Antihyperlipidemics

Question 1

Hypercholesterolemia
HyperTG
Mixed

Answer 1

Inc cholesterol (normally LDL)
Inc TG (usually VLDL)
Inc serum TG and cholesterol

Question 2

Altering VLDL, LDL, and HDL

Answer 2

VLDL - modestly promotes AS…promotes acute pancreatitis
LDL - promotes athero
HDL - prtective against AS

Question 3

HMG-CoA reductase inhibitors

Answer 3

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

Question 4

Statins -use

Answer 4

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

Question 5

Statin MOA

Answer 5

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

Question 6

Pleiotropic effects of statins

Answer 6

Improved endothelial function - inc vasodilation

Anti-inflam…slow plaque progression and stabilizes established plauqes

Question 7

Statin adverse and contraindication

Answer 7

Skeletal muscle toxoicty
Hepatoxicity - asx and modest inc in serum transminases
T2DM - inc in incidnece

Contra in preg or nursing due to skeletal defects

Question 8

Muscle toxicity mech and risk factors for statins

Answer 8

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

Question 9

Summary of
Atorvastitin
Rosuvastatin
Pravastatin

PKs and interactions

Answer 9

Mod sensitivie to CYP3A4 inhibs

Sens to inhibis of biliary drug transporter

Statin least affected by drug interactions

Question 10

PCSK9 inhibitors

Answer 10

Evolocumab

Self adm subq injection every 2 week or month

Only used for very high risk hypercholesterolemia pts

Question 11

PCSK9 fxn

Answer 11

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

Question 12

Effects of PCSK9 inhibs

Answer 12

Dec destruction of LDL receptors

mroe LDL receptors on hepatic membranes

inc uptake of LDL

Question 13

PCSK9 PJs

Answer 13

Slow, prolonged absorption

Slowly cleared by liver

Extensively bound to plasma proteins to extend duration of action

Rapidly acting

Question 14

Evolocumab adverse effects

and guielines

Answer 14

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

Question 15

Selective cholesterol uptake inhibitor

Answer 15

Ezetimibe

Binds and ingibits NPC1L1 in the gut

Dec cholesterol absoprtion also induced upregulation of heptaic LDL receptors and hepatic LDL uptake

Question 16

Ezetimibe use

Answer 16

ALone for hypercholesterolemia who can’t take statins

Single pill combos with statins available - for secondary prevention

Question 17

Bile acid sequestrants

Answer 17

Unabsorbable positively charged resins

Fewer adverse efects

Avoid when significant hypertriglyceridemia present

Question 18

MOA of bile acid sequestration

Answer 18

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

Question 19

Use of sequestrants and adverse effects

Answer 19

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

Question 20

Fibrates

Answer 20

Hepatic elim

Dec VLDL

Can inc LDL in hypertriglyceridemia pts bc converts VLDL to LDL

Question 21

Fenofibrate use

Answer 21

Hypertriglyceridemia

Mod - long term reudciton of risk from AS CV d…statins are highly recommended

Severe- reduction of acute pancreatitis risk, fibrates highly recommened.

Question 22

Fibrate MOA

Answer 22

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

Question 23

Fibrate VLDL effects

Answer 23

Either dec VLDL synthesis or increase metabolism

Question 24

Fibrates adverse effects and in diabetes

Answer 24

Cholelithias, hepatotoxcity

T2DM - dec non-fatal CV events, dec neprhopathy and retinopathy

Question 25

Niacin

Answer 25

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

Question 26

Niacin AE

Answer 26

GI irritation
Cutaenous flushing - PG induced vsodilation (take aspirin)
Dec insulin sensitivity
Hepatocotiy

Question 27

Forms of niacin and AE

Answer 27

Immediate release - flushing

Sustained release (Supplement) - hepatotoxic

Prescription ER - less flushing than immediate