Drugs Uses To Treat Hyperlipidemias Flashcards
Basic Concept of Lipoproteins
Chylomicrons
Produced by intestinal mucosal cells by packaging of TGs and cholesterol from dietary fats. Enter blood strea, lipoprotein lipase: TGs hydrolised into free FA and glycerol (–> adipose tissue and muscles)
Chylomicron Remnant
Have lost most of TGs (still have cholesterol) taken up into liver via R mediated endocytosis
VLDL
Contain highest amount of TGs. Stripped of TGs–> become IDL then –> LDL
LDL
post IDL losing more TGs. Cholesterol rich. Transport cholesterol to extrahepatic tissue via R mediated endocytosis
HDL
produced by liver and enterocytes.
collect cholesterol from extrahepatic tissue then transport to liver –> can be excreted biliarily
Classification of Hyperlipoproteinemias
Hypercholesterolemia
total se cholesterol over 240 mg/dl (increased LDL)
Primary and secondary (ex hypothyroidism, biliary cirrhosis)
Risk: Atherosclerosis, coronary artery disease
Hypertriglyceridemia
se TG over 200 ml/dl (increased VLDL or chylomicron)
Primary (ex familial lipoprotein lipase def.) vs secondary (diabetes, alcoholism, oral contraceptives)
Clinical Management
Physical training (increase LDL R expression)
Diet
Elim. of risk factors ex smoking, hypertension
Pharma: lipid lowering drugs
Groups of lipid lowering drugs
Primarily Cholesterol Lowering Drugs
HMG CoA reductase inhibitors (Statins)
Bile acid binding anion exchange resins
Cholesterol absorption inhibitors
Probucol
PCSK 9 inhibitor monoclonal AB
Primarily TG lowering drugs
Fibrates
Nicotinic Acid
HMG CoA Reductase Inhibitors
(Statins)
Mechanism of Action
Competitive inhibition of HMG CoA Reduc. (rate limiting enzyme)
–> Upregulate LDL R therefore increase uptake of plasma LDL
Cholesterol regulates own level in liver via SREBP (TF)
If hepatic cholesterol decreases–> SREBP activated–> transcription of LDL R gene and HMG CoA Reduc. gene
Dilate atherosclerotic vessels; increase plaque stability by decreasing lipid content. Antiinflammatory effect
HMG CoA Reductase Inhibitors
Pharmacokinetics
Adverse Effects
Orally admin
Extensive hepatic uptake–> good because that’s area of action
Biliary excretion
Adverse Effects:
Liver injury
Muscle injury (myopathy, rhabdomyelosis). Monitoring of CK not useful as already too late at that point.
Contraindicated during pregnancy
Don’t lower se cholesterol in familial hypercholesterolemia because lack of LDL Rs
HMG CoA Reductase Inhibitor
Drug List
Prodrugs:
Lovastatin
Simbastatin
Active drugs:
Pravastatin
Atorvastatin
Fluvastatin
Bile Acid Binding Anion Exchange Resins
Mechanism of Action
Orally absorbed
Bind to bile acids and prevent their reabsorption–> decrease hepatic cholesterol therefore activating SREBP and
increase demand on liver–> hepatocytes increase LDL R expression
Can also be given for Cl. difficile th (trap toxins secreted); limited success
Bile Acid Binding Anion Exchange Resins
Drug List
Cholestyramine
Cholestipol
Cholesterol Absorption Inhibitors
Mechanism of Action
Induce expression of LDL R (activation of SREBP)
Combo with HMG CoA Reduc Inhibitors and Statins
Cholesterol Absorption Inhibitors
Drug List
Ezetimibe
Probucol
Increase rate of LDL catabolism
Inhibits oxidation of cholesterol in LDL–> slows formation of foam cells (regression xanthomas and atheromas)
Esp good in familial hypercholesterolemia
Also reduces HDL
PCSK 9 Inhibiting monoclonal AB
Evolucumab
Absence of PCSK9–> more LDL receptors on surface of liver cells to remove LDL-C from the blood.
Fibrates
Mechanism of Action
Bind to PPAR Alpha–> forms heterodimers with Retinoid X R–> bind to Peroxisome Proliferator Hormone Response Element–> increase transcription–> increase expression of LPL and HDL; decrease expression of TG and LDL
Fibrates
Drug List
Prodrugs:
Clofibrate
Fenofibrate
Active Drugs
Ciprofibrate
Bezafibrate
