Antihyperlipidemics Flashcards
Lipid digestion products associate with bile salts to form ______ (transport poorly soluble products to surface of enterocyte)
micelles
what is choelsterol absorbed thruogh
Monoglycerides and fatty acids diffuse across plasma membrane
NPC1L1 (Niemann-Pick C1 like 1) transporter
synthesis of chylomicrons (exogenous metabolism)
- SI mucosal cells secrete TAG-rich chylomicrons
- Apo C-ll and E are transferred from HDL to nascent chylomicron
- chylomicron –> systemic circulation
- Lipoprotein lipase (Apo C-II activates it) degrades TAG in CM in capillaries –> FA to tissues and glycerol to liver
- Apo E is receptor on liver that allows take up of chylomicron remnants
Endogenous synthesis/metabolism of VLDL, IDL, LDL
- Apo B attachd to Tag-rich VLDL particles in liver
- secretes and Apo C-II and E are added to VLDL
- VLDL enters capillaries and lipoprotein lipase degrades –> FA to tissues and glycerol to liver –> IDL –> LDL
(can be converted to LDL or taken up by liver) - LDL binds to receptors on extrahepatic tissue
what is apoE important for
important for chylomicron elemetns to be taken up and LDL
How is excess cholesterol gotten rid of
HDL takes it up
HDL binds to A-1 and SR-BI in liver
what apolipoprotein is ligand for LDL
what happens if inactivated
Apo B-100
increase in LDL
what apolipoprotein is cofactor for LPL
what happens if inactivated
Apo C-II
increase chylomicrons and VLDL
what apolipoprotein is Ligand for IDL to bind to LDL receptor and chylomicron remnants to bind to remnant receptors
what happens if inactivated
ApoE
increase IDL and chylomicrons
what happens if LPL is inactivated
increase in chylomicrons and VLDL
what happens if LDL-receptor is inactivated
increase LDL
what are the statins target?
HMG CoA reductase inhibitors
what are the fibrates (PPAR activators)?
gemfibrozil
fenofibrate
what are the bile acid sequestrants
Colesevelam
Colestipol
Cholestyramine
what is a cholesterol absorption inhibitor
Ezetimibe
what is fibric acid derivatives used to treat
hypertriglyceridemia
adverse effects of fibrates
Rarely cause rashes, gastrointestinal symptoms, and myopathy
Risk of myopathy increases with combination with statins
Gemfibrozil is contraindicated with what drug
statins
Use caution when combining fenofibrate with statins
what do bile acid-binding resins treat
hypercholesterolemia - for patients whom statins do not provide sufficient LDL reduction
MOA of bile acid-binding resins
***Bind to bile acids and bile salts in intestine
Disrupt enterohepatic circulation of bile acid and bile salts
Liver has to increase synthesis of bile acid to replace lost bile acids and salts
Requires increased liver uptake of cholesterol
Elevation of liver LDL-receptors
MOA of fibrates
activates PPAR receptor
Bile acid-binding resins:
↓ 1
However, can increase plasma 2
Should not generally be used in patients with 3
Can cause 4 and constipation
- LDL
- TG
- hypertriglyceridemia
- bloating
Drug of choice to lower cholesterol in children and women who are pregnant or lactating
(not systemically absorbed)
Bile acid-binding resins
MOA of niacin
Inhibit VLDL synthesis & secretion by liver
what does niacin treat
Can be useful in treatment of all hypertriglyceridemias and hypercholesterolemia
SE of niacin
Cutaneous flushing and itching (most common side effect)
- due to prostacyclin from skin released
- pretreat with NSAID
Hyperuricemia (induce gout attacks in susceptible individuals)
Hepatotoxicity (slight risk)
Slightly increases risk of statin-induced myopathy
Safest combination is niacin with fluvastatin and highest risk is with lovastatin
what is the safest combo for niacin and a statin to decrease risk of statin-induced myopathy
what is the highest risk combo
niacin with fluvastatin
highest risk = lovastatin
what drug inhibits cholesterol absorption at jejunum
Ezetimibe
Ezetimibe (Zetia) blocks intestinal absorption of cholesterol by inhibiting ___
*** Niemann-Pick C1-like 1 protein
Blocks uptake of both dietary cholesterol and reabsorption of cholesterol excreted in bile
Reduces incorporation of cholesterol into chylomicrons
Reduced chylomicron remnants delivered to liver increases expression of hepatic LDL receptors
Reduces plasma LDL levels by 15-20%
What can ezetimibe tx
hypercholesterolemia
what statin is least potent and what are most potent
Least: Fluvastatin
Most: atorvastin and rosuvastatin
MOA of statins
**inhbit HMG CoA reductase –> decrease concentration of cholesterol in cells
low cholesterol –> stimulates synthesis of LDL receptros –> uptake of LDL from blood
low intracellular cholesterol decreases VLDL
what drugs greatly reduce CV risk and mortality
statins
SE of statins
Myopathy
- Patients with an inherited variant in a anion transporter are at higher risk for myopathy
- Baseline creatine kinase measurements recommended
Rarely rhabdomyolysis occurs
*Liver toxicity in low percentage of patients
clinical indictions for statins
Indications
Elevated LDL, CVD, and elevated CVD risk
Used to lower plasma cholesterol levels in many types of hyperlipidemias
Given to patients with clinically evident atherosclerotic disease or at high risk
first line tx of hypercholesterolemia
if pts do not respond adequately then what?
Statins
Add cholesterol absorption inhibitors and/or bile acid binding resins
what is niacin often useful for
both hypercholesterolemia and hypertriglyceridemia
what is often used for Hypertriglyceridemia (generally elevated VLDL and/or chylomicrons)
fibrates
Niacin
