Lecture 13: Hyperlipoproteinemia Flashcards
Function of lipoprotein
transport cholesterol, triglycerides and phospholipids in plasma
Apolipoproteins
function as ligands recognized by cellular lipoprotein receptors induce internalization of lipoproteins
Apo CII and CIII
CII activates lipoprotein lipase
CIII inhibits lipoprotein lipase
Atherosclerosis
hardening of arteries
high plasma LDL, low HDL
narrowed blood vessel lumen
reduce blood flow and plaque breaking off leads to embolus, and the infarct
Foam cells
oxidized LDL and macrophages form foam cells
foam cells cannot be taken up by liver which leads to cell necrosis
Lipoprotein A Lp(a)
strong correlation between elevate Lp(a) to risk of atherosclerosis
competitively inhibits tissue plasminogen activator which breaks down blood clots
promotes thrombus formation, atherogenic
HMg-CoA reductase
HMg-Coa to mevalonic acid to cholesterol
rate limiting enzyme in cholesterol synthesis
hepatic cholesterol level exerts feedback inhibition of HMg-CoA activity, decrease LDL receptor
Statins
structural analogs for HMg-CoA
competitive inhibition
depletes sterol pools
increase LDL receptor expression, LDL uptake
decrease plasma LDL concentration
Atorvastatin and Rosuvastatin
statins
useful for most hyperlipoproteinemias but not for genetic LDL receptor deficiency
acts synergistically with bile acid binding resins (colestipol & cholestyramine) and Ca blockers
Adverse effect of statins
well tolerated
elevated liver transaminase
NOT TO BE USED IN PREGNANCY (cholesterol important in fetal development)
P450 inhibitors (ketoconazole) can increase statin concentration
myositis and rhabdomyolysis (most common)
Cholestyramine and Colestipol
inhibit cholesterol absorption
cationic bile acid binding resins
lead to decrease in bile acid production
increase HMg-CoA reductase activity
decrease cholesterol
increase LDL receptors
increase HDL
USED WITH STATINS can increase efficacy markedly
Adverse effect for cholestyramine and colestipol
few side effect because not absorbed from intestine
might impair intestinal absorption of other drugs
Steatorrhea - excess fat in stools, chronic diarrhea and weight loss, due to impaired absorption of dietary fat
Neomycin
aminoglycoside antibiotic
interferes with absorption of bile acids
similar to cholestyramine and colestipol
Ezetimibe and adverse effect
blocks absorption of dietary and biliary cholesterol at small intestine
block NPC1L protein transporter
used in combination with STATINS but can be used in monotherapy
adverse effect: GALLSTONES
Nicotinic Acid (Niacin)
inhibit release of free fatty acid
decrease VLDL production in liver
decrease IDL and LDL in plasma
ONLY LIPID LOWERING DRUG CURRENTLY TO LOWER Lp(a) levels
synergistic effect with bile acid binding resins
adverse effects of niacin
hyperglycemia
flushing
GI upset
serious liver dysfunction
Clofibrate, Fenofibrate and Gemfibrozil
stimulate PPARa (gene associated with lipid metabolism)
increase lipoprotein lipase expression, promote VLDL conversion to IDL and LDL
LDL levels rise initially but fall due to VLDL and triglycerides depletion
increase HDL levels
decrease ApoCIII (inhibitor of LPL) activity decrease fatty acid synthesis and increase fatty acid oxidation
Antithrombotic effect: inhibit coagulation and enhance fibrinolysis
can produce gallstones
DO NOT USE WITH STATINS
PCSK9 inhibitors (Evolocumab)
monoclonal antibody targeting PCSK9
PCSK9 binds to LDL receptor and increases degradation of LDL receptor after internalization
increases LDL receptor recycling
increase removal of LDL
