atherosclerosis pharm Flashcards
drug therapy goals
reduce formation and rate of progression in coronary and peripheral atherosclerosis from childhood to old age
Prevention of coronary events adn strokes in apparently healthy persons at risks, particularly mig age and elderly
Prevent heart attack, strokes, need for revascularization in persons with established atherosclerosis
prevention and treatment of pancreatitis in Hyper tGemia
HMGcoA reductase inhibitors
Statins (TLDR- major decrease in LDL, 1st line therapy in hypercholesterolemia)
Atorvastatin, Lovastatin, simvastatin
MOA- competitive inhibitor for active site on HMG CoA reductase (the RLS in cholesterol biosynthesis), structutal analog. Decreasing intracellular LDL, leads to increase inLDLR so that hepatocytes take up more LDL from blood
low LDL –> activation of SREBP (via SCAP release on ER membrane)–> SREBP is cleaved by proteases via site 1 a dn 2 proteases S1 and S2 P
Pharmocokinetics- extensive 1st pass metabolism by liver, limits systemic bioavailablity (targets liver as the site of action), OATP1B1. Atorvastatin, lovastatin, simvastatin metoblized by CYP3A4 to inactive metabolite. Atorvastatin (hydroxy acid forms), Simvastatin and Lovastatin (admin as inactive lactones and activated to hydroxyacids)
Adverse effects of statins
Myopathy- muscle pain (usually symmetrical, proximal muscles, w/o CK elevation), muscle weakness/disease, increase to statin dose and plasma concentration
Rhabdomyolysis- CK elevation with creatinine elevation, breakdown of muscle fibers–myoglobin release in blood, harmful to kidney
genetics and statin intolerance
Single nucleotide polymorphism in SLCO1B1 (hepatic uptake of statins),– reduced hepatic uptake and increased statins in blood–myopathy
Contraindications
Drugs also metabolized by CYP3A4- certain macrolides, eryhtromycin, anifungal itraconazole, cyclosporine HIV protease inhibitors–increase plasma concentration and risk of myopathy
HS, acute liver disease
Pregnant or lactating women (inhibit cholesterol signaling such as SHH
Bile synthesis and funciton
Bile acid binding agents
Cholesterol converted to bile acid (7ahydroxylase) function to emulsify lipids in food to enable fat digestion and absroption thru intestinal wall. Most bile acids are reabsorbed thru intestine and delivered to liver. MAking bile and excreting it is the only way by which cholesterol is excreted
CHOLESTYRAMINE
Cholestyramine
MOA: very positive binds to negative bile acid, large sized resin is ecreted in the stool (inhibits the 95% of bile reabsorption), leads to hepatic bile acid synthesis increases
increase in bile salt production–decrease in intracellular cholesterol–> decrease of plasma cholesterol via LDLR
Insoluble in Water
SE: constipation/bloating sensation, gritty consistency, interferes with fat soluble vitamins, MODEST INCREASE IN TG but with time returns to baseline
LDL decrease
Use: hypercholesterolemia (w/o increased TG– contraindicated), common second agent (w/statins to lower LDLC levels)
Ezetimibe
Cholesterol absorption inhibitor
MOA: blocks transporter (NPC1L1) to decrease the rate of cholesteryl ester incorporation into chylomicrons (reduced cholesterol flux from intestine to liver), leads to decrease plasma LDL/ increase in LDLR
SE: myopathy like statins (increases with administered statins)
mainly LDL decrease
USE: primary hypercholesterolemia (usually combines with statin)
nicotinic acid/niacin
Water soluble B complex vitamin, lipid lowering effect unrelated to vitamin, very large does
Main effect is to decrease TGs (with a little cholesterol), used for hypercholesterolemia/triglyceridemia, not 1st line
Lipid panal: decrease TG/LDL, increase HDL, Lp(a) reduced CV disease
MOA: inhibits FFA mobilization, decreases synthesis of VLDL-TG (inhibits DGAT2 that catalyzes TG synthesis)
Oral admin, doses used for lowering cholesterol/TG much greater than those used as vitamin
SE: intense cutaneuous flush, pruritis, mediated by vasodilatory PGs. (sometimes peptic ulcer, liverenzymes elevated esp w/ statin) Containdicated in gout or diabetes
Fibrates/ PPAR activators, Gemfibrozil, fenofibrate (2nd gen drug)
Primarily lower the levels of TG rich lipoproteins
TG decrease, LDL (highly variable, 2nd gen decreases LDL)
MOA: ligands for nuclear transcription regulator, PPARa, in liver and adipose, regulate gene transcription( binds with retinoid X receptor)
PPAR genes–> inc. LDL particle size, increase HDL synthesis, inc Reverse cholesterol transport, dec TGs, and dec inflammation
Gem has shorter half life than fenofibrate (renal impairment)
Feno is activated (60-90% is excreted in urine, Gem is inactivated
SE: increase creatine kinase (esp w/statin)–renal failure.
CONTX- renal impairment pts
GEM inhibits uptake of active hydroxy acid forms of statins by transporter
USE: high TGs and low HDL w/ metabolic or T2DM
OMEGA 3s
MOA: reduced rate of secretion of VLDL Tgs, only one FDA approved
USE: adjunct to diet therapy in treatment of hypertiglyceridemia
Alirocumab
MOA: PCSK9 Ab (prevents binding of PCSK9 to the LDLR/LDL complex)- increasing the availability of cell surface LDLRs
PCSK degrades LDLR
injectable cholesterol lowering drug
USE: heterozygous familial hypercholesterolemia
Lomitapide
MOA: binds and inhibits MTTP (prevents assembly of apoB lipoproteins in enterocytes/hepaotcytes–> reduced production of chylomicrons and VLDL–reduces plasma LDL
Oral, CYP3A4 metabolism
SE: GIT disturbance
Use: homozygous familial hypercholesterolemia
Mipomersen
MOA: Antisense oligonucleotide to inhibit apoB100 (on LDL VLDL anD IDL
SE: injection site reactions, flu like symptoms
homozygous familial hypercholesterolemia
drugs used alone for treatment of hypercholesterolemia
STATINS
