Flashcards in Pharm: Hyperlipidemia drugs Deck (66):
What type of lipid is considered "bad" cholesterol? What about "good" cholesterol?
LDL is bad cholesterol
HDL is good cholesterol
Increased LDL is associated with what disease?
Increased LDL is associated with an increased risk of cardiovascular disease
Describe the composition of lipoprotein particles
Lipid membrane made of phospholipids and cholesterol
Hydrophobic core containing TGs and cholesterol esters
Apolipoproteins, structural proteins and ligands for particle uptake
How does the relative ratio of cholesterol:TG differ between LDL and HDL?
LDL: 60% cholesterol, 25% TG
HDL: 20% cholesterol, 5% TG, 35% phospholipid
What is the function of chylomicrons?
Exogenous lipoprotein: Transport of dietary fat, cholesterol and bile acids from intestine to liver
What is the function of lipoprotein lipase?
Cleaves off free fatty acids from triglycerides of lipoproteins
Describe the endogenous pathway of lipoprotein metabolism
VLDL --> IDL --> LDL
LDL delivers cholesterol to the periphery or back to the liver
How does the handling of LDL change in hypercholesterolemia?
LDL levels are too high in hypercholesterolemia
The LDLR-lysosome degradation of LDL cannot keep up with the high LDL levels
LDL is no longer targeted to peripheral cells, which can lead to the development of atherosclerosis
Describe the formation of atherosclerosis starting with endothelial injury
Endothelial injury allows LDL to enter vessel wall. LDL is oxidized and then taken up by macrophages, which convert to foam cells that promote SMC migration and proliferation as well as ECM synthesis. Foam cells release debris leading to fatty streak formation.
What are the main protective roles of HDL against atherosclerosis?
1) Antioxidant activity: PON1 enzyme
2) Inhibit endothelial adhesion molecules
3) Prevent formation of foam cells
4) Promote reverse cholesterol transport
What is reverse cholesterol transport?
Transport of cholesterol from periphery back to the liver where it can be secreted as bile
What are the causes of hyperlipidemia?
Genetics: familial genetic disorder
Lifestyle: diet, obesity, alcohol, smoking, age, physical inactivity
Diseases: T2 DM, hypothyroidism
Drugs: antiviral, antipsychotics, corticosteroids, oral contraceptives
What levels of LDL and TG are considered "very high"?
LDL > 190 mg/dL
TG > 500 mg/dL
High TG levels lead to an increased risk of what disease?
High TGs increase risk of pancreatitis
What are the general pharmacological strategies used to treat hyperlipidemia?
Decrease in LDL (Primary targets)
Increase HDL (secondary)
Decrease TG (secondary)
What is the treatment for moderate hypercholesterolemia?
Therapeutic lifestyle change is sufficient if there is a low cardiovascular risk
What is the treatment for severe hypercholesterolemia?
Drug therapy: reduce LDL using a statin in order to decrease risk of atherosclerosis
What are the 4 major classes of drugs that reduce LDL levels?
Bile acid-binding resins
Cholesterol absorption inhibitors
What is the mechanism of action of the statins?
HMG-CoA reductase inhibitors
Competitive inhibition of the rate limiting enzyme of cholesterol biosynthesis. SREBP is activated leading to increased LDLR gene expression, increased LDL clearance
What is the effect of statins on concentrations of LDL, HDL, and TGs?
Significant reduction of LDL
Modest increase in HDL
Modest decrease in TGs
What is a clinically important difference between Pravastatin and the rest of the statins?
Pravastatin is not metabolized by CYP450, unlike the other statins
Fewer associated adverse events (decreased incidence of rhabdomyolysis)
How do baseline LDL levels affect the effectiveness of statins?
Statins are effective at reducing CHD risk irrespective of the initial baseline LDL
-They are the drug of choice for primary and secondary CHD prevention
Describe the dose dependence of statins
Decreases in LDL are dose dependent, but there larger doses increase adverse events more than they improve therapeutic effect
Describe the adverse events associated with statins
The most serious adverse effects are muscular: rhabdomyolysis, myalgia, myopathy
-Liver enzyme increase
What commonly precipitates rhabdomyolysis in patients taking statins?
High statin dose OR drug interaction
Drugs that inhibit CYP3A4 (cyclosporins, macrolides, ketaconazole)
What non-drug item can increase the risk of statin adverse events?
What transporter is responsible for liver uptake of statins?
How are statins excreted?
ALL statins are excreted via bile and feces after glucoronidation by UGT1A1/1A3 in the liver
What effect do inducers of CYP3A4 have on statin therapy?
Inducers of CYP3A4 reduce plasma concentrations and thus reduce clinical efficacy of statins
Describe the drug interaction between gemfibrozil and statins
Gemfibrozil inhibits OATP2 transporter, which decreases statin uptake by the liver. This leads to increased statin concentration in the blood and increased risk of myopathy, rhabdomyolysis
Also inhibits glucoronidation leading to increased systemic levels of statin
What are the contraindications for statin therapy?
Pregnancy, nursing mothers and women who may become pregnant
Patients with liver disease
What effect do bile acid-binding resins have on LDL, HDL and TGs?
