-line pharmacotherapy (TG > 1000 mg/dL)
Fibrates cautions
1) C/I = active liver dz, severe renal impairment or ESRD, pre-existing GB dz, breast feeding
2) s/e = dyspepsia, gallstones, myopathy (incr risk w/ statins, esp. gemfibrozil)
Fibrate pharmacokinetics
1) onset = 2-3 days
2) T1/2 = 20 hrs
3) Inactived by glucuronidation in the liver or kidney; ~60% excreted in urine as metabolites
Fibrates interactions w/ natural therapies
1) if combined w/ red yeast rice might incr. risk of myopathy
2) niacin might incr. hepatoxicity
3) alcohol - hepatoxicity
4) other meds that cz liver toxicity
Gemfibrozil increases the risk for what s/e when used with statin therapy?
myopathy
How can we assess severity of myopathy?
creatinine kinase
*rarely, pt. can have really high creatinine kinase w/out sx of myalgia, so it might be good to get a baseline and monitor them a few mo. into tx
Niacin MOA
somewhat unclear
increases lipoprotein lipase (LPL) activity, enhancing removal of TG from plasma; reduces TG synthesis; incr. HDL levels
Niacin indications
hypercholesterolemia or mixed dyslipidemia
- as adjunct therapy in pt. that don’t tolerate fibrates or omega-3 FA
- as monotherapy in pt. that don’t tolerate statins, BAS, fibrates
Niacin cautions
1) C/I = active liver dz (esp. w/ sustained release), gout, or PUD
2) s/e = hepatotoxicity (enhanced SR formulation), hyperglycemia, hyperuricemia, upper GI distress, flushing**, itching
Niacin efficacy
studies haven’t panned out for using niacin as ASCVD preventative
moderate reduction in LDL and TG, moderate incr. in HDL
Niacin pharmacokinetics
1) onset = immediate
2) T1/2 = 30 min
3) quickly converted to NAD+ in liver, but pathways become saturated at doses need to tx hyperlipidemia
4) ~70% excreted in urine
Niacin interactions with natural therapies
1) Red yeast rice - depends on dose
2) alcohol
3) other meds that increase hepatoxicity
Niacin causes flushing, the ER form has less flushing as a s/e. However, it is not used very often because of an increased risk for what s/e?
hepatotoxicity
What is the largest benefit of omega-3 FA?
lowering TG
What is the therapeutic dose of omega-3 FA?
2-4 grams of EPA + DHA (high!)
omega-3 FA MOA
- inhibits release of FA from adipose tissue
- inhibits beta oxidation of hepatic FA
- inhibits FA synthesis
- increased VLDL clearance
- *lowers TG and increases HDL
omega-3 FA indications
hypertriglyceridemia second-line tx (TG > 1000 mg/dL)
omega-3 FA cautions
1) C/I = hypersensitivity to fish oil
2) s/e = eructation, nausea, dyspepsia, taste change
3) may incr. bleeding time (use w/ caution in pt. on anticoagulants and antiplatelets)
omega-3 FA efficacy
no benefit in ASCVD risk has been shown
small incr. in HDL, 20-50% decease in TG
omega-3 FA
1) onset = 2 wks
2) T1/2 = 140 hr
3) 100% bioavailability
4) metabolized by lipid enzymes in liver and tissues
**high bioavail. and long T1/2 is impt to consider in terms of bleeding effects
Bile acid sequestrants (BAS) MOA
they are resins that bind bile acids in the intestine –> reduces enterohepatic recycling –> increases hepatic conversion of cholesterol to bile acid
upregulates LDL receptors on liver
Bile acid sequestrants (BAS) indications
hypercholesterolemia for high risk pt. who are statin-intolerant or are on maximal tolerated doses of a statin
Bile acid sequestrants (BAS) cautions
1) C/I = TG over 300 mg/dL, complete biliary obstruction
2) s/e = constipation, abdominal discomfort, intestinal gas, dyspepsia, heartburn, diarrhea
3) b/c it’s an absorbent, it can bind onto other medications that the pt. is taking
Bile acid sequestrants (BAS) pharmacokinetics
1) onset = 21 days to peak effect
2) T1/2 = variable
3) 100% excreted in feces, not absorbed
What other drugs shares the intestine as a site of action?
ezemtimibe (Zetia)
BAS and Ezetimibe both work to lower GI absorption of cholesterol. What changes occur in the liver to lower LDL?
increased LDL receptors (so that more LDL is taken up from the blood)
Bile acid sequestrants (BAS) interactions with natural therapies
1) Niacin absorption might be inhibited
2) Only moderate interactions, mostly d/t changes in absorption profiles
