Antihyperlipidemics Flashcards
Hypercholesterolemia
HyperTG
Mixed
Inc cholesterol (normally LDL) Inc TG (usually VLDL) Inc serum TG and cholesterol
Altering VLDL, LDL, and HDL
VLDL - modestly promotes AS…promotes acute pancreatitis
LDL - promotes athero
HDL - prtective against AS
HMG-CoA reductase inhibitors
Statins
LActone containing statins are prodrugs that must be hydrolyxed
Statins have very strong effect on total cholesterol and LDL and moderate for TGs and VLDL
Statins -use
Best for treating hypercholesterolemia and preventing CV events in pts with coronary heart dz
ALso used to tx MOD hypertriglyceridemia and mixed hyperlipidemia
Other drugs dec VLDL more but statins dec CV risk most
Other drugs preferred if severe and immediate tx needed
Statin MOA
Act on hepatocytes ot block HMG-CoA reductase…rate limiting step in cholesterol biosyntehsis
Biggest drop in LDL comes from inc hepatic uptake…hepatocyte compensate for dec cholesterol synthesis by inc LDL receptor expression
Pleiotropic effects of statins
Improved endothelial function - inc vasodilation
Anti-inflam…slow plaque progression and stabilizes established plauqes
Statin adverse and contraindication
Skeletal muscle toxoicty
Hepatoxicity - asx and modest inc in serum transminases
T2DM - inc in incidnece
Contra in preg or nursing due to skeletal defects
Muscle toxicity mech and risk factors for statins
Releases K+ (causing arrhythmias) and myoglobin (renal damage)
Higher statin dosease, co-admin of CYP450s, inhibitors of hepatic drug transporters
East asian descenet or OATP1B1 genotypes
Summary of
Atorvastitin
Rosuvastatin
Pravastatin
PKs and interactions
Mod sensitivie to CYP3A4 inhibs
Sens to inhibis of biliary drug transporter
Statin least affected by drug interactions
PCSK9 inhibitors
Evolocumab
Self adm subq injection every 2 week or month
Only used for very high risk hypercholesterolemia pts
PCSK9 fxn
Secreted into blood by hepatocytes, binds to LDL receptors
LDL-R bound with PCSK9 internalized
If PCSK9 is bound, LDL receptor destroyed rather than recylced
Fewer LDL receptors dec hepatocyte uptake of LDL cholesterol
Effects of PCSK9 inhibs
Dec destruction of LDL receptors
mroe LDL receptors on hepatic membranes
inc uptake of LDL
PCSK9 PJs
Slow, prolonged absorption
Slowly cleared by liver
Extensively bound to plasma proteins to extend duration of action
Rapidly acting
Evolocumab adverse effects
and guielines
Injection site rxns
Nasopharyngitis/influenza due to immune suppression
Guidelines - heterozygous famialhypercholesterolemia or established AS dz…supposed to added to dietary changes nad max statin theapy
Selective cholesterol uptake inhibitor
Ezetimibe
Binds and ingibits NPC1L1 in the gut
Dec cholesterol absoprtion also induced upregulation of heptaic LDL receptors and hepatic LDL uptake
Ezetimibe use
ALone for hypercholesterolemia who can’t take statins
Single pill combos with statins available - for secondary prevention
Bile acid sequestrants
Unabsorbable positively charged resins
Fewer adverse efects
Avoid when significant hypertriglyceridemia present
MOA of bile acid sequestration
Dec enterohepatic recirculation of bile acid
Stimulates use of hepatic cholesterol to synthesize replacement bile acids
inc LDL receptor expression to scavenage more LDL cholesterol from blood
Use of sequestrants and adverse effects
Hypercholesterolemia add on therapy
T2DM add on - dec LDL and CV risk…also reduces glycosylated Hb in T2DM
GI issues and dec absorptiojn of neg charged things
Fibrates
Hepatic elim
Dec VLDL
Can inc LDL in hypertriglyceridemia pts bc converts VLDL to LDL
Fenofibrate use
Hypertriglyceridemia
Mod - long term reudciton of risk from AS CV d…statins are highly recommended
Severe- reduction of acute pancreatitis risk, fibrates highly recommened.
Fibrate MOA
Perixosome proliferator-activated receptor alpha agonist
PPAR-alpha is a nuclear receptor that regulates protein expression in liver and muscle
Activated PPAR-alpha trnalsocates into hucleus and heterodimerizes with reitnoid X receptor before binding t DNA and altering gene transcripton
Fibrate VLDL effects
Either dec VLDL synthesis or increase metabolism
Fibrates adverse effects and in diabetes
Cholelithias, hepatotoxcity
T2DM - dec non-fatal CV events, dec neprhopathy and retinopathy
Niacin
Inc HDL and dec VLDL
Dec VLDL in liver by dec triglyceride synthesi
Second line drug for add on of hypertriglyceridemia…best drug to tx low HDL
Niacin AE
GI irritation
Cutaenous flushing - PG induced vsodilation (take aspirin)
Dec insulin sensitivity
Hepatocotiy
Forms of niacin and AE
Immediate release - flushing
Sustained release (Supplement) - hepatotoxic
Prescription ER - less flushing than immediate