Modest reduction of LDL
No effect on HDL
Small increase in TGs
What is the mechanism of action of bile acid-binding resins?
Bind to negatively charged bile acids to prevent small intestinal reabsorption, thus leading to excretion of bile acids via feces.
Increased bile acid production --> decrease cholesterol levels
LDLR is upregulated leading to increased LDL clearance
What is the mechanism for bile acid resins increasing TG levels?
bile acids normally suppress endogenous TG synthesis, so the resins decrease bile acid levels leading to increased TG synthesis
Describe the clinical use of bile acid resins
Not typically used when statin therapy is an option, but are used in combination for aggressive reduciton of LDL.
Statins are contraindicated in children, and women who are lactating/pregnant, so bile acid resins are a useful statin alternative
What are the adverse effects associated with bile acid resins?
Very few side effects because they are not absorbed or metabolized (remain in GI tract)
- GI disturbances
- Impaired absorption of fat soluble vitamins
What drugs interact with bile acid resins?
Many. Do not give drugs at same time as resins (Stagger doses to avoid interactions)
What are the contraindications for bile acid resins?
Type III dysbetalipoproteinemia
Raised TGs (risk for pancreatitis)
What are the bile acid binding resin drug names?
What is the only cholesterol absorption inhibitor drug?
What is the mechanism of action of ezetimibe?
Inhibits NPC1L1 (protein for uptake of dietary and biliary cholesterol in small intestine)
Reduces VLDL and LDL production and increases LDLR
What effect does ezetimibe have on TG levels?
Ezetimibe does not raise TG levels (unlike bile acid resins)
Describe the therapeutic uses of ezetimibe
Used to lower LDL in hypercholesterolemia
Used in combination with statin to decrease LDL using a lower dose of statin (decrease side effects)
What adverse events are associated with ezetimibe?
Flatulence and diarrhea
What role does PCSK9 play in hypercholesterolemia?
PCSK9 is a secreted enzyme responsible for controlling the levels of LDLR expressed on liver cells. Binds to LDLR, triggers internalization and degradation of LDLR
Describe the effect of gain of function and loss of function mutations in the PCSK9 gene
Gain of function: high LDL levels, increased risk for CVD
Loss of function: low LDL levels, decreased risk for CVD
What are the PCSK9 inhibitor drug names?
What is the mechanism of action of PCSK9 inhibitors?
PCSK9 inhibitors are human antibodies that are specific for the PCSK9 protein. They bind PCSK9 and prevent its interaction with LDLR.
Result: increased expression of LDLR
Do PCSK9 inhibitors work if statins are also being used?
Yes. They decrease serum LDL even in the presence of maximally tolerated statin drugs.
What are the new drugs developed for the treatment of homozygous familial hypercholesterolemia?
Lomitapide and Mipomersen
What is the mechanism of action of lomitapide?
Inhibition of MTP enzyme, preventing the formation of chylomicrons by enterocytes and VLDLs by hepatocytes
What is the mechanism of action of mipomersen?
This oligonucleotide reduces the expression of apoB leading to reduced production of VLDLs by hypatocytes
Elevated triglycerides are an independent risk factor for what diseases?
Pancreatitis (at very high TG levels >500mg/dL)
How are HDL levels associated with TG levels?
Elevated TGs are associated with decreased HDL (good cholesterol)
What are the drugs that treat hypertriglyceridemia?
Fibrates (gemfibrozil, fenofibrate)
What effect does niacin have on TGs, LDLs and HDLs?
moderately reduce LDLs
moderately increase HDLs (most effective drug to raise HDL)
What are the therapeutic uses of niacin?
Lower plasma cholesterol and TG
Used in patients with familial combined hyperlipidemia and familial dysbetalipoproteinemia
Describe the mechanism of action of niacin
-decreases release of FFAs, decreasing FA synthesis
-increases HDL via increased apoA1
-decreased macrophage recruitment to lesions
-decreased thrombosis risk by decreasing Lp(a)
-decreased VLDL production, increased clearance
What is Lp(a) and how are Lp(a) levels related to risk of atherosclerosis?
Lp(a) is a lipoprotein that prevents thrombolysis (competitive inhibition of thrombolysis pathway)
Decreased levels are associated with decreased risk for atherosclerosis
What are the major adverse effects associated with niacin?
Skin flushing, itching
Inhibited uric acid secretion can cause gout
Can exacerbate peptic ulcer disease
How do fibrates affect levels of TG, LDL, HDL?
Large reduction in TG
Mild reduction in LDL
Mild increase in HDL
What is the mechanism of action of the fibrates?
Ligands for the PPAR-alpha transcription factor
Promotes expression of genes involved with lipoprotein structure, function and metabolism
What adverse events are associated with fibrates?
Describe the drug interactions with fibrates
Strong protein binders, can displace other albumin bound drugs leading to increased concentrations of other drugs in unbound, active form
Major rxn between gemfibrozil and statins (fenofibrate does not affect statin levels)
What are the contraindications for fibrate usage?
Hepatic dysfunction (drug is hepatotoxic)
Renal dysfunction (drug renally excreted)
Gall bladder disease