10/28 Flashcards
reverse cholesterol transport
acquire cholesterol from tissues and bring it back to the liver
mediated by ApoA-1 and ApoE
ApoB-100
LDL receptor ligand - allows internalization of LDL
atherosclerosis
excess accumulation of cholesterol in vascular smooth muscle
hypertriglyceridemia
pancreatitis, xanthomas, inc risk of CHD
atherosclerosis MOA
inflammatory process, occurs when LDL becomes oxidized and they initiate a response in T cells (secrete cytokines), causes accumulation of monocytes in layer between endothelium and smooth muscle
goals of drug therapy
- decrease reabsorption of excreted bile acids
- decrease secretion of VLDL from liver
- decrease synthesis of cholesterol
- increase hydrolysis of lipoprotein triglycerides
each __% reduction in cholesterol is associated with __% reduction in incidence of CHD
10%; ~10-30%
drugs for high cholesterol
bile acid binding resins
inhibtors of cholesterol absorption
HMG-CoA reductase inhibitors
PCSK9 inhibitors
drugs for high triglycerides
fibrates
niacin
omega 3 FAs
bild acid binding resins MOA
inhibit reabsorption of bild acids from intestine by binding bile acids to form insoluble complex excreted in feces
-up-regulate LDL receptors in the liver
bild acid binding resins therapeutic use
- treatment of primary hypercholesterolemia (inc LDL)
- produces ~20% dec in LDL in 2-4 weeks
- may cause ~5% inc in HDL
- may inc TG
- taken before meals
bile acid binding resins SE
constipation and bloating
bile acid binding resin drug interactions
may bind other drugs and interfere w their absorption: acetaminophen, thiazides, warfarin, digoxin, fibrates, ezetimibe, OC, CS, TZDs`
ezetimibe
cholesterol absorption inhibitor
-inhibits intestinal absorption of phytosterols and cholesterol
ezetimibe mechanism
inhibits intestinal absorption of cholesterol from diet and reabsorption of cholesterol excreted in bile (inhibits NPC1L1)
indication of ezetimibe
- primary clinical effect is reduction of LDL levels (~17%)
- usually used in combination with statins (may enhance statin action 20%)
ezetimibe AE
- (low incidence) liver/skeletal muscle damage
- well tolerated
HMG-CoA reductase inhibitor
“statin”
lovastatin and simvastatin are prodrugs
statin MOA
- completely inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis
- upregulate LDL receptors enabling more LDL delivered to liver, thus dec plasma cholesterol
statin indications
- hypercholesterolemia: elevated LDL, elevated LDL w slightly elevated TGs
- standard practice to initiate therapy immediately after MI, irrespective of lipid levels
statin expected results
20-60% reduction in LDL
10-33% reduction in TG
5-10% increase in HDL
statin dosing
short half-life statins are taken in the evening to inhibit nocturnal cholesterol biosynthesis
- lovastatin should be taken w evening meal (facilitates absorption)
- rosuvastatin, atorvastatin, pravastatin, pitavastatin and fluvastatin XL are QD any time of day
statin AE
skeletal muscle effects -rhabdomolysis with renal dysfunction secondary to myoglobinuria -dose related -monitor serum creatine phosphokinase -inc incidence when co-adm with CYP inhibitors; may occur w gemfibrozil hepatatoxicity -monitor serum transaminase activity -~2% incidence
Juxtapid
ApoB lipoprotein synthesis inhibitor
- small molecule inhibitor of microsomal TG transfer protein
- PO
- indicated as adjunct to other treatments for patients with: homozygous familial hypercholesterolemia - LDLR mutation
- high risk of liver damage
mipomersen
ApoB lipoprotein synthesis inhibitor
- hybridizes ApoB100 mRNA in liver and promotes degradation
- SQ
- indicated as adjunct to other treatments for patients with: homozygous familial hypercholesterolemia
- high risk of liver damage
PCSK9 inhibitors
increase LDLR# and reduce serum LDL levels
fibric acid derivatives
reduce serum TGs
-fibrates bind to PPARa and regulated gene transcription along with the retinoic acid receptor (RXR)
fibric acid derivatives effectiveness
reduce LDL 6-20%
reduce serum TGs 35-53%
elevate HDL 15-30%
fibric acid derivatives indications
hypertriglyceridemia in which VLDL prodominate
fibric acid derivatives SE
gallstones, rhabdomyolysis (use cation w statins)
omega-3-fatty acid indications
severe hypertriglyeridemia >500
omega 3 AE
can inc LDL-C levels
combined w statins to reduce LDL-C levels
niacin
vitamin at dietary levels
high doses lowers serum lipids
niacin targets
- adipose tissue: inhibits TG lipolysis by hormone-sensitive lipase - dec FA transport to liver
- liver: inhibits FA synthesis and esterification (reduce TG export via LDL)
- macrophages: inc expression of CD36 and ABCA1 - dec CE contant via HDL-mediated reverse transport
niacin indications
mixed hyperlipidemia, hypertriglyceridemia w risk of pancreatitis, raising HDLs (15-35%), used in combo w resin drugs to treat severe cases of hyperlipidemia; also combined w statins
niacin AE
vasodilation (flushing), itching, tingling of upper body, HA (treat w aspirin or ibuprofen
hepatotoxicity
