Statins (drugs to treat hyperlipidemia) Flashcards
What is the most associated species with hyperlipidemia?
LDL (not triglycerides)
What are lipoprotein particles composed of?
1) lipid membranes
2) hydrophobic core
3) apolipoproteins
How do LDL differ from HDL?
LDL is 60% cholesterol while HDL is 20% cholesterol
What enzyme makes cholesterol?
HMG-CoA reductase
In normal cholesterol states, where does LDL go?
binds to LDL receptor and is degraded in the lysosome into cholesterol which goes to membranes, steroid hormones, bile acids, lipoproteins
When does LDL become a problem?
When there is too much of it and it isn’t taken up into the cell - stays in blood
- endothelial injury allows entry of LDL
- macrophages take up LDL becoming FOAM cells
- necrosing FOAM cells release cholesterol into matrix making fatty streak
How might HDL prevent atherosclerosis?
HDL promote the REVERSE cholesterol transport (from periphery back to liver where it can be secreted as bile)
What is target LDL?
What is target HDL?
> 50mg/dL
What is target triglyceride?
What 4 drug classes inhibit LDL?
1) statins
2) bile acid-resins
3) chol. absorption inhibs
4) PCSK9 inhibitors
What is the NUMBER ONE causative role of atherosclerosis?
high levels of LDL
What 2 drug classes inhibit triglycerides?
1) niacin
2) fibrates
What is the treatment for moderate hypercholesterolemia with LOW cv risk?
lifestyle change
What is the LDL level that indicates statins?
> 190mg/dL
What are the 6 statins?
atorvastatin fluvastatin lovastatin simvastatin pravastatin rosuvastatin
What are the 3 bile acid binding resins?
cholestryamin
colestipol
colesevelam
What is the primary clinical effect of statins?
REDUCE LDL
moderate reduction in triglycerides and increase in HDL
What is the MOA of statin?
as an analog of the HMG CoA substrate, they inhibit HMG CoA reductase
What is the role of HMG CoA reductase?
to make cholesterol
What is the SREBP transcription factor?
a protein that is activated in the face of reduced cholesterol synthesis and works to INCREASE expression of LDL receptor which increases clearance of serum LDL
What turns SREBP on?
decreased cholesterol levles
What 2 ways do statins decrease cholesterol?
1) reduced cholesterol formation
2) increase LDL receptor expression to sop up serum LDL
True or false: statins are effective at reducing CHD risk irrespective of initial baseline LDL
TRUE (can prevent primary and secondary CHD)
If you double the dose of statins, do you double the effects?
NO (only increases like 5-6% but significantly increasing it can cause adverse effects)
What is the main side effect of statins/
Rhabdomyolysis (also causes myalgia)
Which statin is the best choice for minimizing drug interactions?
Pravastatin
Where are statins absorbed?
intestine (metabolized by CYP3A4)
How are statins taken up into the liver?
OATP2
How are statins excreted?
bile and feces
What is the only statin that is eliminated via the liver and the kidney?
pravastatin
How do CYP3A4 inhibitors affect the potency of statins?
increases it - statins can no longer be metabolized
increases risk of rhabdo
What 2 statins are metabolized via CYP2C9?
fluvastatin and rosuvastatin
What are 5 known inhibitors of CYP3A4?
cyclosporin ritonavir itraconazole erythromycin grapefruit juice
What are inducers of CYP3A4?
phenytoin
barbiturates
rifampin
thiazolidnediones
What is Gemfibrozil?
a fibrate drug that is strongly associated with INCREASED risk of STATIN induced myopathy
What does Gemfibrozil do?
inhibits OAT2P transporter - statins not taken up (increased serum statins)
True or false: gemfibrozil does NOT affect pravastatin
FALSE - causes an increase in systemic levels of all statins
In what 2 ways does gemfribrozil increase serum statins?
1) inhibits OAT2P
2) inhibits glucoronyl transferases
What are 2 big contraindications of statins?
1) pregnancy
2) liver disease
True or false: statins should be prescribed earlier in life
TRUE - usually the arteriolar damage has already been done by the time they are prescribed in the patient’s 40s-50s
What is the clinical effect of bile acid binding resins?
modest reduction in LDL
can increase serum triglycerides
What is the MOA of bile acid binding resins?
resins (cationic) bind to negatively charged bile acids and prevent their absorption in the small intestine
What is the therapeutic benefit of making bile not absorbable in the small intestine
makes liver make more bile therefore resulting in a decrease in hepatic cholesterol clearance (causing upregulation of LDLR)
Why do bile acid binding resins increase serum triglycerides?
because bile acids usually serve to suppress endogenous triglyceride synth
Can bile acid resins be used in combo with a statin?
YES - to aggressively reduce LDL
When are bile acid resins really important?
for pregnant/nursing women
True or false: bile acid resins have serious adverse effects
FALSE very safe/few side effects but GI disturbances and occasionally impair absorption of ADEK vitamins (fat soluble)
What are the contraindications for bile acid resins?
elevated triglycerides
What does ezetimibe do?
inhibit cholesterol absorption (both dietary and biliary cholesterol in small intestine) - results in decreased delivery of cholesterol to the liver reducing VLDL
What receptor does ezetimibe block?
NPC1L1
When might ezetimibe be beneficial?
in patients who do not have an intact LDLR (so like familial hypercholesterolemia)
What are the new anti-hypercholesterolemia drugs?
inhibitors of PCSK9 (a protein that is mutated in patients with FH) which prevents LDLR recycling and instead degrades it
True or false: PCSK9 mutations can be both LOF and GOF
TRUE
What 2 drugs inhibit PCSK9?
alirocumab
evolocumab
(antibodies specific for PCSK9)
Why is there a need for anti-hypercholesterolemia drugs other than statins?
because statins target the LDLR mostly; patients with FH don’t have a functional LDLR
What 2 drugs can treat homozygous FH?
lomitapide
mipomersen
How does mipomersen work?
reduces expression of apoB100 resulting in reduced production of chylomicrons and VLDLs
How does lomitapide work?
inhibits microsomal triglyceride transfer protein (MTP) which is needed for the assembly of chylomicrons and VLDLs
What is the official lab cut off for hypertriglyceridemia?
> 500mg/dL
What pathology is particularly concerning with hypertriglyceridemia?
pancreatitis
True or false: elevated serum triglycerides are associated with a decreased serum conc of HDLs
TRUE (so drugs will have the corollary effect of increasing HDL)
What 2 drugs are used for the treatment of hypertriglyceridemia?
niacin
fibrates
What is the most effective drug at raising HDLs?
Niacin (often combined with statins to lower LDL and also increase HDL)
What is Lp(a) lipoprotein and what does it do?
a modified LDL that can block the conversion of plasminogen to plasmin
Niacin BLOCKS this (promoting thrombolysis)
What is the main adverse effect of niacin?
skin flushing (due to prostaglandins - take an NSAID)
also uric acid build up (gout) and peptic ulcer disease
